Gilles Guillemin

Memantine is protective against cytotoxicity caused by lead and quinolinic acid in cultured rat embryonic hippocampal cells

Publisher: American Chemical Society (ACS)

Date: 05-04-2019

DOI: 10.1021/ACS.CHEMRESTOX.8B00421

Abstract: Quinolinic acid (QA) is an excitotoxic metabolite of the kynurenine pathway of tryptophan metabolism produced in response to inflammation and oxidative stress. Lead (Pb) causes oxidative stress and thus may produce neurotoxicity by increasing QA production. We investigated the in vitro cytotoxic effects of Pb and QA and the protective effects of the NMDA receptor antagonist memantine. Primary cultures of embryonic hippoc al cells from Wistar rats were treated with different concentrations of Pb, QA, and Pb + QA with and without memantine. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Apoptosis was analyzed by flow cytometry after Annexin-V ropidium iodide staining. The numbers of immunostained neurons (with β3-Tubulin Tuj1) and astrocytes (with glial fibrillary acidic protein) were counted. Pb at 20 μg/dL (0.97 μM) and QA at 500 nM concentrations showed significant cytotoxic effects, as evidenced by decreased cell viability, increased apoptosis, and a decrease in the number of both astrocytes and neurons. The combination of Pb and QA showed significant synergistic apoptotic effects at lower doses. Memantine (500 nM) was largely protective against the cytotoxic effects of both Pb and QA, suggesting that Pb's and QA's cytotoxicity involves NMDA receptor activation. Whereas the neuroprotection by memantine from QA-induced toxicity has been previously reported, this is the first study reporting the protection by memantine against Pb-induced cytotoxicity in cultured hippoc al cells. Protection by memantine against these neurotoxicants in vivo needs to be investigated.

The kynurenine pathway in brain tumor pathogenesis

Publisher: American Association for Cancer Research (AACR)

Date: 14-11-2012

DOI: 10.1158/0008-5472.CAN-12-0549

Abstract: Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of l-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the TH17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, l-Kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme α-amino-β-carboxymuconate-ϵ-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2–dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA–mediated immune suppression. Cancer Res 72(22) 5649–57. ©2012 AACR.

A beta 1-42 induces production of quinolinic acid by human macrophages and microglia

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 12-2003

DOI: 10.1097/00001756-200312190-00005

Abstract: We hypothesized that the tryptophan catabolites produced through the kynurenine pathway (KP), and more particularly the excitotoxin quinolinic acid (QUIN), may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, we demonstrated that aggregated amyloid peptide A beta 1-42 induced indoleamine 2,3-dioxygenase (IDO) expression and resulted in a significant increase in production of QUIN by human primary macrophages and microglia. In contrast, A beta 1-40 and prion peptide (PrP) 106-126 did not induce any significant increase in QUIN production. These data imply that local QUIN production may be one of the factors involved in the pathogenesis of neuronal damage in AD.

Understanding the role of the kynurenine pathway in human breast cancer immunobiology

Publisher: Impact Journals, LLC

Date: 04-12-2016

DOI: 10.18632/ONCOTARGET.6467

Metallothionein Treatment Attenuates Microglial Activation and Expression of Neurotoxic Quinolinic Acid Following Traumatic Brain Injury

Publisher: Springer Science and Business Media LLC

Date: 20-03-2009

DOI: 10.1007/S12640-009-9044-Y

Abstract: The kynurenine pathway has been implicated as a major component of the neuroinflammatory response to brain injury and neurodegeneration. We found that the neurotoxic kynurenine pathway intermediate quinolinic acid (QUIN) is rapidly expressed, within 24 h, by reactive microglia following traumatic injury to the rodent neocortex. Furthermore, administration of the astrocytic protein metallothionein attenuated this neuroinflammatory response by reducing microglial activation (by approximately 30%) and QUIN expression. The suppressive effect of MT was confirmed upon cultured cortical microglia, with 1 mug/ml MT almost completely blocking interferon-gamma induced activation of microglia and QUIN expression. These results demonstrate the neuroimmunomodulatory properties of MT, which may have therapeutic applications for the treatment of traumatic brain injury.

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation

Publisher: Springer Science and Business Media LLC

Date: 02-08-2016

DOI: 10.1038/TP.2016.133

Abstract: Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N -methyl- d -aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma s les from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF ( P .001) and blood ( P =0.001 and P .01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer's disease

Publisher: Impact Journals, LLC

Date: 28-07-2016

DOI: 10.18632/ONCOTARGET.10905

Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases

Publisher: Elsevier BV

Date: 2017

DOI: 10.1016/J.NEUROPHARM.2016.03.024

Abstract: The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-γ (IFN-γ), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production. Dysregulated KP metabolism has been strongly associated with neurological diseases in recent years, and is the subject of increasing efforts to understand how the metabolites are causative of disease pathology. Concurrent with these endeavours are drug development initiatives to use inhibitors to block certain enzymes in the pathway, resulting in reduced levels of neurotoxic metabolites (e.g. quinolinic acid, an excitotoxin and N-Methyl-d-Aspartate (NMDA) receptor agonist), while in turn enhancing the bioavailability of the neuroprotective metabolites such as kynurenic acid. Neurodegenerative diseases often have a substantial autoimmune or inflammatory component hence a greater understanding of how KP metabolites influence the inflammatory cascade is required. Additionally, challenges exist in diseases like multiple sclerosis (MS) and motor neurone disease (MND), which do not have reliable biomarkers. Clinical diagnosis can often be prolonged in order to exclude other diseases, and often diagnosis occurs at an advanced state of disease pathology, which does not allow a lengthy time for patient assessment and intervention therapies. This review considers the current evidence for involvement of the KP in several neurological diseases, in biomarkers of disease and also the parallels that exist in KP metabolism with what is known in other diseases such as HIV, Alzheimer's disease/dementia, infection, immune privilege and cardiovascular disease. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

Chronic Treatment with the IDO1 Inhibitor 1-Methyl-D-Tryptophan Minimizes the Behavioural and Biochemical Abnormalities Induced by Unpredictable Chronic Mild Stress in Mice - Comparison with Fluoxetin

Publisher: Public Library of Science (PLoS)

Date: 09-11-2016

DOI: 10.1371/JOURNAL.PONE.0164337

Tetrahydrobiopterin: Beyond Its Traditional Role as a Cofactor

Publisher: MDPI AG

Date: 03-05-2023

DOI: 10.3390/ANTIOX12051037

Abstract: Tetrahydrobiopterin (BH4) is an endogenous cofactor for some enzymatic conversions of essential biomolecules, including nitric oxide, and monoamine neurotransmitters, and for the metabolism of phenylalanine and lipid esters. Over the last decade, BH4 metabolism has emerged as a promising metabolic target for negatively modulating toxic pathways that may result in cell death. Strong preclinical evidence has shown that BH4 metabolism has multiple biological roles beyond its traditional cofactor activity. We have shown that BH4 supports essential pathways, e.g., to generate energy, to enhance the antioxidant resistance of cells against stressful conditions, and to protect from sustained inflammation, among others. Therefore, BH4 should not be understood solely as an enzyme cofactor, but should instead be depicted as a cytoprotective pathway that is finely regulated by the interaction of three different metabolic pathways, thus assuring specific intracellular concentrations. Here, we bring state-of-the-art information about the dependency of mitochondrial activity upon the availability of BH4, as well as the cytoprotective pathways that are enhanced after BH4 exposure. We also bring evidence about the potential use of BH4 as a new pharmacological option for diseases in which mitochondrial disfunction has been implicated, including chronic metabolic disorders, neurodegenerative diseases, and primary mitochondriopathies.

Quantitation of ATP-binding cassette subfamily-A transporter gene expression in primary human brain cells

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 26-06-2006

DOI: 10.1097/01.WNR.0000221833.41340.CD

Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-β

Publisher: Elsevier BV

Date: 09-2022

DOI: 10.1016/J.NBD.2022.105783

Abstract: Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73) cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166) CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an in idual being a progressor (OR 35.3 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.

The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal

Publisher: SAGE Publications

Date: 2019

DOI: 10.1177/1178646919868978

Abstract: The plasma kynurenine to tryptophan ([Kyn]/[Trp]) ratio is frequently used to express or reflect the activity of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase (IDO). This ratio is increasingly used instead of measurement of IDO activity, which is often low or undetectable in immune and other cells under basal conditions, but is greatly enhanced after immune activation. The use of this ratio is valid in in vitro studies, eg, in cell cultures or isolated organs, but its ‘blanket’ use in in vivo situations is not, because of modulating factors, such as supply of nutrients the presence of multiple cell types complex structural and functional tissue arrangements the extracellular matrix and hormonal, cytokine, and paracrine interactions. Determinants other than IDO may therefore be involved in vivo. These are hepatic tryptophan 2,3-dioxygenase (TDO) activity and the flux of plasma-free Trp down the Kyn pathway. In addition, conditions leading to accumulation of Kyn, eg, inhibition of activities of Kyn monooxygenase and kynureninase, could lead to elevation of the aforementioned ratio. In this review, the origin of use of this ratio will be discussed, variations in extent of its elevation will be described, evidence against its indiscriminate use will be presented, and examining determinants other than IDO activity and their correlates will be proposed for future studies.

Tryptophan metabolism through the kynurenine pathway is associated with endoscopic inflammation in ulcerative colitis

Publisher: Oxford University Press (OUP)

Date: 22-05-2018

DOI: 10.1093/IBD/IZY103

New Strategies in Neuroprotection and Neurorepair

Publisher: Springer Science and Business Media LLC

Date: 23-08-2011

DOI: 10.1007/S12640-011-9265-8

Correction: The kynurenine pathway in brain tumor pathogenesis (Cancer Research (2012) 72, (5649-5657))

Publisher: American Association for Cancer Research (AACR)

Date: 15-12-2012

DOI: 10.1158/0008-5472.CAN-12-4230

Differential kynurenine pathway metabolism in highly-metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

Publisher: Research Square Platform LLC

Date: 16-09-2020

DOI: 10.21203/RS.3.RS-57673/V2

Abstract: Background: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanism(s) to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical s les (n = 1,997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry and ultra-high pressure liquid chromatography on these s les to quantify KP enzyme gene, protein and activity respectively. Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

DNA Gyrase Is the Target for the Quinolone Drug Ciprofloxacin in Arabidopsis thaliana

Publisher: Elsevier BV

Date: 02-2016

DOI: 10.1074/JBC.M115.689554

Differential kynurenine pathway metabolism in highly-metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

Publisher: Research Square Platform LLC

Date: 12-08-2020

DOI: 10.21203/RS.3.RS-57673/V1

Abstract: Background: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanism(s) to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical s les (n = 1,997) that represent major subtypes of BrCa (luminal, HER2, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry and ultra-high pressure liquid chromatography on these s les to quantify KP enzyme gene, protein and activity respectively. Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

Excitotoxic potential of the cyanotoxin β-methyl-amino-L-alanine (BMAA) in primary human neurons

Publisher: Elsevier BV

Date: 11-2012

DOI: 10.1016/J.TOXICON.2012.07.169

Abstract: The toxicity of the cyanobacterial modified amino acid, BMAA, has been described in rat, mouse and leech neurons. Particular emphasis has been placed on the potential ability of BMAA to induce neuronal damage via excitotoxic mechanisms. Here we present data indicating that the effects observed on lower organisms are also evident in a human model. Our data indicates that BMAA induces increased intracellular Ca²⁺ influx, DNA damage, mitochondrial activity, lactate dehydrogenase (LDH) release and generation of reactive oxygen species (ROS). The amelioration of LDH release in the presence of the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 indicates that the neurotoxic effects of BMAA are mediated via NMDA receptor activation. Additionally, we have shown that BMAA induces the expression of neuronal nitric oxide synthase (nNOS) and caspase-3 indicating that it can stimulate apoptosis in human neurons, presumably via activation of NMDA receptors.

Combination Drug Therapy of Glioblastoma: Lessons from 3D In Vitro Models and the Roadmap for Future Research

Publisher: Wiley

Date: 09-08-2023

DOI: 10.1002/ADTP.202300197

Abstract: Combination drug therapy addresses the auxiliary cancer pathways of the tumor progression unaffected by the standard adjuvant treatments such as radio‐ and chemotherapy. It is a particularly attractive strategy to improve the treatment outcomes and the quality of life in patients with the deadliest brain cancer, glioblastoma (GB). Testing of combination drug treatment protocols requires reliable, efficient, and biologically accurate preclinical testbeds applicable before the transition to clinical trials. The 3D in vitro models of GB are a promising platform for pharmacological research. However, there is notable methodological uncertainty and a highly scattered data landscape regarding drug testing in 3D in vitro models of GB. In particular, it is not completely clear how to mimic clinically relevant dozing and schedule of the main chemotherapy drug for GB, temozolomide (TMZ) in 3D in vitro GB models. Here, the authors carefully explore the available literature on the application of TMZ in 3D in vitro models of GB, both as a sole agent and in combination with other medications. The joint analysis of the tumor modeling approaches, the employed assays, and the obtained treatment responses provided in this review may be used as a roadmap for future research in combination treatments of GB.

Characterization of the Kynurenine Pathway in CD8⁺ Human Primary Monocyte-Derived Dendritic Cells

Publisher: Springer Science and Business Media LLC

Date: 10-08-2016

DOI: 10.1007/S12640-016-9657-X

Abstract: The kynurenine (KYN) pathway (KP) is a major degradative pathway of the amino acid, L-tryptophan (TRP), that ultimately leads to the anabolism of the essential pyridine nucleotide, nicotinamide adenine dinucleotide. TRP catabolism results in the production of several important metabolites, including the major immune tolerance-inducing metabolite KYN, and the neurotoxin and excitotoxin quinolinic acid. Dendritic cells (DCs) have been shown to mediate immunoregulatory roles that mediated by TRP catabolism. However, characterization of the KP in human DCs has so far only been partly delineated. It is critical to understand which KP enzymes are expressed and which KP metabolites are produced to be able to understand their regulatory effects on the immune response. In this study, we characterized the KP in human monocyte-derived DCs (MDDCs) in comparison with the human primary macrophages using RT-PCR, high-pressure gas chromatography, mass spectrometry, and immunocytochemistry. Our results show that the KP is entirely expressed in human MDDC. Following activation of the KP using interferon gamma, MDDCs can mediate apoptosis of T

Preface

Publisher: Springer International Publishing

Date: 2016

DOI: 10.1007/978-3-319-28383-8

Protective Effects of Myxobacterial Extracts on Hydrogen Peroxide-induced Toxicity on Human Primary Astrocytes

Publisher: Elsevier BV

Date: 02-2019

DOI: 10.1016/J.NEUROSCIENCE.2018.11.033

Abstract: Astrocytes, the main non-neuronal cells in the brain, have significant roles in the maintenance and survival of neurons. Oxidative stress has been implicated in various neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Myxobacteria produce a wide range of bioactive metabolites with notable structures and modes of action, which introduce them as potent natural product producers. In the present study, we evaluated the effects of myxobacterial extracts on hydrogen peroxide (H

The cytokines CXCL10 and CCL2 and the kynurenine metabolite anthranilic acid accurately predict patients at risk of developing dengue with warning signs

Publisher: Oxford University Press (OUP)

Date: 29-06-2022

DOI: 10.1093/INFDIS/JIAC273

Abstract: The resolution or aggravation of dengue infection depends on the patient’s immune response during the critical phase. Cytokines released by immune cells increase with the worsening severity of dengue infections. Cytokines activate the kynurenine pathway (KP) and the extent of KP activation then influences disease severity. KP metabolites and cytokines in plasma s les of patients with dengue infection (dengue without warning signs [DWS–], dengue with warning signs [DWS+], or severe dengue) were analyzed. Cytokines (interferon gamma [IFN-ɣ], tumor necrosis factor, interleukin 6, CXCL10/interferon-inducile protein 10 [IP-10], interleukin 18 [IL-18], CCL2/monocyte chemoattractant protein-1 [MCP-1], and CCL4/macrophage inflammatory protein-1beta [MIP-1β] were assessed by a Human Luminex Screening Assay, while KP metabolites (tryptophan, kynurenine, anthranilic acid [AA], picolinic acid, and quinolinic acid) were assessed by ultra-high-performance liquid chromatography and Gas Chromatography Mass Spectrophotometry [GCMS] assays. Patients with DWS+ had increased activation of the KP where kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid were elevated. These patients also had higher levels of the cytokines IFN-ɣ, CXCL10, CCL4, and IL-18 than those with DWS–. Further receiver operating characteristic analysis identified 3 prognostic biomarker candidates, CXCL10, CCL2, and AA, which predicted patients with higher risks of developing DWS+ with an accuracy of 97%. The data suggest a unique biochemical signature in patients with DWS+. CXCL10 and CCL2 together with AA are potential prognostic biomarkers that discern patients with higher risk of developing DWS+ at earlier stages of infection.

Neuroprotective Effect of Natural Products Against Alzheimer’s Disease

Publisher: Springer Science and Business Media LLC

Date: 22-05-2012

DOI: 10.1007/S11064-012-0799-9

Abstract: Nature has gifted mankind with a plethora of flora-bearing fruits, vegetables and nuts. The erse array of bioactive nutrients present in these natural products plays a pivotal role in prevention and cure of various neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease and other neuronal dysfunctions. Accumulated evidence suggests that naturally occurring phyto-compounds, such as polyphenolic antioxidants found in fruits, vegetables, herbs and nuts, may potentially hinder neurodegeneration, and improve memory and cognitive function. Nuts such as walnut have also demonstrated neuroprotective effect against AD. The molecular mechanisms behind the curative effects rely mainly on the action of phytonutrients on distinct signalling pathways associated with protein folding and neuroinflammation. The neuroprotective effects of various naturally occurring compounds in AD is evaluating in this review.

Impact of neuroinflammation on epigenetic transcriptional control of Sonic Hedgehog members in the central nervous system

Publisher: Elsevier BV

Date: 2023

DOI: 10.1016/J.BRAINRES.2022.148180

Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model

Publisher: Springer Science and Business Media LLC

Date: 06-11-2018

DOI: 10.1186/S13229-018-0239-Z

Does escitalopram reduce neurotoxicity in major depression?

Publisher: Elsevier BV

Date: 07-2015

DOI: 10.1016/J.JPSYCHIRES.2015.04.026

Abstract: A pro-inflammatory state and a dysregulation in the tryptophan/kynurenine pathway have been documented in depression. This study examined whether treatment with the SSRI, escitalopram (ESC), could suppress inflammation and favorably shift metabolites of the kynurenine pathway in patients with major depressive disorder (MDD) within the utilized treatment period. Twenty seven healthy control subjects were included for comparison. Thirty patients were enrolled after completing baseline assessments. They received a 12-week ESC monotherapy. Twenty subjects were completers. Clinical assessments were carried out at each visit using the HAM-D, HAM-A, CGI and BDI rating scales. Blood s les were collected at each assessment and stored until analyzed. Cytokines were analyzed with Randox multiplex assay and tryptophan and kynurenine metabolites were analyzed using HPLC/GCMS. Baseline plasma concentrations of hsCRP, TNFα, IL6 and MCP-1 were significantly higher in patients compared to healthy controls. IL10 trended toward an increase. Baseline plasma IL1β correlated significantly with IL1α, and IL4. Patients showed significant improvement in all outcome measures with a high remission rate. Significant correlations were obtained between specific symptoms and certain biomarkers at baseline but these correlations must be viewed as very preliminary. During ESC treatment concentrations of inflammatory biomarkers did not change except for TNFα that trended lower. Metabolites and ratios of the tryptophan/kynurenine pathway showed reductions of the neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, 3-hydroxykynurenine/kynurenine, quinolinic acid/tryptophan, kynurenic acid/quinolinic acid and quinolinic acid/3-hydroxykynurenine. The results indicate that ESC may exert its antidepressant effect in part through inhibition of synthesis of certain neurotoxic kynurenine metabolites and possibly also through reduction of the inflammatory response, although there was no concordance in the time course of changes between antidepressant efficacy and reversal of the pro-inflammatory status.

Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?

Publisher: Springer Science and Business Media LLC

Date: 2011

DOI: 10.1186/1742-2094-8-94

Induction of TDO2 and IDO2 in Liver by High-Fat Feeding in Mice: Discrepancies with Human Obesity

Publisher: SAGE Publications

Date: 2013

DOI: 10.4137/IJTR.S11717

Abstract: Low-grade and chronic inflammation is elicited in white adipose tissue in human obesity. The presence of inflammatory molecules leads to an increased tryptophan catabolism through the induction of indoleamine-2,3-dioxygenase-1 (IDO1). In order to characterize the mechanisms underlying this dysregulation, we have studied 2 mouse models of obesity. Unexpectedly, we did not detect any IDO1 expression in obese or lean mice adipose tissue. In a previous study, we did not find any significant difference in the liver for IDO2 and tryptophan-2,3-dioxygenase (TDO2) gene expression between normal weight and obese patients. IDO2 and TDO2 expression was increased in the liver of high-fat fed mice, but not in ob/ob mice, and was strongly correlated with hydroxysteroid-(11-beta) dehydrogenase-1 (HSD11B1) expression, an enzyme that generates active cortisol within tissues. In conclusion, despite a dysregulation of tryptophan metabolism, obese mice display discrepancies with human obesity metabolism, rendering them inappropriate for further investigations in this animal model.

A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality

Publisher: Elsevier BV

Date: 2015

DOI: 10.1016/J.BBI.2014.07.012

Abstract: Patients with depression and suicidality suffer from low-grade neuroinflammation. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-d-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient s les n=143, in iduals n=30) and healthy controls (n=36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale. Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression.

Food and your mood: Nutritional psychiatry

Publisher: Elsevier BV

Date: 07-2015

DOI: 10.1016/S2215-0366(15)00241-2

Redox-active Cu(II)-Aβ causes substantial changes in axonal integrity in cultured cortical neurons in an oxidative-stress dependent manner

Publisher: Elsevier BV

Date: 10-2012

DOI: 10.1016/J.EXPNEUROL.2012.06.002

Abstract: The beta-amyloid (Aβ) peptide comprises the amyloid plaques that characterise Alzheimer's disease (AD), and is thought to significantly contribute towards disease pathogenesis. Oxidative stress is elevated in the AD brain, and there is substantial evidence that the interaction between Aβ and redox-active copper is a major contributing factor towards oxidative stress in AD. The major findings of this study are that redox-active Cu(II)-Aβ causes pronounced axonal pathology in long-term neuronal cultures, including axonal fragmentation and the formation of hyperphosphorylated tau-immunoreactive axonal swellings. Notably, MAP-2 expressing dendritic processes remain largely un-affected by Cu(II)-Aβ treatment. These dystrophic axonal manifestations resemble some of the characteristic neuritic pathology of the AD brain. We show that Cu(II)-Aβ directly causes formation of intra-axonal swellings via the generation of free radicals and subsequent efflux of K+ out of neurons. In summary, we report that redox-active Cu(II)-Aβ can induce substantial neurodegenerative changes in mature neurons, and may have an important role to play in the slowly progressing pathogenesis of AD.

Chemical reprogramming enhances homology-directed genome editing in zebrafish embryos

Publisher: Springer Science and Business Media LLC

Date: 23-05-2019

DOI: 10.1038/S42003-019-0444-0

Abstract: Precise genome editing is limited by the inefficiency of homology-directed repair (HDR) compared to the non-homologous end-joining (NHEJ) of double strand breaks (DSBs). The CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 system generates precise, locus-specific DSBs that can serve as substrates for HDR. We developed an in vivo visual reporter assay to quantify HDR-mediated events at single-cell resolution in zebrafish and used this system to identify small-molecule modulators that shift the DNA repair equilibrium in favor of HDR. By further optimizing the reaction environment and repair template, we achieved dramatic enhancement of HDR-mediated repair efficiency in zebrafish. Accordingly, under optimized conditions, inhibition of NHEJ with NU7441 enhanced HDR-mediated repair up to 13.4-fold. Importantly, we demonstrate that the increase in somatic HDR events correlates directly with germline transmission, permitting the efficient recovery of large seamlessly integrated DNA fragments in zebrafish.

The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis

Publisher: Frontiers Media SA

Date: 23-07-2014

DOI: 10.3389/FNAGI.2014.00173

Unravelling the links between maternal infection, kynurenines, schizophrenia and its prevention in an animal model

Publisher: Wiley

Date: 05-11-2015

DOI: 10.1016/J.IJDEVNEU.2015.04.187

Metabolite profiling reveals predictive biomarkers and the absence of β-methyl amino-l-alanine in plasma from individuals diagnosed with amyotrophic lateral sclerosis

Publisher: American Chemical Society (ACS)

Date: 18-05-2020

DOI: 10.1021/ACS.JPROTEOME.0C00216

The involvement of astrocytes and kynurenine pathway in Alzheimer's disease

Publisher: Springer Science and Business Media LLC

Date: 12-2007

DOI: 10.1007/BF03033908

Effect of dietary supplementation of dates in Alzheimer's disease APPsw/2576 transgenic mice on oxidative stress and antioxidant status

Publisher: Informa UK Limited

Date: 21-06-2014

DOI: 10.1179/1476830514Y.0000000134

Serotonin modulates HIV replication in primary culture of human macrophages: involvement of 5-HT1A sub-type receptors | Inhibition par la sérotonine de l'infection par VIH-1 des macrophages en culture primaire : rôle du sous-type 5-HT1A des récepteurs sérotoninergiques

Publisher: Elsevier BV

Date: 12-2007

DOI: 10.1016/J.PATBIO.2007.07.001

Abstract: The neurotransmitter 5-hydroxytryptamine (5-HT), commonly known as serotonin, is released at peripheral sites from activated platelets. At inflammatory sites, macrophages and lymphocytes could be exposed to 5-HT concentrations up to 100 microM. Moreover, 5-HT could modulate cytokine secretion by monocytes/macrophages and immune functions through the uptake of 5-HT at these inflammatory sites from T cells and dendritic cells. HIV infection is also under the control of inflammatory processes (including T cell proliferation and cytokines secretion). On this basis, we studied explored herein the effects of 5-HT on HIV-1/Ba-L (macrophage-tropic virus) replication in primary cultures of human macrophages. This pharmacological study with isotype-selective receptor agonists and antagonist allowed us to show that the 100 microM 5-HT concentration via 5-HT(1A) subtype receptors could decrease HIV replication. This observation was associated with an increase of MIP-1alpha secretion such as an increase of MIP-1alpha mRNA production and with a decrease of HIV-coreceptor CCR5 cell surface expression. Our results point out for the first time the inhibitory effects of 5-HT on HIV replication in primary culture of human macrophages via activation of 5-HT(1A) subtype receptors.

Consumption of fig fruits grown in Oman can improve memory, anxiety, and learning skills in a transgenic mice model of Alzheimer's disease

Publisher: Informa UK Limited

Date: 02-03-2016

DOI: 10.1179/1476830514Y.0000000131

Quinolinic acid, the inescapable neurotoxin

Publisher: Wiley

Date: 27-03-2012

DOI: 10.1111/J.1742-4658.2012.08485.X

Abstract: Over the last two decades, evidence for the involvement of quinolinic acid (QUIN) in neuroinflammatory diseases has been exponentially increasing. Within the brain, QUIN is produced and released by infiltrating macrophages and activated microglia, the very cells that are prominent during neuroinflammation. QUIN acts as an agonist of the N-methyl-D-aspartate receptor and as such is considered to be a brain endogenous excitotoxin. Since the discovery of the excitotoxic activity of QUIN in the early 1980s, several other cytotoxic mechanisms have been identified. We know today that QUIN acts as a neurotoxin, gliotoxin, proinflammatory mediator, pro-oxidant molecule and can alter the integrity and cohesion of the blood-brain barrier. This paper aims to review some of the most recent findings about the effects of QUIN and its mode of action.

Time-dependent effect of oligomeric amyloid-β (1–42)-induced hippocampal neurodegeneration in rat model of Alzheimer’s disease

Publisher: Informa UK Limited

Date: 19-11-2018

DOI: 10.1080/01616412.2018.1544745

Abstract: Alzheimer's disease (AD) is characterized with an abnormal deposition of insoluble amyloid-beta (Aβ) peptide plaques, tangles formation and synaptic dysfunction. These result in impaired functioning of neuronal circuits and alter the behavioral response owing to activation of neurotransmitter receptors. Recently, it has been implicated that Aβ influences N-methyl d-aspartate (NMDA) receptor activation in AD however, the molecular mechanism underlying remains unclear. Thus, emerged specific aim to study the time-course effect of oligomeric Aβ Aggregated forms of synthetic Aβ peptides were injected bilaterally into the intrahippoc al region of rat brain using stereotaxic surgery. Behavioral analysis was performed using eight-arm Radial Arm Maze task at the end of experimental period. Euthanized rat brain hippoc al tissue was used to study the mRNA expression of glutamatergic and cholinergic receptor using semiquantitative reverse transcription-polymerase chain reaction. oAβ Acute exposure of oAβ AD: Alzheimer's disease, Aβ: amyloid-β oAβ

Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone

Publisher: American Physiological Society

Date: 15-07-2012

DOI: 10.1152/AJPREGU.00373.2011

Abstract: Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.

Understanding the Roles of the Kynurenine Pathway in Multiple Sclerosis Progression

Publisher: SAGE Publications

Date: 2010

DOI: 10.4137/IJTR.S4294

Abstract: The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of nicotinamide adenine dinucleotide (NAD + ) and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders including Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Parkinson's disease, schizophrenia, Huntington's disease and brain tumours. However, the KP remains a relatively new topic for the field of multiple sclerosis (MS). Over the last 2–3 years, some evidence has progressively emerged suggesting that the KP is likely to be involved in the pathogenesis of autoimmune diseases especially MS. Some KP modulators are already in clinical trials for other inflammatory diseases and would potentially provide a new and important therapeutic strategy for MS patients. This review summarizes the known relationships between the KP and MS.

Activation of RyR2 by class I kinase inhibitors

Publisher: Wiley

Date: 30-01-2019

DOI: 10.1111/BPH.14562

Bcl11b-A critical neurodevelopmental transcription factor-roles in health and disease

Publisher: Frontiers Media SA

Date: 29-03-2017

DOI: 10.3389/FNCEL.2017.00089

Upregulated pathways and products of tryptophan metabolism is associated with the neoplastic transition in the colon epithelium

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/S0016-5085(16)31694-8

Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress.

Publisher: Springer Science and Business Media LLC

Date: 04-12-2019

DOI: 10.1007/S00018-019-03394-W

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that are related genetically and pathologically. Mutations in the UBQLN2 gene, encoding the ubiquitin-like protein ubiquilin2, are associated with familial ALS/FTD, but the pathophysiological mechanisms remain unclear. Here, we demonstrate that ALS/FTD UBQLN2 mutants P497H and P506T inhibit protein transport from the endoplasmic reticulum (ER) to the Golgi apparatus in neuronal cells. In addition, we observed that Sec31-positive ER exit sites are clustered in UBQLN2

The MAPK-activated protein kinase 2 (MK2) inhibitor CMPD1 is a novel microtubule targeting agent for glioblastoma therapy

Publisher: Elsevier BV

Date: 08-2015

DOI: 10.1016/J.CLINTHERA.2015.05.326

Neopterin preconditioning prevents inflammasome activation in mammalian astrocytes

Publisher: Elsevier BV

Date: 02-2018

DOI: 10.1016/J.FREERADBIOMED.2017.11.022

Abstract: Neopterin, a well-established biomarker for immune system activation, is found at increased levels in the cerebrospinal fluid of in iduals affected by neurological/neurodegenerative diseases. Here, neopterin synthesis was investigated in different nerve cells (rodent and human) and in the mouse hippoc us under inflammatory stimuli. We also aimed to investigate whether neopterin preconditioning could modulate the inflammasome activation, a component of the innate immune system. Increased neopterin was detected in human nerve cells supernatants (highest secretion in astrocytes) exposed to lipopolysaccharide (LPS) and interferon-gamma (INF-γ) and in the hippoc us of mice receiving LPS (0.33mg/kg intraperitoneal). In parallel to the hippoc al-increased neopterin, it was observed a significant increase in the expression of the rate-limiting enzyme of its biosynthetic pathway, and both phenomena occurred before the inflammasome activation. Moreover, a significant inhibition of the inflammasome activation was observed in neopterin pre-conditioned human astrocytes, when challenged with LPS, by reducing IL-1β, caspase-1 and ASC expression or content, components of the NLRP3 inflammasome. Mechanistically, neopterin might induce eletrophilic stress and consequently the nuclear translocation of the transcription factor Nrf-2, and the anti-inflammatory cytokines IL-10 and IL-1ra release, which would induce the inhibition of the inflammasome activation. Altogether, this strongly suggests an essential role of neopterin during inflammatory processes.

Cocoa beans improve mitochondrial biogenesis via PPARγ/PGC1α dependent signalling pathway in MPP⁺intoxicated human neuroblastoma cells (SH-SY5Y)

Publisher: Informa UK Limited

Date: 12-09-2018

DOI: 10.1080/1028415X.2018.1521088

Tg2576 Cortical Neurons That Express Human Ab Are Susceptible to Extracellular Aβ-Induced, K+ Efflux Dependent Neurodegeneration

Publisher: Public Library of Science (PLoS)

Date: 27-04-2011

DOI: 10.1371/JOURNAL.PONE.0019026

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

Publisher: American Association for Cancer Research (AACR)

Date: 30-05-2013

DOI: 10.1158/0008-5472.CAN-12-3831

Abstract: Quinolinic acid is a product of tryptophan degradation and may serve as a precursor for NAD+, an important enzymatic cofactor for enzymes such as the DNA repair protein PARP. Pathologic accumulation of quinolinic acid has been found in neurodegenerative disorders including Alzheimer and Huntington disease, where it is thought to be toxic for neurons by activating the N-methyl-D-aspartate (NMDA) receptor and inducing excitotoxicity. Although many tumors including gliomas constitutively catabolize tryptophan, it is unclear whether quinolinic acid is produced in gliomas and whether it is involved in tumor progression. Here, we show that quinolinic acid accumulated in human gliomas and was associated with a malignant phenotype. Quinolinic acid was produced by microglial cells, as expression of the quinolinic acid-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) was confined to microglia in glioma tissue. Human malignant glioma cells, but not nonneoplastic astrocytes, expressed quinolinic acid phosphoribosyltransferase (QPRT) to use quinolinic acid for NAD+ synthesis and prevent apoptosis when de novo NAD+ synthesis was blocked. Oxidative stress, temozolomide, and irradiation induced QPRT in glioma cells. QPRT expression increased with malignancy. In recurrent glioblastomas after radiochemotherapy, QPRT expression was associated with a poor prognosis in two independent datasets. Our data indicate that neoplastic transformation in astrocytes is associated with a QPRT-mediated switch in NAD+ metabolism by exploiting microglia-derived quinolinic acid as an alternative source of replenishing intracellular NAD+ pools. The elevated levels of QPRT expression increase resistance to oxidative stress induced by radiochemotherapy, conferring a poorer prognosis. These findings have implications for therapeutic approaches inducing intracellular NAD+ depletion, such as alkylating agents or direct NAD+ synthesis inhibitors, and identify QPRT as a potential therapeutic target in malignant gliomas. Cancer Res 73(11) 3225–34. ©2013 AACR.

The next decade in tryptophan metabolism research

Publisher: Springer International Publishing

Date: 2015

DOI: 10.1007/978-3-319-11870-3_31

Species differences in tryptophan metabolism and disposition

Publisher: SAGE Publications

Date: 2022

DOI: 10.1177/11786469221122511

Abstract: Major species differences in tryptophan (Trp) metabolism and disposition exist with important physiological, functional and toxicity implications. Unlike mammalian and other species in which plasma Trp exists largely bound to albumin, teleosts and other aquatic species possess little or no albumin, such that Trp entry into their tissues is not h ered, neither is that of environmental chemicals and toxins, hence the need for strict measures to safeguard their aquatic environments. In species sensitive to toxicity of excess Trp, hepatic Trp 2,3-dioxygenase (TDO) lacks the free apoenzyme and its glucocorticoid induction mechanism. These species, which are largely herbivorous, however, dispose of Trp more rapidly and their TDO is activated by smaller doses of Trp than Trp-tolerant species. In general, sensitive species may possess a higher indoleamine 2,3-dioxygenase (IDO) activity which equips them to resist immune insults up to a point. Of the enzymes of the kynurenine pathway beyond TDO and IDO, 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase (ACMSD) determines the extent of progress of the pathway towards NAD + synthesis and its activity varies across species, with the domestic cat ( Felis catus) being the leading species possessing the highest activity, hence its inability to utilise Trp for NAD + synthesis. The paucity of current knowledge of Trp metabolism and disposition in wild carnivores, invertebrates and many other animal species described here underscores the need for further studies of the physiology of these species and its interaction with Trp metabolism.

Kynurenine pathway metabolites as biomarkers for Amyotrophic Lateral Sclerosis

Publisher: Frontiers Media SA

Date: 20-09-2019

DOI: 10.3389/FNINS.2019.01013

Granulocyte macrophage colony stimulating factor stimulates in vitro proliferation of astrocytes derived from simian mature brains

Publisher: No publisher found

Date: 1996

DOI: 10.1002/(SICI)1098-1136(199601)16:1<71::AID-GLIA8>3.0.CO;2-E

Abstract: Hydatidosis is a rare parasitic disease that is endemic in many countries of the Mediterranean basin caused by the larval form of Echinococcus Granulosus. Among unusual localizations, renal involvement is rare, especially extension to the pleural cavity. Herein, we report a rare case of 75-year-old woman with giant renal hydatid cyst complicated by pleural extension. The patient was successfully treated with a median phreno-laparotomy.The renal hydatid cyst was completely emptied with resection of the epiploic hydatid cyst.The diaphragmatic breach was closed after resection of the necrotic margins. With 1 month albendazole therapy.

Potential Mechanism of Cellular Uptake of the Excitotoxin Quinolinic Acid in Primary Human Neurons

Publisher: Springer Science and Business Media LLC

Date: 06-09-2021

DOI: 10.1007/S12035-020-02046-6

Association Between Tryptophan Metabolites, Physical Performance, and Frailty in Older Persons

Publisher: SAGE Publications

Date: 2022

DOI: 10.1177/11786469211069951

Abstract: Frailty is defined as a syndrome of physiological decline in late life, characterized by marked vulnerability to adverse health outcomes. A robust biomarker for frailty is still lacking. Tryptophan (TRP) metabolism through the kynurenine pathway (KP) plays essential roles in aging, the musculoskeletal system, and physical performance. In this study, we quantified 7 KP metabolites, including kynurenine (KYN), kynurenine acid (KYNA), quinolinic acid (QUIN), picolinic acid (PIC), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), and anthranilic acid (AA) using ultra-high-performance liquid chromatography and gas chromatography-mass spectrometry in the serum of 85 participants (median age 75 65% female 28 non-frail, 29 pre-frail, and 28 frail) at the Nepean Osteoporosis and Frailty (NOF) Study. We looked at the association between TRP metabolites and physical performance, sarcopenia, and frailty. After adjusting for age and sex, our results showed that KYN and KYN/TRP were associated with higher interleukin (IL)-6 levels ( r = .324 and r = .390, respectively). KYNA and its ratios to other products (mainly KYNA/KYN, KYNA/QUIN, and KYNA/PIC) were associated with a lower likelihood of frailty by Fried’s criteria (OR 0.93 [0.88, 0.98], P = .009) and Rockwood index ( r = −.241, P = .028) as well as a lower likelihood of sarcopenia (OR 0.88 [0.78, 1.00], P = .049). QUIN and QUIN/KYN showed an association with increased IL-6 ( r = .293 and .204 respectively), higher likelihood of frailty (OR 1.02 [1.00, 1.04], P = .029 and OR 6.43 [2.23, 18.51], P = .001 respectively) and lower physical function ( r = −.205 and r = −.292). In conclusion, different TRP metabolites have various associations with physical performance, frailty, and sarcopenia. Defining the underlying mechanisms may permit the development and validation of new biomarkers and therapeutics for frailty and musculoskeletal conditions targeting specific metabolites of the TRP catabolic pathway.

Asiatic Acid Attenuated Aluminum Chloride-Induced Tau Pathology, Oxidative Stress and Apoptosis Via AKT/GSK-3β Signaling Pathway in Wistar Rats

Publisher: Springer Science and Business Media LLC

Date: 22-01-2019

DOI: 10.1007/S12640-019-9999-2

Abstract: Asiatic acid (AA), a triterpenoid present in Centella asiatica, possesses the ability to cross blood brain barrier and received considerable attention for its neuroprotective role. We have reported the benefit of AA against aluminum chloride (AlCl

Characterization of the kynurenine pathway in human neurons

Publisher: Society for Neuroscience

Date: 21-11-2007

DOI: 10.1523/JNEUROSCI.4101-07.2007

Abstract: The kynurenine pathway is a major route of l -tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.

Cross-linking cellular prion protein induces neuronal type 2-like hypersensitivity

Publisher: Frontiers Media SA

Date: 30-07-2021

DOI: 10.3389/FIMMU.2021.639008

Abstract: Previous reports identified proteins associated with ‘apoptosis’ following cross-linking PrP C with motif-specific anti-PrP antibodies in vivo and in vitro . The molecular mechanisms underlying this IgG-mediated neurotoxicity and the role of the activated proteins in the apoptotic pathways leading to neuronal death has not been properly defined. Previous reports implicated a number of proteins, including apolipoprotein E, cytoplasmic phospholipase A2, prostaglandin and calpain with anti-PrP antibody-mediated ‘apoptosis’, however, these proteins are also known to play an important role in allergy. In this study, we investigated whether cross-linking PrP C with anti-PrP antibodies stimulates a neuronal allergenic response. Initially, we predicted the allergenicity of the epitope sequences associated with ‘neurotoxic’ anti-PrP antibodies using allergenicity prediction servers. We then investigated whether anti-PrP antibody treatment of mouse primary neurons (MPN), neuroblastoma cells (N2a) and microglia (N11) cell lines lead to a neuronal allergenic response. In-Silico studies showed that both tail- and globular-epitopes were allergenic. Specifically, binding regions that contain epitopes for previously reported ‘neurotoxic’ antibodies such as ICSM18 (146-159), ICSM35 (91-110), POM 1 (138-147) and POM 3 (95-100) lead to activation of allergenic related proteins. Following direct application of anti-PrP C antibodies on N2a cells, we identified 4 neuronal allergenic-related proteins when compared with untreated cells. Furthermore, we identified 8 neuronal allergenic-related proteins following treatment of N11 cells with anti-PrP C antibodies prior to co-culture with N2a cells when compared with untreated cells. Antibody treatment of MPN or MPN co-cultured with antibody-treated N11 led to identifying 10 and 7 allergenic-related proteins when compared with untreated cells. However, comparison with 3F4 antibody treatment revealed 5 and 4 allergenic-related proteins respectively. Of importance, we showed that the allergenic effects triggered by the anti-PrP antibodies were more potent when antibody-treated microglia were co-cultured with the neuroblastoma cell line. Finally, co-culture of N2a or MPN with N11-treated with anti-PrP antibodies resulted in significant accumulation of NO and IL6 but not TNF-α in the cell culture media supernatant. This study showed for the first time that anti-PrP antibody binding to PrP C triggers a neuronal hypersensitivity response and highlights the important role of microglia in triggering an IgG-mediated neuronal hypersensitivity response. Moreover, this study provides an important impetus for including allergenic assessment of therapeutic antibodies for neurodegenerative disorders to derive safe and targeted biotherapeutics.

Central kynurenine pathway shift with age in women

Publisher: Wiley

Date: 20-01-2016

DOI: 10.1111/JNC.13496

Abstract: Age is considered a dominant risk factor in the development of most neurodegenerative disorders. The kynurenine pathway, a major metabolic pathway of tryptophan is altered in the majority of neurodegenerative disorders. In this study, we have analysed CSF s les from 49 healthy women across a wide age range (0-90) for kynurenine pathway metabolites and the inflammatory marker neopterin. Our results show central tryptophan metabolism is increased with age in women, with an apparent shift towards the neurotoxin quinolinic acid. We also observed an increase in central levels of the inflammatory marker neopterin with age and a positive correlation between neopterin and kynurenine pathway activation. We conclude that, the changes that occur in the kynurenine pathway as a result of normal ageing are mechanistically linked to increased inflammatory signalling and have some explanatory potential with regard to age-associated degenerative diseases in the CNS. Management of health in ageing and (preventative) treatment would do well to look to the kynurenine pathway for potentially novel solutions. Both the inflammation marker neopterin and kynurenine pathway activity were increased with age in the CSF of female subjects. While levels of quinolinic acid (QUIN), picolinic acid (PIC), kynurenine and quinaldic acid (QA) were increased, 3-hydroxykynurenine (3HK) was decreased and 3-hydroxyanthranilic acid (3HAA) and kynurenic acid (KYNA) remained unchanged. Of particular interest is the increase in QUIN, a neuroexcitotoxin associated with neurodegeneration.

Anti-inflammatory activities of Coleus forsteri (formerly Plectranthus forsteri) extracts on human macrophages and chemical characterization

Publisher: Frontiers Media SA

Date: 09-01-2023

DOI: 10.3389/FPHAR.2022.1081310

Abstract: Introduction: Formerly named Plectranthus forsteri , Coleus forsteri (Benth.) A.J.Paton, 2019 is a Lamiaceae traditionally used to treat flu-like symptoms and shock-related ecchymosis, especially in the Pacific region. Few studies investigated chemical composition and anti-inflammatory potential of this plant. Method: Herein, we investigated anti-inflammatory potential of C. forsteri ethanolic (ePE) and cyclohexane (cPE) plant extract on LPS-induced human macrophages models and quantified cytokines and quinolinic acid (QUIN) as inflammatory markers. Results: Our results show that extract of ePE and cPE significantly inhibit inflammatory cytokine IL-6 and TNF-α induced by LPS on PMA-derived THP-1 macrophages. QUIN production is also diminished under ePE and cPE treatment in activated human monocyte-derived macrophages (MDMs). Seven abietane diterpenes were characterized from C. forsteri cPE including coleon U ( 1 ), coleon U-quinone ( 2 ), 8α,9α-epoxycoleon U-quinone ( 3 ), horminone or 7α-hydroxyroyleanone ( 4 ), 6β,7α-dihydroxyroyleanone ( 5 ), 7α-acetoxy-6β-hydroxyroyleanone ( 6 ) and 7α-formyloxy-6β-hydroxyroyleanone ( 7 ). Discussion: We discussed potential contributions of these molecules from C. forsteri extracts for their anti-inflammatory activities.

Kynurenine Pathway in Skin Cells: Implications for UV-Induced Skin Damage

Publisher: SAGE Publications

Date: 2013

DOI: 10.4137/IJTR.S9835

Abstract: The kynurenine pathway (KP) is the principle route of catabolism of the essential amino acid tryptophan, leading to the production of several neuroactive and immunoregulatory metabolites. Alterations in the KP have been implicated in various neuropsychiatric and neurodegenerative diseases, immunological disorders, and many other diseased states. Although the role of the KP in the skin has been evaluated in small niche fields, limited studies are available regarding the effect of acute ultra violet exposure and the induction of the KP in human skin-derived fibroblasts and keratinocytes. Since UV exposure can illicit an inflammatory component in skin cells, it is highly likely that the KP may be induced in these cells in response to UV exposure. It is also possible that some KP metabolites may act as pro-inflammatory and anti-inflammatory mediators, since the KP is important in immunomodulation.

Activation of the Kynurenine Pathway and Production of Inflammatory Cytokines by Astrocytes and Microglia Infected With Neospora caninum

Publisher: SAGE Publications

Date: 2022

DOI: 10.1177/11786469211069946

Abstract: In the central nervous system, astrocytes and microglia contribute to homeostasis, regulating the immune response to infectious agents. Neospora caninum is an obligate intracellular protozoan that infects different animal species and it is encysted in their nervous tissue while triggering an immune response modulated by glia. This study aimed to evaluate the infection of primary cultures of rat glial cells by N. caninum through the catabolites of tryptophan, the expression of inflammatory mediators and the integrity of neural tissue. Infection with this coccidium resulted in morphological and functional changes, particularly astrogliosis and microgliosis, and increased the expression of the inflammatory mediators TNF, IL1β, IL-10, and arginase, as well as mRNA for CCL5 and CCL2, molecules involved in the CNS chemotaxis. The infection with N. caninum in glial cells also triggered the activation of the tryptophan pathway, characterized by increased kynurenine 2,3 monooxygenase (KMO) mRNA expression, and by the production of the excitotoxin quinolinic acid (QUIN). Moreover, glia-neuron co-cultures, when exposed to the secretome derived from N. caninum infected glial cells, presented greater neurons distribution and formation of neurite extensions, associated to morphological changes in astrocytes compatible with neuro-preservation. Considering that the tryptophan catabolism is associated to immune response, these findings suggest that glial activation in N. caninum infection should be responsible for modulating the inflammatory status in an attempt to restore the nervous system homeostasis, since excessive inflammatory response can cause irreversible damage to tissue preservation.

Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans

Publisher: Springer Science and Business Media LLC

Date: 30-05-2015

DOI: 10.1186/S12974-015-0328-2

Biological Factors Underpinning Suicidal Behaviour: An Update

Publisher: MDPI AG

Date: 16-03-2023

DOI: 10.3390/BRAINSCI13030505

Abstract: Suicide, a global health burden, represents the 17th leading cause of death worldwide (1.3%), but the 4th among young people aged between 15 and 29 years of age, according to World Health Organization (WHO), 2019. Suicidal behaviour is a complex, multi-factorial, polygenic and independent mental health problem caused by a combination of alterations and dysfunctions of several biological pathways and disruption of normal mechanisms in brain regions that remain poorly understood and need further investigation to be deciphered. Suicide complexity and unpredictability gained international interest as a field of research. Several studies have been conducted at the neuropathological, inflammatory, genetic, and molecular levels to uncover the triggers behind suicidal behaviour and develop convenient and effective therapeutic or at least preventive procedures. This review aims to summarise and focus on current knowledge of erse biological pathways involved in the neurobiology of suicidal behaviour, and briefly highlights future potential therapeutic pathways to prevent or even treat this significant public health problem.

Dendritic spines: Revisiting the physiological role

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1016/J.PNPBP.2019.01.005

Abstract: Dendritic spines are small, thin, specialized protrusions from neuronal dendrites, primarily localized in the excitatory synapses. Sophisticated imaging techniques revealed that dendritic spines are complex structures consisting of a dense network of cytoskeletal, transmembrane and scaffolding molecules, and numerous surface receptors. Molecular signaling pathways, mainly Rho and Ras family small GTPases pathways that converge on actin cytoskeleton, regulate the spine morphology and dynamics bi-directionally during synaptic activity. During synaptic plasticity the number and shapes of dendritic spines undergo radical reorganizations. Long-term potentiation (LTP) induction promote spine head enlargement and the formation and stabilization of new spines. Long-term depression (LTD) results in their shrinkage and retraction. Reports indicate increased spine density in the pyramidal neurons of autism and Fragile X syndrome patients and reduced density in the temporal gyrus loci of schizophrenic patients. Post-mortem reports of Alzheimer's brains showed reduced spine number in the hippoc us and cortex. This review highlights the spine morphogenesis process, the activity-dependent structural plasticity and mechanisms by which synaptic activity sculpts the dendritic spines, the structural and functional changes in spines during learning and memory using LTP and LTD processes. It also discusses on spine status in neurodegenerative diseases and the impact of nootropics and neuroprotective agents on the functional restoration of dendritic spines.

Characterisation of the expression of NMDA receptors in human astrocytes

Publisher: Public Library of Science (PLoS)

Date: 30-11-2010

DOI: 10.1371/JOURNAL.PONE.0014123

Quinolinic acid toxicity on oligodendroglial cells: Relevance for multiple sclerosis and therapeutic strategies

Publisher: Springer Science and Business Media LLC

Date: 12-2014

DOI: 10.1186/S12974-014-0204-5

Amelioration of Aluminum Maltolate-Induced Inflammation and Endoplasmic Reticulum Stress-Mediated Apoptosis by Tannoid Principles of Emblica officinalis in Neuronal Cellular Model

Publisher: Springer Science and Business Media LLC

Date: 21-09-0008

DOI: 10.1007/S12640-018-9956-5

Abstract: The neuroprotective role of tannoid principles of Emblica officinalis (EoT), an Indian and Chinese traditional medicinal plant against memory loss in aluminum chloride-induced in vivo model of Alzheimer's disease through attenuating AChE activity, oxidative stress, amyloid and tau toxicity, and apoptosis, was recently reported in our lab. However, to further elucidate the mechanism of neuroprotective effect of EoT, the current study was designed to evaluate endoplasmic reticulum stress-suppressing and anti-inflammatory role of EoT in PC 12 and SH-SY 5Y cells. These cells were ided into four groups: control (aluminum maltolate (Al(mal)

Neurodegenerative Diseases: Tryptophan Metabolism

Publisher: Springer Berlin Heidelberg

DOI: 10.1007/978-3-540-29678-2_3821

Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease

Publisher: Informa UK Limited

Date: 08-2002

DOI: 10.1179/135100002125000550

Abstract: The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid (QUIN), is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. Alzheimer's disease is the major dementing disorder of the elderly that affects over 20 million peoples world-wide. Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the KP being associated with Alzheimer's disease. Disturbances of the KP have already been described in Alzheimer's disease. Recently, we demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of QUIN, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of QUIN toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease. Together, these data imply that QUIN may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the KP and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of QUIN neurotoxicity, emphasizing its roles in lipid peroxidation and the lification of the local inflammation.

Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression

Publisher: Springer Science and Business Media LLC

Date: 03-02-2017

DOI: 10.1038/SREP41473

Abstract: Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease. To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients. Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA). The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor. We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity. A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%. After validation in another independent cohort, sensitivity was maintained at 85%. Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers.

Sleep, brain vascular health and ageing

Publisher: Springer Science and Business Media LLC

Date: 03-08-2020

DOI: 10.1007/S11357-020-00235-8

Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of Alzheimer-like neuritic cytoskeletal striations

Publisher: Society for Neuroscience

Date: 14-10-2009

DOI: 10.1523/JNEUROSCI.3531-09.2009

Abstract: In Alzheimer's disease (AD), rod-like cofilin aggregates (cofilin–actin rods) and thread-like inclusions containing phosphorylated microtubule-associated protein (pMAP) tau form in the brain (neuropil threads), and the extent of their presence correlates with cognitive decline and disease progression. The assembly mechanism of these respective pathological lesions and the relationship between them is poorly understood, yet vital to understanding the causes of sporadic AD. We demonstrate that, during mitochondrial inhibition, activated actin-depolymerizing factor (ADF)/cofilin assemble into rods along processes of cultured primary neurons that recruit pMAP/tau and mimic neuropil threads. Fluorescence resonance energy transfer analysis revealed colocalization of cofilin-GFP (green fluorescent protein) and pMAP in rods, suggesting their close proximity within a cytoskeletal inclusion complex. The relationship between pMAP and cofilin–actin rods was further investigated using actin-modifying drugs and small interfering RNA knockdown of ADF/cofilin in primary neurons. The results suggest that activation of ADF/cofilin and generation of cofilin–actin rods is required for the subsequent recruitment of pMAP into the inclusions. Additionally, we were able to induce the formation of pMAP-positive ADF/cofilin rods by exposing cells to exogenous amyloid-β (Aβ) peptides. These results reveal a common pathway for pMAP and cofilin accumulation in neuronal processes. The requirement of activated ADF/cofilin for the sequestration of pMAP suggests that neuropil thread structures in the AD brain may be initiated by elevated cofilin activation and F-actin bundling that can be caused by oxidative stress, mitochondrial dysfunction, or Aβ peptides, all suspected initiators of synaptic loss and neurodegeneration in AD.

Recent advances in clinical trials targeting the kynurenine pathway

Publisher: Elsevier BV

Date: 08-2022

DOI: 10.1016/J.PHARMTHERA.2021.108055

Abstract: The kynurenine pathway (KP) is the major catabolic pathway for the essential amino acid tryptophan leading to he production of nicotinamide adenine dinucleotide. In inflammatory conditions, the activation of the KP leads to the production of several bioactive metabolites including kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid and quinolinic acid. These metabolites can have redox and immune suppressive activity, be neurotoxic or neuroprotective. While the activity of the pathway is tightly regulated under normal physiological condition, it can be upregulated by immunological activation and inflammation. The dysregulation of the KP has been implicated in wide range of neurological diseases and psychiatric disorders. In this review, we discuss the mechanisms involved in KP-mediated neurotoxicity and immune suppression, and its role in diseases of our expertise including cancer, chronic pain and multiple sclerosis. We also provide updates on the clinical trials evaluating the efficacy of KP inhibitors and/or analogues in each respective disease.

Beneficial Effects of Coating Alginate Microcapsules with Macromolecular Heparin Conjugates–In VitroandIn VivoStudy

Publisher: Mary Ann Liebert Inc

Date: 2014

DOI: 10.1089/TEN.TEA.2013.0254

Application of N-methyl-D-aspartate receptor nanopore in screening ligand molecules

Publisher: Elsevier BV

Date: 08-2020

DOI: 10.1016/J.BIOELECHEM.2020.107534

Sphingosine 1‐phosphate but not Fingolimod protects neurons against excitotoxic cell death by inducing neurotrophic gene expression in astrocytes

Publisher: Wiley

Date: 06-12-2019

DOI: 10.1111/JNC.14917

Abstract: Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through a family of five G protein-coupled receptors, S1PR1-S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) is a potent S1P receptor agonist that causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties of FTY720 in several neurodegenerative paradigms however, neuroprotective properties of the native ligand S1P have not been established. We aimed to establish the significance of neurotrophic factor up-regulation by S1P for neuroprotection, comparing S1P with FTY720. S1P induced brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), platelet-derived growth factor B (PDGFB), and heparin-binding EGF-like growth factor (HBEGF) gene expression in primary human and murine astrocytes, but not in neurons, and to a much greater extent than FTY720. Accordingly, S1P but not FTY720 protected cultured neurons against excitotoxic cell death in a primary murine neuron-glia coculture model, and a neutralizing antibody to LIF blocked this S1P-mediated neuroprotection. Antagonists of S1PR1 and S1PR2 both inhibited S1P-mediated neurotrophic gene induction in human astrocytes, indicating that simultaneous activation of both receptors is required. S1PR2 signaling was transduced through Gα

Sodium butyrate and indole-3-propionic acid prevent the increase of cytokines and kynurenine levels in LPS-induced human primary astrocytes

Publisher: SAGE Publications

Date: 2020

DOI: 10.1177/1178646920978404

Abstract: The crosstalk between central nervous system (CNS) and gut microbiota plays key roles in neuroinflammation and chronic immune activation that are common features of all neurodegenerative diseases. Imbalance in the microbiota can lead to an increase in the intestinal permeability allowing toxins to diffuse and reach the CNS, as well as impairing the production of neuroprotective metabolites such as sodium butyrate (SB) and indole-3-propionic acid (IPA). The aim of the present study was to evaluate the effect of SB and IPA on LPS-induced production of cytokines and tryptophan metabolites in human astrocytes. Primary cultures of human astrocytes were pre-incubated with SB or IPA for 1 hour before treatment with LPS. Cell viability was not affected at 24, 48 or 72 hours after pre-treatment with SB, IPA or LPS treatment. SB was able to significantly prevent the increase of GM-CSF, MCP-1, IL-6 IL-12, and IL-13 triggered by LPS. SB and IPA also prevented inflammation indicated by the increase in kynurenine and kynurenine/tryptophan ratio induced by LPS treatment. IPA pre-treatment prevented the LPS-induced increase in MCP-1, IL-12, IL-13, and TNF-α levels 24 hours after pre-treatment, but had no effect on tryptophan metabolites. The present study showed for the first time that bacterial metabolites SB and IPA have potential anti-inflammatory effect on primary human astrocytes with potential therapeutic benefit in neurodegenerative disease characterized by the presence of chronic low-grade inflammation.

Possible role of tryptophan and melatonin in COVID-19

Publisher: SAGE Publications

Date: 2020

DOI: 10.1177/1178646920951832

Neuroprotective Effects of a Variety of Pomegranate Juice Extracts against MPTP-Induced Cytotoxicity and Oxidative Stress in Human Primary Neurons

Publisher: Hindawi Limited

Date: 2013

DOI: 10.1155/2013/685909

Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an environmental toxin which selectively induces oxidative damage and mitochondrial and proteasomal dysfunctions to dopaminergic neurons in the substantia nigra leading to Parkinsonian syndrome in animal models and humans. MPTP is one of the most widely used in vitro models to investigate the pathophysiology of Parkinson's disease (PD) and, screen for novel therapeutic compounds that can slow down or ameliorate this progressive degenerative disease. We investigated the therapeutic effect of pomegranate juice extracts (PJE), Helow, Malasi, Qusum, and Hamadh against MPTP-induced neurotoxicity in primary human neurons by examining extracellular LDH activity, intracellular NAD + and ATP levels, and endogenous antioxidant levels including lipid peroxidation products, catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, and reduced glutathione (GSH) levels. MPTP induced a reduction in SOD and GPx activities and intracellular NAD + , ATP, and GSH levels parallel to an increase in extracellular LDH and CAT activities, although lipid peroxidation was not altered. We report that helow and malasi can ameliorate MPTP-induced neurotoxicity by attenuating the observed changes in redox function to a greater extent than qusum and hamedh. Selected PJE varieties may exhibit properties which may be of therapeutic value to slow down age-related degeneration and neurodegeneration in particular.

Microbiota alterations in Alzheimer’s disease

Publisher: Springer Science and Business Media LLC

Date: 14-05-2019

DOI: 10.1007/S12640-019-00057-3

Abstract: Alzheimer's disease (AD) is a neurodegenerative disease considered the major cause of dementia in the elderly. The main pathophysiological features of the disease are neuronal loss (mainly cholinergic neurons), glutamatergic excitotoxicity, extracellular accumulation of amyloid beta, and intracellular neurofibrillary tangles. However, other pathophysiological features of the disease have emerged including neuroinflammation and dysregulation of the kynurenine pathway (KP). The intestinal microbiota is a large and erse collection of microorganisms that play a crucial role in regulating host health. Recently, studies have highlighted that changes in intestinal microbiota contribute to brain dysfunction in various neurological diseases including AD. Studies suggest that microbiota compositions are altered in AD patients and animal models and that these changes may increase intestinal permeability and induce inflammation. Considering that microbiota can modulate the kynurenine pathway and in turn neuroinflammation, the gut microbiome may be a valuable target for the development of new disease-modifying therapies. The present review aims to link the interactions between AD, microbiota, and the KP.

Kynurenine-3-monooxygenase expression is activated in the pancreatic endocrine cells by diabetes and its blockade improves glucose-stimulated insulin secretion

Publisher: Elsevier BV

Date: 11-2022

DOI: 10.1016/J.BBADIS.2022.166509

Abstract: Type 2 diabetes is associated with an inflammatory phenotype in the pancreatic islets. We previously demonstrated that proinflammatory cytokines potently activate the tryptophan/kynurenine pathway (TKP) in INS-1 cells and in normal rat islets. Here we examined: (1) the TKP enzymes expression in the diabetic GK islets (2) the TKP enzymes expression profiles in the GK islets before and after the onset of diabetes (3) The glucose-stimulated insulin secretion (GSIS) in vitro in GK islets after KMO knockdown using specific morpholino-oligonucleotides against KMO or KMO blockade using the specific inhibitor Ro618048 (4) The glucose tolerance and GSIS after acute in vivo exposure to Ro618048 in GK rats. We report a remarkable induction of the kmo gene in GK islets and in human islets exposed to proinflammatory conditions. It occurred prominently in beta cells. The increased expression and activity of KMO reflected an acquired adaptation. Both KMO knockdown and specific inhibitor Ro618048 enhanced GSIS in vitro in GK islets. Moreover, acute administration of Ro618048 in vivo improved glucose tolerance, GSIS and basal blood glucose levels in GK rats. These results demonstrate that targeting islet TKP is able to correct defective GSIS. KMO inhibition could represent a potential therapeutic strategy for type 2 diabetes.

Involvement of the Kynurenine Pathway in Alzheimer's Disease

Publisher: Wiley

Date: 12-09-2010

DOI: 10.1111/J.1471-4159.2010.06943.X

ISTRY 2013 special issue

Publisher: SAGE Publications

Date: 1970

DOI: 10.4137/IJTR.S12327

Toward a neuroprotective shift

Publisher: Elsevier BV

Date: 08-2021

DOI: 10.1016/J.BBI.2021.04.020

Connecting inflammation with glutamate agonism in suicidality

Publisher: Springer Science and Business Media LLC

Date: 03-12-2012

DOI: 10.1038/NPP.2012.248

Genetic basis of hindlimb loss in a naturally occurring vertebrate model

Publisher: The Company of Biologists

Date: 18-02-2016

DOI: 10.1242/BIO.016295

Abstract: Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS) of T-box transcription factor 4 (Tbx4) that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V G79A) are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.

Metabolome analysis reveals the association between the kynurenine pathway and human herpesvirus 6 encephalopathy in immunocompetent children

Publisher: Springer Science and Business Media LLC

Date: 20-09-2017

DOI: 10.1007/S11306-017-1268-X

Pharmacological Benefits of Active Components of Natural Products Against Traumatic Brain Injury - A Review

Publisher: Bentham Science Publishers Ltd.

Date: 12-05-2016

DOI: 10.2174/1875692114999160502125941

10 Persian herbal medicines used for brain health

Publisher: Elsevier

Date: 2021

DOI: 10.1016/B978-0-12-820593-8.00008-2

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.EBIOM.2023.104589

Long-Term Dietary Supplementation of Pomegranates, Figs and Dates Alleviate Neuroinflammation in a Transgenic Mouse Model of Alzheimer’s Disease

Publisher: Public Library of Science (PLoS)

Date: 25-03-2015

DOI: 10.1371/JOURNAL.PONE.0120964

Quantitative metabolome profiling reveals the involvement of the kynurenine pathway in influenza-associated encephalopathy

Publisher: Springer Science and Business Media LLC

Date: 15-03-2016

DOI: 10.1007/S11306-016-1011-Z

Involvement of the kynurenine pathway in the pathogenesis of Parkinson's disease

Publisher: Elsevier BV

Date: 08-2015

DOI: 10.1016/J.PNEUROBIO.2015.12.009

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Neuroinflammation leads to microglia activation and release of a large number of proinflammatory mediators. The kynurenine pathway (KP) of tryptophan catabolism is one of the major regulators of the immune response and is also likely to be implicated in the inflammatory and neurotoxic events in Parkinsonism. Several neuroactive compounds are produced through the KP that can be either a neurotoxic, neuroprotective or immunomodulator. Among these metabolites kynurenic acid (KYNA), produced by astrocytes, is considered as neuroprotective whereas quinolinic acid (QUIN), released by activated microglia, can activate the N-methyl-d-aspartate (NMDA) receptor-signalling pathway, leading to excitotoxicity and lify the inflammatory response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that some of the KP metabolites could be used as prognostic biomarkers and that pharmacological modulators of the KP enzymes could represent a new therapeutic strategy for PD.

Global cellular responses to β-methyl-amino-l-alanine (BMAA) by olfactory ensheathing glial cells (OEC)

Publisher: Elsevier BV

Date: 06-2015

DOI: 10.1016/J.TOXICON.2015.03.009

Abstract: This study utilised a proteomics approach to identify any differential protein expression in a glial cell line, rat olfactory ensheathing cells (OECs), treated with the cyanotoxin β-methylamino-l-alanine (BMAA). Five proteins of interest were identified, namely Rho GDP-dissociation inhibitor 1 (RhoGDP1), Nck-associated protein 1 (NCKAP1), voltage-dependent anion-selective channel protein 1 (VDAC1), 3-hydroxyacyl-CoA dehydrogenase type-2 (3hCoAdh2), and ubiquilin-4 (UBQLN4). Four of these candidates, nuclear receptor subfamily 4 group A member 1 (Nur77), cyclophilin A (CyPA), RhoGDP1 and VDAC1, have been reported to be involved in cell growth. A microarray identified UBQLN4, palladin and CyPA, which have been implicated to have roles in excitotoxicity. Moreover, the NCKAP1, UBQLN4, CyPA and 3hCoAdh2 genes have been associated with abnormal protein aggregation. Differential expression of genes involved in mitochondrial activity, Nur77, 3hCoAdh2, VDAC1 and UBQLN4, were also identified. Confirmatory reverse transcription quantitative PCR (RT-qPCR) analysis of transcripts generated from the genes of interest corroborated the differential expression trends identified in the global protein analysis. BMAA induced cell cycle arrest in the G2/M phase of OEC and apoptosis after 48 h at concentrations of 250 μM and 500 μM. Collectively, this work advances our understanding of the mechanism of BMAA-mediated glial-toxicity in vitro.

Epithelial indoleamine 2,3-dioxygenase 1 modulates aryl hydrocarbon receptor and notch signaling to increase differentiation of secretory cells and alter mucus-associated microbiota

Publisher: Elsevier BV

Date: 10-2019

DOI: 10.1053/J.GASTRO.2019.07.013

Role of Rho/ROCK signaling in the interaction of melanoma cells with the blood–brain barrier

Publisher: Wiley

Date: 23-10-2013

DOI: 10.1111/PCMR.12169

Abstract: We have investigated the role of the Rho/ROCK signaling pathway in the interaction of metastatic melanoma cells with the brain endothelium. ROCK inhibition induced a shift of melanoma cells to the mesenchymal phenotype, increased the number of melanoma cells attached to the brain endothelium, and strengthened the adhesion force between melanoma and endothelial cells. Inhibition of ROCK raised the number of melanoma cells migrating through the brain endothelial monolayer and promoted the formation of parenchymal brain metastases in vivo. We have shown that inhibition of the Rho/ROCK pathway in melanoma, but not in brain endothelial cells, is responsible for this phenomenon. Our results indicate that the mesenchymal type of tumor cell movement is primordial in the transmigration of melanoma cells through the blood-brain barrier.

Use of a Recombinant Biomarker Protein DDA Library Increases DIA Coverage of Low Abundance Plasma Proteins

Publisher: American Chemical Society (ACS)

Date: 22-03-2021

DOI: 10.1021/ACS.JPROTEOME.0C00898

Abstract: Credible detection and quantification of low abundance proteins from human blood plasma is a major challenge in precision medicine biomarker discovery when using mass spectrometry (MS). In this proof-of-concept study, we employed a mixture of selected recombinant proteins in DDA libraries to subsequently identify (not quantify) cancer-associated low abundance plasma proteins using SWATH/DIA. The exemplar DDA recombinant protein spectral library (rPSL) was derived from tryptic digestion of 36 recombinant human proteins that had been previously implicated as possible cancer biomarkers from both our own and other studies. The rPSL was then used to identify proteins from nondepleted colorectal cancer (CRC) EDTA plasmas by SWATH-MS. Most (32/36) of the proteins used in the rPSL were reliably identified from CRC plasma s les, including 8 proteins (i.e., BTC, CXCL10, IL1B, IL6, ITGB6, TGFα, TNF, TP53) not previously detected using high-stringency protein inference MS according to PeptideAtlas. The rPSL SWATH-MS protocol was compared to DDA-MS using MARS-depleted and postdigestion peptide fractionated plasmas (here referred to as a human plasma DDA library). Of the 32 proteins identified using rPSL SWATH, only 12 could be identified using DDA-MS. The 20 additional proteins exclusively identified using the rPSL SWATH approach were almost exclusively lower abundance (i.e., <10 ng/mL) proteins. To mitigate justified FDR concerns, and to replicate a more typical library creation approach, the DDA rPSL library was merged with a human plasma DDA library and SWATH identification repeated using such a merged library. The majority (33/36) of the low abundance plasma proteins added from the rPSL were still able to be identified using such a merged library when high-stringency HPP Guidelines v3.0 protein inference criteria were applied to our data set. The MS data set has been deposited to ProteomeXchange Consortium via the PRIDE partner repository (PXD022361).

Kynurenine-3-monooxygenase: a review of structure, mechanism, and inhibitors

Publisher: Elsevier BV

Date: 02-2016

DOI: 10.1016/J.DRUDIS.2015.11.001

Abstract: Kynurenine monooxygenase (KMO) is an enzyme of the kynurenine (Kyn) pathway (KP), which is the major catabolic route of tryptophan. Kyn represents a branch point of the KP, being converted into the neurotoxin 3-hydroxykynurenine via KMO, neuroprotectant kynurenic acid, and anthranilic acid. As a result of this branch point, KMO is an attractive drug target for several neurodegenerative and/or neuroinflammatory diseases, especially Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases. Although a neurological target, administration of KMO inhibitors in the periphery has demonstrated promising pharmacological results. In light of a recent crystal structure release and reports of preclinical candidates, here we provide a concise yet comprehensive update on the current state of research into the enzymology of KMO and related drug discovery efforts, highlighting areas where further work is required.

Kynurenine and tetrahydrobiopterin pathways crosstalk in pain hypersensitivity

Publisher: Frontiers Media SA

Date: 24-06-2020

DOI: 10.3389/FNINS.2020.00620

Expression of Tryptophan 2,3-Dioxygenase and Production of Kynurenine Pathway Metabolites in Triple Transgenic Mice and Human Alzheimer's Disease Brain

Publisher: Public Library of Science (PLoS)

Date: 22-04-2013

DOI: 10.1371/JOURNAL.PONE.0059749

Effects of Sleep Deprivation on the Tryptophan Metabolism

Publisher: SAGE Publications

Date: 2020

DOI: 10.1177/1178646920970902

Abstract: Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.

Psychological stresses in children trigger cytokine- and kynurenine metabolite-mediated abdominal pain and proinflammatory changes

Publisher: Frontiers Media SA

Date: 09-2021

DOI: 10.3389/FIMMU.2021.702301

Abstract: Recurrent abdominal pain (RAP) is a common medically unexplained symptom among children worldwide. However, the biological mechanisms behind the development of functional and behavioral symptoms and changes in blood markers have not been well explored. This study aimed to assess changes in the concentrations of inflammatory markers, including cytokines and tryptophan catabolites, in the serum of children with RAP compared to those with subclinical infections. Children with RAP but without organic diseases were included, and those with asymptomatic intestinal parasitic infections were used as a subclinical infection cohort. Blood s les were collected and used to measure the cytokine profile using Multiplex Immunoassay and tryptophan catabolites using high performance liquid chromatography. Children with RAP showed significantly higher concentrations of serum tumor necrotic factor-α, p & .05, but lower concentrations of IL-10, p & .001, IL-6, p & .001 and brain-derived neurotrophic factors (BDNF) p & .01. In addition, a significant increase in the metabolite of the kynurenine pathway, 3-hydroxyanthranilic acid (3-HAA) p & .01, a significant decrease in the concentrations of anthranilic acid (AA) p & .001, together with an increased ratio of serum 3-HAA to AA (3-HAA/AA) p & .001, was found in this cohort. These findings indicate the significant activation of the immune system and presence of inflammation in children with RAP than those with subclinical parasitic infections. Moreover, children with RAP tested with the Strengths and Difficulties Questionnaire (SDQ ) , displayed high psychological problems though these SDQ scores were not statistically associated with measured cytokines and kynurenine metabolites. We however could hypothesize that the pro-inflammatory state together with concomitant low concentrations of BDNF in those children with RAP could play a role in psychological stress and experiencing medically unexplained symptoms.

Increased Markers of Oxidative Stress in Autistic Children of the Sultanate of Oman

Publisher: Springer Science and Business Media LLC

Date: 30-11-2011

DOI: 10.1007/S12011-011-9280-X

Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder of early childhood, and an enumeration about its etiology and consequences is still limited. Oxidative stress-induced mechanisms are believed to be the major cause for ASD. In this study 19 autistic and 19 age-matched normal Omani children were recruited to analyze their degree of redox status and a prewritten consent was obtained. Blood was withdrawn from subjects in heparin-coated tube, and plasma was separated. Plasma oxidative stress indicators such as nitric oxide (NO), malondialdehyde (MDA), protein carbonyl, and lactate to pyruvate ratio were quantified using commercially available kits. A significant elevation was observed in the levels of NO, MDA, protein carbonyl, and lactate to pyruvate ratio in the plasma of Omani autistic children as compared to their age-matched controls. These oxidative stress markers are strongly associated with major cellular injury and manifest severe mitochondrial dysfunction in autistic pathology. Our results also suggest that oxidative stress might be involved in the pathogenesis of ASD, and these parameters could be considered as diagnostic markers to ensure the prevalence of ASD in Omani children. However, the oxidative stress-induced molecular mechanisms in ASD should be studied in detail.

SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation

Publisher: Springer Science and Business Media LLC

Date: 31-10-2015

DOI: 10.1186/S13024-015-0053-4

Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo

Publisher: Springer Science and Business Media LLC

Date: 20-08-2021

DOI: 10.1186/S13041-021-00839-X

Abstract: Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.

Involvement of quinolinic acid in aids dementia complex

Publisher: Springer Science and Business Media LLC

Date: 2005

DOI: 10.1007/BF03033781

Cytotoxic Effects of Environmental Toxins on Human Glial Cells

Publisher: Springer Science and Business Media LLC

Date: 29-10-2017

DOI: 10.1007/S12640-016-9678-5

Abstract: Toxins produced by cyanobacteria and dinoflagellates have increasingly become a public health concern due to their degenerative effects on mammalian tissue and cells. In particular, emerging evidence has called attention to the neurodegenerative effects of the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA). Other toxins such as the neurotoxins saxitoxin and ciguatoxin, as well as the hepatotoxic microcystin, have been previously shown to have a range of effects upon the nervous system. However, the capacity of these toxins to cause neurodegeneration in human cells has not, to our knowledge, been previously investigated. This study aimed to examine the cytotoxic effects of BMAA, microcystin-LR (MC-LR), saxitoxin (STX) and ciguatoxin (CTX-1B) on primary adult human astrocytes. We also demonstrated that α-lipoate attenuated MC-LR toxicity in primary astrocytes and characterised changes in gene expression which could potentially be caused by these toxins in primary astrocytes. Herein, we are the first to show that all of these toxins are capable of causing physiological changes consistent with neurodegeneration in glial cells, via oxidative stress and excitotoxicity, leading to a reduction in cell proliferation culminating in cell death. In addition, MC-LR toxicity was reduced significantly in astrocytes-treated α-lipoic acid. While there were no significant changes in gene expression, many of the probes that were altered were associated with neurodegenerative disease pathogenesis. Overall, this is important in advancing our current understanding of the mechanism of toxicity of MC-LR on human brain function in vitro, particularly in the context of neurodegeneration.

NAD Deficiency, Congenital Malformations, and Niacin Supplementation

Publisher: Massachusetts Medical Society

Date: 10-08-2017

DOI: 10.1056/NEJMOA1616361

Telmisartan Ameliorates Astroglial and Dopaminergic Functions in a Mouse Model of Chronic Parkinsonism

Publisher: Springer Science and Business Media LLC

Date: 13-07-2018

DOI: 10.1007/S12640-018-9921-3

Abstract: Many studies reported the neuroprotective effects of angiotensin II type 1 receptor (AT1R) antagonists in Parkinson's disease (PD). However, the role of AT1R blockade on astroglial, in turn, dopaminergic functions in chronic PD is still to be studied. In the present study, telmisartan (TEL 3 and 10 mg/kg/day p.o), was used to study the effects AT1R blockade on astrocytic and dopaminergic functions in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinsonism (250 mg/kg, i.p, in 10 equally ided doses at 3.5 days interval) in C57BL/6 J mice. TEL significantly downregulated glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS), TNFα and IL1β expressions and nitric oxide (NO) content. Significant upregulation glial cell derived neurotrophic factor (GDNF) expression and increased glutathione (GSH) content reveal the ameliorating effects of TEL on astroglial functions. On the other hand, TEL upregulated tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) expressions. Finally, TEL improved dopamine and its turnover and restored locomotor performance. Present experiment reveals that TEL has the potential to alleviate astroglial functions, apart from restoring dopaminergic functions, at least in part. To conclude, TEL may be a better disease-modifying therapeutic regimen in the management of Parkinsonism, acting primarily via astroglial-dopaminergic functions.

Ionotropic receptors in the central nervous system and neurodegenerative disease

Publisher: Springer New York

Date: 2014

DOI: 10.1007/978-1-4614-5836-4_126

Mechanisms of l-Serine Neuroprotection in vitro Include ER Proteostasis Regulation

Publisher: Springer Science and Business Media LLC

Date: 02-11-2017

DOI: 10.1007/S12640-017-9829-3

Abstract: β-N-methylamino-L-alanine (L-BMAA) is a neurotoxic non-protein amino acid produced by cyanobacteria. Recently, chronic dietary exposure to L-BMAA was shown to trigger neuropathology in nonhuman primates consistent with Guamanian ALS/PDC, a paralytic disease that afflicts Chamorro villagers who consume traditional food items contaminated with L-BMAA. However, the addition of the naturally occurring amino acid L-serine to the diet of the nonhuman primates resulted in a significant reduction in ALS/PDC neuropathology. L-serine is a dietary amino acid that plays a crucial role in central nervous system development, neuronal signaling, and synaptic plasticity and has been shown to impart neuroprotection from L-BMAA-induced neurotoxicity both in vitro and in vivo. We have previously shown that L-serine prevents the formation of autofluorescent aggregates and death by apoptosis in human cell lines and primary cells. These effects are likely imparted by L-serine blocking incorporation of L-BMAA into proteins hence preventing proteotoxic stress. However, there are likely other mechanisms for L-serine-mediated neuroprotection. Here, we explore the molecular mechanisms of L-serine neuroprotection using a human unfolded protein response real-time PCR array with genes from the ER stress and UPR pathways, and western blotting. We report that L-serine caused the differential expression of many of the same genes as L-BMAA, even though concentrations of L-serine in the culture medium were ten times lower than that of L-BMAA. We propose that L-serine may be functioning as a small proteostasis regulator, in effect altering the cells to quickly respond to a possible oxidative insult, thus favoring a return to homeostasis.

“STRESSED OUT”

Publisher: Elsevier BV

Date: 09-2020

DOI: 10.1016/J.BIOCEL.2020.105821

Serum Leukocyte immunoglobulin-like receptor A3 (LILRA3) is increased in patients with multiple sclerosis and is a strong independent indicator of disease severity; 6.7kbp LILRA3 gene deletion is not associated with diseases susceptibility

Publisher: Public Library of Science (PLoS)

Date: 12-02-2016

DOI: 10.1371/JOURNAL.PONE.0149200

Boswellia Gum Resin and Essential Oils: Potential Health Benefits − An Evidence Based Review

Publisher: Medknow

Date: 2019

DOI: 10.4103/IJNPND.IJNPND_11_19

Interference of α-Synuclein Uptake by Monomeric β-Amyloid1–40 and Potential Core Acting Site of the Interference

Publisher: Springer Science and Business Media LLC

Date: 30-06-2016

DOI: 10.1007/S12640-016-9644-2

Abstract: Increasing evidence suggests an important role of alpha-synuclein (α-Syn) in the pathogenesis of Parkinson's disease (PD). The inter-neuronal spread of α-Syn via exocytosis and endocytosis has been proposed as an explanation for the neuropathological findings of PD in sub-clinical and clinical phases. Therefore, interfering the uptake of α-Syn by neurons may be an important step in slowing or modifying the propagation of the disease. The purposes of our study were to investigate if the uptake of α-Syn fibrils can be specifically interfered with monomeric β-Amyloid1-40 (Aβ40) and to characterise the core acting site of interference. Using a radioisotope-labelled uptake assay, we found an 80 % uptake reduction of α-Syn fibrils in neurons interfered with monomeric Aβ40, but not β-Amyloid1-42 (Aβ42) as compared to controls. This finding was further confirmed by enzyme-linked immunosorbent assay (ELISA) with α-Syn uptake reduced from about 80 % (Aβ42) to about 20 % (Aβ40) relative to controls. To define the region of Aβ40 peptide capable of the interference, we explored shorter peptides with less amino acid residues from both the C-terminus and N-terminus. We found that the interference effect was preserved if amino acid residue was trimmed to position 11 (from N-terminus) and 36 (from C-terminus), but dropped off significantly if residues were trimmed beyond these positions. We therefore deduced that the "core acting site" lies between amino acid residue positions 12-36. These findings suggest α-Syn uptake can be interfered with monomeric Aβ40 and that the core acting site of interference might lie between amino acid residue positions 12-36.

Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis

Publisher: Springer Science and Business Media LLC

Date: 13-01-2022

DOI: 10.1007/S12640-021-00455-6

Abstract: The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential environmental etiology factor for some sporadic neurodegenerative diseases. Climate change and eutrophication significantly increase the frequency and intensity of cyanobacterial bloom in water bodies. This review evaluates different neuropathological mechanisms of BMAA at molecular and cellular levels and compares the related studies to provide some useful recommendations. Additionally, the structure and properties of BMAA as well as its microbial origin, especially by gut bacteria, are also briefly covered. Unlike previous reviews, we hypothesize the possible neurotoxic mechanism of BMAA through iron overload. We also discuss the involvement of BMAA in excitotoxicity, TAR DNA-binding protein 43 (TDP-43) translocation and accumulation, tauopathy, and other protein misincorporation and misfolding.

Decreased cerebrospinal fluid kynurenic acid in epileptic spasms

Publisher: Elsevier BV

Date: 10-2022

DOI: 10.1016/J.EBIOM.2022.104280

Primary human astrocytes produce 24(S),25-epoxycholesterol with implications for brain cholesterol homeostasis

Publisher: Wiley

Date: 17-08-0001

DOI: 10.1111/J.1471-4159.2007.04913.X

Abstract: Cholesterol is an essential component of the CNS and its metabolism in the brain has been implicated in various neurodegenerative diseases. The oxysterol produced from cholesterol, 24(S)-hydroxycholesterol, is known to be an important regulator of brain cholesterol homeostasis. In this study, we focussed on another oxysterol, 24(S),25-epoxycholesterol (24,25EC), which has not been studied before in a neurological context. 24,25EC is unique in that it is synthesized in a shunt in the mevalonate pathway, parallel to cholesterol and utilizing the same enzymes. Considering that all the cholesterol present in the brain is derived from de novo synthesis, we investigated whether or not primary human neurons and astrocytes can produce 24,25EC. We found that astrocytes produced more 24,25EC than neurons under basal conditions, but both cell types had the capacity to synthesize this oxysterol when the enzyme 2,3-oxidosqualene cyclase was partially inhibited. Furthermore, both added 24,25EC and stimulated cellular production of 24,25EC (by partial inhibition of 2,3-oxidosqualene cyclase) modulated expression of key cholesterol-homeostatic genes regulated by the liver X receptor and the sterol regulatory element-binding protein-2. Moreover, we found that 24,25EC synthesized in astrocytes can be taken up by neurons and exert downstream effects on gene regulation. In summary, we have identified 24,25EC as a novel neurosterol which plays a likely role in brain cholesterol homeostasis.

Altered kynurenine pathway metabolism in autism: Implication for immune‐induced glutamatergic activity

Publisher: Wiley

Date: 24-10-2015

DOI: 10.1002/AUR.1565

Abstract: Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621-631. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Publisher: Springer Science and Business Media LLC

Date: 15-04-2016

DOI: 10.1038/NCOMMS11253

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase complex (SCF Cyclin F ). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF Cyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

FKBP12 binds to the cardiac ryanodine receptor with negative cooperativity: implications for heart muscle physiology in health and disease.

Publisher: The Royal Society

Date: 05-2023

DOI: 10.1098/RSTB.2022.0169

Abstract: Cardiac ryanodine receptors (RyR2) release the Ca 2+ from intracellular stores that is essential for cardiac myocyte contraction. The ion channel opening is tightly regulated by intracellular factors, including the FK506 binding proteins, FKBP12 and FKBP12.6. The impact of these proteins on RyR2 activity and cardiac contraction is debated, with often apparently contradictory experimental results, particularly for FKBP12. The isoform that regulates RyR2 has generally been considered to be FKBP12.6, despite the fact that FKBP12 is the major isoform associated with RyR2 in some species and is bound in similar proportions to FKBP12.6 in others, including sheep and humans. Here, we show time- and concentration-dependent effects of adding FKBP12 to RyR2 channels that were partly depleted of FKBP12/12.6 during isolation. The added FKBP12 displaced most remaining endogenous FKBP12/12.6. The results suggest that FKBP12 activates RyR2 with high affinity and inhibits RyR2 with lower affinity, consistent with a model of negative cooperativity in FKBP12 binding to each of the four subunits in the RyR tetramer. The easy dissociation of some FKBP12/12.6 could dynamically alter RyR2 activity in response to changes in in vivo regulatory factors, indicating a significant role for FKBP12/12.6 in Ca 2+ signalling and cardiac function in healthy and diseased hearts. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

Current evidence for a role of the kynurenine pathway of tryptophan metabolism in multiple sclerosis

Publisher: Frontiers Media SA

Date: 04-08-0002

DOI: 10.3389/FIMMU.2016.00246

Kynurenine 3-Monooxygenase Activity in Human Primary Neurons and Effect on Cellular Bioenergetics Identifies New Neurotoxic Mechanisms

Publisher: Springer Science and Business Media LLC

Date: 21-01-2019

DOI: 10.1007/S12640-019-9997-4

Abstract: Upregulation of the kynurenine pathway (KP) of tryptophan metabolism is commonly observed in neurodegenerative disease. When activated, L-kynurenine (KYN) increases in the periphery and central nervous system where it is further metabolised to other neuroactive metabolites including 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA) and quinolinic acid (QUIN). Particularly biologically relevant metabolites are 3-HK and QUIN, formed downstream of the enzyme kynurenine 3-monooxygenase (KMO) which plays a pivotal role in maintaining KP homeostasis. Indeed, excessive production of 3-HK and QUIN has been described in neurodegenerative disease including Alzheimer's disease and Huntington's disease. In this study, we characterise KMO activity in human primary neurons and identified new mechanisms by which KMO activation mediates neurotoxicity. We show that while transient activation of the KP promotes synthesis of the essential co-enzyme nicotinamide adenine dinucleotide (NAD

Involvement of the kynurenine pathway in breast cancer: updates on clinical research and trials

Publisher: Springer Science and Business Media LLC

Date: 11-04-2023

DOI: 10.1038/S41416-023-02245-7

Abstract: Breast cancer (BrCa) is the leading cause of cancer incidence and mortality in women worldwide. While BrCa treatment has been shown to be highly successful if detected at an early stage, there are few effective strategies to treat metastatic tumours. Hence, metastasis remains the main cause in most of BrCa deaths, highlighting the need for new approaches in this group of patients. Immunotherapy has been gaining attention as a new treatment for BrCa metastasis and the kynurenine pathway (KP) has been suggested as one of the potential targets. The KP is the major biochemical pathway in tryptophan (TRP) metabolism, catabolising TRP to nicotinamide adenine dinucleotide (NAD + ). The KP has been reported to be elevated under inflammatory conditions such as cancers and that its activity suppresses immune surveillance. Dysregulation of the KP has previously been reported implicated in BrCa. This review aims to discuss and provide an update on the current mechanisms involved in KP-mediated immune suppression and cancer growth. Furthermore, we also provide a summary on 58 studies about the involvement of the KP and BrCa and five clinical trials targeting KP enzymes and their outcome.

Effects of kynurenine pathway inhibition on NAD + metabolism and cell viability in human primary astrocytes and neurons

Publisher: SAGE Publications

Date: 2011

DOI: 10.4137/IJTR.S7052

Abstract: The kynurenine pathway (KP) is the principle route of L-Tryptophan (TRP) metabolism, producing several neurotoxic and neuroprotective metabolic precursors before complete oxidation to the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD + ). KP inhibition may prove therapeutic in central nervous system (CNS) inflammation by reducing the production of excitotoxins such as quinolinic acid (QUIN). However, KP metabolism may also be cytoprotective through the de novo synthesis of intracellular NAD + . We tested the hypothesis that the KP is directly involved in the maintenance of intracellular NAD + levels and SIRT1 function in primary astrocytes and neurons through regulation of NAD + synthesis. Competitive inhibition of indoleamine 2,3 dioxygenase (IDO), and quinolinic acid phosphoribosyltransferase (QPRT) activities with 1-methyl-L-Tryptophan (1-MT), and phthalic acid (PA) respectively, resulted in a dose-dependent decrease in intracellular NAD + levels and sirtuin deacetylase-1 (SIRT1) activity, and correlated directly with reduced cell viability. These results support the hypothesis that the primary role of KP activation during neuroinflammation is to maintain NAD + levels through de novo synthesis from TRP. Inhibition of KP metabolism under these conditions can compromise cell viability, NAD-dependent SIRT1 activity and CNS function, unless alternative precursors for NAD + synthesis are made available.

Is exposure to BMAA a risk factor for neurodegenerative diseases?

Publisher: Springer Science and Business Media LLC

Date: 02-2021

DOI: 10.1007/S12640-020-00302-0

Abstract: In a literature survey, Chernoff et al. (2017) dismissed the hypothesis that chronic exposure to β- N -methylamino-L-alanine (BMAA) may be a risk factor for progressive neurodegenerative disease. They question the growing scientific literature that suggests the following: (1) BMAA exposure causes ALS/PDC among the indigenous Chamorro people of Guam (2) Guamanian ALS/PDC shares clinical and neuropathological features with Alzheimer’s disease, Parkinson’s disease, and ALS (3) one possible mechanism for protein misfolds is misincorporation of BMAA into proteins as a substitute for L-serine and (4) chronic exposure to BMAA through diet or environmental exposures to cyanobacterial blooms can cause neurodegenerative disease. We here identify multiple errors in their critique including the following: (1) their review selectively cites the published literature (2) the authors reported favorably on HILIC methods of BMAA detection while the literature shows significant matrix effects and peak coelution in HILIC that may prevent detection and quantification of BMAA in cyanobacteria (3) the authors build alternative arguments to the BMAA hypothesis, rather than explain the published literature which, to date, has been unable to refute the BMAA hypothesis and (4) the authors erroneously attribute methods to incorrect studies, indicative of a failure to carefully consider all relevant publications. The lack of attention to BMAA research begins with the review’s title which incorrectly refers to BMAA as a “non-essential” amino acid. Research regarding chronic exposure to BMAA as a cause of human neurodegenerative diseases is emerging and requires additional resources, validation, and research. Here, we propose strategies for improvement in the execution and reporting of analytical methods and the need for additional and well-executed inter-lab comparisons for BMAA quantitation. We emphasize the need for optimization and validation of analytical methods to ensure that they are fit-for-purpose. Although there remain gaps in the literature, an increasingly large body of data from multiple independent labs using orthogonal methods provides increasing evidence that chronic exposure to BMAA may be a risk factor for neurological illness.

Therapeutic potential of mitophagy-inducing microflora metabolite, urolithin A for alzheimer’s disease

Publisher: MDPI AG

Date: 23-10-2021

DOI: 10.3390/NU13113744

Abstract: Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neurodegenerative disorders including Alzheimer’s disease (AD). Apart from traditionally targeting amyloid beta (Aβ), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bioactive food components, known as nutraceuticals, may serve as such agents to combat AD. Urolithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, anti-inflammatory, anti-atherogenic, anti-Aβ, and pro-mitophagy properties are increasingly recognized. However, the underlying mechanisms of urolithin A in inducing mitophagy is poorly understood. This review discusses the mitophagy deficits in AD and examines potential molecular mechanisms of its activation. Moreover, the current knowledge of urolithin A is discussed, focusing on its neuroprotective properties and its potential to induce mitophagy. Specifically, this review proposes potential mechanisms by which urolithin A may activate and promote mitophagy.

An in vitro evidence for caffeic acid, rosmarinic acid and trans cinnamic acid as a skin protectant against γ-radiation

Publisher: Inderscience Publishers

Date: 2014

DOI: 10.1504/IJLR.2014.063414

Papaverine, a phosphodiesterase 10A inhibitor, ameliorates quinolinic acid-induced synaptotoxicity in human cortical neurons

Publisher: Springer Science and Business Media LLC

Date: 29-04-2021

DOI: 10.1007/S12640-021-00368-4

Abstract: Phosphodiesterase-10A (PDE10A) hydrolyse the secondary messengers cGMP and cAMP, two molecules playing important roles in neurodevelopment and brain functions. PDE10A is associated to progression of neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's diseases, and a critical role in cognitive functions. The present study was undertaken to determine the possible neuroprotective effects and the associated mechanism of papaverine (PAP), a PDE10A isoenzyme inhibitor, against quinolinic acid (QUIN)-induced excitotoxicity using human primary cortical neurons. Cytotoxicity potential of PAP was analysed using MTS assay. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured by DCF-DA and JC10 staining, respectively. Caspase 3/7 and cAMP levels were measured using ELISA kits. Effect of PAP on the CREB, BNDF and synaptic proteins such as SAP-97, synaptophysin, synapsin-I, and PSD-95 expression was analysed by Western blot. Pre-treatment with PAP increased intracellular cAMP and nicotinamide adenine dinucleotide (NAD

l-Serine-Mediated Neuroprotection Includes the Upregulation of the ER Stress Chaperone Protein Disulfide Isomerase (PDI)

Publisher: Springer Science and Business Media LLC

Date: 10-0100

DOI: 10.1007/S12640-017-9817-7

Abstract: The unfolded protein response (UPR) is a highly evolutionarily conserved response to endoplasmic reticulum (ER) stress, which functions to return cells to homeostasis or send them into apoptosis, depending on the degree of cellular damage. β-N-methylamino-L-alanine (L-BMAA) has been shown to induce ER stress in a variety of models and has been linked to several types of neurodegenerative disease including Guamanian amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC). L-Serine, an amino acid critical for cellular metabolism and neurological signaling, has been shown to be protective against L-BMAA-induced neurotoxicity in both animal and cell culture models. While the mechanisms of L-BMAA neurotoxicity have been well characterized, less is known about L-serine neuroprotection. We recently reported that L-serine and L-BMAA generate similar differential expression profiles in a human ER stress/UPR array, despite L-serine being neuroprotective and L-BMAA being linked to neurodegenerative disease. Here, we further investigate the mechanism(s) of L-serine-induced UPR dysregulation by examining key genes and proteins in the ER stress/UPR pathways. We report that L-serine selectively increased protein disulfide isomerase (PDI) protein translation, an ER chaperone involved in refolding misfolded proteins, suggesting it may be modulating the UPR to favor recovery from ER stress. This constitutes a new mechanism for L-serine-mediated neuroprotection and has implications for its use as a therapy for neurodegenerative illnesses.

Sleep Deprivation and Neurological Disorders

Publisher: Hindawi Limited

Date: 23-11-2020

DOI: 10.1155/2020/5764017

Abstract: Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended.

Machine learning workflows identify a microRNA signature of insulin transcription in human tissues.

Publisher: Elsevier BV

Date: 04-2021

DOI: 10.1016/J.ISCI.2021.102379

Expression of the kynurenine pathway in human peripheral blood mononuclear cells: Implications for inflammatory and neurodegenerative disease

Publisher: Public Library of Science (PLoS)

Date: 26-06-2015

DOI: 10.1371/JOURNAL.PONE.0131389

Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis.

Publisher: Oxford University Press (OUP)

Date: 09-04-2015

DOI: 10.1093/HMG/DDV126

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily affecting motor neurons. Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. These findings also indicate that optineurin-myosin VI dysfunction is a common feature of both sporadic and familial ALS.

Great expectations: Nutritional medicine as a mainstream in clinical psychiatry and weighing opportunities against risks

Publisher: Elsevier BV

Date: 03-2016

DOI: 10.1016/J.MEHY.2016.01.004

Kynurenine pathway metabolism in human astrocytes: A paradox for neuronal protection

Publisher: Wiley

Date: 15-08-2001

DOI: 10.1046/J.1471-4159.2001.00498.X

Abstract: There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN), play a role in the pathogenesis of neurological diseases, in particular AIDS dementia complex. Although QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the role of astrocytes in QUIN production is controversial. Using cytokine-stimulated cultures of human astrocytes, we assayed key enzymes and products of the KP. We found that human astrocytes lack kynurenine hydroxylase so that large amounts of kynurenine and the QUIN antagonist kynurenic acid were produced. However, the amounts of QUIN that were synthesized were subsequently completely degraded. We then showed that kynurenine in concentrations comparable with those produced by astrocytes led to significant production of QUIN by macrophages. These results suggest that astrocytes alone are neuroprotective by minimizing QUIN production and maximizing synthesis of kynurenic acid. However, it is likely that, in the presence of macrophages and/or microglia, astrocytes become indirectly neurotoxic by the production of large concentrations of kynurenine that can be secondarily metabolized by neighbouring or infiltrating monocytic cells to form the neurotoxin QUIN.

Neuroprotective Effect of Myxobacterial Extracts on Quinolinic Acid-Induced Toxicity in Primary Human Neurons

Publisher: Springer Science and Business Media LLC

Date: 28-09-2019

DOI: 10.1007/S12640-018-9945-8

Abstract: Quinolinic acid (QUIN) is a neurotoxin, gliotoxin, and proinflammatory molecule involved in the pathogenesis of several neurological diseases. Myxobacteria have been known as a rich source of secondary metabolites with erse structures and mode of actions. In this study, we examined the potential neuroprotective effects of myxobacterial extracts on QUIN-induced excitotoxicity in primary human neurons. For this purpose, primary cultures of human neurons were pre-incubated with myxobacterial extracts and subsequently treated with QUIN at a pathophysiological concentration of 550 nM. The results showed that some myxobacterial extracts can significantly attenuate formation of reactive oxygen species (ROS), nitric oxide (NO) production, and extracellular lactate dehydrogenase (LDH) activity of human neurons. Moreover, myxobacterial extracts were also able to reduce neuronal nitric oxide synthase (nNOS) activity. Some extracts prevented cell death by reducing the activation of poly (ADP-ribose) polymerase (PARP1) by QUIN, therefore by maintaining NAD

Does Exercise Influence Kynurenine/Tryptophan Metabolism and Psychological Outcomes in Persons With Age-Related Diseases? A Systematic Review

Publisher: SAGE Publications

Date: 2021

DOI: 10.1177/1178646921991119

Abstract: The kynurenine (KYN) pathway has been implicated in many diseases associated with inflammation and aging (“inflammaging”). Targeting the kynurenine pathway to modify disease outcomes has been trialled pharmacologically, but the evidence of non-pharmacological means (ie, exercise) remains unclear. We aim to assess the evidence of the effects of exercise on the kynurenine pathway and psychological outcomes. Under Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, a systematic literature search was performed in MEDLINE, EMBASE, EMCARE, and the Cochrane Central Registry of Controlled Trials. The main outcomes were changes in kynurenine pathway metabolite levels and psychological outcomes. Six studies were analyzed (total n = 379) with exercise demonstrating significant concomitant effects on kynurenine pathway metabolite levels and associated psychological outcomes in domains of somatization, anxiety, and depression. Exercise has significant concomitant effect on kynurenine pathway metabolite levels and psychological outcomes. However, clear limitations exist in determining if the changes in the kynurenine pathway can fully explain the changes in psychological outcomes, or whether different diseases and exercise interventions act as confounding factors.

Detrimental activation of AhR pathway in cancer

Publisher: Elsevier BV

Date: 06-2021

DOI: 10.1016/J.COI.2020.12.003

Abstract: Sustained transcriptional activation of the aryl hydrocarbon receptor (AhR) promotes tumour growth and impairs the immune defence, at least for cutaneous melanoma and glioma. AhR ligands are produced by the tumour microenvironment (TME) and by the tumour itself (intracrine). The recent identification of interleukin-4-induced-1 (IL4I1), a parallel pathway to indoleamine 2 3-dioxygenase 1 (IDO1)/ tryptophan 2,3-dioxygenase (TDO), and its ability to generate AhR ligands, confirms that a complete inhibition of AhR ligand production might be difficult to reach. Here, we have focused on recent discoveries explaining the large varieties of AhR ligands and the functional consequences in terms of cancer cell plasticity and consecutive therapy resistance. We also examined therapeutic strategies targeting the AhR signalling pathway and their possible adverse effects. Since the end of 2019, two phase I clinical trials have investigated the ability of the AhR antagonist to 'reset' the immune system and re-sensitize the cancer cells to therapies by preventing their dedifferentiation.

Kynurenine pathway modulation reverses the experimental autoimmune encephalomyelitis mouse disease progression

Publisher: Springer Science and Business Media LLC

Date: 06-06-2020

DOI: 10.1186/S12974-020-01844-Y

Abstract: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, neuroinflammation, and neurodegeneration. Activation of the kynurenine pathway (KP) results from acute and chronic neuroinflammation leading to both immune suppression and neurotoxicity. However, the exact effects of KP metabolites and changes in neurodegenerative diseases over time are not fully understood. Studies, including those in MS models, have reported that short-term KP activation is beneficial through immune tolerance. However, the effects of long-term KP activation are poorly understood. We hypothesized that such chronic activation is responsible for the neurodegeneration in MS, and further, modulating the KP in EAE-induced mice could significantly decrease the EAE disease severity. We biochemically altered the KP at different stages of the disease in experimental allergic encephalomyelitis (EAE) mouse model of MS and at two different enzymatic levels of the KP (IDO-1 (indoleamine 2,3 dioxygenase)) and KMO (kynurenine monooxygenase). CNS tissue and blood s les were analyzed longitudinally using GCMS, HPLC, IHC, and RT-PCR. We showed that the KP was steadily upregulated correlating with disease severity and associated with a shift towards increasing concentrations of the KP metabolite quinolinic acid, a neuro- and gliotoxin. KP modulation by inhibition of IDO-1 with 1-methyl tryptophan (1-MT) was dependent on the timing of treatment at various stages of EAE. IDO-1 inhibition at EAE score 2 led to significantly higher numbers of FoxP3 cells ( p 0.001) in the spleen than earlier IDO-1 inhibition (prophylactic 1-MT treatment group ( p 0.001)), 1-MT treatment after EAE induction (EAE score 0 p 0.001), and 1-MT treatment at EAE score of 1 ( p 0.05). Significant improvement of disease severity was observed in EAE mice treated with 1-MT at EAE score 2 compared to the untreated group ( p 0.05). KP modulation by KMO inhibition with Ro 61-8048 led to significantly greater numbers of Foxp3 cells ( p 0.05) in Ro 61-8048 treated mice and even more significant amelioration of EAE disease compared to the 1-MT treatment groups. These results provide a new mechanistic link between neuroinflammation and neurodegeneration and point to KP modulation at the KMO level to preserve immune tolerance and limit neurodegeneration in EAE. They provide the foundation for new clinical trials for MS.

Galantamine-memantine combination and kynurenine pathway enzyme inhibitors in the treatment of neuropsychiatric disorders

Publisher: S. Karger AG

Date: 2021

DOI: 10.1159/000515066

Abstract: The kynurenine pathway (KP) is a major route for L-tryptophan (L-TRP) metabolism, yielding a variety of bioactive compounds including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC). These tryptophan catabolites are involved in the pathogenesis of many neuropsychiatric disorders, particularly when the KP becomes dysregulated. Accordingly, the enzymes that regulate the KP such as indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase, kynurenine aminotransferases (KATs), and kynurenine 3-monooxygenase (KMO) represent potential drug targets as enzymatic inhibition can favorably rebalance KP metabolite concentrations. In addition, the galantamine-memantine combination, through its modulatory effects at the alpha7 nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors, may counteract the effects of KYNA. The aim of this review is to highlight the effectiveness of IDO-1, KAT II, and KMO inhibitors, as well as the galantamine-memantine combination in the modulation of different KP metabolites. KAT II inhibitors are capable of decreasing the KYNA levels in the rat brain by a maximum of 80%. KMO inhibitors effectively reduce the central nervous system (CNS) levels of 3-HK, while markedly boosting the brain concentration of KYNA. Emerging data suggest that the galantamine-memantine combination also lowers L-TRP, kynurenine, KYNA, and PIC levels in humans. Presently, there are only 2 pathophysiological mechanisms (cholinergic and glutamatergic) that are FDA approved for the treatment of cognitive dysfunction for which purpose the galantamine-memantine combination has been designed for clinical use against Alzheimer’s disease. The alpha7 nicotinic-NMDA hypothesis targeted by the galantamine-memantine combination has been implicated in the pathophysiology of various CNS diseases. Similarly, KYNA is well capable of modulating the neuropathophysiology of these disorders. This is known as the KYNA-centric hypothesis, which may be implicated in the management of certain neuropsychiatric conditions. In line with this hypothesis, KYNA may be considered as the “conductor of the orchestra” for the major pathophysiological mechanisms underlying CNS disorders. Therefore, there is great opportunity to further explore and compare the biological effects of these therapeutic modalities in animal models with a special focus on their effects on KP metabolites in the CNS and with the ultimate goal of progressing to clinical trials for many neuropsychiatric diseases.

Uptake and mitochondrial dysfunction of alpha-synuclein in human astrocytes, cortical neurons and fibroblasts

Publisher: Springer Science and Business Media LLC

Date: 04-10-2013

DOI: 10.1186/2047-9158-2-20

Abstract: The accumulation and aggregation of alpha-synuclein (α-syn) in several tissue including the brain is a major pathological hallmark in Parkinson’s disease (PD). In this study, we show that α-syn can be taken up by primary human cortical neurons, astrocytes and skin-derived fibroblasts in vitro . Our findings that brain and peripheral cells exposed to α-syn can lead to impaired mitochondrial function, leading to cellular degeneration and cell death, provides additional evidence for the involvement of mitochondrial dysfunction as a mechanism of toxicity of α-syn in human cells.

Excitotoxicity in the Pathogenesis of Autism

Publisher: Springer New York

Date: 2014

DOI: 10.1007/978-1-4614-5836-4_148

Epigallocatechin-3-gallate induces oxidative phosphorylation by activating cytochrome c oxidase in human cultured neurons and astrocytes

Publisher: Impact Journals, LLC

Date: 09-01-2016

DOI: 10.18632/ONCOTARGET.6863

Keratin 14 expression in epithelial progenitor cells of the developing human cornea

Publisher: Mary Ann Liebert Inc

Date: 05-2016

DOI: 10.1089/SCD.2016.0039

Abstract: A healthy and transparent cornea is essential for exquisite vision. During adulthood, its epithelium is constantly replenished through the activity of its stem cells (SCs). Precisely when these cells develop and their distribution across the ocular surface remain incompletely characterized in man. We postulated that the human fetal cornea harbors SCs that can be identified with keratin (K) 14 and αv-integrin, two markers we and others previously used to identify their adult counterparts. Immunofluorescence, cell culture, quantitative real-time polymerase chain reaction (qRT-PCR), and colony-forming assays were performed on fetal and adult biomaterial to locate progenitors and establish their phenotypic and functional properties. K14 was used to map the spatiotemporal distribution of precursor cell activity across the developing cornea, ulging a dynamic pattern of vertical and horizontal consolidated expression with increasing gestational age. K14 was coexpressed with αv-integrin in fetal and adult corneas and cultured corneolimbal epithelium, and colony-forming efficiency (an indicator of SC activity) was similar in cells from both sources. Finally, fetal cells were adherent, grew well, and maintained a K14 phenotype on contact lenses, a substrate we previously used to deliver cells to patients with blinding corneal disease. This study provides valuable insights into the development of the cornea, including the formation of the SC repository, the distribution of these cells across the ocular surface, and a preliminary attempt at harnessing, phenotyping, and functionally characterizing these cells. Future studies will focus on isolating fetal SCs to determine their utility as an alternative cell therapy for patients suffering from corneal blindness.

Microorganisms’ footprint in neurodegenerative diseases

Publisher: Frontiers Media SA

Date: 04-12-2018

DOI: 10.3389/FNCEL.2018.00466

Elevated 3-Hydroxykynurenine serum levels in Alzheimer's disease

Publisher: Wiley

Date: 07-2009

DOI: 10.1016/J.JALZ.2009.04.1209

Modulation of amyloid precursor protein processing by synthetic ceramide analogues

Publisher: Elsevier BV

Date: 08-2010

DOI: 10.1016/J.BBALIP.2010.05.012

Abstract: Previous studies suggest that membrane lipids may regulate proteolytic processing of the amyloid precursor protein (APP) to generate amyloid-beta peptide (Abeta). In the present study, we have assessed the capacity for a series of structurally related synthetic ceramide analogues to modulate APP processing in vitro. The compounds tested are established glucosylceramide synthase (GS) inhibitors based on the d-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) structure. PDMP and related compounds PPMP and EtDO-P4 inhibited Abeta secretion from Chinese hamster ovary cells expressing human APP (CHO-APP) with approximate IC(50) values of 15, 5, and 1 microM, respectively. A trend for reduced secretion of the APP alpha-secretase product, sAPPalpha, was also observed in PDMP-treated cells but not in PPMP- or ETDO-P4-treated cells, whereas levels of the cellular beta-secretase product APP C-terminal fragment, CTFbeta, were increased by both PDMP and PPMP but unaltered with EtDO-P4 treatment. Our data also revealed that EtDO-P4 inhibits endogenous Abeta production by human neurons. In conclusion, this study provides novel information regarding the regulation of APP processing by synthetic ceramide analogues and reveals that the most potent of these compounds is EtDO-P4.

Recent rodent models for Alzheimer's disease: Clinical implications and basic research

Publisher: Springer Science and Business Media LLC

Date: 16-11-2012

DOI: 10.1007/S00702-011-0731-5

Abstract: Alzheimer's disease (AD) is the most common origin of dementia in the elderly. Although the cause of AD remains unknown, several factors have been identified that appear to play a critical role in the development of this debilitating disorder. In particular, amyloid precursor protein (APP), tau hyperphosphorylation, and the secretase enzymes, have become the focal point of recent research. Over the last two decades, several transgenic and non-transgenic animal models have been developed to elucidate the mechanistic aspects of AD and to validate potential therapeutic targets. Transgenic rodent models over-expressing human β-amyloid precursor protein (β-APP) and mutant forms of tau have become precious tools to study and understand the pathogenesis of AD at the molecular, cellular and behavioural levels, and to test new therapeutic agents. Nevertheless, none of the transgenic models of AD recapitulate fully all of the pathological features of the disease. Octodon degu, a South American rodent has been recently found to spontaneously develop neuropathological signs of AD in old age. This review aims to address the limitations and clinical relevance of transgenic rodent models in AD, and to highlight the potential for O. degu as a natural model for the study of AD neuropathology.

Treatment of microglia with Anti-PrP monoclonal antibodies induces neuronal apoptosis in vitro

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.HELIYON.2021.E08644

Kynurenines, Gender and Neuroinflammation; Showcase Schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 24-06-2016

DOI: 10.1007/S12640-016-9641-5

Abstract: Schizophrenia has a clear sexual dimorphism in age of onset and progression. The underlying mechanisms of this dimorphism are not known, but may be found in the interactions of sex hormones with the tryptophan catabolising kynurenine pathway. Schizophrenia is associated with general inflammation and disruption of glutamatergic and dopaminergic signalling. Metabolites of the kynurenine pathway have been shown to be immunomodulatory and have effects on glutamatergic and dopaminergic signalling. This review discusses the currently available literature on sex hormones and their effect on the kynurenine pathway in the context of the glutamatergic, dopaminergic and immunological features of schizophrenia.

Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes

Publisher: Wiley

Date: 28-01-2003

DOI: 10.1002/GLIA.10175

Abstract: Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immunoregulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified primary human fetal astrocyte cultures, we determined chemokine production using ELISA assays and RT-PCR and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNFalpha, IL-1beta, and IFNgamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2) and lesser amounts of RANTES (CCL5) and IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9), and fractalkine (CX(3)CL1) mRNA expression. Moreover, QUIN leads to upregulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human fetal astrocytes. Most of these effects were comparable to those induced by TNFalpha, IL-1beta, and IFNgamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the lification of brain inflammation, particularly in ADC.

P38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells

Publisher: Springer Science and Business Media LLC

Date: 19-04-2012

DOI: 10.1007/S11060-012-0875-7

Abstract: Increasing evidence suggests that an inflammatory microenvironment promotes invasion by glioblastoma (GBM) cells. Together with p38 mitogen-activated protein kinase (MAPK) activation being regarded as promoting inflammation, we hypothesized that elevated inflammatory cytokine secretion and p38 MAPK activity contribute to expansion of GBMs. Here we report that IL-1β, IL-6, and IL-8 levels and p38 MAPK activity are elevated in human glioblastoma specimens and that p38 MAPK inhibitors attenuate the secretion of pro-inflammatory cytokines by microglia and glioblastoma cells. RNAi knockdown and immunoprecipitation experiments suggest that the p38α MAPK isoform drives inflammation in GBM cells. Importantly, p38 MAPK inhibition strongly reduced invasion of U251 glioblastoma cells in an inflammatory microenvironment, providing evidence for a p38 MAPK-regulated link between inflammation and invasiveness in GBM pathophysiology.

Effect of prolonged gelling time on the intrinsic properties of barium alginate microcapsules and its biocompatibility

Publisher: Informa UK Limited

Date: 10-08-2011

DOI: 10.3109/02652048.2011.586067

Abstract: Pericapsular fibrotic overgrowth (PFO) may be attributed to an immune response against microcapsules themselves or to antigen shedding through microcapsule pores from encapsulated islet tissue. Modification of microcapsules aimed at reducing pore size should prevent PFO and improve graft survival. This study investigated the effect of increased gelling time (20 vs. 2 min) in barium chloride on intrinsic properties of alginate microcapsules and tested their biocompatibility in vivo. Prolonged gelling time affected neither permeability nor size of the microcapsules. However, prolonged gelling time for 20 min produced brittle microcapsules compared to 2 min during compression test. Encapsulation of human islets in both types of microcapsules affected neither islet viability nor function. The presence of PFO when transplanted into a large animal model such as baboon and its absence in small animal models such as rodents suggest that the host immune response towards alginate microcapsules is species rather than alginate specific.

Post-Bariatric Surgery Changes in Quinolinic and Xanthurenic Acid Concentrations Are Associated with Glucose Homeostasis

Publisher: Public Library of Science (PLoS)

Date: 21-06-2016

DOI: 10.1371/JOURNAL.PONE.0158051

Picolinic Acid, a Catabolite of Tryptophan, Has an Anabolic Effect on Bone In Vivo

Publisher: Wiley

Date: 17-08-2020

DOI: 10.1002/JBMR.4125

Lycopene pretreatment ameliorates acute ethanol induced NAD⁺ depletion in human astroglial cells

Publisher: Hindawi Limited

Date: 2015

DOI: 10.1155/2015/741612

Abstract: Excessive alcohol consumption is associated with reduced brain volume and cognition. While the mechanisms by which ethanol induces these deleterious effects in vivo are varied most are associated with increased inflammatory and oxidative processes. In order to further characterise the effect of acute ethanol exposure on oxidative damage and NAD + levels in the brain, human U251 astroglioma cells were exposed to physiologically relevant doses of ethanol (11 mM, 22 mM, 65 mM, and 100 mM) for ≤ 30 minutes. Ethanol exposure resulted in a dose dependent increase in both ROS and poly(ADP-ribose) polymer production. Significant decreases in total NAD(H) and sirtuin 1 activity were also observed at concentrations ≥ 22 mM. Similar to U251 cells, exposure to ethanol (≥22 mM) decreased levels of NAD(H) in primary human astrocytes. NAD(H) depletion in primary astrocytes was prevented by pretreatment with 1 μ M of lycopene for 3.5 hours. Unexpectedly, in U251 cells lycopene treatment at concentrations ≥ 5 μ M resulted in significant reductions in [NAD(H)]. This study suggests that exposure of the brain to alcohol at commonly observed blood concentrations may cause transitory oxidative damage which may be at least partly ameliorated by lycopene.

Beneficial effects of desferrioxamine on encapsulated human islets-in vitro and in vivo study

Publisher: Elsevier BV

Date: 09-2010

DOI: 10.1111/J.1600-6143.2010.03209.X

Abstract: As many as 2000 IEQs (islet equivalent) of encapsulated human islets are required to normalize glucose levels in diabetic mice. To reduce this number, encapsulated islets were exposed to 100 μM desferrioxamine (DFO) prior to transplantation. Cell viability, glucose-induced insulin secretion, VEGF (Vascular endothelial growth factor), HIF-1α (Hypoxia inducible factor-1 alpha), caspase-3 and caspase-8 levels were assessed after exposure to DFO for 12, 24 or 72 h. Subsequently, 1000, 750 or 500 encapsulated IEQs were infused into peritoneal cavity of diabetic mice after 24 h exposure to DFO. Neither viability nor function in vitro was affected by DFO, and levels of caspase-3 and caspase-8 were unchanged. DFO significantly enhanced VEGF secretion by 1.6- and 2.5-fold at 24 and 72 h, respectively, with a concomitant increase in HIF-1α levels. Euglycemia was achieved in 100% mice receiving 1000 preconditioned IEQs, as compared to only 36% receiving unconditioned IEQs (p < 0.001). Similarly, with 750 IEQ, euglycemia was achieved in 50% mice receiving preconditioned islets as compared to 10% receiving unconditioned islets (p = 0.049). Mice receiving preconditioned islets had lower glucose levels than those receiving unconditioned islets. In summary, DFO treatment enhances HIF-1α and VEGF expression in encapsulated human islets and improves their ability to function when transplanted.

Melatonin ameliorates disease severity in a mouse model of multiple sclerosis by modulating the kynurenine pathway

Publisher: Springer Science and Business Media LLC

Date: 24-09-2022

DOI: 10.1038/S41598-022-20164-0

Abstract: Melatonin (MT), a neurohormone with immunomodulatory properties, is one of the metabolites produced in the brain from tryptophan (TRP) that has already strong links with the neuropathogenesis of Multiple sclerosis (MS). However, the exact molecular mechanisms behind that are not fully understood. There is some evidence showing that MS and MT are interconnected via different pathways: Relapses of MS has a direct correlation with a low level of MT secretion and a growing body of evidence suggest that MT be therapeutic in Experimental Autoimmune Encephalomyelitis (EAE, a recognise animal model of MS) severity. Previous studies have demonstrated that the kynurenine pathway (KP), the main pathway of TRP catabolism, plays a key role in the pathogenesis of MS in humans and in EAE. The present study aimed to investigate whether MT can improve clinical signs in the EAE model by modulating the KP. C57BL/6 mice were induced with EAE and received different doses of MT. Then the onset and severity of EAE clinical symptoms were recorded. Two biological factors, aryl hydrocarbon receptor (AhR) and NAD + which closely interact in the KP were also assessed. The results indicated that MT treatment at all tested doses significantly decrease the EAE clinical scores and the number of demyelinating plaques. Furthermore, MT treatment reduced the mRNA expression of the KP regulatory enzyme indoleamine 2,3-dioxygenase 1(IDO-1) and other KP enzymes. We also found that MT treatment reduces the mRNA expression of the AhR and inhibits the enzyme Nicotinamide N-Methyltransferase (Nnmt) overexpression leading to an increase in NAD + levels. Collectively, this study suggests that MT treatment may significantly attenuates the severity of EAE by altering the KP, AhR and NAD + metabolism.

Age related changes in NAD+ metabolism oxidative stress and sirt1 activity in wistar rats

Publisher: Public Library of Science (PLoS)

Date: 26-04-2011

DOI: 10.1371/JOURNAL.PONE.0019194

Impaired antioxidant status and reduced energy metabolism in autistic children

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.RASD.2012.12.006

Increased 3-Hydroxykynurenine serum concentrations differentiate Alzheimer's disease patients from controls

Publisher: Springer Science and Business Media LLC

Date: 29-11-2013

DOI: 10.1007/S00406-012-0384-X

Abstract: Increased degradation of tryptophan (TRP) through the kynurenine (KYN) pathway (KP) is known to be involved in the molecular mechanisms resulting in the neuropathogenesis of Alzheimer's disease (AD). Activation of the KP leads to the production of neurotoxic metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) by immune cells and neuroprotective derivates kynurenic acid (KYNA) and picolinic acid (PIC) by astrocytes and neurons. We therefore investigated whether an imbalance between neurotoxic and neuroprotective kynurenine metabolites could be detected in patients with AD. We measured serum levels of TRP, KYNA, 3-HK, PIC and QUIN in 20 patients with AD and for comparison in 20 patients with major depression, and 19 subjectively cognitive impaired subjects. Serum levels of 3-HK were markedly increased in AD patients compared to the comparison groups (p < .0001). Serum levels of the other KP metabolites were not significantly different between groups. Our data indicate an increased production of the neurotoxic KP metabolite 3-HK in AD. In contrast to its downstream metabolites QUIN and PIC, 3-HK can cross the blood-brain barrier via an active transport process. Our data therefore indicate an enhanced availability of 3-HK in the brain of AD patients, which may be related to the previously reported higher production of QUIN in AD brains.

Temporal profile of kynurenine pathway metabolites in a rodent model of autosomal recessive polycystic kidney disease

Publisher: SAGE Publications

Date: 2022

DOI: 10.1177/11786469221126063

Abstract: Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls ( P ⩽ .05). LPK kidneys also showed an age effect ( P ⩽ .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls ( P ⩽ .05). Plasma XA and 3-HK also showed an age effect ( P ⩽ .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P ⩽ .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect ( P ⩽ .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD.

Serum nicotinamide adenine dinucleotide levels through disease course in multiple sclerosis

Publisher: Elsevier BV

Date: 11-2013

DOI: 10.1016/J.BRAINRES.2013.08.025

Abstract: The levels of the essential pyridine nucleotide, NAD(+) and its reduced form NADH have not been documented in MS patients. We aimed to investigate NAD(+) and NADH levels in serum in patients with different disease stages and forms of MS. NAD(+) and NADH levels were measured in the serum from 209 patients with relapsing remitting MS (RRMS), 136 with secondary progressive MS (SPMS), 51 with primary progressive MS (PPMS), and 99 healthy controls. All patients were in a clinically stable phase. Serum NAD(+) levels declined by at least 50% in patients with MS compared to controls (17.9 ± 3.2 μg/ml p=0.0012). Within the MS sub-groups NAD(+) levels were higher in RRMS (9.9 ± 2.9 μg/ml p=0.001) compared to PPMS (6.3 ± 2.1 μg/ml p=0.003) and SPMS (7.8 ± 2.0 μg/ml p=0.005). A two-fold increase in NADH levels (p=0.002) and at least three-fold reduction in the NAD(+)/NADH ratio (p=0.009) were observed in MS patients compared to controls. Serum NAD(+) and NADH levels are may be associated with disease progression in MS. Given the importance of NAD(+) in the maintenance of normal cellular function, it is likely that this molecule is of therapeutic relevance in MS.

Transpiration efficiency of three Mediterranean annual pasture species and wheat

Publisher: Springer Science and Business Media LLC

Date: 08-06-1998

DOI: 10.1007/S004420050488

Abstract: Attempts to improve water use efficiency in regions with Mediterranean climates generally focus on increasing plant transpiration relative to evaporation from the soil and increasing transpiration efficiency. Our aim was to determine if transpiration efficiency differs among key species occurring in annual pastures in southern Australia. Two glasshouse experiments were conducted with three key pasture species, subterranean clover (Trifolium subterraneum L.), capeweed [Arctotheca calendula (L.) Levyns] and annual ryegrass (Lolium rigidum Gaudin), and wheat (Triticum aestivum L.). Transpiration efficiency was assessed at the levels of␣whole-plant biomass and water use (W), leaf gas exchange measurements of the ratio of CO

Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis

Publisher: S. Karger AG

Date: 2006

DOI: 10.1159/000089622

Abstract: The kynurenine pathway (KP) is a major route of i L /i -tryptophan catabolism leading to production of several neurobiologically active molecules. Among them is the excitotoxin quinolinic acid (QUIN) that is known to be involved in the pathogenesis of several major inflammatory neurological diseases. In amyotrophic lateral sclerosis (ALS) degeneration of motor neurons is associated with a chronic and local inflammation (presence of activated microglia and astrocytes). There is emerging evidence that the KP is important in ALS. Recently, we demonstrated that QUIN is significantly increased in serum and CSF of ALS patients. Moreover, most of the factors associated with QUIN toxicity are found in ALS, implying that QUIN may play a substantial role in the neuropathogenesis of ALS. This review details the potential role the KP has in ALS and advances a testable hypothetical model.

Oncolytic viruses as a promising therapeutic strategy against the detrimental health impacts of air pollution: The case of glioblastoma multiforme

Publisher: Elsevier BV

Date: 11-2022

DOI: 10.1016/J.SEMCANCER.2021.05.013

Abstract: Human livelihood highly depends on applying different sources of energy whose utilization is associated with air pollution. On the other hand, air pollution may be associated with glioblastoma multiforme (GBM) development. Unlike other environmental causes of cancer (e.g., irradiation), air pollution cannot efficiently be controlled by geographical borders, regulations, and policies. The unavoidable exposure to air pollution can modify cancer incidence and mortality. GBM treatment with chemotherapy or even its surgical removal has proven insufficient (100% recurrence rate patient's survival mean of 15 months 90% fatality within five years) due to glioma infiltrative and migratory capacities. Given the barrage of attention and research investments currently plowed into next-generation cancer therapy, oncolytic viruses are perhaps the most vigorously pursued. Provision of an insight into the current state of the research and future direction is essential for stimulating new ideas with the potentials of filling research gaps. This review manuscript aims to overview types of brain cancer, their burden, and different causative agents. It also describes why air pollution is becoming a concerning factor. The different opinions on the association of air pollution with brain cancer are reviewed. It tries to address the significant controversy in this field by hypothesizing the air-pollution-brain-cancer association via inflammation and atopic conditions. The last section of this review deals with the oncolytic viruses, which have been used in, or are still under clinical trials for GBM treatment. Engineered adenoviruses (i.e., DNX-2401, DNX-2440, CRAd8-S-pk7 loaded Neural stem cells), herpes simplex virus type 1 (i.e., HSV-1 C134, HSV-1 rQNestin34.5v.2, HSV-1 G207, HSV-1 M032), measles virus (i.e., MV-CEA), parvovirus (i.e., ParvOryx), poliovirus (i.e., Poliovirus PVSRIPO), reovirus (i.e., pelareorep), moloney murine leukemia virus (i.e., Toca 511 vector), and vaccinia virus (i.e., vaccinia virus TG6002) as possible life-changing alleviations for GBM have been discussed. To the best of our knowledge, this review is the first review that comprehensively discusses both (i) the negative ositive association of air pollution with GBM and (ii) the application of oncolytic viruses for GBM, including the most recent advances and clinical trials. It is also the first review that addresses the controversies over air pollution and brain cancer association. We believe that the article will significantly appeal to a broad readership of virologists, oncologists, neurologists, environmentalists, and those who work in the field of (bio)energy. Policymakers may also use it to establish better health policies and regulations about air pollution and (bio)fuels exploration, production, and consumption.

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

Publisher: Hindawi Limited

Date: 16-08-2018

DOI: 10.1155/2018/1095459

Abstract: Metastasis is the most deadly aspect of cancer and results from acquired gene regulation abnormalities in tumor cells. Transcriptional regulation is an essential component of controlling of gene function and its failure could contribute to tumor progression and metastasis. During cancer progression, deregulation of oncogenic or tumor suppressive transcription factors, as well as master cell fate regulators, collectively influences multiple steps of the metastasis cascade, including local invasion and dissemination of the tumor to distant organs. Transcription factor PAX3/Pax3, which contributes to erse cell lineages during embryonic development, plays a major role in tumorigenesis. Mutations in this gene can cause neurodevelopmental disease and the existing literature supports that there is a potential link between aberrant expression of PAX3 genes in adult tissues and a wide variety of cancers. PAX3 function is tissue-specific and could contribute to tumorigenesis either directly as oncogene or as a tumor suppressor by losing its function. In this review, we discuss comprehensively the differential role played by PAX3 in various tissues and how its aberrant expression is implicated in disease development. This review particularly highlights the oncogenic and tumor suppressor role played by PAX3 in different cancers and underlines the importance of precisely identifying tissue-specific role of PAX3 in order to determine its exact role in development of cancer.

The p38-MK2-HuR pathway potentiates EGFRvIII-IL-1β-driven IL-6 secretion in glioblastoma cells

Publisher: Springer Science and Business Media LLC

Date: 04-08-2014

DOI: 10.1038/ONC.2014.225

Abstract: The microenvironment of glioblastoma (GBM) contains high levels of inflammatory cytokine interleukin 6 (IL-6), which contributes to promote tumour progression and invasion. The common epidermal growth factor receptor variant III (EGFRvIII) mutation in GBM is associated with significantly higher levels of IL-6. Furthermore, elevated IL-1β levels in GBM tumours are also believed to activate GBM cells and enhance IL-6 production. However, the crosstalk between these intrinsic and extrinsic factors within the oncogene-microenvironment of GBM causing overproduction of IL-6 is poorly understood. Here, we show that EGFRvIII potentiates IL-1β-induced IL-6 secretion from GBM cells. Importantly, exacerbation of IL-6 production is most effectively attenuated in EGFRvIII-expressing GBM cells with inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) and MAPK-activated protein kinase 2 (MK2). Enhanced IL-6 production and increased sensitivity toward pharmacological p38 MAPK and MK2 inhibitors in EGFRvIII-expressing GBM cells is associated with increased MK2-dependent nuclear-cytoplasmic shuttling and accumulation of human antigen R (HuR), an IL-6 mRNA-stabilising protein, in the cytosol. IL-1β-stimulated activation of the p38 MAPK-MK2-HuR pathway significantly enhances IL-6 mRNA stability in GBM cells carrying EGFRvIII. Further supporting a role for the p38 MAPK-MK2-HuR pathway in the development of inflammatory environment in GBM, activated MK2 is found in more than 50% of investigated GBM tissues and correlates with lower grade and secondary GBMs. Taken together, p38 MAPK-MK2-HuR signalling may enhance the potential of intrinsic (EGFRvIII) and extrinsic (IL-1β) factors to develop an inflammatory GBM environment. Hence, further improvement of brain-permeable and anti-inflammatory inhibitors targeting p38 MAPK, MK2 and HuR may combat progression of lower grade gliomas into aggressive GBMs.

Thermal characteristics of a water soluble extract obtained from pomegranate skin: Developing a state diagram for determining stability

Publisher: Elsevier BV

Date: 07-2013

DOI: 10.1016/J.INDCROP.2013.04.021

Lead dysregulates serine/threonine protein phosphatases in human neurons

Publisher: Springer Science and Business Media LLC

Date: 04-11-2011

DOI: 10.1007/S11064-010-0300-6

Human tick-borne diseases in Australia

Publisher: Frontiers Media SA

Date: 28-01-2019

DOI: 10.3389/FCIMB.2019.00003

Antibodies to myelin oligodendrocyte glycoprotein have a demyelination phenotype in children and affect oligodendrocyte cytoskeleton

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/J.JNEUROIM.2014.08.049

Promotion of cellular NAD+ anabolism: Therapeutic potential for oxidative stress in ageing and alzheimer's disease

Publisher: Springer Science and Business Media LLC

Date: 09-2008

DOI: 10.1007/BF03033501

Characterization of the Kynurenine pathway and quinolinic acid production in macaque macrophages

Publisher: SAGE Publications

Date: 2012

DOI: 10.4137/IJTR.S11789

Abstract: The kynurenine pathway (KP) and one of its end-products, the excitotoxin quinolinic acid (QUIN), are involved in the pathogenesis of several major neuroinflammatory brain diseases. A relevant animal model to study KP metabolism is now needed to assess whether intervention in this pathway may improve the outcome of such diseases. Humans and macaques share a very similar genetic makeup. In this study, we characterized the KP metabolism in macaque primary macrophages of three different species in comparison to human cells. We found that the KP profiles in simian macrophages were very similar to those in humans when challenged with inflammatory cytokines. Further, we found that macaque macrophages are capable of producing a pathophysiological concentration of QUIN. Our data validate the simian model as a relevant model to study the human cellular KP metabolism in the context of inflammation.

Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 03-04-2020

DOI: 10.1038/S41380-019-0401-9

Abstract: The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain s les from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N -methyl- d -aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.

Obtention and characterization of primary astrocyte and microglial cultures from adult monkey brains

Publisher: Wiley

Date: 09-1997

DOI: 10.1002/(SICI)1097-4547(19970901)49:5<576::AID-JNR8>3.0.CO;2-8

Abstract: Pseudomonas sp. strain RGM 3321 is a phyllosphere endophyte from Fragaria chiloensis subsp.

Effect of alginate encapsulation on the cellular transcriptome of human islets

Publisher: Elsevier BV

Date: 11-2011

DOI: 10.1016/J.BIOMATERIALS.2011.06.044

Abstract: Encapsulation of human islets may prevent their immune rejection when transplanted into diabetic recipients. To assist in understanding why clinical outcomes with encapsulated islets were not ideal, we examined the effect of encapsulation on their global gene (mRNA) and selected miRNAs (non-coding (nc)RNA) expression. For functional studies, encapsulated islets were transplanted into peritoneal cavity of diabetic NOD-SCID mice. Genomics analysis and transplantation studies demonstrate that islet origin and isolation centres are a major source of variation in islet quality. In contrast, tissue culture and the encapsulation process had only a minimal effect, and did not affect islet viability. Microarray analysis showed that as few as 29 genes were up-regulated and 2 genes down-regulated (cut-off threshold 0.1) by encapsulation. Ingenuity analysis showed that up-regulated genes were involved mostly in inflammation, especially chemotaxis, and vascularisation. However, protein expression of these factors was not altered by encapsulation, raising doubts about the biosignificance of the gene changes. Encapsulation had no effect on levels of islet miRNAs. In vivo studies indicate differences among the centres in the quality of the islets isolated. We conclude that microencapsulation of human islets with barium alginate has little effect on their transcriptome.

Quinolinic acid is produced by macrophages stimulated platelet activating factor, Nef and Tat

Publisher: Springer Science and Business Media LLC

Date: 2001

DOI: 10.1080/135502801300069692

Abstract: Activated macrophages produce quinolinic acid (QUIN), a neurotoxin, in several inflammatory brain diseases including AIDS dementia complex. We hypothesized that IL1-beta, IL6, transforming growth factor (TGF-beta2 and platelet activating factor could increase macrophage QUIN production. And that the HIV-1 proteins Nef, Tat and gp41 may also increase synthesis of QUIN by macrophages. At 72 h there were significant increases in QUIN production in the cells stimulated with PAF (914 +/- 50 nM) and Nef (2781 +/- 162 nM), with somewhat less production by Tat stimulation (645 +/- 240 nM). The increases in QUIN production approximated in vitro concentrations of QUIN shown to be neurotoxic and correlated closely with indoleamine 2,3-dioxygenase induction. IL1-beta, IL6, TGF-beta2 and gp41 stimulation produced no significant increase in QUIN production. These results suggest that some of the neurotoxicity of PAF, nef and tat may be mediated by QUIN.

Prophylactic and therapeutic effect of kynurenine for experimental autoimmune encephalomyelitis (EAE) disease

Publisher: SAGE Publications

Date: 2022

DOI: 10.1177/11786469221118657

Abstract: The essential amino acid, tryptophan, is predominantly metabolised through the kynurenine pathway (KP) to generate kynurenine, an aryl-hydrocarbon receptor (AhR) pro-ligand that exerts its effects in a ligand-dependent manner. Interaction between kynurenine and the AhR is an effector mechanism of immunosuppression. We previously found that the KP is involved in multiple sclerosis (MS) disease progression. We postulated that AhR activation by kynurenine might be neuroprotective by encouraging differentiation of Tregs. In this study, we assess both the prophylactic and therapeutic efficiency of kynurenine on disease severity and progression in mice with experimental autoimmune encephalomyelitis (EAE), an MS model. Myelin oligodendrocyte glycoprotein induced EAE mice (n = 6 per group) were treated with 200 mg/kg L-kynurenine once daily for 10 days beginning on either day 1 of EAE induction (prophylactic) or once they demonstrated motor weakness (therapeutic). Clinical disease severity measured by disease score, time on rotarod, and body weight. The prophylactic kynurenine treatment significantly ( P .0001) prevented the development of a more severe disease course with mice demonstrating diminished relapse rate and improved clinical and behavioural outcomes. However, therapeutic kynurenine did not significantly ( P = .4463) decrease the clinical signs until 36 days following induction of disease after 36 days, it also significantly ( P = .0479) reduced disease relapse. Mean body weight measurements only correlated with time on rotarod ( r = −.6410 P = .0007) but not clinical scores ( r = .1925 P = .3674). Kynurenine ameliorates EAE disease progression prophylactically and reduces relapses therapeutically. Further investigations are needed to elucidate the molecular mechanism explaining the therapeutic role of kynurenine for MS.

A role for glial-associated kynurenine pathway activation in modulating neuronal outgrowth and complexity

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1016/S0924-977X(15)30211-X

Characterization of functional polymorphisms and glucocorticoid-responsive elements in the promoter of TDO2, a candidate gene for ethanol-induced behavioural disorders

Publisher: Oxford University Press (OUP)

Date: 04-04-2013

DOI: 10.1093/ALCALC/AGT028

Abstract: In response to acute ethanol consumption, tryptophan 2,3-dioxygenase (TDO) induces the kynurenine pathway (KP) through a glucocorticoid-mediated mechanism, which could lead to a dramatic accumulation of neurotoxic metabolites in association with serotonin depletion. As a result, interin idual variability in ethanol-induced behavioural disorders, such as black-outs and violent impulsive behaviours (BOVIBs) following binge drinking, could be partly explained by genetic polymorphisms affecting the KP. The aim of this study was to identify polymorphisms on the promoter of the TDO2 gene that could affect expression and/or activity of TDO through glucocorticoid induction. Polymorphisms were screened using a PCR-sequencing strategy applied to 31 alcohol-dependent patients and 49 unrelated healthy volunteers, and functionally analysed with bioinformatic prediction tools and gene reporter assays in HepG2 and A549 cell lines. We identified 12 polymorphisms in the human TDO2 promoter region, 2 of them corresponding to previously unknown single-nucleotide polymorphisms (SNPs) and 3 of them located in putative glucocorticoid-responsive elements (GREs). Gene reporter assays using HepG2 and A549 cell lines confirmed the presence of several functional GREs in the promoter region of TDO2 and revealed that some of the identified polymorphisms affect the promoter activity under glucocorticoid receptor over-expression and dexamethasone exposure conditions. Correlational studies in larger s les could help to determine whether these polymorphisms are responsible for variations of expression and/or activity of TDO, in particular under conditions where release of glucocorticoids is increased, such as acute ethanol intake. If confirmed, such results would be of major interest in explaining part of the interin idual variability observed in behavioural responses to acute ethanol consumption.

Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: Amelioration by COX-2 inhibition

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/J.BBI.2014.05.011

Abstract: Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31-33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3mg/kg) in adulthood (PND>90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31-33 (105%, p=0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p=0.027, and 31% p=0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p=0.014). Adolescent treatment with celecoxib (2.5 and 5mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.

Serum tryptophan metabolites and Ido1 expression as biomarkers of mucosal inflammation in ulcerative colitis

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/S0016-5085(16)31882-0

Proinflammatory cytokine interferon-γ increases induction of indoleamine 2,3-dioxygenase in monocytic cells primed with amyloid β peptide 1-42: Implications for the pathogenesis of Alzheimer's disease

Publisher: Wiley

Date: 13-07-2009

DOI: 10.1111/J.1471-4159.2009.06175.X

Abstract: Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme of the kynurenine pathway of tryptophan metabolism, ultimately leading to production of the excitotoxin quinolinic acid (QUIN) by monocytic cells. In the Tg2576 mouse model of Alzheimer's disease, systemic inflammation induced by lipopolysaccharide leads to an increase in IDO expression and QUIN production in microglia surrounding amyloid plaques. We examined whether the IDO over-expression in microglia could be mediated by brain proinflammatory cytokines induced during the peripheral inflammation using THP-1 cells and peripheral blood mononuclear cells (PBMC) as models for microglia. THP-1 cells pre-treated with 5-25 muM amyloid beta peptide (Abeta) (1-42) but not with Abeta (1-40) or Abeta (25-35) became an activated state as indicated by their morphological changes and enhanced adhesiveness. IDO expression was only slightly increased in the reactive cells but strongly enhanced following treatment with proinflammatory cytokine interferon-gamma (IFN-gamma) but not with interleukin-1beta, tumor necrosis factor-alpha, or interleukin-6 at 100 U/mL. The concomitant addition of Abeta (1-42) with IFN-gamma was totally ineffective, indicating that Abeta pre-treatment is prerequisite for a high IDO expression. The priming effect of Abeta (1-42) for the IDO induction was also observed for PBMC. These findings suggest that IFN-gamma induces IDO over-expression in the primed microglia surrounding amyloid plaques.

Preventing Quinolinic acid-induced toxicity in oligodendrocytes with antagonizing monoclonal antibodies and kynurenine pathway inhibitors

Publisher: SAGE Publications

Date: 06-2014

DOI: 10.1177/1352458514531864

Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/J.PHRS.2020.105078

Involvement of quinolinic acid in the neuropathogenesis of amyotrophic lateral sclerosis

Publisher: Elsevier BV

Date: 2017

DOI: 10.1016/J.NEUROPHARM.2016.05.011

Abstract: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by a progressive degeneration of central and peripheral motor neurons, leading to the atrophy of voluntary muscles. It has been previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in ALS. In particular, the neuroactive intermediate, quinolinic acid (QUIN) has been shown to accumulate with a concomitant decrease in other neuroprotective and immunomodulatory KP metabolites. Furthermore, multiple biochemical phenomena associated with QUIN cytotoxicity are present in ALS, suggesting that QUIN may play a substantial role in the pathogenesis of ALS. This review highlights the potential roles of QUIN in ALS, and explores KP modulation as a therapeutic candidate in ALS. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

The excitotoxin quinolinic acid induces tau phosphorylation in human neurons

Publisher: Public Library of Science (PLoS)

Date: 22-07-2009

DOI: 10.1371/JOURNAL.PONE.0006344

Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain

Publisher: Frontiers Media SA

Date: 21-08-2020

DOI: 10.3389/FNINS.2020.00890

Development of a rapid fluorescence-based high-throughput screening assay to identify novel kynurenine 3-monooxygenase inhibitor scaffolds

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1177/2472555218757180

Abstract: Kynurenine 3-monooxygenase (KMO) is a well-validated therapeutic target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). This work reports a facile fluorescence-based KMO assay optimized for high-throughput screening (HTS) that achieves a throughput approximately 20-fold higher than the fastest KMO assay currently reported. The screen was run with excellent performance (average Z' value of 0.80) from 110,000 compounds across 341 plates and exceeded all statistical parameters used to describe a robust HTS assay. A subset of molecules was selected for validation by ultra-high-performance liquid chromatography, resulting in the confirmation of a novel hit with an IC

Synthesis of liquid biofuels from biomass by hydrothermal gasification: A critical review

Publisher: Elsevier BV

Date: 10-2022

DOI: 10.1016/J.RSER.2022.112833

HIV, prospective memory, and cerebrospinal fluid concentrations of quinolinic acid and phosphorylated Tau

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.JNEUROIM.2018.03.007

Kynurenine Pathway Metabolism is Involved in the Maintenance of the Intracellular NAD+ Concentration in Human Primary Astrocytes

Publisher: SAGE Publications

Date: 2010

DOI: 10.4137/IJTR.S4779

Abstract: Efficient synthesis of NAD + is critical to maintaining cell viability in all organs of the body. However, little is known of the pathway(s) by which cells of the central nervous system produce NAD + . The aim of this study was to investigate the relationship, between tryptophan degradation via the kynurenine pathway (KP) and de novo NAD + synthesis in human astrocytes, a major cell type within the brain. In this study we observed that inhibition of single enzymes of the KP resulted in significant decreases in NAD + levels in astroglial cells after a 24 hr period. We also observed that astrocytes cultured in media deficient in tryptophan, nicotinic acid and nicotinamide resulted in a 50% decrease in NAD + levels after 24 hrs. This decrease in NAD + was partially restored by supplementation of the culture media with either tryptophan or kynurenine, or nicotinic acid or with supply of the salvage pathway precursor nicotinamide.

Inflammatory effects of Aβ alloforms and conformations on human astrocytes

Publisher: Wiley

Date: 07-2009

DOI: 10.1016/J.JALZ.2009.04.741

Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease

Publisher: Springer Science and Business Media LLC

Date: 10-10-2019

DOI: 10.1186/S12974-019-1567-4

Abstract: Blood markers indicative of neurodegeneration (neurofilament light chain NFL), Alzheimer’s disease amyloid pathology (amyloid-β Aβ), and neuroinflammation (kynurenine pathway KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly in iduals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly in iduals aged 65–90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed ( r = .451, p .0001). Positive correlations were also observed between NFL and kynurenine ( r = .364, p .0005), kynurenic acid ( r = .384, p .0001), 3-hydroxykynurenine ( r = .246, p = .014), anthranilic acid ( r = .311, p = .002), and quinolinic acid ( r = .296, p = .003). Further, significant associations were observed between plasma Aβ40 and the K/T ( r = .375, p .0005), kynurenine ( r = .374, p .0005), kynurenic acid ( r = .352, p .0005), anthranilic acid ( r = .381, p .0005), and quinolinic acid ( r = .352, p .0005). Significant associations were also observed between plasma Aβ42 and the K/T ratio ( r = .215, p = .034), kynurenic acid ( r = .214, p = .035), anthranilic acid ( r = .278, p = .006), and quinolinic acid ( r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aβ load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status however, associations between plasma Aβ and KP metabolites were only pronounced in in iduals with high NAL while associations in in iduals with low NAL were nearly absent. The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aβ seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.

Microglia are both a source and target of extracellular cyclophilin A

Publisher: Elsevier BV

Date: 09-2019

DOI: 10.1016/J.HELIYON.2019.E02390

NAD + metabolism and oxidative stress: The golden nucleotide on a crown of thorns

Publisher: Informa UK Limited

Date: 2012

DOI: 10.1179/1351000212Y.0000000001

Changes in Cathepsin D and Beclin-1 mRNA and protein expression by the excitotoxin quinolinic acid in human astrocytes and neurons

Publisher: Springer Science and Business Media LLC

Date: 16-05-2014

DOI: 10.1007/S11011-014-9557-9

Abstract: Quinolinic acid (QUIN) is an excitotoxin that has been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer's disease (AD). While QUIN has been shown to induce neuronal and astrocytic apoptosis as well as excitotoxic cell death, other mechanisms such as autophagy remain unexplored. We investigated the role of Cathepsin D (CatD) and Beclin-1 (Bc1) in QUIN-treated primary human astrocytes and neurons. We demonstrated that the expression patterns of CatD, a lysosomal aspartic protease associated with autophagy, are increased at 24 h after QUIN treatment. However, unlike CatD, the expression patterns of Bc1, a tumour suppressor protein, are significantly reduced at 24 h after QUIN treatment in both brain cell types. Furthermore, we showed that the NMDA ion channel blockers, MK801, can attenuate QUIN-induced changes CatD and Bc1 expression in both astrocytes and neurons. Taken together, these results suggest that induction of deficits in CatD and Bc1 is a significant mechanism for QUIN toxicity in glial and neuronal cells. Maintenance of autophagy may play a crucial role in neuroprotection in the setting of AD.

The kynurenine pathway in stem cell biology

Publisher: SAGE Publications

Date: 2013

DOI: 10.4137/IJTR.S12626

Abstract: The kynurenine pathway (KP) is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental areas of cell biology have independently been the focus of a burgeoning research interest in recent years. A systematic review of how the two interact has not yet been conducted. Several inflammatory and infectious diseases in which the KP has been implicated include those for which stem cell therapies are being actively explored at a clinical level. Therefore, it is highly relevant to consider the evidence showing that the KP influences stem cell biology and impacts the functional behavior of progenitor cells.

Progesterone alters kynurenine pathway activation in IFN-γ-activated macrophages - relevance for neuroinflammatory diseases

Publisher: SAGE Publications

Date: 2016

DOI: 10.4137/IJTR.S40332

Abstract: We have previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in many inflammatory disorders that are often associated with sexual dimorphisms. We aimed to identify a potential functional interaction between the KP and gonadal hormones. We have treated primary human macrophages with progesterone in the presence and absence of inflammatory cytokine interferongamma (interferon-γ) that is known to be a potent inducer of regulating the KP enzyme. We found that progesterone attenuates interferon-γ-induced KP activity, decreases the levels of the excitotoxin quinolinic acid, and increases the neuroprotective kynurenic acid levels. We also showed that progesterone was able to reduce the inflammatory marker neopterin. These results may shed light on the gender disparity in response to inflammation.

Correction: Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission?

Publisher: Springer Science and Business Media LLC

Date: 02-03-2013

DOI: 10.1186/1742-2094-10-34

Inflammation, immunology, stress and depression: A role for kynurenine metabolism in physical exercise and skeletal muscle

Publisher: Cambridge University Press (CUP)

Date: 02-02-2016

DOI: 10.1017/NEU.2015.69

The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease: A Mini Review

Publisher: Hindawi Limited

Date: 2016

DOI: 10.1155/2016/8590578

Abstract: Neurodegenerative diseases affect not only the life quality of aging populations, but also their life spans. All forms of neurodegenerative diseases have a massive impact on the elderly. The major threat of these brain diseases includes progressive loss of memory, Alzheimer’s disease (AD), impairments in the movement, Parkinson’s disease (PD), and the inability to walk, talk, and think, Huntington’s disease (HD). Oxidative stress and mitochondrial dysfunction are highlighted as a central feature of brain degenerative diseases. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, has been known to play a vital role in the pathophysiology of neurodegenerative diseases including AD, PD, and HD. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of these neurodegenerative diseases and medications are available, but these only treat the symptoms. In traditional medicine, a large number of medicinal plants have been used to treat the symptoms of these neurodegenerative diseases. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases using suitable animal models. This short review focuses the role of oxidative stress in the pathogenesis of AD, PD, and HD and the protective efficacy of natural products against these diseases.

The involvement of neuroinflammation and Kynurenine pathway in Parkinson's disease

Publisher: Hindawi Limited

Date: 2011

DOI: 10.4061/2011/716859

Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Activated microglia themselves release a large number of inflammatory mediators thus perpetuating neuroinflammation and neurotoxicity. The Kynurenine pathway (KP), the main catabolic pathway for tryptophan, is one of the major regulators of the immune response and may also be implicated in the inflammatory response in parkinsonism. The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. Several of these molecules produced by microglia can activate the N-methyl-D-aspartate (NMDA) receptor-signalling pathway, leading to an excitotoxic response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro . There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD.

Modulation of indoleamine-2,3-dioxygenase expression and activity by HIV-1 in human macrophages

Publisher: Wiley

Date: 04-09-2009

DOI: 10.1111/J.1472-8206.2009.00703.X

Abstract: Human immunodeficiency virus (HIV) infection is often complicated by the development of acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). Implications of kynurenine pathway (KP) are suggested in ADC and other inflammatories brain diseases. The first and regulatory enzyme of the KP is the indoleamine-2,3-dioxygenase (IDO). IDO activation is known to contribute to the modulation of the immune response during various infectious diseases particularly in AIDS. HIV and viral proteins can activate IDO in immune cells leading to an increase catabolism of tryptophan through the KP the consequence being the production of immuno-modulative and neuroactive metabolites. This mechanism is likely to favour HIV persistence. The present study analysed concomitantly several parameters involved in IDO regulation and activity associated with HIV-1-infection. We investigated relevant intracellular and extracellular mechanisms involved in the regulation of IDO expression and activity during the HIV infection and replication in human monocyte-derived macrophages (MdM). Using a complementary set of in vitro experiments, we found that HIV-1/Ba-L infection induces IDO expression and increases its activity in MdM. We also showed that IDO activation by HIV-1 is likely to be a direct effect of the infection and seems to be independent of IFN-gamma production.

The role of kynurenine pathway and NAD+ metabolism in myalgic encephalomyelitis/chronic fatigue syndrome

Publisher: Aging and Disease

Date: 2022

DOI: 10.14336/AD.2021.0824

Soluble LILRA3 promotes neurite outgrowth and synapses formation through a high-affinity interaction with Nogo 66

Publisher: The Company of Biologists

Date: 2016

DOI: 10.1242/JCS.182006

Abstract: Inhibitory proteins, particularly Nogo 66, a highly conserved 66 amino acid loop of Nogo A, play key roles in limiting the intrinsic capacity of the central nervous system to regenerate after injury. Ligation of surface Nogo receptors (NgRs) and/or leukocyte immunoglobulin like receptor B2 (LILRB2) and its mouse orthologue the paired-immunoglobulin-like receptor B (PIRB) by Nogo 66 transduces inhibitory signals that potently inhibit neurite outgrowth. Here we show that soluble leukocyte immunoglobulin-like receptor A3 (LILRA3) is a high affinity receptor for Nogo 66, suggesting that LILRA3 might be a competitive antagonist to these cell surface inhibitory receptors. Consistent with this, LILRA3 significantly reversed Nogo 66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons via regulation of the MEK/ERK pathway. LILRA3 represents a new antagonist to Nogo 66-mediated inhibition of neurite outgrowth in the CNS, a function distinct from its immune-regulatory role in leukocytes. This report is also the first to demonstrate that a member of LILR family normally not expressed in rodents exerts functions on mouse neurons through the highly homologous Nogo 66 ligand.

Low Molecular Weight Sulfated Chitosan: Neuroprotective Effect on Rotenone-Induced In Vitro Parkinson’s Disease

Publisher: Springer Science and Business Media LLC

Date: 13-11-2018

DOI: 10.1007/S12640-018-9978-Z

Abstract: The present investigation was an attempt to study the effect of low molecular weight sulfated chitosan (LMWSC) on in vitro rotenone model of Parkinson's disease (PD) by evaluating cell viability, oxidative stress, mitochondrial membrane potential, DNA fragmentation, and apoptosis. Incubation of SH-SY5Y cells with 100 nm rotenone resulted in neuronal cell death, redox imbalanced mitochondrial dysfunction, DNA fragmentation, condensation, and apoptotic cellular morphology. Rotenone exposure enhanced the expression of preapoptotic (cytochrome C (cyto c), caspase-3, -8, -9, and Bax) and down-regulated the expression of anti-apoptotic (Bcl-2) markers. Reduction of the intracellular reactive oxygen species (ROS) levels ensued due to pretreatment of LMWSC along with consequent normalization of antioxidant enzymes, mitigation of rotenone induced mitochondrial dysfunction and apoptosis. Our current findings suggested that LMWSC exhibit the pronounced neuroprotective effects, which could be due to its antioxidant, mitochondrial protection, and anti-apoptotic properties. We thus conclude that LMWSC could be developed as a novel therapeutic molecule for the benefit of reducing the consequences of PD. However, further extensive preclinical and clinical studies are warranted.

Protective Effects of Antioxidants in Huntington’s Disease: an Extensive Review

Publisher: Springer Science and Business Media LLC

Date: 11-01-2019

DOI: 10.1007/S12640-018-9989-9

Abstract: Huntington's disease (HD) is a hereditary neurodegenerative disease of the central nervous system (CNS). Onset of HD occurs between the ages of 30 and 50 years, although few cases are reported among children and elderly. HD appears to be less common in some populations such as those of Japanese, Chinese, and African descent. Clinical features of HD include motor dysfunction (involuntary movements of the face and body, abnormalities in gait, posture and balance), cognitive impairment (obsessive-compulsive disorder), and psychiatric disorders (dementia). Mutation in either of the two copies of a gene called huntingtin (HTT), which codes genetic information for a protein called "huntingtin (Htt)", precipitates the disease in an in idual. Expansion of cytosine-adenine-guanine (CAG) triplet repeats in the HTT gene results in an abnormal Htt protein. Intracellular neuronal accumulation of the mutated Htt protein (mHtt) causes distinctive erratic movements associated with HD. Further, excessive accumulation of the HTT gene repeats causes abnormal production of reactive oxygen species (ROS) and the ensuing mitochondrial (MT) oxidative stress in neurons. Since there is neither a cure nor a promising strategy to delay onset or progression of HD currently available, therapeutics are mainly focusing only on symptomatic management. Several studies have shown that MT dysfunction-mediated oxidative stress is a key factor for the neurodegeneration observed in HD. Supplementation of antioxidants and nutraceuticals has been widely studied in the management of oxidative damage, an associated complication in HD. Therefore, various antioxidants are used as therapeutics for managing and/or treating HD. The present review aimed at delving into the abnormal cellular changes and energy kinetics of the neurons expressing the mHtt gene and the therapeutic roles of antioxidants in HD.

The kynurenine pathway in chronic diseases

Publisher: Elsevier BV

Date: 10-2021

DOI: 10.1016/J.MOLMED.2021.07.006

Abstract: The kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism is dysregulated in inflammation-driven pathologies including oncological and brain diseases [e.g., multiple sclerosis (MS), depression] and thus is a promising therapeutic target. Both pathological and compensatory mechanisms underlie disease-associated KP activation. There is growing evidence for bioenergetic roles of certain KP metabolites such as kynurenic acid (KA), or quinolinic acid (QA) as an NAD

Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats

Publisher: Wiley

Date: 28-10-2011

DOI: 10.1111/J.1742-4658.2011.08366.X

Abstract: The kynurenine pathway of tryptophan catabolism plays an important role in several biological systems affected by aging. We quantified tryptophan and its metabolites kynurenine (KYN), kynurenine acid (KYNA), picolinic acid (PIC) and quinolinic acid (QUIN), and activity of the kynurenine pathway enzymes indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase (TDO) and quinolinic acid phosphoribosyltransferase (QPRTase), in the brain, liver and kidney of young, middle-aged and old female Wistar rats. Tryptophan levels and TDO activity decreased in all tissues with age. In contrast, brain IDO activity increased with age, while liver and kidney IDO activity decreased with age. The levels of KYN, KYNA, QUIN and PIC in brain all increased with age, while the levels of KYN in the liver and kidney showed a tendency to decrease. The levels of KYNA in the liver did not change, but the levels of KYNA in the kidney increased. The levels of PIC and QUIN increased significantly in the liver but showed a tendency to decrease in the kidney. QPRTase activity in both brain and liver decreased with age but was elevated in the kidney in middle-aged (12-month-old) rats. These age-associated changes in tryptophan metabolism have the potential to impact upon major biological processes, including lymphocyte function, pyridine (NAD(P)(H)) synthesis and N-methyl-d-aspartate (NMDA)-mediated synaptic transmission, and may therefore contribute to several degenerative changes of the elderly.

The cyanotoxin and non-protein amino acid β-methylamino-L-alanine (L-BMAA) in the food chain

Publisher: Springer Science and Business Media LLC

Date: 03-08-2019

DOI: 10.1007/S12640-019-00089-9

Abstract: The size and frequency of cyanobacterial blooms are increasing concomitantly with rising global temperatures and increased eutrophication, and this has implications for human health. Cyanotoxins, including L-BMAA, have been implicated in triggering neurodegenerative diseases such as ALS/PDC and Alzheimer's disease. L-BMAA is a water-soluble non-protein amino acid that can bioaccumulate up the food chain, in a free- and protein-bound form. While some data exists on the degree of environmental enrichment of L-BMAA in water bodies, cyanobacteria-derived supplements, fruit bats, and seafood, virtually nothing is known about the presence of L-BMAA in other foodstuffs. It has now been shown several times in laboratory settings that plants can absorb L-BMAA into their leaves and stems, but data from wild-grown plants is nascent. One of the mechanisms implicated in L-BMAA bioaccumulation is misincorporation into proteins in the place of the canonical amino acid L-serine. We first identified this as a mechanism of action of L-BMAA in 2013, and since then, several groups have replicated these findings, but others have not. Here, we discuss in detail the experimental approaches, why they may have produced negative findings and propose several ways forward for developing consistency within the field. We emphasize the need to standardize cell culture methods, using L-serine-free medium to study misincorporation of BMAA, and urge accurate reporting of the components present in cell culture media.

Regarding letter on “Kynurenine pathway dysregulation in postpartum depression”, by Achtyes et al, 2020

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.BBI.2020.10.001

Myxobacterial natural products

Publisher: Elsevier BV

Date: 05-2018

DOI: 10.1016/J.NEURO.2018.02.017

Abstract: Age-related disorders impose noticeable financial and emotional burdens on society. This impact is becoming more prevalent with the increasing incidence of neurodegenerative diseases and is causing critical concerns for treatment of patients worldwide. Parkinson's disease, Alzheimer's disease, multiple sclerosis and motor neuron disease are the most prevalent and the most expensive to treat neurodegenerative diseases globally. Therefore, exploring effective therapies to overcome these disorders is a necessity. Natural products and their derivatives have increasingly attracted attention in drug discovery programs that have identified microorganisms which produce a large range of metabolites with bioactive properties. Myxobacteria, a group of Gram-negative bacteria with large genome size, produce a wide range of secondary metabolites with significant chemical structures and a variety of biological effects. They are potent natural product producers. In this review paper, we attempt to overview some secondary metabolites synthesized by myxobacteria with neuroprotective activity through known mechanisms including production of polyunsaturated fatty acids, reduction of apoptosis, immunomodulation, stress reduction of endoplasmic reticulum, stabilization of microtubules, enzyme inhibition and serotonin receptor modulation.

Differential expression of sirtuins in the aging rat brain

Publisher: Frontiers Media SA

Date: 08-05-2015

DOI: 10.3389/FNCEL.2015.00167

Chronic HIV infection leads to an Alzheimer's disease like illness. Involvement of the kynurenine pathway

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1016/J.ICS.2007.07.031

Gliotoxicity of the cyanotoxin, β-methyl-amino-L-alanine (BMAA)

Publisher: Springer Science and Business Media LLC

Date: 19-03-2013

DOI: 10.1038/SREP01482

Neuroprotective ability of PACAPs against oxidative stress and excitotoxicity in human primary cortical neurons

Publisher: Springer Science and Business Media LLC

Date: 22-09-2013

DOI: 10.1007/S12031-013-0105-6

Correction: Cardiac ryanodine receptor activation by a high Ca2+ store load is reversed in a reducing cytoplasmic redox environment.

Publisher: The Company of Biologists

Date: 15-11-2016

DOI: 10.1242/JCS.198705

The gut microbiota, kynurenine pathway, and immune system interaction in the development of brain cancer

Publisher: Frontiers Media SA

Date: 19-11-2020

DOI: 10.3389/FCELL.2020.562812

Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis

Publisher: Frontiers Media SA

Date: 14-06-2021

DOI: 10.3389/FIMMU.2021.701550

Abstract: The essential amino acid tryptophan (TRP) is the initiating metabolite of the kynurenine pathway (KP), which can be upregulated by inflammatory conditions in cells. Neuroinflammation-triggered activation of the KP and excessive production of the KP metabolite quinolinic acid are common features of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In addition to its role in the KP, genes involved in TRP metabolism, including its incorporation into proteins, and synthesis of the neurotransmitter serotonin, have also been genetically and functionally linked to these diseases. ALS is a late onset neurodegenerative disease that is classified as familial or sporadic, depending on the presence or absence of a family history of the disease. Heritability estimates support a genetic basis for all ALS, including the sporadic form of the disease. However, the genetic basis of sporadic ALS (SALS) is complex, with the presence of multiple gene variants acting to increase disease susceptibility and is further complicated by interaction with potential environmental factors. We aimed to determine the genetic contribution of 18 genes involved in TRP metabolism, including protein synthesis, serotonin synthesis and the KP, by interrogating whole-genome sequencing data from 614 Australian sporadic ALS cases. Five genes in the KP ( AFMID, CCBL1, GOT2, KYNU, HAAO ) were found to have either novel protein-altering variants, and/or a burden of rare protein-altering variants in SALS cases compared to controls. Four genes involved in TRP metabolism for protein synthesis ( WARS ) and serotonin synthesis ( TPH1, TPH2, MAOA ) were also found to carry novel variants and/or gene burden. These variants may represent ALS risk factors that act to alter the KP and lead to neuroinflammation. These findings provide further evidence for the role of TRP metabolism, the KP and neuroinflammation in ALS disease pathobiology.

Novel immune biomarkers in complex regional pain syndrome

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/J.JNEUROIM.2020.577330

Roflumilast, a cAMP-specific phosphodiesterase-4 inhibitor, reduces oxidative stress and improves synapse functions in human cortical neurons exposed to the excitotoxin quinolinic acid

Publisher: American Chemical Society (ACS)

Date: 02-12-2020

DOI: 10.1021/ACSCHEMNEURO.0C00636

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Publisher: Springer Science and Business Media LLC

Date: 10-2011

DOI: 10.1038/NATURE10491

Abstract: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine aracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.

Identification of T-cell epitopes adjacent to neutralizing antigenic domains on the fusion protein of respiratory syncytial virus

Publisher: Elsevier BV

Date: 1993

DOI: 10.1016/S0923-2516(06)80022-1

Abstract: F glycoprotein has been identified as an important target structure in the immunological response following respiratory syncytial virus (RSV) infection. Two sequential B epitopes corresponding to amino acids 200 to 225 and 255 to 278 have already been defined with anti-RSV rabbit serum. The T helper response to peptides which belong to these sequences was investigated in this study. Proliferative T-cell responses to these peptides were analysed in BALB/c mice (H-2d) and others strains: SJL (H-2s), C3H/He (H-2k), B10.BR (H-2k) and C57BL/6 (H-2b). By using various strategies, two T-cell epitopes were identified in the amino acid 200 to 225 and 255 to 278 regions, close to a neutralizing epitope. The T-cell responses to these peptides were H-2- restricted. In addition, the peptide 255-278 was able to stimulate T cells that responded to a subsequent immunization with F glycoprotein in vitro.

Importance of the dysregulation of the kynurenine pathway on cognition in schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 02-12-2023

DOI: 10.1007/S00406-022-01519-0

Bioethanol production from food wastes rich in carbohydrates

Publisher: Elsevier BV

Date: 02-2022

DOI: 10.1016/J.COFS.2021.11.001

Detection of the cyanotoxins L-BMAA uptake and accumulation in primary neurons and astrocytes

Publisher: Springer Science and Business Media LLC

Date: 30-08-2018

DOI: 10.1007/S12640-017-9787-9

Abstract: We show for the first time that a newly developed polyclonal antibody (pAb) can specifically target the cyanotoxin β-methylamino-L-alanine (BMAA) and can be used to enable direct visualization of BMAA entry and accumulation in primary brain cells. We used this pAb to investigate the effect of acute and chronic accumulation, and toxicity of both BMAA and its natural isomer 2,4-diaminobutyric acid (DAB), separately or in combination, on primary cultures of rat neurons. We further present evidence that co-treatment with BMAA and DAB increased neuronal death, as measured by MAP2 fluorescence level, and appeared to reduce BMAA accumulation. DAB is likely to be acting synergistically with BMAA resulting in higher level of cellular toxicity. We also found that glial cells such as microglia and astrocytes are also able to directly uptake BMAA indicating that additional brain cell types are affected by BMAA-induced toxicity. Therefore, BMAA clearly acts at multiple cellular levels to possibly increase the risk of developing neurodegenerative diseases, including neuro- and gliotoxicity and synergetic exacerbation with other cyanotoxins.

Mapping NAD+ metabolism in the brain of ageing Wistar rats: Potential targets for influencing brain senescence

Publisher: Springer Science and Business Media LLC

Date: 17-12-2014

DOI: 10.1007/S10522-013-9489-5

Abstract: Over the last decade, the importance of NAD(+) has expanded beyond its role as an essential cofactor for energy metabolism. NAD(+) has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or CD38, and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD(+) levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD(+) metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD(+) metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD(+) levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of H2AX levels was also observed together with increased PARP-1 and PARP-2 expression, and CD38 activity, concomitantly with reduced NAD(+) and ATP levels and SIRT1 function in the cortex, brainstem, hippoc us and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD(+) catabolism, our discovery of CD38 as the major regulator of cellular NAD(+) levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases.

Social and Biological Parameters Involved in Suicide Ideation During the COVID-19 Pandemic: A Narrative Review

Publisher: SAGE Publications

Date: 2020

DOI: 10.1177/1178646920978243

Abstract: Fear is an indispensable characteristic of any infectious disease, and the alarm will be further lified when the infection spreads uncontrollable, unpredictable, and global. The novel corona virus (SARS CoV-2) lead Covid-19, has been declared as a global emergency by WHO as it has affected millions of people with a high mortality rate. The non-availability of medicine for Covid-19 and the various control measures such as social distancing, self-isolation, house quarantine, and the new normal implementation by different nations across the world to control the spread of Covid-19 made people vulnerable to fear and anxiety. As a result, considerable number of Covid-19-related suicidal deaths has been reported across the world during this pandemic. There have been several studies which describe the psychosocial aspects of suicidal ideation. However, the research on the biological aspects of suicidal ideation/suicidal risk factors that are related to pandemic are unreported. Hence this review article is intended to provide a comprehensive analysis of suicidal deaths during Covid-19 and also aimed to addresses the possible link between suicidal ideation and different factors, including psycho-social, behavioral, neurobiological factors (proximal, distal, and inflammatory) and immunity. The alterations in glutamatergic and GABAergic neurotransmitters had upregulated the GABARB3, GABARA4, GABARA3, GABARR1, GABARG2, and GAD2 gene expressions in suicidal victims. The changes in the Kynurenine (KYN) pathway, Hypothalamus-Pituitary-Adrenal axis (HPA axis) hyperactivation, and dysregulation of serotonin biosynthesis would significantly alter the brain chemistry in people with suicide ideation.

Major developments in the design of inhibitors along the kynurenine pathway

Publisher: Bentham Science Publishers Ltd.

Date: 11-09-2017

DOI: 10.2174/0929867324666170502123114

Concurrent quantification of quinolinic, picolinic, and nicotinic acids using electron-capture negative-ion gas chromatography - Mass spectrometry

Publisher: No publisher found

Date: 2002

DOI: 10.1006/ABIO.2001.5490

A new cytoplasmic interaction between junctin and ryanodine receptor Ca2+ release channels.

Publisher: The Company of Biologists

Date: 2015

DOI: 10.1242/JCS.160689

Abstract: Junctin, a non-catalytic splice variant of the aspartate-β-hydroxylase gene, is inserted into the membrane of the sarcoplasmic reticulum (SR) Ca2+ store where it modifies Ca2+ signalling in the heart and skeletal muscle through its regulation of ryanodine receptor (RyR) Ca2+ release channels. Junctin is required for normal muscle function as its knockout leads to abnormal Ca2+ signalling, muscle dysfunction and cardiac arrhythmia. However, junctin's binding interactions with RyRs are largely unknown and have been assumed to occur only in the SR lumen. We find robust binding of RyRs to full junctin, its luminal and unexpectedly its cytoplasmic domain, each with distinct effects on RyR1 and RyR2 activity. Full junctin in the luminal solution increases channel activity by ∼3-fold. The C-terminal luminal interaction inhibits RyR channel activity by ∼50%. The N-terminal cytoplasmic binding produces a ∼5-fold increase in RyR activity. The cytoplasmic interaction is required for luminal binding to replicate the influence of full junctin on RyR1 and RyR2 activity. The C-terminal domain of junctin binds to residues including S1–S2 linker of RyR1 and N-terminal junctin binds between RyR1 residues 1078-2156.

Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington’s Disease

Publisher: Hindawi Limited

Date: 2017

DOI: 10.1155/2017/3279061

Abstract: Huntington’s disease (HD) is characterised by movement disorders, cognitive impairments, and psychiatric problems. The abnormal generation of reactive oxygen species and the resulting oxidative stress-induced mitochondrial damage in neurons upon CAG mutations in the HTT gene have been hypothesized as the contributing factors of neurodegeneration in HD. The potential use of antioxidants against free radical toxicity has been an emerging field in the management of ageing and many neurodegenerative disorders. Neural stem cells derived adult neurogenesis represents the regenerative capacity of the adult brain. The process of adult neurogenesis has been implicated in the cognitive functions of the brain and is highly modulated positively by different factors including antioxidants. The supportive role of antioxidants to reduce the severity of HD via promoting the functional neurogenesis and neuroprotection in the pathological adult brain has great promise. This review comprehends the recent studies describing the therapeutic roles of antioxidants in HD and other neurologic disorders and highlights the scope of using antioxidants to promote adult neurogenesis in HD. It also advocates a new line of research to delineate the mechanisms by which antioxidants promote adult neurogenesis in HD.

Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study

Publisher: Cold Spring Harbor Laboratory

Date: 07-06-2022

DOI: 10.1101/2022.06.07.22276020

Abstract: Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12- months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p .001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p .001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.

Evaluating the toxicity of escalating dose of oral picolinic acid in Sprague-Dawley rats

Publisher: Elsevier BV

Date: 10-2021

DOI: 10.1016/J.TOX.2021.152960

Abstract: Picolinic acid (PIC) is a byproduct of tryptophan catabolism through the kynurenine pathway, with anabolic effects on bone in vivo and in vitro. Hence, PIC has been nominated as a possible candidate to treat and/or prevent osteoporosis. However, the effective dose and toxicity of PIC are not known yet. To test the effect of escalating and very high doses of oral PIC, male Sprague-Dawley rats were gavaged PIC: Group 1 (n = 3) received incremental doses of 125, 250 and 500 mg/kg/day PIC on days 1, 3 and 5. Group 2 (n = 3) received 500 mg/kg BID (8 h apart i.e. 1000 mg/kg/day) PIC on Day 1. Group 3 (n = 3) received 125 mg/kg/day PIC for seven consecutive days. Group 4 (n = 3) received 250 mg/kg/day PIC for seven consecutive days. Groups 1, 3 and 4 rats were euthanized on Day 8. Group 5 (n = 6) received 500 mg/kg/day PIC for two consecutive days and then once a week dose (Days 9, 16 and 23) of 500 mg/kg/dose PIC, until euthanasia (Day 30). Blood and cerebrospinal fluid (CSF) were s led at euthanasia, and tissues showing abnormalities at necropsy underwent histopathology evaluation. All rats displayed some degree of mild hypercalcemia and hyperkalemia. Rats receiving high doses (500 or 1000 mg/kg/day) of PIC died or were euthanized on humane grounds within the first week after showing clinical neurological signs, with animals later revealed to have brain necrosis and hemorrhage at histopathology. Rats receiving lower doses (125 or 250 mg/kg/day) of PIC completed treatment course without apparent clinical adverse events. In summary, very high doses of PIC (≥500 mg/kg/day) were vascular-neurotoxic. Possible future experiments must consider significantly lower doses.

Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-beta peptide generation

Publisher: Elsevier BV

Date: 02-2007

DOI: 10.1074/JBC.M607831200

Indoleamine 2,3 dioxygenase and quinolinic acid Immunoreactivity in Alzheimer's disease hippocampus

Publisher: Wiley

Date: 25-05-2005

DOI: 10.1111/J.1365-2990.2005.00655.X

Abstract: The present immunohistochemical study provides evidence that the kynurenine pathway is up-regulated in Alzheimer's disease (AD) brain, leading to increases in the excitotoxin quinolinic acid (QUIN). We show that the regulatory enzyme of the pathway leading to QUIN synthesis, indoleamine 2,3 dioxygenase (IDO) is abundant in AD compared with controls. In AD hippoc us, both IDO- and QUIN-immunoreactivity (-IR) was detected in cortical microglia, astrocytes and neurones, with microglial and astrocytic expression of IDO and QUIN highest in the perimeter of senile plaques. QUIN-IR was present in granular deposits within the neuronal soma of AD cortex and was also seen uniformly labelling neurofibrillary tangles. Our data imply that QUIN may be involved in the complex and multifactorial cascade leading to neuro-degeneration in AD. These results may open a new therapeutic door for AD patients.

Is neurocognitive ageing accelerated in virally suppressed people with HIV and multimorbidity?

Publisher: Oxford University Press (OUP)

Date: 07-02-2023

DOI: 10.1093/BRAIN/AWAD035

Abstract: This scientific commentary refers to ‘Twelve-year neurocognitive decline in HIV is associated with comorbidities, not age: a CHARTER study’ by Heaton et al. (0.1093/brain/awac465).

M. tuberculosis induces potent activation of IDO-1, but this is not essential for the immunological control of infection

Publisher: Public Library of Science (PLoS)

Date: 23-05-2012

DOI: 10.1371/JOURNAL.PONE.0037314

Neuroinflammation in multiple system atrophy: Response to and cause of α-synuclein aggregation

Publisher: Frontiers Media SA

Date: 12-11-2015

DOI: 10.3389/FNCEL.2015.00437

Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma

Publisher: Springer Science and Business Media LLC

Date: 14-11-2018

DOI: 10.1038/S41467-018-06951-2

Abstract: BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.

Metacaspase deletion increases carbonylated and tyrosine-phosphorylated proteins associated with protein synthesis and carbohydrate metabolism in Saccharomyces cerevisiae

Publisher: Medknow

Date: 2022

DOI: 10.4103/IJNPND.IJNPND_18_21

Engineered bacteria for valorizing lignocellulosic biomass into bioethanol

Publisher: Elsevier BV

Date: 2022

DOI: 10.1016/J.BIORTECH.2021.126212

Abstract: Appropriate bioprocessing of lignocellulosic materials into ethanol could address the world's insatiable appetite for energy while mitigating greenhouse gases. Bioethanol is an ideal gasoline extender and is widely used in many countries in blended form with gasoline at specific ratios to improve fuel characteristics and engine performance. Although the bioethanol production industry has long been operational, finding a suitable microbial agent for the efficient conversion of lignocelluloses is still an active field of study. Among available microbial candidates, engineered bacteria may be promising ethanol producers while may show other desired traits such as thermophilic nature and high ethanol tolerance. This review provides the current knowledge on the introduction, overexpression, and deletion of the genes that have been performed in bacterial hosts to achieve higher ethanol yield, production rate and titer, and tolerance. The constraints and possible solutions and economic feasibility of the processes utilizing such engineered strains are also discussed.

Cytotoxic activity of the MK2 inhibitor CMPD1 in glioblastoma cells is independent of MK2

Publisher: Springer Science and Business Media LLC

Date: 07-09-2015

DOI: 10.1038/CDDISCOVERY.2015.28

Abstract: MAPK-activated protein kinase 2 (MK2) is a checkpoint kinase involved in the DNA damage response. MK2 inhibition enhances the efficacy of chemotherapeutic agents however, whether MK2 inhibition alone, without concurrent chemotherapy, would attenuate survival of cancer cells has not been investigated. CMPD1 is a widely used non-ATP competitive inhibitor that prevents MK2 phosphorylation. We employed CMPD1 together with MK2 knock-down and ATP-competitive MK2 inhibitor III (MK2i) in a panel of glioblastoma cells to assess whether MK2 inhibition could induce cancer cell death. While CMPD1 was effective at selective killing of cancer cells, MK2i and MK2 knock-down had no effect on viability of glioblastoma cells. CMPD1 treatment induced a significant G2/M arrest but MK2i-treated cells were only minimally arrested at G1 phase. Intriguingly, at doses that were cytotoxic to glioblastoma cells, CMPD1 did not inhibit phosphorylation of MK2 and of its downstream substrate Hsp27. These results suggest that CMPD1 exhibits cytotoxic activity independently of MK2 inhibition. Indeed, we identified tubulin as a primary target of the CMPD1 cytotoxic activity. This study demonstrates how functional and mechanistic studies with appropriate selection of test compounds, combining genetic knock-down and pharmacological inhibition, coordinating timing and dose levels enabled us to uncover the primary target of an MK2 inhibitor commonly used in the research community. Tubulin is emerging as one of the most common non-kinase targets for kinase inhibitors and we propose that potential tubulin-targeting activity should be assessed in preclinical pharmacology studies of all novel kinase inhibitors.

The humanized NOD/SCID mouse as a preclinical model to study the fate of encapsulated human islets

Publisher: JCFCorp SG PTE LTD

Date: 2010

DOI: 10.1900/RDS.2010.7.62

The NRTIs Lamivudine, Stavudine and Zidovudine Have Reduced HIV-1 Inhibitory Activity in Astrocytes

Publisher: Public Library of Science (PLoS)

Date: 16-04-2013

DOI: 10.1371/JOURNAL.PONE.0062196

A comprehensive review on anaerobic fungi applications in biofuels production

Publisher: Elsevier BV

Date: 07-2022

DOI: 10.1016/J.SCITOTENV.2022.154521

Abstract: Anaerobic fungi (Neocallimastigomycota) are promising lignocellulose-degrading microorganisms that can be exploited by the biofuel industry. While natural production of ethanol by these microorganisms is very low, there is a greater potential for their use in the biogas industry. More specifically, anaerobic fungi can contribute to biogas production by either releasing holocellulose or reducing sugars from lignocelluloses that can be used as a substrate by bacteria and methanogens involved in the anaerobic digestion (AD) process or by metabolizing acetate and formate that can be directly consumed by methanogens. Despite their great potential, the appropriate tools for engineering anaerobic fungi have not been established yet. The first section of this review justifies how the biofuel industry can benefit from using anaerobic fungi and is followed by their taxonomy. In the third section, the possibility of using anaerobic fungi for the consolidated production of bioethanol is briefly discussed. Nevertheless, the main focus of this review is on the upstream and mainstream effects of bioaugmentation with anaerobic fungi on the AD process. The present review also scrutinizes the constraints on the way of efficient engineering of anaerobic rumen fungi. By providing this knowledge, this review aims to help research in this field with identifying the challenges that must be addressed by future experiments to achieve the full potentials of these promising microorganisms. To sum up, the pretreatment of lignocelluloses by anaerobic fungi can prevent carbohydrate loss due to respiration (compared to white-rot fungi). Following fungal mixed acid fermentation, the obtained slurry containing sugars and more susceptible holocellulose can be directly consumed by AD microorganisms (bacteria, methanogens). The bioaugmentation of anaerobic fungi into the AD process can increase methane biosynthesis by >3.3 times. Despite this, for the commercial AD process, novel genetic engineering techniques and kits must be developed to efficiently improve anaerobic fungi viability throughout the AD process.

Characterisation of the kynurenine pathway in skin-derived fibroblasts and keratinocytes

Publisher: Wiley

Date: 10-04-2015

DOI: 10.1002/JCB.25019

Abstract: Acute UVB exposure triggers inflammation leading to the induction of indoleamine 2,3 dioxygenase (IDO1), one of the first enzymes in the kynurenine pathway (KP) for tryptophan degradation. However, limited studies have been undertaken to determine the catabolism of tryptophan within the skin. The aim of this study was two fold: (1) to establish if the administration of the proinflammatory cytokine interferon‐gamma (IFN‐γ) and/or UVB radiation elicits differential KP expression patterns in human fibroblast and keratinocytes and (2) to evaluate the effect of KP metabolites on intracellular nicotinamide adenine dinucleotide (NAD + ) levels, and cell viability. Primary cultures of human fibroblasts and keratinocytes were used to examine expression of the KP at the mRNA level using qPCR, and at the protein level using immunocytochemistry. Cellular responses to KP metabolites were assessed by examining extracellular lactate dehydrogenase (LDH) activity and intracellular NAD + levels. Major downstream KP metabolites were analyzed using GC/MS and HPLC. Our data shows that the KP is fully expressed both in human fibroblasts and keratinocytes. Exposure to UVB radiation and/or IFN‐γ causes significant changes in the expression pattern of downstream KP metabolites and enzymes. Exposure to various concentrations of KP metabolites showed marked differences in cell viability and intracellular NAD + production, providing support for involvement of the KP in the de novo synthesis of NAD + in the skin. This new information will have a significant impact on our understanding of the pathogenesis of UV related skin damage and the diagnosis of KP related disease states. J. Cell. Biochem. 116: 903–922, 2015. © 2015 Wiley Periodicals, Inc.

Fungal-contaminated grass and well water and sporadic amyotrophic lateral sclerosis

Publisher: Medknow

Date: 2019

DOI: 10.4103/1673-5374.255959

Effect of quinolinic acid on human astrocytes morphology and functions: Implications in Alzheimer's disease

Publisher: Springer Science and Business Media LLC

Date: 12-2009

DOI: 10.1186/1742-2094-6-36

Abstract: The excitotoxin quinolinic acid (QUIN) is synthesized through the kynurenine pathway (KP) by activated monocyte lineage cells. QUIN is likely to play a role in the pathogenesis of several major neuroinflammatory diseases including Alzheimer's disease (AD). The presence of reactive astrocytes, astrogliosis, increased oxidative stress and inflammatory cytokines are important pathological hallmarks of AD. We assessed the stimulatory effects of QUIN at low physiological to high excitotoxic concentrations in comparison with the cytokines commonly associated with AD including IFN-γ and TNF-α on primary human astrocytes. We found that QUIN induces IL-1β expression, a key mediator in AD pathogenesis, in human astrocytes. We also explored the effect of QUIN on astrocyte morphology and functions. At low concentrations, QUIN treatment induced concomitantly a marked increase in glial fibrillary acid protein levels and reduction in vimentin levels compared to controls features consistent with astrogliosis. At pathophysiological concentrations QUIN induced a switch between structural protein expressions in a dose dependent manner, increasing VIM and concomitantly decreasing GFAP expression. Glutamine synthetase (GS) activity was used as a functional metabolic test for astrocytes. We found a significant dose-dependent reduction in GS activity following QUIN treatment. All together, this study showed that QUIN is an important factor for astroglial activation, dysregulation and cell death with potential relevance to AD and other neuroinflammatory diseases.

Exosomes in Alzheimer’s Disease: Potential Role as Pathological Mediators, Biomarkers and Therapeutic Targets

Publisher: Springer Science and Business Media LLC

Date: 25-08-2020

DOI: 10.1007/S11064-020-03111-1

Abstract: The concept of exosomes has been progressively changed from the status of cellular trashcans to multitasking organelles involved in many processes, including internalization, transport and transfer of macromolecules such as proteins, lipids and nucleic acids. While underpinning the mechanisms behind neurodegeneration and neuronal loss, exosomes were shown to be involved in carrying pathological misfolded proteins, propagation of β-amyloid protein and hyper-phosphorylated tau proteins across the brain that ultimately leads to the onset of Alzheimer's disease (AD), the most prevailing multifactorial neurodegenerative disorder. A potential novel therapeutic role of exosomes in AD intervention is suggested by their ability to increase Aβ clearance. This review aims to highlight the important pathological mechanisms as well as therapeutic strategies involving exosomes towards AD prevention.

Involvement of the kynurenine pathway in human glioma pathophysiology

Publisher: Public Library of Science (PLoS)

Date: 21-11-2014

DOI: 10.1371/JOURNAL.PONE.0112945

Excitotoxicity in the Pathogenesis of Autism

Publisher: Springer Science and Business Media LLC

Date: 13-10-2012

DOI: 10.1007/S12640-012-9354-3

Abstract: Autism is a debilitating neurodevelopment disorder characterised by stereotyped interests and behaviours, and abnormalities in verbal and non-verbal communication. It is a multifactorial disorder resulting from interactions between genetic, environmental and immunological factors. Excitotoxicity and oxidative stress are potential mechanisms, which are likely to serve as a converging point to these risk factors. Substantial evidence suggests that excitotoxicity, oxidative stress and impaired mitochondrial function are the leading cause of neuronal dysfunction in autistic patients. Glutamate is the primary excitatory neurotransmitter produced in the CNS, and overactivity of glutamate and its receptors leads to excitotoxicity. The over excitatory action of glutamate, and the glutamatergic receptors NMDA and AMPA, leads to activation of enzymes that damage cellular structure, membrane permeability and electrochemical gradients. The role of excitotoxicity and the mechanism behind its action in autistic subjects is delineated in this review.

Dietary Supplements/Antioxidants: Impact on Redox Status in Brain Diseases

Publisher: Hindawi Limited

Date: 2017

DOI: 10.1155/2017/5048432

The kynurenine pathway and inflammation in amyotrophic lateral sclerosis

Publisher: Springer Science and Business Media LLC

Date: 18-11-2010

DOI: 10.1007/S12640-009-9129-7

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS s les. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.

Tissue‐specific effects of exercise as NAD+‐boosting strategy: Current knowledge and future perspectives

Publisher: Wiley

Date: 10-01-2023

DOI: 10.1111/APHA.13921

Abstract: Nicotinamide adenine dinucleotide (NAD + ) is an evolutionarily highly conserved coenzyme with multi‐faceted cell functions, including energy metabolism, molecular signaling processes, epigenetic regulation, and DNA repair. Since the discovery that lower NAD + levels are a shared characteristic of various diseases and aging per se, several NAD + ‐boosting strategies have emerged. Other than pharmacological and nutritional approaches, exercise is thought to restore NAD + homeostasis through metabolic adaption to chronically recurring states of increased energy demand. In this review we discuss the impact of acute exercise and exercise training on tissue‐specific NAD + metabolism of rodents and humans to highlight the potential value as NAD + ‐boosting strategy. By interconnecting results from different investigations, we aim to draw attention to tissue‐specific alterations in NAD + metabolism and the associated implications for whole‐body NAD + homeostasis. Acute exercise led to profound alterations of intracellular NAD + metabolism in various investigations, with the magnitude and direction of changes being strongly dependent on the applied exercise modality, cell type, and investigated animal model or human population. Exercise training elevated NAD + levels and NAD + metabolism enzymes in various tissues. Based on these results, we discuss molecular mechanisms that might connect acute exercise‐induced disruptions of NAD + /NADH homeostasis to chronic exercise adaptions in NAD + metabolism. Taking this hypothesis‐driven approach, we hope to inspire future research on the molecular mechanisms of exercise as NAD + ‐modifying lifestyle intervention, thereby elucidating the potential therapeutic value in NAD + ‐related pathologies.

Novel venom-derived inhibitors of the human EAG channel, a putative antiepileptic drug target

Publisher: Elsevier BV

Date: 12-2018

DOI: 10.1016/J.BCP.2018.08.038

Abstract: Recently, we and other groups revealed that gain-of-function mutations in the human ether à go-go voltage-gated potassium channel hEAG1 (K

Characterization of the kynurenine pathway in NSC-34 cell line: Implications for amyotrophic lateral sclerosis

Publisher: Wiley

Date: 28-01-2011

DOI: 10.1111/J.1471-4159.2010.07159.X

Abstract: Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron degenerative disease for which the aetiology is still unknown. The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of NAD(+) and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders. Among the KP intermediates, quinolinic acid (QUIN) is a potent excitotoxin, while kynurenic acid and picolinic acid are both neuroprotectant. This study aimed to (i) characterize the components of the KP in NSC-34 cells (a rodent motor neuron cell line) and (ii) assess the effects of QUIN on the same cells. RT-PCR and immunocytochemistry were used to characterize the KP enzymes, and lactate dehydrogenase (LDH) test was used to assess the effect of QUIN in the absence and presence of NMDA receptor antagonists, kynurenines and 1-methyl tryptophan. Our data demonstrate that a functional KP is present in NSC-34 cells. LDH tests showed that (i) QUIN toxicity on NSC-34 cells increases with time and concentration (ii) NMDA antagonists, 2-amino-5-phosphonopentanoic acid, MK-801 and memantine, can partially decrease QUIN toxicity (iii) kynurenic acid can decrease LDH release in a linear manner, whereas picolinic acid does the same but non-linearly and (iv) 1-methyl tryptophan is effective in decreasing QUIN release by the rodent microglial cell line BV-2 and thus protects NSC-34 from cell death. There is currently a lack of effective treatment for ALS and our in vitro results provide a novel therapeutic strategy for ALS patients.

Chapter 20: Role of the kynurenine pathway in stem cell biology

Publisher: Springer International Publishing

Date: 2015

DOI: 10.1007/978-3-319-11870-3_20

Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression

Publisher: Springer Science and Business Media LLC

Date: 27-10-2020

DOI: 10.1186/S13058-020-01351-1

Abstract: Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa. To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical s les ( n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these s les to quantify the KP enzyme gene, protein, and activity, respectively. We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA). Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

Visualization of Incrementally Learned Projection Trajectories for Longitudinal Data

Publisher: Cold Spring Harbor Laboratory

Date: 25-11-2022

DOI: 10.1101/2022.11.25.515889

Abstract: Human-induced pluripotent stem cell derived brain organoids provide models to study the human brain and its diseases. The neuronal activities of these organoids are recorded over time by Multi-electrode Arrays, calling for approaches to analyze their longitudinal variations to study the organoids’ electrophysiological maturation. We introduce a pipeline (Il-Vis) that incrementally learns and visualizes a progression trajectory representing the organoids’ electrophysiological properties. Unlike a static model that runs at the end of the experiment, Il-Vis generates a progression trajectory thus far at each s ling timepoint. Results on simulated data, for which the true progression trajectories are known, verified Il-Vis’s ability to capture and visualize the trajectories accurately and relative to each other. Results on brain organoid data revealed useful insights about organoids’ electrophysiological maturation stages and response patterns when exposed to Quinolinic Acid (and its blocking antibody), a metabolite contributing to many neuroinflammatory diseases including Alzheimer’s.

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?

Publisher: Springer Science and Business Media LLC

Date: 11-07-2022

DOI: 10.1007/S00018-022-04380-5

Abstract: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on in iduals and their community. Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers. To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated however, these studies have failed to report a consistent result. These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP). KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH). In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites. This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS.

Neurotoxicity of the cyanotoxin BMAA through axonal degeneration and intercellular spreading

Publisher: Springer Science and Business Media LLC

Date: 25-08-2018

DOI: 10.1007/S12640-017-9790-1

Abstract: β-Methylamino-L-alanine (BMAA) is implicated in neurodegeneration and neurotoxicity, particularly in ALS-Parkinson Dementia Complex. Neurotoxic properties of BMAA have been partly elucidated, while its transcellular spreading capacity has not been examined. Using reconstructed neuronal networks in microfluidic chips, separating neuronal cells into two subcompartments-(1) the proximal, containing first-order neuronal soma and dendrites, and (2) a distal compartment, containing either only axons originating from first-order neurons or second-order striatal neurons-creates a cortico-striatal network. Using this system, we investigated the toxicity and spreading of BMAA in murine primary neurons. We used a newly developed antibody to detect BMAA in cells. After treatment with 10 μM BMAA, the cyanotoxin was incorporated in first-degree neurons. We also observed a rapid trans-neuronal spread of BMAA to unexposed second-degree neurons in 48 h, followed by axonal degeneration, with limited somatic death. This in vitro study demonstrates BMAA axonal toxicity at sublethal concentrations and, for the first time, the transcellular spreading abilities of BMAA. This neuronal dying forward spread that could possibly be associated with progression of some neurodegenerative diseases especially amyotrophic lateral sclerosis.

Neuroprotective role of Asiatic acid in aluminium chloride induced rat model of Alzheimer rsquo s disease

Publisher: IMR Press

Date: 2018

DOI: 10.2741/S514

Abstract: Alzheimer's disease (AD) is the most common form of dementia, characterized by memory loss, cognitive impairment and personality disorders accompanied by diffuse structural abnormalities in the brain of elderly people. The current investigation explored the neuroprotective potential of asiatic acid (AA), a natural triterpene of

The Anthracycline Metabolite Doxorubicinol Abolishes RyR2 Sensitivity to Physiological Changes in Luminal Ca²⁺through an Interaction with Calsequestrin

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 15-09-2017

DOI: 10.1124/MOL.117.108183

Abstract: The chemotherapeutic anthracycline metabolite doxorubicinol (doxOL) has been shown to interact with and disrupt the function of the cardiac ryanodine receptor Ca

Mass spectrometric detection of quinolinic acid in microdissected Alzheimer's disease plaques

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1016/J.ICS.2007.07.012

Effect of quinolinic acid on gene expression in human astrocytes: Implications for Alzheimer's disease

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1016/J.ICS.2007.07.010

Characterization of the kynurenine pathway in human oligodendrocytes

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1016/J.ICS.2007.07.011

Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue

Publisher: Public Library of Science (PLoS)

Date: 27-07-2012

DOI: 10.1371/JOURNAL.PONE.0042357

Design and Screening of a Glial Cell-Specific, Cell Penetrating Peptide for Therapeutic Applications in Multiple Sclerosis

Publisher: Public Library of Science (PLoS)

Date: 25-09-2012

DOI: 10.1371/JOURNAL.PONE.0045501

Sphingosine kinase 2 potentiates amyloid deposition but protects against hippocampal volume loss and demyelination in a mouse model of Alzheimer's disease

Publisher: Society for Neuroscience

Date: 22-10-2019

DOI: 10.1523/JNEUROSCI.0524-19.2019

Abstract: Sphingosine 1-phosphate (S1P) is a potent vasculoprotective and neuroprotective signaling lipid, synthesized primarily by sphingosine kinase 2 (SK2) in the brain. We have reported pronounced loss of S1P and SK2 activity early in Alzheimer's disease (AD) pathogenesis, and an inverse correlation between hippoc al S1P levels and age in females, leading us to speculate that loss of S1P is a sensitizing influence for AD. Paradoxically, SK2 was reported to mediate amyloid β (Aβ) formation from amyloid precursor protein (APP) in vitro . To determine whether loss of S1P sensitizes to Aβ-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APP SwInd ) mice. SK2 deficiency greatly reduced Aβ content in J20 mice, associated with significant improvements in epileptiform activity and cross-frequency coupling measured by hippoc al electroencephalography. However, several key measures of APP SwInd -dependent neurodegeneration were enhanced on the SK2-null background, despite reduced Aβ burden. These included hippoc al volume loss, oligodendrocyte attrition and myelin loss, and impaired performance in Y-maze and social novelty memory tests. Inhibition of the endosomal cholesterol exporter NPC1 greatly reduced sphingosine phosphorylation in glial cells, linking loss of SK2 activity and S1P in AD to perturbed endosomal lipid metabolism. Our findings establish SK2 as an important endogenous regulator of both APP processing to Aβ, and oligodendrocyte survival, in vivo . These results urge greater consideration of the roles played by oligodendrocyte dysfunction and altered membrane lipid metabolic flux as drivers of neurodegeneration in AD. SIGNIFICANCE STATEMENT Genetic, neuropathological, and functional studies implicate both Aβ and altered lipid metabolism and/or signaling as key pathogenic drivers of Alzheimer's disease. In this study, we first demonstrate that the enzyme SK2, which generates the signaling lipid S1P, is required for Aβ formation from APP in vivo . Second, we establish a new role for SK2 in the protection of oligodendrocytes and myelin. Loss of SK2 sensitizes to Aβ-mediated neurodegeneration by attenuating oligodendrocyte survival and promoting hippoc al atrophy, despite reduced Aβ burden. Our findings support a model in which Aβ-independent sensitizing influences such as loss of neuroprotective S1P are more important drivers of neurodegeneration than gross Aβ concentration or plaque density.

Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 22-05-2014

DOI: 10.1212/NXI.0000000000000012

The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation

Publisher: Wiley

Date: 08-09-2015

DOI: 10.1002/OBY.21199

Abstract: This study characterized the kynurenine pathway (KP) in human obesity by evaluating circulating levels of kynurenines and the expression of KP enzymes in adipose tissue. Tryptophan and KP metabolite levels were measured in serum of in iduals from the D.E.S.I.R. cohort (case-cohort study: 212 diabetic, 836 randomly s led) and in women with obesity, diabetic or normoglycemic, from the ABOS cohort (n = 100). KP enzyme gene expressions were analyzed in omental and subcutaneous adipose tissue of women from the ABOS cohort, in human primary adipocytes and in monocyte-derived macrophages. In the D.E.S.I.R. cohort, kynurenine levels were positively associated with body mass index (BMI) (P = 4.68 × 10(-19) ) and with a higher HOMA2-IR insulin resistance index (P = 6.23 × 10(-4) ). The levels of kynurenine, kynurenic acid, and quinolinic acid were associated with higher BMI (P < 0.05). The expression of several KP enzyme genes (indoleamine 2,3-dioxygenase 1 [IDO1], kynureninase [KYNU], kynurenine 3-monooxygenase [KMO], and kynurenine aminotransferase III [CCBL2]) was increased in the omental adipose tissue of women with obesity compared to lean (P < 0.05), and their expression was induced by proinflammatory cytokines in human primary adipocytes (P < 0.05), except for KMO that is not expressed in these cells. The expressions of IDO1, KYNU, KMO, and CCBL2 were higher in proinflammatory than in anti-inflammatory macrophages (P < 0.05). In the context of obesity, the presence of macrophages in adipose tissue may contribute to erting KP toward KMO activation.

Risk Factors for Surgical Site Infection in Minor Dermatological Surgery: A Systematic Review

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2019

DOI: 10.1097/01.ASW.0000546118.25057.1A

Antioxidant therapies in attention deficit hyperactivity disorder

Publisher: IMR Press

Date: 2019

DOI: 10.2741/4720

Abstract: Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder among children and adults. Impulsivity, inattention, and hyperactivity are hallmark of ADHD. While ADHD is not on the autism spectrum, they are related in several ways as they have some overlapping symptoms. The pathogenesis of ADHD has so far remained enigmatic, however, there is some evidence suggesting critical association among ADHD and the level of oxidative stress which trigger cell membrane damage, changes in inner structure and function of proteins, as well as structural damage to DNA which eventually culminate into development of ADHD. Although stimulants as well as some classes of non-stimulants are used to ameliorate symptom of ADHD, various adverse effects have been associated with such compounds. To date, treatment of ADHD is done with a combination of medications, behavior modifications, psycho-education, family therapy and life-style changes. The American Academy of Pediatrics officially promote stimulant medications and/or behavior therapy as 'first line of therapy'. In addition to the presently therapeutic armamentarium, evidences are emerging on relevancy of natural products. There has been an interest on the therapeutic role of antioxidants in the treatment of ADHD. The present review aims to highlight the beneficiary role played by different antioxidants in mitigating the symptoms of ADHD.

Detection of the suspected neurotoxin β-methylamino-L-alanine (BMAA) in cyanobacterial blooms from multiple water bodies in Eastern Australia

Publisher: Elsevier BV

Date: 04-2018

DOI: 10.1016/J.HAL.2018.03.004

Abstract: The emerging toxin β-methylamino-l-alanine (BMAA) has been linked to the development of a number of neurodegenerative diseases in humans including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease. BMAA has been found to be produced by a range of cyanobacteria, diatoms, and dinoflagellates worldwide, and is present in freshwater, saltwater, and terrestrial ecosystems. Surface scum s les were collected from waterways in rural and urban New South Wales, Australia and algal species identified. Reverse phase liquid chromatography-tandem mass spectrometry was used to analyse sixteen cyanobacterial scum for the presence of BMAA as well as its toxic structural isomer 2,4-diaminobutyric acid (2,4-DAB). BMAA was detected in ten of the s les analysed, and 2,4-DAB in all sixteen. The presence of these toxins in water used for agriculture raises concerns for public health and food security in Australia.

Neuroprotective Effects of Rosmarinic Acid on Ciguatoxin in Primary Human Neurons

Publisher: Springer Science and Business Media LLC

Date: 05-10-2013

DOI: 10.1007/S12640-013-9429-9

Abstract: Ciguatoxin (CTX), is a toxic compound produced by microalgae (dinoflagellate) Gambierdiscus spp., and is bio-accumulated and bio-transformed through the marine food chain causing neurological deficits. To determine the mechanism of CTX-mediated cytotoxicity in human neurons, we measured extracellular lactate dehydrogenase (LDH) activity, intracellular levels of nicotinamide adenine dinucleotide (NAD(+)) and H2AX phosphorylation at serine 139 as a measure for DNA damage in primary cultures of human neurons treated with Pacific (P)-CTX-1B and P-CTX-3C. We found these marine toxins can induce a time and dose-dependent increase in extracellular LDH activity, with a concomitant decline in intracellular NAD(+) levels and increased DNA damage at the concentration range of 5-200 nM. We also showed that pre- and post-treatment with rosmarinic acid (RA), the active constituent of the Heliotropium foertherianum (Boraginaceae) can attenuate CTX-mediated neurotoxicity. These results further highlight the potential of RA in the treatment of CTX-induced neurological deficits.

Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status

Publisher: SAGE Publications

Date: 2019

DOI: 10.1177/1178646919852996

Abstract: The kynurenine pathway is important in cellular energy generation and limiting cellular ageing as it degrades about 90% of dietary tryptophan into the essential co-factor NAD + (nicotinamide adenine dinucleotide). Prior to the production of NAD + , various intermediate compounds with neuroactivity (kynurenic acid, quinolinic acid) or antioxidant activity (3-hydroxykynurenine, picolinic acid) are synthesized. The kynurenine metabolites can participate in numerous neurodegenerative disorders (Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease) or other diseases such as AIDS, cancer, cardiovascular diseases, inflammation, and irritable bowel syndrome. Recently, the role of gut in affecting the emotional and cognitive centres of the brain has attracted a great deal of attention. In this review, we focus on the bidirectional communication between the gut and the brain, known as the gut-brain axis. The interaction of components of this axis, namely, the gut, its microbiota, and gut pathogens tryptophan the kynurenine pathway on tryptophan availability the regulation of kynurenine metabolite concentration and ersity and population of gut microbiota, has been considered.

Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau

Publisher: Elsevier BV

Date: 08-2019

DOI: 10.1016/J.NEUROBIOLAGING.2019.03.015

Abstract: Chronic kynurenine pathway (KP) activation is implicated in Alzheimer's disease (AD) pathophysiology and results in quinolinic acid-induced excitotoxic stimulation of the N-methyl-D-aspartate receptor. However, most studies focus on plasma and it is unclear if peripheral concentrations reflect brain concentrations and how these may correlate to the AD biomarkers amyloid-β, total-tau (t-tau), or phosphorylated-tau (p-tau). We characterized the KP in matched plasma and cerebrospinal fluid (CSF) s les from 20 AD patients and 18 age-matched control subjects. Plasma concentrations of kynurenine (KYN), 3-hydroxykynurenine, anthranilic acid, picolinic acid, and neopterin significantly correlated with their respective CSF levels. In patients with AD, plasma KYN (r = -0.48, p = 0.033) and picolinic acid (r = -0.57, p = 0.009) inversely correlated with CSF p-tau and t-tau, respectively. Furthermore, in AD CSF, increased 3-hydroxykynurenine/KYN ratio correlated with t-tau (r = 0.58, p = 0.009) and p-tau (r = 0.52, p = 0.020). These data support KP involvement in AD pathogenesis and add to the case for the therapeutic modulation of the KP in AD.

The kynurenine pathway in traumatic brain injuries and concussion

Publisher: Frontiers Media SA

Date: 09-06-2023

DOI: 10.3389/FNEUR.2023.1210453

Abstract: Up to 10 million people per annum experience traumatic brain injury (TBI), 80–90% of which are categorized as mild. A hit to the brain can cause TBI, which can lead to secondary brain injuries within minutes to weeks after the initial injury through unknown mechanisms. However, it is assumed that neurochemical changes due to inflammation, excitotoxicity, reactive oxygen species, etc., that are triggered by TBI are associated with the emergence of secondary brain injuries. The kynurenine pathway (KP) is an important pathway that gets significantly overactivated during inflammation. Some KP metabolites such as QUIN have neurotoxic effects suggesting a possible mechanism through which TBI can cause secondary brain injury. That said, this review scrutinizes the potential association between KP and TBI. A more detailed understanding of the changes in KP metabolites during TBI is essential to prevent the onset or at least attenuate the severity of secondary brain injuries. Moreover, this information is crucial for the development of biomarker/s to probe the severity of TBI and predict the risk of secondary brain injuries. Overall, this review tries to fill the knowledge gap about the role of the KP in TBI and highlights the areas that need to be studied.

Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation

Publisher: Elsevier BV

Date: 05-2015

DOI: 10.1016/J.EJMECH.2015.03.003

Abstract: LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 μM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show anti-neuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1β stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.

Novel dual‐action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine‐specific histone demethylase 1A inhibitor

Publisher: Wiley

Date: 03-02-2019

DOI: 10.1111/JNC.14655

Development of a translational inflammation panel for the quantification of cerebrospinal fluid Pterin, Tryptophan-Kynurenine and Nitric oxide pathway metabolites

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.EBIOM.2022.103917

Alteration in gene pair correlations in tryptophan metabolism as a hallmark in cancer diagnosis

Publisher: SAGE Publications

Date: 2020

DOI: 10.1177/1178646920977013

Abstract: Tryptophan metabolism plays essential roles in both immunomodulation and cancer development. Indoleamine 2,3-dioxygenase, a rate-limiting enzyme in the metabolic pathway, is overexpressed in different types of cancer. To get a better understanding of the involvement of tryptophan metabolism in cancer development, we evaluated the expression and pairwise correlation of 62 genes in the metabolic pathway across 12 types of cancer. Only gene AOX1, encoding aldehyde oxidase 1, was ubiquitously downregulated, Furthermore, we observed that the 62 genes were widely and strongly correlated in normal controls, however, the gene pair correlations were significantly lost in tumor patients for all 12 types of cancer. This implicated that gene pair correlation coefficients of the tryptophan metabolic pathway could be applied as a prognostic and/or diagnostic biomarker for cancer.

Neurodegeneration and ageing in the HAART era

Publisher: Springer Science and Business Media LLC

Date: 06-12-2009

DOI: 10.1007/S11481-008-9143-1

Abstract: Cognitive impairment and neurodegeneration still occur despite highly active antiretroviral therapy (HAART). While there are many potential reasons for this, there is increasing evidence that such impairment occurs in the absence of a clear cause. Furthermore, there are data that some neurodegenerative diseases, especially Alzheimer's or an Alzheimer-like illness, are becoming more common in the context of HAART-treated human immunodeficiency virus (HIV) disease. This review will critically examine the evidence underpinning these observations. Potential mechanisms will be discussed with particular emphasis on the effect of ageing and how it overlaps with the effects of HIV disease itself thereby leading to neurodegeneration. The nature of this overlap will then be explored for its potential role in the facilitated expression and development of neurodegenerative diseases. Lastly, there will be a brief discussion of interventions to minimize such neurodegeneration including optimization of HAART for brain entry.

Microglia, macrophages, perivascular macrophages, and pericytes: A review of function and identification

Publisher: Oxford University Press (OUP)

Date: 11-11-2004

DOI: 10.1189/JLB.0303114

Abstract: The phenotypic differentiation of systemic macrophages that have infiltrated the central nervous system, pericytes, perivascular macrophages, and the “real” resident microglial cells is a major immunocytochemical and immunohistochemical concern for all users of cultures of brain cells and brain sections. It is not only important in assessing the purity of cell cultures it is also of fundamental importance in the assessment of the pathogenetic significance of perivascular inflammatory phenomena within the brain. The lack of a single membranous and/or biochemical marker allowing conclusive identification of these cells is still a major problem in neurobiology. This review briefly discusses the functions of these cells and catalogs a large number of membranous and biochemical markers, which can assist in the identification of these cells.

Cardiac ryanodine receptor activation by high Ca2+ store load is reversed in a reducing cytoplasmic redox environment

Publisher: The Company of Biologists

Date: 2014

DOI: 10.1242/JCS.156760

Abstract: We report the impact of redox potential on isolated cardiac ryanodine receptor (RyR2) channel activity and its response to physiological changes in luminal [Ca2+]. Basal leak from the sarcoplasmic reticulum (SR) is required for normal Ca2+ handling, but excess diastolic Ca2+ leak attributed to oxidative stress is thought to lower RyR2 threshold for spontaneous SR Ca2+ release to induce arrhythmia in pathological situations. Therefore we examined RyR2 response to luminal [Ca2+] under reducing or oxidising cytoplasmic redox conditions. Unexpectedly as luminal [Ca2+] increased from 0.1–1.5 mM RyR2 activity declined when pretreated with cytoplasmic 1 mM DTT, or GSH∶GSSG buffered to a “healthy” reduced cytoplasmic redox potential (−220 mV). Conversely, with 20 µM cytoplasmic 4,4′-DTDP, or redox buffered to an oxidising −180 mV, RyR2 activity increased with increasing luminal [Ca2+]. The luminal redox potential was constant at −180 mV in each case. These responses to luminal Ca2+ were maintained with 2 mM Na2ATP or 5 mM MgATP (1 mM free Mg2+). Overall the results suggest that the redox potential in the RyR2 junctional microdomain is normally more oxidised than the bulk cytoplasm.

Neuroprotective effects of naturally occurring polyphenols on quinolinic acid-induced excitotoxicity in human neurons

Publisher: Wiley

Date: 2010

DOI: 10.1111/J.1742-4658.2009.07487.X

Abstract: Quinolinic acid (QUIN) excitotoxicity is mediated by elevated intracellular Ca(2+) levels, and nitric oxide-mediated oxidative stress, resulting in DNA damage, poly(ADP-ribose) polymerase (PARP) activation, NAD(+) depletion and cell death. We evaluated the effect of a series of polyphenolic compounds [i.e. epigallocatechin gallate (EPCG), catechin hydrate, curcumin, apigenin, naringenin and gallotannin] with antioxidant properties on QUIN-induced excitotoxicity on primary cultures of human neurons. We showed that the polyphenols, EPCG, catechin hydrate and curcumin can attenuate QUIN-induced excitotoxicity to a greater extent than apigenin, naringenin and gallotannin. Both EPCG and curcumin were able to attenuate QUIN-induced Ca(2+) influx and neuronal nitric oxide synthase (nNOS) activity to a greater extent compared with apigenin, naringenin and gallotannin. Although Ca(2+) influx was not attenuated by catechin hydrate, nNOS activity was reduced, probably through direct inhibition of the enzyme. All polyphenols reduced the oxidative effects of increased nitric oxide production, thereby reducing the formation of 3-nitrotyrosine and poly (ADP-ribose) polymerase activity and, hence, preventing NAD(+) depletion and cell death. In addition to the well-known antioxidant properties of these natural phytochemicals, the inhibitory effect of some of these compounds on specific excitotoxic processes, such as Ca(2+) influx, provides additional evidence for the beneficial health effects of polyphenols in excitable tissue, particularly within the central nervous system.

Corrigendum to “PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer”

Publisher: Hindawi Limited

Date: 09-12-2019

DOI: 10.1155/2019/3401505

Inflammation and kynurenine pathway dysregulation in post-partum women with severe and suicidal depression

Publisher: Elsevier BV

Date: 2020

DOI: 10.1016/J.BBI.2019.10.017

The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC

Publisher: Wiley

Date: 15-06-2023

DOI: 10.1002/ACN3.51825

Abstract: To determine the prevalence and natural history of post‐acute COVID‐19 objective cognitive impairment and function, and their relationship to demographic, clinical factors, post‐acute sequelae of COVID‐19 (PASC), and biomarkers. A total of 128 post‐acute COVID‐19 patients (age = 46 ± 15 42% women, acute disease severity: not hospitalized: 38.6% mild: 0–1 symptoms, 52% 2+ symptoms 9.4% hospitalized) completed standard cognition, olfaction, and mental health examinations 2‐, 4‐, and 12‐month post diagnosis. Over the same time frame, WHO‐defined PASC was determined. Blood cytokines, peripheral neurobiomarkers, and kynurenine pathway (KP) metabolites were measured. Objective cognitive function was demographically ractice corrected, and impairment prevalence was determined using the evidence‐based Global Deficit Score method to detect at least mild cognitive impairment (GDS 0.5). Linear mixed effect regression models with time effect (month post diagnosis) evaluated the relationships to cognition. Across the 12‐month study period, mild to moderate cognitive impairment ranged from 16% to 26%, and 46.5% were impaired at least once. Impairment associated with poorer work capacity ( p 0.05), and 2‐month objectively tested anosmia ( p 0.05). PASC with ( p = 0.01) and without disability ( p 0.03) associated with acute COVID‐19 severity. KP measures showed prolonged activation (2 to 8 months) ( p 0.0001) linked to IFN‐beta in those with PASC. Of the blood analytes, only the KP metabolites (elevated quinolinic acid, 3‐hydroxyanthranilic acid, kynurenine, the kynurenine/tryptophan ratio) associated ( p 0.001) with poorer cognitive performance and greater likelihood of impairment. PASC, independent of disability associated with abnormal kynurenine/tryptophan ( p 0.03). The kynurenine pathway relates to post‐acute COVID‐19 objective cognitive impairment and PASC, thereby enabling biomarker and therapeutic possibilities.

Editorial: Glial cells: Managers of neuro-immunity

Publisher: Frontiers Media SA

Date: 23-03-2016

DOI: 10.3389/FNCEL.2016.00060

Perinatal exposure to the cyanotoxin β-N-méthylamino-L-alanine (BMAA) results in long-lasting behavioral changes in offspring

Publisher: Springer Science and Business Media LLC

Date: 06-09-2018

DOI: 10.1007/S12640-017-9802-1

Abstract: We recently demonstrated that perinatal exposure to the glutamate-related herbicide, glufosinate ammonium, has deleterious effects on neural stem cell (NSC) homeostasis within the sub-ventricular zone (SVZ), probably leading to ASD-like symptoms in offspring later in life. In the present study, we aimed to investigate whether perinatal exposure to another glutamate-related toxicant, the cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA), might also trigger neurodevelopmental disturbances. With this aim, female mice were intranasally exposed to low doses of BMAA, 50 mg kg

Effects of Tryptophan Supplementation and Exercise on the Fate of Kynurenine Metabolites in Mice and Humans

Publisher: MDPI AG

Date: 03-08-2021

DOI: 10.3390/METABO11080508

Abstract: The kynurenine pathway of tryptophan (TRP) degradation (KP) generates metabolites with effects on metabolism, immunity, and mental health. Endurance exercise training can change KP metabolites by changing the levels of KP enzymes in skeletal muscle. This leads to a metabolite pattern that favors energy expenditure and an anti-inflammatory immune cell profile and reduces neurotoxic metabolites. Here, we aimed to understand if TRP supplementation in untrained vs. trained subjects affects KP metabolite levels and biological effects. Our data show that chronic TRP supplementation in mice increases all KP metabolites in circulation, and that exercise reduces the neurotoxic branch of the pathway. However, in addition to increasing wheel running, we did not observe other effects of TRP supplementation on training adaptations, energy metabolism or behavior in mice. A similar increase in KP metabolites was seen in trained vs. untrained human volunteers that took a TRP drink while performing a bout of aerobic exercise. With this acute TRP administration, TRP and KYN were higher in the trained vs. the untrained group. Considering the many biological effects of the KP, which can lead to beneficial or deleterious effects to health, our data encourage future studies of the crosstalk between TRP supplementation and physical exercise.

Accumulation of an Endogenous Tryptophan-Derived Metabolite in Colorectal and Breast Cancers

Publisher: Public Library of Science (PLoS)

Date: 16-04-2015

DOI: 10.1371/JOURNAL.PONE.0122046

Human regulatory macrophages are potent in suppression of the xenoimmune response via indoleamine-2,3-dioxygenase-involved mechanism(s)

Publisher: Wiley

Date: 02-08-2017

DOI: 10.1111/XEN.12326

Abstract: For xenotransplantation to truly succeed, we must develop immunomodulatory strategies to suppress the xenoimmune response but by minimizing immunosuppression over the long term. Regulatory macrophages (Mreg) have been shown to suppress polyclonal T-cell proliferation in vitro and prolong allograft survival in vivo. However, the question of whether they are capable of suppressing xenoimmune responses remains unknown. This study assessed the potential of human Mreg to be used as an effective immunomodulatory method in xenotransplantation. CD14+ monocytes selected from human peripheral blood mononuclear cells (PBMC) were cultured with macrophage colony-stimulating factor (M-CSF) for 7 days with IFN-γ added at day 6 for Mreg induction. Mreg phenotyping was performed by flow cytometric analysis, and the in vitro suppressive function was assessed by mixed lymphocyte reaction (MLR) using irradiated pig PBMC as the xenogeneic stimulator cells, human PBMC as responder cells, and autologous Mreg as suppressor cells. To assess mRNA expression of Mreg functional molecules indoleamine-2,3-dioxygenase (IDO), IL-10, inducible nitric oxide synthase (iNOS) and TGF-β were measured by real-time PCR. Supernatants were collected from the MLR cultures for IDO activity assay by high-performance liquid chromatography (HPLC). The effects of the IDO inhibitor 1-D/L-methyl-tryptophan (1-MT), iNOS inhibitor N We demonstrated that induced Mreg with a phenotype of CD14 This study demonstrates that human Mreg are capable of suppressing the xenoimmune response in vitro via IDO-involved mechanism(s), suggesting their potential role as an effective immunomodulatory tool in xenotransplantation.

Neurological infection, kynurenine pathway, and parasitic infection by Neospora caninum

Publisher: Frontiers Media SA

Date: 26-01-2022

DOI: 10.3389/FIMMU.2021.714248

Abstract: Neuroinflammation is one of the most frequently studied topics of neurosciences as it is a common feature in almost all neurological disorders. Although the primary function of neuroinflammation is to protect the nervous system from an insult, the complex and sequential response of activated glial cells can lead to neurological damage. Depending on the type of insults and the time post-insult, the inflammatory response can be neuroprotective, neurotoxic, or, depending on the glial cell types, both. There are multiple pathways activated and many bioactive intermediates are released during neuroinflammation. One of the most common one is the kynurenine pathway, catabolizing tryptophan, which is involved in immune regulation, neuroprotection, and neurotoxicity. Different models have been used to study the kynurenine pathway metabolites to understand their involvements in the development and maintenance of the inflammatory processes triggered by infections. Among them, the parasitic infection Neospora caninum could be used as a relevant model to study the role of the kynurenine pathway in the neuroinflammatory response and the subset of cells involved.

Extracellular vesicles released by glioblastoma cells stimulate normal astrocytes to acquire a tumor-supportive phenotype via p53 and MYC signaling pathways

Publisher: Springer Science and Business Media LLC

Date: 23-10-2019

DOI: 10.1007/S12035-018-1385-1

Effects of stress associated with academic examination on the kynurenine pathway profile in healthy students

Publisher: Public Library of Science (PLoS)

Date: 03-06-2021

DOI: 10.1371/JOURNAL.PONE.0252668

Abstract: The effects of stress on the neuroendocrine, central nervous and immune systems are extremely complex. The kynurenine pathway (KP) of the tryptophan metabolism is recognised as a cross-link between the neuroendocrine- and immune systems. However, the effects of acute stress from everyday life on KP activation have not yet been studied. This study aims to investigate changes in the levels of the KP neuroactive metabolites and cytokines in response to stress triggered by academic examinations. Ninety-two healthy first year medical students benevolently participated in the study. Parameters were measured pre- examination, which is considered to be a high-stress period, and post-examination, as a low-stress period. Stress induced by academic examinations significantly increases the perceived stress scores ( p .001), serum cortisol levels ( p .001) and brain-derived neurotrophic factor (BDNF) levels ( p .01). It decreased IL-10 levels ( p .05) but had no effect on IL-6 and TNF-alpha levels. Only the KP neuroactive metabolite, 3-hydroxykynurenine (3-HK) significantly increased ( p .01) in the post-examination period. In addition, the stress scores positively correlated with the levels of cortisol ( r 2 = 0.297, p .01) at post examination. Acute stress triggered by academic examinations increases cortisol and BDNF production and suppresses the anti-inflammatory cytokine, IL-10, but did not increase significantly the levels of other pro-inflammatory cytokines, tryptophan, kynurenine and downstream KP metabolites. The concomitant increased levels of BDNF under the duress of acute examination stress appear to limit the levels pro-inflammatory markers, which may attenuate the action of cortisol and the neuroinflammatory branch of the KP.

Diet rich in date palm fruits improves memory, learning and reduces beta amyloid in transgenic mouse model of Alzheimer′s disease

Publisher: Elsevier BV

Date: 2015

DOI: 10.4103/0975-9476.159073

Bcl11b: A New Piece to the Complex Puzzle of Amyotrophic Lateral Sclerosis Neuropathogenesis?

Publisher: Springer Science and Business Media LLC

Date: 12-11-2016

DOI: 10.1007/S12640-015-9573-5

Abstract: Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, neurodegenerative disease of the human motor system. The pathogenesis of ALS is a topic of fascinating speculation and experimentation, with theories revolving around intracellular protein inclusions, mitochondrial structural issues, glutamate excitotoxicity and free radical formation. This review explores the rationale for the involvement of a novel protein, B-cell lymphoma/leukaemia 11b (Bcl11b) in ALS. Bcl11b is a multifunctional zinc finger protein transcription factor. It functions as both a transactivator and genetic suppressor, acting both directly, binding to promoter regions, and indirectly, binding to promoter-bound transcription factors. It has essential roles in the differentiation and growth of various cells in the central nervous system, immune system, integumentary system and cardiovascular system, to the extent that Bcl11b knockout mice are incompatible with extra-uterine life. It also has various roles in pathology including the suppression of latent retroviruses, thymic tumourigenesis and neurodegeneration. In particular its functions in neurodevelopment, viral latency and T-cell development suggest potential roles in ALS pathology.

Mechanisms and Effects Posed by Neurotoxic Products of Cyanobacteria/Microbial Eukaryotes/Dinoflagellates in Algae Blooms: a Review

Publisher: Springer Science and Business Media LLC

Date: 23-08-2018

DOI: 10.1007/S12640-017-9780-3

Abstract: Environmental toxins produced by cyanobacteria and dinoflagellates have increasingly become a public health concern due to their ability to damage several tissues in humans. In particular, emerging evidence has called attention to the neurodegenerative effects of the cyanobacterial toxin β-N-methylamino-L-alanine (BMAA). Furthermore, other toxins such as anatoxin, saxitoxin, microcystin, nodularin and ciguatoxin also have a different range of effects on human tissues, including hepatotoxicity, neurotoxicity and gastrointestinal irritation. However, the vast majority of known environmental toxins have not yet been examined in the context of neurodegenerative disease. This review aims to investigate whether neurotoxic mechanisms can be demonstrated in all aforementioned toxins, and whether there exists a link to neurodegeneration. Management of toxin exposure and potential neuroprotective compounds is also discussed. Collectively, all aforementioned microbial toxins are likely to exert some form of neuronal damage, with many of their modes of action consistent with neurodegeneration. This is important in advancing our current understanding of the cytotoxic potential of environmental toxins upon human brain function, particularly in the context of age-related neurodegenerative disease.

3Rs-based optimization of mice behavioral testing: The habituation/dishabituation olfactory test

Publisher: Elsevier BV

Date: 02-2020

DOI: 10.1016/J.JNEUMETH.2019.108550

Abstract: There is clear evidence that most of the paradigms that are used in the field of behavioral neuroscience suffer from a lack of reliability mainly because of oversimplification of both testing procedures and interpretations. In the present study we show how an already existing behavioral test, the olfactory habituation / dishabituation task, can be optimized in such a way that animal number and animal distress could be minimized, number/confidence of behavioral outcomes and number of explored behavioral dimensions could be increased. We used ethologically relevant technical and procedural changes associated with videotracking-based automated quantification of sniffing behavior to validate our new setup. Mainly internal and construct validity were challenged through the implementation of a series of simple experiments. We show that the new version of the test: 1) has very good within and inter laboratory replicability, 2) is sensitive to some environmental / experimental factors while insensitive to others, 3) allows investigating hedonism, both state and trait anxiety, efficacy of anxiolytic molecules, acute stress, mental retardation-related social impairments and learning and memory. 4) We also show that interest for both nonsocial and social odors is stable over time which makes repetitive testing possible. This work paves the way for future studies showing how behavioral tests / procedures may be improved by using ethologically relevant changes, in order to question laboratory animals more adequately. Refining behavioral tests may considerably increase predictivity of preclinical tests and, ultimately, help reinforcing translational research.

Climate change and debilitating symptom complexes attributed to ticks in Australia

Publisher: CABI

Date: 2021

DOI: 10.1079/9781789249637.0056

Abstract: his expert opinion focuses on the impact of global warming and climate change on the spread and distribution of Australian ticks and the prevalence and intensity of associated human diseases.

Quinolinic acid

Publisher: Wiley

Date: 27-03-2012

DOI: 10.1111/J.1742-4658.2012.08493.X

Abstract: This minireview series reviews some of the most recent findings about quinolinic acid's cellular toxicity and its implications in diseases such as HIV associated neurocognitive disorders, depressive disorders and schizophrenia, and finally therapeutic strategies with drugs able to interfere with quinolinic acid production and/or effects.

Alterations in Tryptophan Metabolism Affect Vascular Functions: Connected to Ageing Population Vulnerability to COVID-19 Infection?

Publisher: SAGE Publications

Date: 2022

DOI: 10.1177/11786469221083946

Recent advances in the treatment of amyotrophic lateral sclerosis. Emphasis on kynurenine pathway inhibitors

Publisher: Bentham Science Publishers Ltd.

Date: 03-2009

DOI: 10.2174/187152409787601941

Abstract: Amyotrophic lateral sclerosis (ALS) is an adult onset, progressive and fatal motor neuron degenerative disease [1]. The aetiology of ALS is currently unknown, though strongly suggested to be multifactorial. Recently, the kynurenine pathway (KP) has emerged as a potential contributing factor [2]. The KP is a major route for the metabolism of tryptophan, generating neuroactive intermediates in the process. These catabolites include the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid (QUIN) [3] and the neuroprotective NMDA receptor antagonist, kynurenic acid (KYNA) [4,5]. These catabolites appear to play a key role in the communication between the nervous and immune systems, and also in modulating cell proliferation and tissue function [6]. As the cause of ALS is still unknown, there is presently no efficient treatment for it. Currently, Riluzole is the drug of choice but its effect is relatively modest [7]. Targeting the KP, hence, could offer a new therapeutic option to improve ALS treatment [8]. Several drugs that block the KP are already under investigation by our laboratory and others, some of which are in or about to enter clinical trials for other diseases. For ex le, the KP inhibitors, Teriflunomide (Sanofi-Aventis) and Laquinimod (Teva Neuroscience). Recently, a KP inhibitor has also reached the Japan market as an immunomodulative drug [9]: Tranilast/Rizaben (Angiogen Ltd.) is an anthranilic acid derivative [8]. Finally, the 8-hydroxyquinolinine metal attenuating compounds, Clioquinol and PBT2, interestingly have close structural similarity with KYNA and QUIN. Such drugs would open a new and important therapeutic door for ALS.

Inflammation and Parkinson's Disease

Publisher: Hindawi Limited

Date: 2011

DOI: 10.4061/2011/729054

A bivalent remipede toxin promotes calcium release via ryanodine receptor activation.

Publisher: Springer Science and Business Media LLC

Date: 23-02-2023

DOI: 10.1038/S41467-023-36579-W

Abstract: Multivalent ligands of ion channels have proven to be both very rare and highly valuable in yielding unique insights into channel structure and pharmacology. Here, we describe a bivalent peptide from the venom of Xibalbanus tulumensis , a troglobitic arthropod from the enigmatic class Remipedia, that causes persistent calcium release by activation of ion channels involved in muscle contraction. The high-resolution solution structure of φ-Xibalbin3-Xt3a reveals a tandem repeat arrangement of inhibitor-cysteine knot (ICK) domains previously only found in spider venoms. The in idual repeats of Xt3a share sequence similarity with a family of scorpion toxins that target ryanodine receptors (RyR). Single-channel electrophysiology and quantification of released Ca 2+ stores within skinned muscle fibers confirm Xt3a as a bivalent RyR modulator. Our results reveal convergent evolution of RyR targeting toxins in remipede and scorpion venoms, while the tandem-ICK repeat architecture is an evolutionary innovation that is convergent with toxins from spider venoms.

BMAA and Neurodegenerative Illness

Publisher: Springer Science and Business Media LLC

Date: 24-05-2017

DOI: 10.1007/S12640-017-9753-6

Abstract: The cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) now appears to be a cause of Guamanian amyotrophic lateral sclerosis arkinsonism dementia complex (ALS/PDC). Its production by cyanobacteria throughout the world combined with multiple mechanisms of BMAA neurotoxicity, particularly to vulnerable subpopulations of motor neurons, has significantly increased interest in investigating exposure to this non-protein amino acid as a possible risk factor for other forms of neurodegenerative illness. We here provide a brief overview of BMAA studies and provide an introduction to this collection of scientific manuscripts in this special issue on BMAA.

Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons

Publisher: Springer Science and Business Media LLC

Date: 18-04-2009

DOI: 10.1007/S12640-009-9051-Z

Abstract: There is growing evidence implicating the kynurenine pathway (KP) and particularly one of its metabolites, quinolinic acid (QUIN), as important contributors to neuroinflammation in several brain diseases. While QUIN has been shown to induce neuronal and astrocytic apoptosis, the exact mechanisms leading to cell death remain unclear. To determine the mechanism of QUIN-mediated excitotoxicity in human brain cells, we measured intracellular levels of nicotinamide adenine dinucleotide (NAD(+)) and poly(ADP-ribose) polymerase (PARP) and extracellular lactate dehydrogenase (LDH) activities in primary cultures of human neurons and astrocytes treated with QUIN. We found that QUIN acts as a substrate for NAD(+) synthesis at very low concentrations ( 150 nM) in both the cell types. We have shown that the NMDA ion channel blockers, MK801 and memantine, and the nitric oxide synthase (NOS) inhibitor, L-NAME, significantly attenuate QUIN-mediated PARP activation, NAD(+) depletion, and LDH release in both neurons and astrocytes. An increased mRNA and protein expression of the inducible (iNOS) and neuronal (nNOS) forms of nitric oxide synthase was also observed following exposure of both cell types to QUIN. Taken together these results suggests that QUIN-induced cytotoxic effects on neurons and astrocytes are likely to be mediated by an over activation of an NMDA-like receptor with subsequent induction of NOS and excessive nitric oxide (NO(*))-mediated free radical damage. These results contribute significantly to our understanding of the pathophysiological mechanisms involved in QUIN neuro- and gliotoxicity and are relevant for the development of therapies for neuroinflammatory diseases.

IV Neurotoxicity Society Meeting: Neurochemical Mechanisms of Neurodegenerative Disorders

Publisher: Springer Science and Business Media LLC

Date: 23-06-2010

DOI: 10.1007/S12640-009-9062-9

Autism and Gut–Brain Axis: Role of Probiotics

Publisher: Springer International Publishing

Date: 2020

DOI: 10.1007/978-3-030-30402-7_21

Quinolinic acid selectively induces apoptosis of human astocytes: Potential role in AIDS dementia complex

Publisher: Springer Science and Business Media LLC

Date: 26-07-2005

DOI: 10.1186/1742-2094-2-16

Abstract: There is evidence that the kynurenine pathway (KP) and particularly one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neuroinflammatory diseases, and more particularly AIDS dementia complex (ADC). We hypothesized that QUIN may be involved in astrocyte apoptosis because: 1) apoptotic astrocytes have been observed in the brains of ADC patients, 2) ADC patients have elevated cerebrospinal fluid QUIN concentrations, and 3) QUIN can induce astrocyte death. Primary cultures of human fetal astrocytes were treated with three pathophysiological concentrations of QUIN. Numeration of apoptotic cells was assessed using double immunocytochemistry for expression of active caspase 3 and for nucleus condensation. We found that treatment of human astrocytes with QUIN induced morphological (cell body shrinking) and biochemical changes (nucleus condensation and over-expression of active caspase 3) of apoptosis. After 24 hours of treatment with QUIN 500 nM and 1200 nM respectively 10 and 14% of astrocytes were undergoing apoptosis. This would be expected to lead to a relative lack of trophic support factors with consequent neuronal dysfunction and possibly death. Astroglial apoptosis induced by QUIN provides another potential mechanism for the neurotoxicity of QUIN during ADC.

Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load

Publisher: Springer Science and Business Media LLC

Date: 22-05-2018

DOI: 10.1038/S41598-018-25968-7

Abstract: The kynurenine pathway (KP) is dysregulated in neuroinflammatory diseases including Alzheimer’s disease (AD), however has not been investigated in preclinical AD characterized by high neocortical amyloid-β load (NAL), prior to cognitive impairment. Serum KP metabolites were measured in the cognitively normal KARVIAH cohort. Participants, aged 65–90 y, were categorised into NAL+ (n = 35) and NAL− (n = 65) using a standard uptake value ratio cut-off = 1.35. Employing linear models adjusting for age and APOE ε4, higher kynurenine and anthranilic acid (AA) in NAL+ versus NAL− participants were observed in females (kynurenine, p = 0.004 AA, p = 0.001) but not males (NALxGender, p = 0.001, 0.038, respectively). To evaluate the predictive potential of kynurenine or/and AA for NAL+ in females, logistic regressions with NAL+/− as outcome were carried out. After age and APOE ε4 adjustment, kynurenine and AA were in idually and jointly significant predictors (p = 0.007, 0.005, 0.0004, respectively). Areas under the receiver operating characteristic curves were 0.794 using age and APOE ε4 as predictors, and 0.844, 0.866 and 0.871 when kynurenine, AA and both were added. Findings from the current study exhibit increased KP activation in NAL+ females and highlight the predictive potential of KP metabolites, AA and kynurenine, for NAL+. Additionally, the current study also provides insight into he influence of gender in AD pathogenesis.

Expression of chemokines and their receptors in human and simian astrocytes: Evidence for a central role of TNFα and IFNγ in CXCR4 and CCR5 modulation

Publisher: Wiley

Date: 23-01-2003

DOI: 10.1002/GLIA.10181

Abstract: Chemokines are key mediators of the selective migration of leukocytes that occurs in neurodegenerative diseases and related inflammatory processes. Astrocytes, the most abundant cell type in the CNS, have an active role in brain inflammation. To ascertain the role of astrocytes during neuropathological processes, we have investigated in two models of primary cells (human fetal and simian adult astrocytes) the repertoire of chemokines and their receptors expressed in response to inflammatory stimuli. We demonstrated that, in the absence of any stimulation, human fetal and simian adult astrocytes express mRNA for receptors APJ, BOB/GPR15, Bonzo/CXCR6, CCR2, CCR3, CCR5, CCR8, ChemR23, CXCR3/GPR9, CXCR4, GPR1, and V28/CX3CR1. Moreover, TNFalpha and IL-1beta significantly increase BOB/GPR15, CCR2, and V28/CX3CR1 mRNA levels in both models. Furthermore, TNFalpha and IFNgamma act synergistically to induce expression of the major coreceptors for HIV infection, CXCR4 and CCR5, at both the mRNA and protein levels in human and simian astrocytes, whereas CCR3 expression was not affected by cytokine treatment. Finally, TNFalpha/IFNgamma was the most significant cytokine combination in leading to a pronounced upregulation in a comparable, time-dependent manner of the production of chemokines IP-10/CXCL10, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IL-8/CXCL8. In summary, these data suggest that astrocytes serve as an important source of chemokines under the dependence of a complex cytokine regulation, and TNFalpha and IFNgamma are important modulators of chemokines and chemokine receptor expression in human as well as simian astrocytes. Finally, with the conditions we used, there was no difference between species or age of tissue.

Protein Nutrition in Autism

Publisher: Springer International Publishing

Date: 2020

DOI: 10.1007/978-3-030-30402-7_20

Treating depression with exercise

Publisher: Open Access Text Pvt, Ltd.

Date: 2016

DOI: 10.15761/JSIN.1000147

IFN-β 1b induces kynurenine pathway metabolism in human macrophages: Potential implications for multiple sclerosis treatment

Publisher: Mary Ann Liebert Inc

Date: 12-2001

DOI: 10.1089/107999001317205231

Abstract: Interferon-beta(1b) (IFN-beta(1b)) has limited efficacy in the treatment of relapsing-remitting multiple sclerosis (RRMS). The kynurenine pathway (KP) is chiefly activated by IFN-gamma and IFN-alpha, leading to the production of a variety of neurotoxins. We sought to determine whether IFN-beta(1b) induces the KP in human monocyte-derived macrophages, as one explanation for its limited efficacy. Serial dilutions of IFN-beta(1b) (at concentrations comparable to those found in the sera of IFN-beta(1b)-treated patients) were added to human macrophage cultures. Supernatants were collected at various time points and assayed for the KP end product, quinolinic acid (QUIN). The effect of IFN-beta(1b) on the KP enzymes indoleamine 2,3-dioxygenase (IDO), 3-hydroxyanthranilate dioxygenase (3HAO), and quinolinate phosphoribosyltransferase (QPRTase) mRNA expression was assessed by semiquantitative RT-PCR. IFN-beta(1b) (> or =10 IU/ml) led to increased mRNA expression of both IDO and QUIN production (7901 +/- 715 nM) after 72 h at 50 IU/ml IFN-beta(1b) (p < 0.0001). This study demonstrates that IFN-beta(1b), in pharmacologically relevant concentrations, induces KP metabolism in human macrophages and may be a limiting factor in its efficacy in the treatment of MS. Inhibitors of the KP may be able to augment the efficacy of IFN-beta in MS.

Mechanisms of palmitate-induced cell death in human osteoblasts

Publisher: The Company of Biologists

Date: 06-11-2013

DOI: 10.1242/BIO.20136700

Abstract: Lipotoxicity is an overload of lipids in non-adipose tissues that affects function and induces cell death. Lipotoxicity has been demonstrated in bone cells in vitro using osteoblasts and adipocytes in coculture. In this condition, lipotoxicity was induced by high levels of saturated fatty acids (mostly palmitate) secreted by cultured adipocytes acting in a paracrine manner. In the present study, we aimed to identify the underlying mechanisms of lipotoxicity in human osteoblasts. Palmitate induced autophagy in cultured osteoblasts, which was preceded by the activation of autophagosomes that surround palmitate droplets. Palmitate also induced apoptosis though the activation of the Fas/Jun kinase (JNK) apoptotic pathway. In addition, osteoblasts could be protected from lipotoxicity by inhibiting autophagy with the phosphoinositide kinase inhibitor 3-methyladenine or by inhibiting apoptosis with the JNK inhibitor SP600125. In summary, we have identified two major molecular mechanisms of lipotoxicity in osteoblasts and in doing so we have identified a new potential therapeutic approach to prevent osteoblast dysfunction and death, which are common features of age-related bone loss and osteoporosis.

Alpha-synuclein transmission and mitochondrial toxicity in primary human foetal enteric neurons in vitro

Publisher: Springer Science and Business Media LLC

Date: 12-09-2014

DOI: 10.1007/S12640-013-9420-5

Abstract: Parkinson's disease (PD) is a multicentred neurodegenerative disorder characterised by the accumulation and aggregation of alpha-synuclein (α-syn) in several parts of the central nervous system. However, it is well established that PD can generate symptoms of constipation and other gastrointestinal problems and α-syn containing lesions have been identified in intestinal nerve cells. In this study, we show that α-syn can be taken up and accumulate in primary human foetal enteric neurons from the gastrointestinal tract and can be transferred between foetal enteric neurons. Impaired proteosomal/lysosomal degradation can promote the uptake and accumulation of α-syn in enteric neurons. Enteric neurons exposed to α-syn can also lead to impaired mitochondrial complex I activity, reduced mitochondrial function, and NAD(+) depletion culminating in cell death via energy restriction. These findings demonstrate neuron-to-neuron transmission of α-syn in enteric neurons, providing renewed evidence for Braak's hypothesis and the aetiology of PD.

Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis

Publisher: Oxford University Press (OUP)

Date: 13-07-2015

DOI: 10.1093/HMG/DDX268

Serotonin decreases HIV-1 replication in primary cultures of human macrophages through 5-HT 1A receptors

Publisher: Wiley

Date: 05-2008

DOI: 10.1038/BJP.2008.80

Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons

Publisher: Wiley

Date: 06-07-2005

DOI: 10.1002/GLIA.20090

Abstract: There is good evidence that the kynurenine pathway (KP) and one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neurological diseases. While QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the capacity of astrocytes and neurons to produce QUIN is controversial. Using interferon gamma (IFN-gamma)-stimulated primary cultures of human mixed brain cells, we assayed expression of the KP regulatory enzyme indoleamine 2,3-dioxygenase (IDO) and QUIN production by immunocytochemistry. Using IFN-gamma-stimulated purified cultures of neurons, astrocytes, microglia and macrophages, we studied IDO expression by RT-PCR and production of QUIN using mass spectrometry. We found that astrocytes, neurons, and microglia expressed IDO but only microglia were able to produce detectable amounts of QUIN. However, astrocytes and neurons had the ability to catabolize QUIN. This study also provides the first evidence of IDO expression and lack of production of QUIN in culture of primary human neurons.

1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis

Publisher: Elsevier BV

Date: 10-2021

DOI: 10.1016/J.EJPHAR.2021.174309

Abstract: Kynurenine Pathway (KP) is the dominant metabolic route of tryptophan which is catalyzed by indoleamine-2,3-dioxygenase (IDO). This pathway is upregulated in liver disease where the level of KP metabolites correlates with the severity of disease. Cirrhosis is associated with cardiac dysfunction, which manifests itself during severe physiological challenges such as liver transplantation. Cardiac dysfunction in cirrhosis is linked to systemic inflammation and impaired cardiac beta-adrenergic signaling pathways. The KP pathway is involved in modulation of cardiac signaling and is upregulated by systemic inflammation. Therefore, this study aimed to evaluate the effect of IDO inhibition on development of cardiac dysfunction in an experimental model of cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). Experimental groups were given either 1-methyl tryptophan (1-MT, 1, 3, 9 mg/kg), or saline. 28 days after BDL, cardiac chronotropic response to epinephrine was assessed ex vivo. HPLC was employed to measure hepatic and cardiac levels of tryptophan, kynurenine and kynurenic acid. Cirrhosis in rats was associated with impaired cardiac chronotropic responsiveness to adrenergic stimulation. 1-MT dose-dependently improved cirrhosis-induced chronotropic dysfunction as well as elevated serum levels of CRP and IL-6 in BDL rats. Hepatic and cardiac kynurenine/tryptophan ratio were elevated in cirrhotic rats and were reduced following 1-MT administration. Chronic administration of 1-MT could also reduce hepatic inflammation, fibrosis and ductular proliferation. 1-MT attenuates cardiac dysfunction in rats with biliary cirrhosis. This protective effect is not limited to the cardiac function as liver histopathologic changes were also improved following chronic 1-MT administration.

The crossroads of neuroinflammation in infectious diseases: Endothelial cells and astrocytes

Publisher: Elsevier BV

Date: 08-2012

DOI: 10.1016/J.PT.2012.05.008

Abstract: Homeostasis implies constant operational defence mechanisms, against both external and internal threats. Infectious agents are prominent among such threats. During infection, the host elicits the release of a vast array of molecules and numerous cell-cell interactions are triggered. These pleiomorphic mediators and cellular effects are of prime importance in the defence of the host, both in the systemic circulation and at sites of tissue injury, for ex le, the blood-brain barrier (BBB). Here, we focus on the interactions between the endothelium, astrocytes, and the molecules they release. Our review addresses these interactions during infectious neurological diseases of various origins, especially cerebral malaria (CM). Two novel elements of the interplay between endothelium and astrocytes, microparticles and the kynurenine pathway, will also be discussed.

Long-term (15 mo) dietary supplementation with pomegranates from Oman attenuates cognitive and behavioral deficits in a transgenic mice model of Alzheimer's disease

Publisher: Elsevier BV

Date: 2015

DOI: 10.1016/J.NUT.2014.06.004

Abstract: Transgenic (Tg) mice, which possess an amyloid precursor protein (APP) gene mutation, develop extracellular amyloid β (Aβ) deposition in the brain, and severe memory and behavioral deficits with age. These mice serve as an important animal model for testing the efficacy of novel drug candidates for the treatment and management of symptoms of Alzheimer's disease (AD). Several reports have suggested that oxidative stress is the underlying cause of Aβ neurotoxicity in AD. Pomegranates contain very high levels of antioxidants and several medicinal properties that may be useful for improving quality of life in in iduals with AD. The aim of this study was to investigate the effect of dietary supplementation of Omani pomegranate extract on memory, anxiety, and learning skills in an AD mouse model possessing the double Swedish APP mutation (APPsw/Tg2576). The experimental groups of APP-Tg mice from the age of 4 mo were fed a custom mixed diet (pellets) containing 4% pomegranate. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4 to 5 mo and 18 to 19 mo using the Morris water maze test, rotarod performance test, elevated plus-maze test, and open field test. APPsw/Tg2576 mice that were fed a standard chow diet without pomegranates showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability, and motor coordination compared with the wild-type mice on the same diet, at the age of 18 to 19 mo. In contrast, APPsw/Tg2576 mice that were fed a diet containing 4% pomegranates showed significant improvements in memory, learning, locomotor function, as well as reduction in anxiety, compared with APPsw/Tg2576 mice fed the standard chow diet. Our results suggest that dietary supplementation with pomegranates may slow the progression of cognitive and behavioral impairments in AD.

Editorial: Multiple Implications of the Kynurenine Pathway in Inflammatory Diseases: Diagnostic and Therapeutic Applications

Publisher: Frontiers Media SA

Date: 11-02-2022

DOI: 10.3389/FIMMU.2022.860867

Characterization of the phenotypic and lymphokine profile associated with strong CD8+ anti-HIV-1 suppressor activity (CASA)

Publisher: Oxford University Press (OUP)

Date: 2002

DOI: 10.1046/J.1365-2249.2002.01744.X

Abstract: A panel of 22 CD8+ T cell lines, with a broad range of CD8+ anti-HIV-1 suppressor activity (CASA) were generated from a single patient with HIV-1 infection. CD8+ T cell lines with either strong or weak CASA were examined and compared for cell surface and intracellular markers, constitutive chemokine and lymphokine mRNA levels and inducible lymphokine expression. Strong CASA significantly correlated with CD8+ T cell lines that highly coexpressed the molecule CD28+ (r = 0·52, P = 0·01) and Ki67+ (r = 0·88, P = 0·02), with strong CASA CD8+ T cell lines demonstrating significantly higher (P & 0·05) expression of CD8+CD28+ and CD8+Ki67+ compared to those with weak activity. No such correlations or findings were observed for the markers CD38, HLA-DR, CD57 or perforin. The Th1 cytokines were expressed at greater levels than the Th2 cytokines, with strong CASA significantly associated with an increased inducible level of IL-2 production (P = 0·05). Constitutive RANTES, IP-10 and I-309 mRNA expression were significantly (P & 0·05) elevated in CD8+ T cell lines exhibiting strong CASA compared to those with weak CASA. There was no significant difference in the mRNA expression of the lymphokines IL-2, 4, 5, 8, 9, 10, 14, 15, or chemokines MIP-1α, MIP-1β, MCP-1, and Ltn. Strong CASA was therefore associated with rapidly replicating CD8+ T cells of the phenotype CD8+CD28+Ki67+ that expressed greater levels of IL-2 and the ligands RANTES and I-309.

Involvement of Kynurenine Pathway in Hepatocellular Carcinoma

Publisher: MDPI AG

Date: 15-10-2021

DOI: 10.3390/CANCERS13205180

Abstract: As the second and third leading cancer-related death in men and the world, respectively, primary liver cancer remains a major concern to human health. Despite advances in diagnostic technology, patients with primary liver cancer are often diagnosed at an advanced stage. Treatment options for patients with advanced hepatocarcinoma (HCC) are limited to systemic treatment with multikinase inhibitors and immunotherapy. Furthermore, the 5-year survival rate for these late-stage HCC patients is approximately 12% worldwide. There is an unmet need to identify novel treatment options and/or sensitive blood-based biomarker(s) to detect this cancer at an early stage. Given that the liver harbours the largest proportion of immune cells in the human body, understanding the tumour–immune microenvironment has gained increasing attention as a potential target to treat cancer. The kynurenine pathway (KP) has been proposed to be one of the key mechanisms used by the tumour cells to escape immune surveillance for proliferation and metastasis. In an inflammatory environment such as cancer, the KP is elevated, suppressing local immune cell populations and enhancing tumour growth. In this review, we collectively describe the roles of the KP in cancer and provide information on the latest research into the KP in primary liver cancer.

Erratum to: Neuroprotective Effect of Natural Products Against Alzheimer’s Disease

Publisher: Springer Science and Business Media LLC

Date: 31-08-2012

DOI: 10.1007/S11064-012-0865-3

John Curtin School Of Medical Research

Location: Australia

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Victor Chang Cardiac Research Institute

Location: Australia

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Macquarie University

Location: Australia

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Universite De Bourgogne UFR De Pharmacie

Location: France

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Discovery Projects - Grant ID: DP160105005

Start Date: 03-2016

End Date: 12-2020

Amount: $653,300.00

Funder: Australian Research Council

ARC Future Fellowships - Grant ID: FT120100397

Start Date: 11-2012

End Date: 11-2016

Amount: $818,856.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE160100204

Start Date: 2016

End Date: 12-2016

Amount: $550,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100075

Start Date: 2017

End Date: 12-2017

Amount: $315,000.00

Funder: Australian Research Council

Industrial Transformation Training Centres - Grant ID: IC210100040

Start Date: 02-2022

End Date: 02-2027

Amount: $4,997,903.00

Funder: Australian Research Council