ORCID Profile
0000-0001-6359-3382
Current Organisation
Curtin University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.PHRS.2019.01.009
Abstract: Type-2 diabetes (T2D) increases the risk of dementia by ˜5-fold, however the mechanisms by which T2D increases dementia risk remain unclear. Evidence suggests that the heightened inflammation and oxidative stress in T2D may lead to disruption of the blood-brain barrier (BBB), which precedes premature cognitive decline. Studies show that vascular-targeted anti-inflammatory treatments protect the BBB by attenuating neuroinflammation, and in some studies attenuate cognitive decline. Yet, this potential pathway is understudied in T2D-associated cognitive impairment. In recent years, therapeutic potential of cannabinoids has gained much interest. The two major cannabinoids, cannabidiol and tetrahydrocannabinol, exert anti-inflammatory and vascular protective effects, however few studies report their potential for reversing BBB dysfunction, particularly in T2D. Therefore, in this review, we summarize the current findings on the role of BBB dysfunction in T2D-associated dementia and consider the potential therapeutic use of cannabinoids as a protectant of cerebrovascular BBB protection.
Publisher: American Chemical Society (ACS)
Date: 17-07-2017
DOI: 10.1021/ACS.MOLPHARMACEUT.7B00220
Abstract: In previous studies, we developed a new technique (ionic gelation vibrational jet flow IGVJF) in order to encapsulate pancreatic β-cells, for insulin in vivo delivery, and diabetes treatment. The fabricated microcapsules showed good morphology but limited cell functions. Thus, this study aimed to optimize the IGVJF technique, by utilizing integrated electrode tension, coupled with high internal vibration, jet-flow polymer stream rate, ionic bath-gelation concentrations, and gelation time stay. The study also utilized double inner/outer nozzle segmented-ingredient flow of microencapsulating dispersion, in order to form β-cell microcapsules. Furthermore, a microcapsule-stabilizing bile acid was added, and microcapsule's stability and cell functions measured. Buchi-based built-in system utilizing IGVJF technology was screened to produce best microcapsule-containing β-cells with or without a stabilizing-enhancing bile acid. Formed microcapsules were examined, for physical characteristics, and encapsulated cells were examined for survival, insulin release, and inflammatory profiles. Optimized microencapsulating parameters, using IGJVF, were: 1000 V voltage, 2500 Hz frequency, 1 mL/min flow rate, 3% w/v ionic-bath gelation concentration, and 20 min gelation time. Microcapsules showed good morphology and stability, and the encapsulated cells showed good survival, and insulin secretion, which was optimized by the bile acid. Deployed IGVJF-based microencapsulating parameters utilizing stability-enhancing bile acid produced best microcapsules with best pancreatic β-cells functions and survival rate, which, suggests potential application in cell transplantation.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2014
Publisher: Elsevier BV
Date: 06-2007
Publisher: Informa UK Limited
Date: 12-11-2018
DOI: 10.1080/21691401.2018.1511572
Abstract: The ratio of secondary to primary bile acids changes during Type 1 Diabetes (T1D) development and these effects might be ameliorated by using cholesterol lowering drugs or hydrophilic bile acids. Probucol is a cholesterol-lowering drug, while ursodeoxycholic acid is a hydrophilic bile acid. This study investigated whether nanoencapsulated probucol with ursodeoxycholic acid altered bile acid ratios and the development of diabetes. Balb/c mice were ided into three groups and gavaged daily with either free probucol, nanoencapsulated probucol or nanoencapsulated probucol with ursodeoxycholic acid for seven days. Alloxan was injected and once T1D was confirmed the mice continued to receive daily gavages until euthanasia. Blood, tissues, faeces and urine were collected for analysis of insulin and bile acids. Nanoencapsulated probucol-ursodeoxycholic acid resulted in significant levels of insulin in the blood, lower levels of secondary bile acids in liver and lower levels of primary bile acids in brain, while ratio of secondary to primary bile acids remains similar among all groups, except in the faeces. Findings suggests that nanoencapsulated probucol-ursodeoxycholic acid may exert a protective effect on pancreatic β-cells and reserve systemic insulin load via modulation of bile acid concentrations in the liver and brain.
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.ATHEROSCLEROSISSUP.2010.04.002
Abstract: Amyloid-β (Aβ) is secreted as an apolipoprotein of nascent triglyceride-rich lipoproteins (TRL) derived from both liver and intestine, but is better recognized as the principal protein component of senile plaque in subjects with Alzheimer's disease. Recent studies suggest that exaggerated exposure to plasma Aβ can compromise cerebrovascular integrity, resulting thereafter in blood to brain delivery of plasma proteins including TRL-Aβ. Parenchymal deposits of Aβ show significant immunoreactivity to apolipoprotein B (apo B), consistent with the notion of lipoprotein-Aβ entrapment. In wild type mice chronically fed physiologically relevant diets, saturated fats (SFA) enhance chylomicron-Aβ concomitant with disturbances in blood-brain barrier integrity. Similarly, dietary cholesterol promotes cerebrovascular extravasation of apo B lipoprotein-Aβ. In this study, we investigated the effects of atorvastatin, pravastatin and probucol on dietary-fat induced disturbances in BBB function. Atorvastatin, a lipid soluble HMG-CoA reductase inhibitor prevented SFA induced parenchymal extravasation of apo B-Aβ at 28 days when incorporated into the diet at 20 mg/kg. In contrast, pravastatin a water soluble agent had no effect on BBB integrity at an equivalent dose. In cholesterol supplemented mice, probucol maintained BBB function and extravasation of apo B-Aβ was not evident. The findings suggest that some lipid-modulating agents may be effective in ameliorating the negative effects of saturated fats and cholesterol on cerebrovascular integrity.
Publisher: Wiley
Date: 2004
Abstract: The multistage induction theory is generally regarded as the mechanism of carcinogenesis. In order to prevent the initiation stage of carcinogenesis, it is meaningful to discover the functional components of edible plants. The objective of this research was to test the antimutagenicity of the functional components of several typical traditional herbs used in Japan. The traditional herbs, gennoshoko (Geranium nepalense var. thunbergii), yomogi (Artemisia vulgaris var. indica), senburi (Swertia japonica), iwa‐tobacco (Conandron ramondioides), sarunokoshikake (Elfvingia applanata), kanzo (Glycyeehiza uralensis Fisch) and matatabi (Actinidia polygama) were examined by Ames mutagenesis assay test with Salmonella typhimurium TA98 and TA100 against mutagens, Trp‐P‐1, Trp‐P‐2 and B(a)P. The water‐soluble components or volatile oil of the herbs were extracted in boiling water. The extracts of gennoshoko showed strong antimutagenicity against B(a)P with S. typhimurium TA98 and TA100, as well as Trp‐P‐1 and Trp‐P‐2 with S. typhimurium TA98. Yomogi, senburi and iwa‐tobacco were also proved to have good antimutagenicity against Trp‐P‐1 and Trp‐P‐2 with S. typhimurium TA98, but weaker antimutagenicity against B(a)P. Other herbs did not show any obvious antimutagenicity against these mutagens. In addition, the volatile oil of yomogi also had remarkable antimutagenic effect against the mutagens we used with S. typhimurium TA98.
Publisher: Frontiers Media SA
Date: 29-05-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-11-2021
Publisher: Cambridge University Press (CUP)
Date: 28-10-2009
DOI: 10.1017/S0007114509992194
Abstract: Some dietary fats are a risk factor for Alzheimer's disease (AD) but the mechanisms for this association are presently unknown. In the present study we showed in wild-type mice that chronic ingestion of SFA results in blood–brain barrier (BBB) dysfunction and significant delivery into the brain of plasma proteins, including apo B lipoproteins that are endogenously enriched in amyloid-β (Aβ). Conversely, the plasma concentration of S100B was used as a marker of brain-to-blood leakage and was found to be increased two-fold because of SFA feeding. Consistent with a deterioration in BBB integrity in SFA-fed mice was a diminished cerebrovascular expression of occludin, an endothelial tight junction protein. In contrast to SFA-fed mice, chronic ingestion of MUFA or PUFA had no detrimental effect on BBB integrity. Utilising highly sensitive three-dimensional immunomicroscopy, we also showed that the cerebral distribution and co-localisation of Aβ with apo B lipoproteins in SFA-fed mice are similar to those found in amyloid precursor protein resenilin-1 (APP/PS1) amyloid transgenic mice, an established murine model of AD. Moreover, there was a strong positive association of plasma-derived apo B lipoproteins with cerebral Aβ deposits. Collectively, the findings of the present study provide a plausible explanation of how dietary fats may influence AD risk. Ingestion of SFA could enhance peripheral delivery to the brain of circulating lipoprotein–Aβ and exacerbate the amyloidogenic cascade.
Publisher: Frontiers Media SA
Date: 03-05-2021
Abstract: Energy drinks containing significant quantities of caffeine and sugar are increasingly consumed, particularly by adolescents and young adults. Chronic ingestion of energy drinks may potentially regulate vascular risk factors. This study investigated the effects of chronic ingestion of energy drinks on blood-brain barrier (BBB) integrity and neuroinflammation. Male C57BL/6J mice were maintained on water (control), Mother TM (ED), sugar-free Mother TM (sfED), or Coca Cola TM soft drink (SD) for 13 weeks. The BBB integrity and neuroinflammation were analyzed with semi-quantitative immunofluorescent microscopy. Blood pressure, plasma inflammatory cytokine levels and blood glucose were also considered. Following 13 weeks of intervention, mice treated with ED, sfED, and SD showed significant disruption of BBB. However, marked neuroinflammation was observed only in sfED group mice. The consumption of ED and sfED significantly altered the blood pressure and plasma concentrations of inflammatory cytokines, TNF-a, IL-4, IL-6, and IL-10, and both increased plasma glucose. Correlation analyses showed significant associations between BBB dysfunction and hypotension, hyperglycaemia and cytokine dyshomeostasis. The intake of energy drink, particularly the sugar free formulation, may compromise the integrity of BBB and induce neuroinflammation via hypotension, hyperglycaemia and inflammatory pathways.
Publisher: Cold Spring Harbor Laboratory
Date: 21-11-2021
DOI: 10.1101/2021.11.20.21266372
Abstract: Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid-beta (Aβ) in the peripheral circulation is causally related to the development of Alzheimer’s disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aβ compromises the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aβ moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aβ secretion, concomitant with maintaining blood-brain-barrier function and suppressing neurovascular inflammation. Probucol has also been shown to protect cognitive function in dietary-induced amyloidogenic mice. This protocol details the Probucol in Alzheimer’s Study (PIA-study), a double-blind, randomised, placebo-controlled drug intervention trial investigating if Probucol attenuates cognitive decline in patients with mild-to-moderate AD. The primary objective of the 104-week study is to assess whether Probucol supports cognitive function and delays brain atrophy in AD patients. A secondary objective is to determine whether Probucol treatment will reduce cerebral amyloid burden. The study is a phase II single-site, randomised, placebo-controlled, double-blind clinical trial assessing the efficacy of Probucol in AD. A total of 300 participants with mild-to-moderate AD will be recruited and randomised 1:1 (active: placebo). Cognitive function, regional volumetric changes in brain and cerebral amyloid load will be evaluated via the cognitive subscale test, AD assessment scales (ADAS-Cog), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, respectively, after a 104-week intervention. The study has been approved by the Bellberry Limited Human Research Ethics Committee (Approval number: HREC2019-11-1063 Version 4, 6 th October 2021). The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events. This trial has been registered with the Australian New Zealand Clinical Trial Registry (ACTRN12621000726853). This is the first-in-human (FIH) randomised double-blind placebo-controlled study to assess the efficacy of Probucol in delaying cognitive decline in in iduals with mild cognitive impairment (MCI) and mild-to-moderate dementia due to Alzheimer’s disease (AD). The 24-month intervention study will be the first to investigate whether treatment with Probucol will stabilise structural/functional changes in brain and if cerebral amyloid load will decrease in in iduals with AD, following treatment with Probucol. Probucol is clinically used to treat cardiovascular disease with well-characterised efficacy and safety profiles, thus reducing risk of the study, and if applicable, accelerate clinical translation of the study findings.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2020
Publisher: MDPI AG
Date: 18-08-2020
DOI: 10.3390/NU12082487
Abstract: Studies suggest that migraine pain has a vascular component. The prevailing dogma is that peripheral vasoconstriction activates baroreceptors in central, large arteries. Dilatation of central vessels stimulates nociceptors and induces cortical spreading depression. Studies investigating nitric oxide (NO) donors support the indicated hypothesis that pain is lified when acutely administered. In this review, we provide an alternate hypothesis which, if substantiated, may provide therapeutic opportunities for attenuating migraine frequency and severity. We suggest that in migraines, heightened sympathetic tone results in progressive central microvascular constriction. Suboptimal parenchymal blood flow, we suggest, activates nociceptors and triggers headache pain onset. Administration of NO donors could paradoxically promote constriction of the microvasculature as a consequence of larger upstream central artery vasodilatation. Inhibitors of NO production are reported to alleviate migraine pain. We describe how constriction of larger upstream arteries, induced by NO synthesis inhibitors, may result in a compensatory dilatory response of the microvasculature. The restoration of central capillary blood flow may be the primary mechanism for pain relief. Attenuating the propensity for central capillary constriction and promoting a more dilatory phenotype may reduce frequency and severity of migraines. Here, we propose consideration of two dietary nutraceuticals for reducing migraine risk: L-arginine and aged garlic extracts.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 23-12-2012
Abstract: Dysfunction of the blood-brain barrier (BBB) is an early pathological feature of vascular dementia and Alzheimer's disease (AD) and is triggered by inflammatory stimuli. Probucol is a lipid-lowering agent with potent anti-oxidant properties once commonly used for the treatment of cardiovascular disease. Probucol therapy was found to stabilize cognitive symptoms in elderly AD patients, whereas in amyloid transgenic mice probucol was shown to attenuate amyloidosis. However, the mechanisms underlying the effects of probucol have note been determined. In the present study we investigated whether probucol can prevent BBB disturbances induced by chronic ingestion of proinflammatory diets enriched with either 20% (w/w) saturated fats (SFA) or 1% (w/w) cholesterol. Mice were fed the diets for 12 weeks before they were killed and BBB integrity was measured. Mice maintained on either the SFA- or cholesterol-supplemented diets were found to have a 30- and sevenfold greater likelihood of BBB dysfunction, respectively, as determined by the parenchymal extravasation of plasma-derived immunoglobulins and endogenous lipoprotein enrichment with β-amyloid. In contrast, mice fed the SFA- or cholesterol-enriched diets that also contained 1% (w/w) probucol showed no evidence of BBB disturbance. The parenchymal expression of glial fibrillary acidic protein, a marker of cerebrovascular inflammation, was significantly greater in mice fed the SFA-enriched diet. Plasma lipid, β-amyloid and apolipoprotein B levels were not increased by feeding of the SFA- or cholesterol-enriched diets. However, mice fed the SFA- or cholesterol-enriched diets did exhibit increased plasma non-esterified fatty acid levels that were not reduced by probucol. The data suggest that probucol prevents disturbances of BBB induced by chronic ingestion of diets enriched in SFA or cholesterol by suppressing inflammatory pathways rather than by modulating plasma lipid homeostasis.
Publisher: Japanese Society of Nutrition and Food Science
Date: 2005
DOI: 10.4327/JSNFS.58.185
Publisher: Oxford University Press (OUP)
Date: 05-03-2015
DOI: 10.1093/NTR/NTV044
Abstract: Emerging evidence suggests that integrity of blood-brain barrier (BBB) is pivotal to pathology and pathogenesis of vascular-based neurodegenerative disorders. We have recently reported BBB protective effects of nutraceutical agents with anti-inflammatory properties in an established dietary-induced BBB dysfunction model. Studies also reported that nicotine exhibits anti-oxidative/-inflammatory effects and improve cognitive impairment in Alzheimer's disease. However there has been no studies reporting the effect of nicotine on high-fat-induced BBB dysfunction. In the present study, we investigated the effect of nicotine on BBB integrity and neuro-inflammation in an established mouse model of BBB disruption induced by a diet enriched in saturated fatty acids (SFA). Wild-type C57BL/6J mice were fed chow enriched in SFA (23% w/w) with/without nicotine for 10 weeks. Compared to mice maintained on SFA-free and low-fat (LF) chow (4% w/w), capillary permeability indicated by the parenchymal extravasation of plasma derived IgG, was significantly greater in the SFA treatment group. Nicotine provided concomitantly with the SFA diet significantly attenuated IgG extravasation, however it remained significantly greater than LF-controls. Markers of neurovascular inflammation glial fibrillary acidic protein, cyclooxygenase-2, and glucose regulated protein 78 remained exaggerated in SFA+nicotine treated mice compared to LF-controls. Nicotine did however modestly, but not significantly, improve plasma total anti-oxidative status in SFA fed mice. Nicotine moderately attenuated BBB disruption induced by chronic ingestion of high-SFA diet, but had no significant effect on neuroinflammation per se.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2016
DOI: 10.1038/NUTD.2016.19
Abstract: Coffee consumption has been reported to reduce the risk of type 2 diabetes in experimental and epidemiological studies. This anti-diabetic effect of coffee may be attributed to its high content in polyphenols especially caffeic acid and chlorogenic acid. However, the association between plasma coffee polyphenols and diabetic risks has never been investigated in the literature. In this study, fasting plasma s les were collected from 57 generally healthy females aged 38–73 (mean 52, s.d. 8) years recruited in Himeji, Japan. The concentrations of plasma coffee polyphenols were determined by liquid chromatography coupled with mass tandem spectrometer. Diabetes biomarkers in the plasma/serum s les were analysed by a commercial diagnostic laboratory. Statistical associations were assessed using Spearman’s correlation coefficients. The results showed that plasma chlorogenic acid exhibited negative associations with fasting blood glucose, glycated hemoglobin and C-reactive protein, whereas plasma total coffee polyphenol and plasma caffeic acid were weakly associated with these biomarkers. Our preliminary data support previous findings that coffee polyphenols have anti-diabetic effects but further replications with large s les of both genders are recommended.
Publisher: Elsevier BV
Date: 11-2018
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000356967
Abstract: Background: Albumin serves a range of physiological functions that are vital to overall brain and cognitive health. Indeed, associations between cognitive performance and albumin have been demonstrated in in iduals with chronic liver or kidney disease and in patients with a high urinary excretion of albumin. However, an association of plasma albumin with cognitive performance has not been reported in otherwise healthy participants with clinically acceptable plasma albumin concentrations. Method: This study utilized a wide-ranging neuropsychological test battery to investigate the relationship between cognitive performance and plasma albumin homeostasis in 222 healthy participants (143 females) between the ages of 43 and 84 years (mean 65 years). Results: Albumin both with and without the covariates of age, sex and acute-phase proteins was positively associated with enhanced performance on a range of neuropsychological domains including perceptual speed, Stroop and verbal ability. Albumin manifested generally positive but less robust associations with secondary and primary memory. Conclusion: The results indicate that there is a positive association between albumin and cognitive performance in physiologically healthy participants free of chronic renal or liver disease.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.NUTRES.2015.11.010
Abstract: This study investigated green tea catechins in plasma and urine and chronic disease biomarkers. We hypothesized that plasma and urinary concentration of green tea catechins are associated with cardiovascular disease and diabetes biomarkers. First void urine and fasting plasma s les were collected from 57 generally healthy females aged 38 to 73 years (mean, 52 ± 8 years) recruited in Himeji, Japan. The concentrations of plasma and urinary green tea catechins were determined by liquid chromatography coupled with mass tandem spectrometer. Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, glucose, insulin, glycated hemoglobin, and C-reactive protein in plasma/serum s les were analyzed by a commercial diagnostic laboratory. Statistical associations were assessed using Spearman correlation coefficients. The results showed weak associations between plasma total catechin and triglyceride (r = -0.30) and LDL cholesterol (r = -0.28), whereas plasma (-)-epigallocatechin-3-gallate, (-)-epigallocatechin, (-)-epicatechin-3-gallate, and (-)-epicatechin exhibited weak to moderate associations with triglyceride or LDL cholesterol, but little associations with HDL cholesterol, body fat, and body mass index were evident. Urinary total catechin was weakly associated with triglyceride (r = -0.19) and LDL cholesterol (r = -0.15), whereas urinary (-)-epigallocatechin-3-gallate (r = -0.33), (-)-epigallocatechin (r = -0.23), and (-)-epicatechin-3-gallate (r = -0.33) had weak to moderate correlations with triglyceride and similarly with body fat and body mass index. Both plasma (r = -0.24) and urinary (r = -0.24) total catechin, as well as in idual catechins, were weakly associated with glycated hemoglobin. Plasma total and in idual catechins were weakly to moderately associated with C-reactive protein, but not the case for urinary catechins. In conclusion, we found weak to moderate associations between plasma and urinary green tea catechin concentrations and plasma biomarkers of cardiovascular disease and diabetes.
Publisher: Bentham Science Publishers Ltd.
Date: 07-2021
DOI: 10.2174/1570159X19666210101130258
Abstract: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, no gold-standard treatments exist to alleviate the core socio-behavioural impairments of ASD. Meanwhile, the prosocial empathogen/entactogen 3,4- methylene-dioxy-meth hetamine (MDMA) is known to enhance sociability and empathy in both humans and animal models of psychological disorders. We review the evidence obtained from behavioural tests across the current literature, showing how MDMA can induce prosocial effects in animals and humans, where controlled experiments were able to be performed. Six electronic databases were consulted. The search strategy was tailored to each database. Only Englishlanguage papers were reviewed. Behaviours not screened in this review may have affected the core ASD behaviours studied. Molecular analogues of MDMA have not been investigated. We find that the social impairments may potentially be alleviated by postnatal administration of MDMA producing prosocial behaviours in mostly the animal model. MDMA and/or MDMA-like molecules appear to be an effective pharmacological treatment for the social impairments of autism, at least in animal models. Notably, clinical trials based on MDMA use are now in progress. Nevertheless, larger and more extended clinical studies are warranted to prove the assumption that MDMA and MDMA-like molecules have a role in the management of the social impairments of autism.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2009
Abstract: Amyloid-β is recognized as the major constituent of senile plaque found in subjects with Alzheimer's disease. However, there is increasing evidence that in a physiological context amyloid-β may serve as regulating apolipoprotein, primarily of the triglyceride enriched lipoproteins. To consider this hypothesis further, this study utilized an in vivo immunological approach to explore in lipogenic tissue whether amyloid-β colocalizes with nascent triglyceride-rich lipoproteins. In murine absorptive epithelial cells of the small intestine, amyloid-β had remarkable colocalization with chylomicrons (Manders overlap coefficient = 0.73 ± 0.03 (SEM)), the latter identified as immunoreactive apolipoprotein B. A diet enriched in saturated fats doubled the abundance of both amyloid-β and apo B and increased the overlap coefficient of the two proteins (0.87 ± 0.02). However, there was no evidence that abundance of the two proteins was interdependent within the enterocytes (Pearson's Coefficient 0.02 ± 0.03), or in plasma (Pearson's Coefficient 0.01). The findings of this study are consistent with the possibility that amyloid-β is secreted by enterocytes as an apolipoprotein component of chylomicrons. However, secretion of amyloid-β appears to be independent of chylomicron biogenesis.
Publisher: Frontiers Media SA
Date: 23-07-2019
Publisher: Springer Science and Business Media LLC
Date: 03-10-2018
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2AN01271E
Abstract: Ex vivo FTIR imaging reveals lipid distributions (red) alongside other spectroscopic markers in brain tissue, which can be used to provide greater biochemical insight when combined with in vivo MRI data sets collected from the same brain.
Publisher: BMJ
Date: 02-2022
DOI: 10.1136/BMJOPEN-2021-058826
Abstract: Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid beta (Aβ) in the peripheral circulation is causally related to the development of Alzheimer’s disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aβ compromise the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aβ moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aβ secretion, concomitant with maintaining blood–brain-barrier function, suppressing neurovascular inflammation and supporting cognitive function. This protocol details the probucol in Alzheimer’s study, a drug intervention trial investigating if probucol has potential to attenuate cognitive decline, delay brain atrophy and reduce cerebral amyloid burden in patients with mild-to-moderate AD. The study is a phase II, randomised, placebo-controlled, double-blind single-site clinical trial held in Perth, Australia. The target s le is 314 participants with mild-to-moderate AD. Participants will be recruited and randomised (1:1) to a 104-week intervention consisting of placebo induction for 2 weeks followed by 102 weeks of probucol (Lorelco) or placebo. The primary outcome is changed in cognitive performance determined via the Alzheimer’s Disease Assessment Scales-Cognitive Subscale test between baseline and 104 weeks. Secondary outcomes measures will be the change in brain structure and function, cerebral amyloid load, quality of life, and the safety and tolerability of Lorelco, after a 104week intervention. The study has been approved by the Bellberry Limited Human Research Ethics Committee (approval number: HREC2019-11-1063 Version 4, 6 October 2021). Informed consent will be obtained from participants prior to any study procedures being performed. The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events. Australian New Zealand Clinical Trials Registry (ACTRN12621000726853).
Publisher: Springer Science and Business Media LLC
Date: 26-02-2008
DOI: 10.1007/S00418-008-0404-0
Abstract: Double immunolabelling is a useful technique to determine cellular colocalization of proteins, but is prone to false-positive staining because of cross-reactivity between antibodies. In this study, we established a simple and quick method to demonstrate the immunofluorescent double labelling with two rabbit-derived polyclonal antibodies. The principle used was to establish a dilution of primary antibody for the first protein of interest, which would only be detectable following biotin-avidin lification. Thereafter, the second protein of interest was assessed via standard secondary antibody detection, ensuring no cross-reactivity with the first protein antibody-antigen complex. We successfully demonstrated the three-dimensional colocalization of enterocytic apolipoprotein B, an equivocal marker of intestinal lipoproteins with Golgi apparatus. Colocalization of apo B and Golgi apparatus (75.2 +/- 8.5%) is consistent with the purported mode of secretion of these macromolecules.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.PLIPRES.2009.10.004
Abstract: An emerging body of evidence is consistent with the hypothesis that dietary fats influence Alzheimer's disease (AD) risk, but less clear is the mechanisms by which this occurs. Alzheimer's is an inflammatory disorder, many consider in response to fibrillar formation and extracellular deposition of amyloid-beta (Abeta). Alternatively, amyloidosis could notionally be a secondary phenomenon to inflammation, because some studies suggest that cerebrovascular disturbances precede amyloid plaque formation. Hence, dietary fats may influence AD risk by either modulating Abeta metabolism, or via Abeta independent pathways. This review explores these two possibilities taking into consideration (i) the substantial affinity of Abeta for lipids and its ordinary metabolism as an apolipoprotein (ii) evidence that Abeta has potent vasoactive properties and (iii) studies which show that dietary fats modulate Abeta biogenesis and secretion. We discuss accumulating evidence that dietary fats significantly influence cerebrovascular integrity and as a consequence altered Abeta kinetics across the blood-brain barrier (BBB). Specifically, chronic ingestion of saturated fats or cholesterol appears to results in BBB dysfunction and exaggerated delivery from blood-to-brain of peripheral Abeta associated with lipoproteins of intestinal and hepatic origin. Interestingly, the pattern of saturated fat/cholesterol induced cerebrovascular disturbances in otherwise normal wild-type animal strains is analogous to established models of AD genetically modified to overproduce Abeta, consistent with a causal association. Saturated fats and cholesterol may exacerbate Abeta induced cerebrovascular disturbances by enhancing exposure of vessels of circulating Abeta. However, presently there is no evidence to support this contention. Rather, SFA and cholesterol appear to more broadly compromise BBB integrity with the consequence of plasma protein leakage into brain, including lipoprotein associated Abeta. The latter findings are consistent with the concept that AD is a dietary-fat induced phenotype of vascular dementia, reflecting the extraordinary entrapment of peripherally derived lipoproteins endogenously enriched in Abeta. Rather than being the initiating trigger for inflammation in AD, accumulation of extracellular lipoprotein-Abeta may be a secondary lifier of dietary induced inflammation, or possibly, simply be consequential. Clearly, delineating the mechanisms by which dietary fats increase AD risk may be informative in developing new strategies for prevention and treatment of AD.
Publisher: Informa UK Limited
Date: 22-09-2021
Publisher: Springer Science and Business Media LLC
Date: 19-02-2009
DOI: 10.1007/S00418-009-0567-3
Abstract: Parenchymal accumulation of amyloid-beta (A beta) is a hallmark pathological feature of Alzheimer's disease. An emerging hypothesis is that blood-to-brain delivery of A beta may increase with compromised blood-brain barrier integrity. In plasma, substantial A beta is associated with triglyceride-rich lipoproteins (TRLs) secreted by the liver and intestine. Utilizing apolipoprotein B as an exclusive marker of hepatic and intestinal TRLs, here we show utilizing an highly sensitive 3-dimensional immuno-microscopy imaging technique, that in APP/PS1 amyloid transgenic mice, concomitant with substantially increased plasma A beta, there is a significant colocalization of apolipoprotein B with cerebral amyloid plaque. The findings are consistent with the possibility that circulating lipoprotein-A beta contributes to cerebral amyloidosis.
Publisher: Frontiers Media SA
Date: 22-01-2020
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S12944-019-1162-9
Abstract: Consumption of a Western-styled diet enriched in saturated fatty acids (SFA) relative to polyunsaturated fatty acids is positively associated with risk for Alzheimer’s disease. Whilst potential causal mechanism are unclear, there is increasing evidence that chronic ingestion of SFA enriched diets promote increase the plasma levels of lipoprotein-associated amyloid-β (Aβ). However, the effects of dietary mono- and poly-unsaturated fats (MUFA/PUFA) on nascent lipoprotein Aβ abundance have not been previously reported. Wild-type C57BL/6 J mice were maintained on low-fat control chow (LF) or diets enriched in either SFA, MUFA, or PUFA for 9 months. Enterocytic abundance of Aβ was determined with quantitative immunofluorescent microscopy and plasma Aβ was measured by ELISA. The chronic ingestion of SFA-enriched diet increased the enterocytic abundance and plasma concentration of Aβ compared to LF control mice. The mice maintained on MUFA or PUFA diet showed comparable enterocytic and plasma Aβ levels to the LF control mice. The data indicates that a diet enriched in SFA significantly increases the enterocytic Aβ production and secretion into the circulation, whilst MUFA and PUFA enriched diet do not exert such effects.
Publisher: Future Science Ltd
Date: 09-2019
Abstract: Aim: Common features in insulin-resistance diabetes include inflammation and liver damage due to bile acid accumulation. Results & methodology: This study aimed to test in vivo pharmacological effects of combining two drugs, ursodeoxycholic acid that has bile acid regulatory effects, and probucol (PB) that has potent anti-oxidative stress effects, using a new poly(meth)acrylate nano-targeting formulation on prediabetic mice. Mice were made diabetic and were fed daily with either PB, nanoencapsulated PB or nanoencapsulated PB-ursodeoxycholic acid before blood, tissues, urine and feces were collected for inflammation and bile acid measurements. The nanoencapsulated PB-ursodeoxycholic acid formulation increased plasma IL-10, and increased the concentration of primary bile acids in the liver and heart. Conclusion: Results suggest potential applications in regulating IL-10 in insulin-resistance prediabetes.
Publisher: American Chemical Society (ACS)
Date: 14-06-2018
DOI: 10.1021/ACSCHEMNEURO.8B00193
Abstract: Western society is facing a health epidemic due to the increasing incidence of dementia in aging populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Aging is the greatest risk factor for memory loss that occurs during the natural aging process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Greater understanding of the biochemical pathways that drive a healthy aging brain toward dementia (pathological aging or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein overexpression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural aging process. A promising animal model reported to model mechanisms of accelerated natural aging and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain aging. A limitation to traditional methods of biochemical characterization is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or microspatial resolution. Therefore, in this investigation, we report the first multimodal biospectroscopic characterization of the SAMP8 model, and have identified important biochemical and elemental alterations, and colocalizations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of Zn deficiency within specific subregions of the hippoc al CA3 sector, which colocalize with decreased lipid unsaturation. Our findings also revealed colocalization of decreased lipid unsaturation and increased lactate in the corpus callosum white matter, adjacent to the hippoc us. Such findings may have important implication for future research aimed at elucidating specific biochemical pathways for therapeutic intervention.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.NEULET.2011.02.001
Abstract: Alzheimer's disease (AD) is characterized by cerebral proteinaceous deposits comprised of amyloid beta (Aβ). Evidence suggests that enhanced blood-to-brain delivery of Aβ occurs when plasma concentration is increased, exacerbating amyloidosis. In blood, significant Aβ is associated with apolipoprotein (apo) B lipoproteins. In this study, immunofluorescent microscopy was utilised to explore if there is an association between apo B lipoproteins and proteoglycan expression within Aβ-rich plaques in transgenic-amyloid mice. Focal accumulation of apo B was found with Aβ-plaque in APP/PS1 mice. There was enrichment in the proteoglycans, agrin, perlecan, biglycan and decorin within the core of dense Aβ-plaque. Perlecan, biglycan and decorin were positively associated with apo B lipoprotein abundance within amyloid plaque consistent with a cause-for-retention effect. These findings show that proteoglycans are an integral component of Aβ deposits in APP/PS1 mice. This study suggests that some proteoglycans contribute to Aβ retention, whilst other proteoglycans have different functions in the aetiology of AD.
Publisher: MDPI AG
Date: 06-04-2021
DOI: 10.3390/NU13041202
Abstract: Energy drinks containing significant quantities of caffeine, taurine and sugar are increasingly consumed, particularly by adolescents and young adults. The putative effects of chronic ingestion of either standard energy drink, MotherTM (ED), or its sugar-free formulation (sfED) on metabolic syndrome were determined in wild-type C57BL/6J mice, in comparison to a soft drink, Coca-Cola (SD), a Western-styled diet enriched in saturated fatty acids (SFA), and a combination of SFA + ED. Following 13 weeks of intervention, mice treated with ED were hyperglycaemic and hypertriglyceridaemic, indicating higher triglyceride glucose index, which was similar to the mice maintained on SD. Surprisingly, the mice maintained on sfED also showed signs of insulin resistance with hyperglycaemia, hypertriglyceridaemia, and greater triglyceride glucose index, comparable to the ED group mice. In addition, the ED mice had greater adiposity primarily due to the increase in white adipose tissue, although the body weight was comparable to the control mice receiving only water. The mice maintained on SFA diet exhibited significantly greater weight gain, body fat, cholesterol and insulin, whilst blood glucose and triglyceride concentrations remained comparable to the control mice. Collectively, these data suggest that the consumption of both standard and sugar-free forms of energy drinks induces metabolic syndrome, particularly insulin resistance.
Publisher: Pharmaceutical Society of Japan
Date: 06-2021
Publisher: Informa UK Limited
Date: 18-12-2016
DOI: 10.3109/10408363.2015.1115820
Abstract: An increasing body of evidence suggests that cerebrovascular dysfunction and microvessel disease precede the evolution of hallmark pathological features that characterise Alzheimer's disease (AD), consistent with a causal association for onset or progression. Recent studies, principally in genetically unmanipulated animal models, suggest that chronic ingestion of diets enriched in saturated fats and cholesterol may compromise blood-brain barrier (BBB) integrity resulting in inappropriate blood-to-brain extravasation of plasma proteins, including lipid macromolecules that may be enriched in amyloid-β (Aβ). Brain parenchymal retention of blood proteins and lipoprotein bound Aβ is associated with heightened neurovascular inflammation, altered redox homeostasis and nitric oxide (NO) metabolism. Therefore, it is a reasonable proposition that lipid-lowering agents may positively modulate BBB integrity and by extension attenuate risk or progression of AD. In addition to their robust lipid lowering properties, reported beneficial effects of lipid-lowering agents were attributed to their pleiotropic properties via modulation of inflammation, oxidative stress, NO and Aβ metabolism. The review is a contemporary consideration of a complex body of literature intended to synthesise focussed consideration of mechanisms central to regulation of BBB function and integrity. Emphasis is given to dietary fat driven significant epidemiological evidence consistent with heightened risk amongst populations consuming greater amounts of saturated fats and cholesterol. In addition, potential neurovascular benefits associated with the use of hypolipidemic statins, probucol and fenofibrate are also presented in the context of lipid-lowering and pleiotropic properties.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Frontiers Media SA
Date: 16-04-2021
DOI: 10.3389/FNINS.2021.617221
Abstract: An increase in blood brain barrier permeability commonly precedes neuro-inflammation and cognitive impairment in models of dementia. Common methods to estimate capillary permeability have potential confounders, or require laborious and subjective semi-manual analysis. Here we used snap frozen mouse and rat brain sections that were double-immunofluorescent labeled for immunoglobulin G (IgG plasma protein) and laminin-α4 (capillary basement membrane). A Machine Learning Image Analysis program (Zeiss ZEN Intellisis) was trained to recognize and segment laminin-α4 to equivocally identify blood vessels in large sets of images. An IgG subclass based on a threshold intensity was segmented and quantitated only in extravascular regions. The residual parenchymal IgG fluorescence is indicative of blood-to-brain extravasation of IgG and was accurately quantitated. Automated machine-learning and threshold based segmentation of only parenchymal IgG extravasation accentuates otherwise indistinct capillary permeability, particularly frequent in minor BBB leakage. Comparison with Existing Methods: Large datasets can be processed and analyzed quickly and robustly to provide an overview of vascular permeability throughout the brain. All human bias or ambiguity involved in classifying and measuring leakage is removed. Here we describe a fast and precise method of visualizing and quantitating BBB permeability in mouse and rat brain tissue, while avoiding the confounding influence of unphysiological conditions such as perfusion and eliminating any human related bias from analysis.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2021
DOI: 10.1038/S41598-021-88854-9
Abstract: Repeated sub-concussive impact (e.g . soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippoc al formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippoc us and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.
Publisher: Elsevier BV
Date: 06-2010
Publisher: Elsevier BV
Date: 09-2008
DOI: 10.1016/J.ATHEROSCLEROSISSUP.2008.05.010
Abstract: Alzheimer's disease is characterized by inflammatory proteinaceous deposits comprised principally of the protein amyloid-beta (Abeta). Presently, the origins of cerebral amyloid deposits are controversial, though pivotal for the prevention of Alzheimer's disease. Recent evidence suggests that in blood, Abeta may serve as a regulating apoprotein of the triglyceride-rich-lipoproteins and we have found that the synthesis of Abeta in enterocytes and thereafter secretion as part of the chylomicron cascade is regulated by dietary fats. It is our contention that chronically elevated plasma levels of Abeta in response to diets rich in saturated fats may lead to disturbances within the cerebrovasculature and exaggerated blood-to-brain delivery of circulating Abeta, thereby exacerbating amyloidosis. Consistent with this hypothesis we show that enterocytic Abeta is increased concomitant with apolipoprotein B48. Furthermore, cerebral extravasation of immunoglobulin G, a surrogate marker of plasma proteins is observed in a murine model of Alzheimer's disease maintained on a saturated-fat diet and there is diminished expression of occludin within the cerebrovasculature, an endothelial tight junction protein.
Publisher: American Chemical Society (ACS)
Date: 04-03-2005
DOI: 10.1021/JF048309F
Abstract: Epidemiological studies suggest that the consumption of red wine lowers the risk of cardiovascular disease. Although the cardioprotective effect of red wine has been attributed to its polyphenolic content, presently, very little is known about the mechanisms by which these compounds benefit the cardiovascular system. Therefore, the aim of this study was to elucidate whether red wine polyphenolics attenuate the synthesis and secretion of proatherogenic chylomicrons from intestinal cells. Apolipoprotein B48 levels (marker of intestinal chylomicrons), quantitated by western blotting, were significantly reduced by 30% in cultured CaCo-2 cells and medium when cells were incubated with either dealcoholized red wine, alcoholized red wine, or atorvastatin compared with controls. Intracellular cholesterol availability was also attenuated in cells incubated with dealcoholized red wine (72.5%), alcoholized red wine (81.5%), and atorvastatin (83.5%) compared to control cells. Collectively, this study suggests that red wine polyphenolics downregulate the production of atherogenic chylomicrons from intestinal cells, which may explain the reduced CVD mortality rates following its consumption.
Publisher: Elsevier BV
Date: 06-2010
Publisher: MDPI AG
Date: 26-11-2021
DOI: 10.3390/NU13124266
Abstract: Brown adipose tissue (BAT) activation is associated with increased energy expenditure by inducing non-shivering thermogenesis. The ingestion of a milk fat globule membrane (MFGM) supplement and a high calorie diet are reported gateways into BAT activation. However, little is known about the effect of the MFGM and high calorie diets on BAT volume. To gain insight into this, mice were maintained on a high-fat (HF) or low-fat (LF) diet in conjunction with either full-cream (FC) or skim bovine dairy milk (BDM). After being maintained on their respective diets for 13 weeks, their body composition, including BAT volume, was measured using X-ray microtomography. A high calorie diet resulted in an increase in the BAT volume and mice consuming an HF diet in conjunction with FC BDM had a significantly greater BAT volume than all the other groups. Conversely, mice consuming an HF diet in addition to skim milk had a lower BAT volume compared to the HF control. The data presented suggest that the consumption of a high calorie diet in conjunction with FC BDM increases the BAT volume in wild-type mice. This study may provide valuable insight into future studies investigating BAT volume and BAT activity in relation to environmental factors, including diet.
Publisher: Frontiers Media SA
Date: 12-2017
Publisher: Informa UK Limited
Date: 09-05-2018
DOI: 10.1080/10837450.2017.1321664
Abstract: Ideal cell-containing microcapsules should be capable of maintaining cell viability and exhibit significant structural stability to support cellular functionality. To date, such microcapsules remain unavailable thus, this study used our well-established microencapsulating methods to examine a total of 32 different microencapsulating formulations and correlate polymers' molecular weights (M MIN6 mouse-cloned pancreatic β-cells were microencapsulated using control (n = 16 without UDCA) and test (n = 16 with UDCA) different polymers. Confocal microscopic imaging, cell viability, and microcapsules' stability were assessed. Best cell viability (>50%) was obtained at average M UDCA addition improved microenvironmental conditions within the microcapsules but this effect was largely dependent on the polymer systems used.
Publisher: MDPI AG
Date: 20-12-2016
DOI: 10.3390/NU8120828
Publisher: Public Library of Science (PLoS)
Date: 13-04-2015
Publisher: Springer Science and Business Media LLC
Date: 09-2021
DOI: 10.1007/S11095-021-03100-1
Abstract: The evidence shows that in iduals with type-1 diabetes mellitus (T1DM) are at greater risk of accelerated cognitive impairment and dementia. Although, to date the mechanisms are largely unknown. An emerging body of literature indicates that dysfunction of cerebral neurovascular network and plasma dyshomeostasis of soluble amyloid-β in association with impaired lipid metabolism are central to the onset and progression of cognitive deficits and dementia. However, the latter has not been extensively considered in T1DM. Therefore, in this review, we summarised the literature concerning altered lipid metabolism and cerebrovascular function in T1DM as an implication for potential pathways leading to cognitive decline and dementia.
Publisher: Wiley
Date: 20-07-2016
DOI: 10.1111/JMI.12446
Abstract: Semiquantitative immunofluorescence microscopy has become a key methodology in biomedical research. Typical statistical workflows are considered in the context of avoiding pseudo-replication and marginalising experimental error. However, immunofluorescence microscopy naturally generates hierarchically structured data that can be leveraged to improve statistical power and enrich biological interpretation. Herein, we describe a robust distribution fitting procedure and compare several statistical tests, outlining their potential advantages/disadvantages in the context of biological interpretation. Further, we describe tractable procedures for power analysis that incorporates the underlying distribution, s le size and number of images captured per s le. The procedures outlined have significant potential for increasing understanding of biological processes and decreasing both ethical and financial burden through experimental optimization.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2008
Abstract: Amyloid-β (Aβ), a key protein found in amyloid plaques of subjects with Alzheimer's disease is expressed in the absorptive epithelial cells of the small intestine. Ingestion of saturated fat significantly enhances enterocytic Aβ abundance whereas fasting abolishes expression. Apolipoprotein (apo) E has been shown to directly modulate Aβ biogenesis in liver and neuronal cells but it's effect in enterocytes is not known. In addition, apo E modulates villi length, which may indirectly modulate Aβ as a consequence of differences in lipid absorption. This study compared Aβ abundance and villi length in wild-type (WT) and apo E knockout (KO) mice maintained on either a low-fat or high-fat diet. Wild-type C57BL/6J and apo E KO mice were randomised for six-months to a diet containing either 4% (w/w) unsaturated fats, or chow comprising 16% saturated fats and 1% cholesterol. Quantitative immunohistochemistry was used to assess Aβ abundance in small intestinal enterocytes. Apo E KO mice given the low-fat diet had similar enterocytic Aβ abundance compared to WT controls. The saturated fat diet substantially increased enterocytic Aβ in WT and in apo E KO mice, however the effect was greater in the latter. Villi height was significantly greater in apo E KO mice than for WT controls when given the low-fat diet. However, WT mice had comparable villi length to apo E KO when fed the saturated fat and cholesterol enriched diet. There was no effect of the high-fat diet on villi length in apo E KO mice. The findings of this study are consistent with the notion that lipid substrate availability modulates enterocytic Aβ. Apo E may influence enterocytic lipid availability by modulating absorptive capacity.
Publisher: Cold Spring Harbor Laboratory
Date: 08-11-2021
DOI: 10.1101/2021.11.07.467371
Abstract: Brown adipose tissue (BAT) activation is associated with increased energy expenditure by inducing non-shivering thermogenesis. Ingestion of a milk fat globule membrane (MFGM) supplement and a high calorie diet are reported gateways into BAT activation. However, little is known about the effect of MFGM and high calorie diets on BAT volume. To gain insight into this, mice were maintained on a high fat (HF) or low-fat (LF) diet in conjunction with either full-cream (FC) or skim bovine dairy milk (BDM). After being maintained on their respective diets for 13 weeks, body composition, including BAT volume, was measured using X-ray microtomography. A high calorie diet resulted in an increase in BAT volume and mice consuming a HF diet in conjunction with FC BDM had significantly greater BAT volume than all other groups. Conversely, mice consuming a HF diet in addition to skim milk had lower BAT volume compared to the HF control. The data presented suggests that consumption of a high calorie diet in conjunction with FC BDM increases BAT volume in wild-type mice. This study may provide valuable insight into future studies investigating BAT volume and BAT activity in relation to environmental factors including diet.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0JA00323A
Abstract: Transition metal ions (Fe, Mn, Cu, Zn) are essential for healthy brain function, but common s le preparations, such as sucrose cryo-protection alter their distribution, which can confound studies of brain disease.
Publisher: Elsevier BV
Date: 09-2008
Publisher: Informa UK Limited
Date: 04-08-2018
DOI: 10.1080/21691401.2017.1362416
Abstract: Current trials for β-cell transplantation have been hindered by poor cell viability and function post-transplantation. Recently, electric charges of the microencapsulating formulation carrying β-cells have shown significant effects on cell survival and function. Thus, this study aimed at investigating the effects of electric charge, of novel colloidal formulation containing β-cells, on cell viability, biological activity and insulin release. A new formulation, containing high ratios of poly-L-ornithine, suspending electrical-stimulation hydrogel and polystyrene sulphone (1:1:0.1 ratio), was used to form microcapsules utilizing 800 V and 2000 Hz encapsulating conditions. The bile acid, ursodeoxycholic acid, was added into the microcapsules to measure its effects on electric charges. The electric charge of the microencapsulating formulation was enhanced by bile acid addition, and resulted in better cell viability and function. Ursodeoxycholic acid microencapsulated with poly-L-ornithine, suspending electrical-stimulation hydrogel and polystyrene sulphone at 1:1:0.1 ratio, using 800 V and 2000 Hz microencapsulating conditions, produced enhanced electrokinetic parameters of microcapsules with optimized cell functions. This suggests that electric charge of formulations containing pancreatic β-cell may have significant effects on cell mass and functions, post-transplantation.
Publisher: Public Library of Science (PLoS)
Date: 12-2016
Publisher: Public Library of Science (PLoS)
Date: 14-09-2021
DOI: 10.1371/JOURNAL.PBIO.3001358
Abstract: Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippoc al-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.
Publisher: Frontiers Media SA
Date: 24-07-2017
Publisher: Informa UK Limited
Date: 11-09-2019
Publisher: Walter de Gruyter GmbH
Date: 2005
Abstract: Studies in healthy humans have shown that consumption of conjugated linoleic acid (CLA) significantly reduced very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) blood concentrations. We propose that decreased concentrations are due to the inhibition of VLDL production and secretion [measured by apolipoprotein B100 (apoB100)] from the liver. To investigate the effects of a mixture of CLA isomers on VLDL metabolism, HepG2 liver cells were incubated for 24h with 50μmol/L of the different fatty acids. Effects of CLA were compared to a saturated fatty acid (palmitic acid), an n-6 fatty acid (linoleic acid) and no treatment (control). HepG2-cell apoB100 levels were measured using Western blotting. ApoB100 secretion was significantly decreased in cells treated with CLA (44%, p .005) compared to control cells and those enriched with palmitic acid. Treatment of cells with CLA also decreased intracellular cholesterol levels. Collectively, these results demonstrate that CLA reduces apoB100 production and secretion compared to saturated and polyunsaturated fatty acids, possibly by limiting the availability of free cholesterol (required for apoB100 production). A reduction in apoB100 production in the body would decrease the levels of VLDL and atherogenic LDL and thus reduce the risk of developing cardiovascular disease.
Publisher: Springer Science and Business Media LLC
Date: 07-03-2015
Publisher: Frontiers Media SA
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 17-09-2012
Abstract: Several studies have identified use of non-steroidal-anti-inflammatory drugs and statins for prevention of dementia, but their efficacy in slowing progression is not well understood. Cerebrovascular disturbances are common pathological feature of Alzheimer’s disease. We previously reported chronic ingestion of saturated fatty acids (SFA) compromises blood–brain barrier (BBB) integrity resulting in cerebral extravasation of plasma proteins and inflammation. However, the SFA-induced parenchymal accumulation of plasma proteins could be prevented by co-administration of some cholesterol lowering agents. Restoration of BBB dysfunction is clinically relevant, so the purpose of this study was to explore lipid-lowering agents could reverse BBB disturbances induced by chronic ingestion of SFA’s. Wild-type mice were fed an SFA diet for 12 weeks to induce BBB dysfunction, and then randomised to receive atorvastatin, pravastatin or ibuprofen in combination with the SFA-rich diet for 2 or 8 weeks. Abundance of plasma-derived immunoglobulin-G (IgG) and amyloid-β enriched apolipoprotein (apo)-B lipoproteins within brain parenchyme were quantified utilising immunofluorescence microscopy. Atorvastatin treatment for 2 and 8 weeks restored BBB integrity, indicated by a substantial reduction of IgG and apo B, particularly within the hippoc us. Pravastatin, a water-soluble statin was less effective than atorvastatin (lipid-soluble). Statin effects were independent of changes in plasma lipid homeostasis. Ibuprofen, a lipid-soluble cyclooxygenase inhibitor attenuated cerebral accumulation of IgG and apo B as effectively as atorvastatin. Our findings are consistent with the drug effects being independent of plasma lipid homeostasis. Our findings suggest that BBB dysfunction induced by chronic ingestion of SFA is reversible with timely introduction and sustained treatment with agents that suppress inflammation.
Publisher: Wiley
Date: 09-09-2022
DOI: 10.1002/LIO2.917
Abstract: This study aimed to identify significant differences in cochlea microvessel size between a diabetic mouse model (db/db) and normal mice using three‐dimensional (3D) quantitative analysis. Six control heterozygote db/+ as well as 18 male B6/BKS(D)‐Lepr db /J (db/db) mice aged 14 ( n = 9) and 28 ( n = 9) weeks were examined. After clearing the cochlea, we reconstructed the 3D volumes of the spiral modiolar artery (SMA) in the cochlea using light‐sheet microscopy and analyzed vessel wall thickness, cross‐sectional area, short and long diameter, and vessel height. The average SMA‐wall thickness in the db/db‐mouse group (3.418 ± 0.328 μm) was greater than that in the control group (2.388 ± 0.411 μm). The average cross‐sectional outer area, short diameter, and long diameter of the SMA in db/db mice were significantly larger than those in control mice (all p 0.001). The cross‐sectional areas increased with age (control: 221.782 ± 121.230 μm, 14 weeks 294.378 ± 151.008 μm, and 28 weeks 312.925 ± 147.943 μm). The db/db mice had thicker and larger proximal‐SMA vessel walls and diameters than control mice, respectively, thus potentially inducing increased blood viscosity or vascular insufficiency and aggravating hearing loss in type 2 diabetes mellitus. IIb
Publisher: Wiley
Date: 30-01-2014
DOI: 10.1002/JAT.2985
Abstract: Epidemiological studies indicate that exposure to diesel exhaust (DE) is associated with vascular-based disorders. To investigate the effect of DE on blood-brain barrier (BBB) function and integrity, 8-week-old BALB/c mice were randomized to DE in a cyclical treatment regimen over a 2-week period. Functional integrity of BBB was determined by considering brain parenchymal abundance of IgG within the hippoc al formation and cortex at 6 h and 24 h intervals following final exposure treatment. Neurovascular inflammation was expressed as the abundance of glial fibrillar acidic protein. Two doses of DE were studied and compared to air-only treated mice. Mice exposed to DE had substantially greater abundance of parenchymal IgG compared to control mice not exposed to DE. Increased parenchymal glial fibrillar acidic protein at 24 h post-DE exposure suggested heightened neurovascular inflammation. Our findings are proof-of-concept that inhalation of DE can compromise BBB function and support the broader contention that DE exposure may contribute to neurovascular disease risk.
Publisher: Cold Spring Harbor Laboratory
Date: 06-2022
DOI: 10.1101/2022.05.31.494083
Abstract: Obesity is linked to a higher incidence of Alzheimer’s disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied. We hypothesised that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalise plasma concentrations of Aβ. Plasma concentrations of Aβ 40 , Aβ 42 and Aβ 42/40 ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations. Plasma Aβ 42/40 ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p .0001), and 11.76% lower compared to participants with an overweight BMI (p .0001). The weight loss regimen decreased BMI by an average of 4.02% (p=0.0005) and was associated with a 6.5% decrease in plasma Aβ 40 (p=0.0425). However, weight loss showed negligible correlations with plasma Aβ 40 , Aβ 42 and Aβ 42/40 ratio. Obesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ 40 , but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis.
Publisher: Oxford University Press (OUP)
Date: 12-2020
DOI: 10.1039/D0MT00198H
Abstract: Zinc is a prominent trace metal required for normal memory function. Memory loss and cognitive decline during natural ageing and neurodegenerative disease have been associated with altered brain-Zn homeostasis. Yet, the exact chemical pathways through which Zn influences memory function during health, natural ageing, or neurodegenerative disease remain unknown. The gap in the literature may in part be due to the difficulty to simultaneously image, and therefore, study the different chemical forms of Zn within the brain (or biological s les in general). To this extent, we have begun developing and optimising protocols that incorporate X-ray absorption near-edge structure (XANES) spectroscopic analysis of tissue at the Zn K-edge as an analytical tool to study Zn speciation in the brain. XANES is ideally suited for this task as all chemical forms of Zn are detected, the technique requires minimal s le preparation that may otherwise redistribute or alter the chemical form of Zn, and the Zn K-edge has known sensitivity to coordination geometry and ligand type. Herein, we report our initial results where we fit K-edge spectra collected from micro-dissected flash-frozen brain tissue, to a spectral library prepared from standard solutions, to demonstrate differences in the chemical form of Zn that exist between two brain regions, the hippoc us and cerebellum. Lastly, we have used an X-ray microprobe to demonstrate differences in Zn speciation within sub-regions of thin air-dried sections of the murine hippoc us but, the corresponding results highlight that the chemical form of Zn is easily perturbed by s le preparation such as tissue sectioning or air-drying, which must be a critical consideration for future work.
Publisher: American Chemical Society (ACS)
Date: 18-07-2017
DOI: 10.1021/ACS.BIOCHEM.7B00262
Abstract: Alzheimer's disease (AD) is a major international health and economic concern. A key pathological feature of AD is so-called "amyloid-β-plaques", or "Aβ-plaques", which are deposits of aggregated protein, enriched with the Aβ fragment of amyloid precursor protein. Despite their name, the deposits are not pure Aβ and have a heterogeneous, chemically complex composition that can include multiple proteins, lipids, and metal ions (Fe, Cu, or Zn). Despite extensive research, it is still uncertain whether Aβ-plaques are a cause or a consequence of AD pathology. Further characterization of the elemental and biochemical composition within and surrounding Aβ-plaques, and knowledge of how composition varies with disease state or progression, may provide important insight into the relationship between Aβ-plaques and AD pathology. With this aim in mind, herein we demonstrate a multimodal spectroscopic imaging workflow to better characterize the complex composition of Aβ-plaques. Our approach incorporates several spectroscopic imaging techniques, such as Fourier transform infrared spectroscopic imaging (FTIR), Raman microscopy, and X-ray fluorescence microscopy (XFM). While FTIR, Raman, and XFM have been used previously, mostly in isolation, to study Aβ-plaques, application of all three techniques, in combination with histology and fluorescence microscopy, has not been reported previously. We demonstrate that a multimodal workflow, incorporating all three methods on adjacent or serial tissue sections, can reveal substantial complementary information about the biochemical and elemental composition of Aβ-plaques. Information revealed by the method includes the relative content and distribution of aggregated protein, total lipid, lipid esters, cholesterol, and metals (Fe, Cu, or Zn).
Publisher: Public Library of Science (PLoS)
Date: 17-06-2020
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.PLIPRES.2018.06.003
Abstract: Recent advances in analytical techniques have greatly enhanced the depth of coverage, however lipidomic studies are still restricted to analysing only a subset of known lipids. Numerous complementary techniques are used for investigation of cellular lipidomes, including mass spectrometry (MS), nuclear magnetic resonance and vibrational spectroscopy. The development in electrospray ionization (ESI) MS has accelerated lipidomics research in the past two decades and represents one of the most widely used technique. The versatility of ESI-MS systems allows development of methods to detect and quantify a large ersity of lipid species and classes. However, highly targeted and specific approaches can preclude global analysis of many lipid classes. Indeed, experimental procedures are generally optimised for the lipid species, or lipid class of interest. Therefore, careful consideration of experimental procedures is required for characterisation of biological lipidomes. The current review will describe the lipidomic approaches for considering tissue lipid physiology. Discussion of the main sequences in a lipidomics workflow will be presented, including preparation of s les, accurate quantitation of lipid species and statistical modelling.
Publisher: Frontiers Media SA
Date: 28-08-2018
Publisher: S. Karger AG
Date: 02-11-2012
DOI: 10.1159/000343211
Abstract: b i Background: /i /b Disturbances in blood-brain barrier (BBB) integrity contribute to the onset and progression of neurodegenerative diseases including Alzheimer's disease (AD) and vascular dementia (VaD). Aging is positively associated with AD and VaD risk, but this may reflect comorbidities or the effects of other chronic modulators of vascular function such as diet. b i Objective: /i /b To explore putative synergistic effects of aging with diet, in this study genetically unmanipulated mice were maintained on diets enriched in saturated fatty acids (SFA) or cholesterol and compared to mice provided with low-fat (LF) feed formula. b i Methods: /i /b The functional integrity of the BBB was assessed following 3, 6 and 12 months of dietary intervention commenced at 6 weeks of age, by determining the brain parenchymal extravasation of immunoglobulin G (IgG). b i Results: /i /b Mice maintained on the SFA- or cholesterol-enriched diet showed significant parenchymal IgG abundance following 3 months of feeding, concomitant with diminished expression of the tight junction protein occludin. LF control mice had essentially no evidence of BBB disturbances. Six months of SFA feeding exacerbated the difference in IgG abundance compared to the LF mice. At 12 months of feeding, the control LF mice also had significant parenchymal IgG that was comparable to mice fed the SFA- or cholesterol-enriched diet for 3 months. However, there may have been an adaptation to the fat-enriched diets because SFA and cholesterol did not exacerbate IgG parenchymal accumulation beyond 6 months of feeding. b i Conclusion: /i /b Collectively, the study suggests that diets enriched in SFA or cholesterol accelerate the onset of BBB dysfunction that otherwise occurs with aging.
Publisher: Georg Thieme Verlag KG
Date: 24-05-2017
Abstract: Hypertension is a significant comorbidity associated with insulin resistance and type-2 diabetes. Limited evidence show that ursodeoxycholic acid (UDCA) has some anti-hypertensive effects. However, the potential effect of UDCA on hypertension induced by type-2 diabetic insulin resistance has not been reported. In C57Bl6 wild-type mice, insulin resistance was induced by the chronic ingestion of diet enriched in fat and fructose (HFF). HFF mice were randomized to treatment with UDCA or candersartan incorporated into the diet to achieve an ingested dose of approximately 70 mg/kg/day of UDCA or 3 mg/kg/day respectively. Systolic and diastolic blood pressure were measured with tail-cuff method. At 4 weeks of dietary treatment systolic and diastolic blood pressure were comparable in HFF and low-fat (LF) control mice. Co-administration of candesartan at 4 weeks significantly decreased systolic and diastolic blood pressure, UDCA showed no anti-hypertensive effect at 4 weeks. At 24 weeks of dietary intervention, HFF fed mice had substantially elevated systolic blood pressure compared to LF controls. The provision of UDCA substantially attenuated the dietary HFF induced increase in systolic blood pressure concomitant with significantly lower plasma angiotensin II. The anti-hypertensive effect of UDCA in HFF mice was comparable to candesartan. The data suggests that long term supplementation of UDCA effectively lowers hypertension in a dietary induced model of type-2 diabetic insulin resistance.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2017
DOI: 10.1038/IJO.2017.57
Abstract: While vascular risk factors including Western-styled diet and obesity are reported to induce cognitive decline and increase dementia risk, recent reports consistently suggest that compromised integrity of cerebrovascular blood-brain barrier (BBB) may have an important role in neurodegeneration and cognitive deficits. A number of studies report that elevated blood pressure increases the permeability of BBB. In this study, we investigated the effects of antihypertensive agents, candesartan or ursodeoxycholic acid (UDCA), on BBB dysfunction and cognitive decline in wild-type mice maintained on high fat and fructose (HFF) diet for 24 weeks. In HFF-fed mice, significantly increased body weight with elevated blood pressure, plasma insulin and glucose compared with mice fed with low-fat control chow was observed. Concomitantly, significant disruption of BBB and cognitive decline were evident in the HFF-fed obese mice. Hypertension was completely prevented by the coprovision of candesartan or UDCA in mice maintained on HFF diet, while only candesartan significantly reduced the body weight compared with HFF-fed mice. Nevertheless, BBB dysfunction and cognitive decline remained unaffected by candesartan or UDCA. These data conclusively indicate that modulation of blood pressure and/or body weight may not be directly associated with BBB dysfunction and cognitive deficits in Western diet-induced obese mice, and hence antihypertensive agents may not be effective in preventing BBB disruption and cognitive decline. The findings may provide important mechanistical insights to obesity-associated cognitive decline and its therapy.
Publisher: Wiley
Date: 28-02-2017
DOI: 10.1111/JNC.13964
Abstract: Accumulation of ceramide is implicated in mediating the cellular responses to stress and aberrant sphingolipid metabolism is frequently associated with metabolic and neurodegenerative diseases. It is often assumed that (i) peripheral disturbances in sphingolipid concentrations are reflective of processes occurring in the brain, or (ii) circulating sphingolipids directly influence cerebral sphingolipid abundance. In order to address these assumptions, this study explores, in a physiological system, the metabolic pathways regulating sphingolipid metabolism in the brain and plasma of mice. Male C57Bl/6 were maintained on a low fat (control diet) or saturated fat enriched (SFA) diet with, or without the provision of sphingolipid modulating agents. Following 6 months of feeding, the abundance of seven sphingolipid classes was assessed by LC-ESI-MS/MS in the hippoc us (HPF), cerebral cortex (CTX), and plasma. Long-term consumption of the SFA diet increased ceramide and dihydroceramide in the plasma. Inhibiting de novo synthesis ameliorated this effect, while inhibition of acidic sphingomyelinase, or the sphingosine-1-phosphate receptor agonist did not. SFA feeding did not influence sphingolipid levels in either the HPF or CTX. De novo synthesis inhibition reduced ceramide in the CTX, while treatment with a sphingosine-1-phosphate receptor agonist reduced ceramides in the HPF. Analysis of the in idual ceramide species revealed the effects were chain-length dependent. Both positive and negative correlations were observed between plasma and HPF/CTX ceramide species. The findings in this study show that HPF and CTX sphingolipid concentration are influenced by distinct pathways, independent of peripheral sphingolipid concentration.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2018
DOI: 10.1007/S13346-017-0473-5
Abstract: Probucol (PB) is an hypolipidaemic drug with potential antidiabetic effects. We showed recently using in vitro studies that when PB was incorporated with stabilising lipophilic bile acids and microencapsulated using the polymer sodium alginate, the microcapsules showed good stability but poor and irregular PB release. This suggests that PB microcapsules may exhibit better release profile and hence better absorption, if more hydrophilic bile acids were used, such as ursodeoxycholic acid (UDCA). Accordingly, this study aimed to produce PB-UDCA microcapsules and examine PB absorption and antidiabetic effects in our mouse-model of insulin-resistance and diabetes (fed high-fat diet HFD). The study also aimed to examine the effects of the microcapsules on the bile acid profile. Healthy mice (fed low-fat diet LFD) were used as control. Seventy mice were randomly allocated into seven equal groups: LFD, HFD given empty microcapsules, HFD given metformin (M), HFD given standard-dose probucol (PB-SD), HFD given high-dose probucol (PB-H), HFD given UDCA microcapsules and HFD given PB-UDCA microcapsules. Blood glucose (BG), inflammatory biomarkers (TNF-α, IFN-γ, IL-1β, IL-6, IL-10, IL-12 and IL-17), plasma cholesterol, non-esterified fatty acids and triglycerides were analysed together with plasma bile acid and probucol concentrations. PB-UDCA microcapsules reduced BG in HFD mice, but did not reduce inflammation or improve lipid profile, compared with positive control (HFD) group. Although PB-UDCA microcapsules did not exert hypolipidaemic or antiinflammatory effects, they resulted in significant hypoglycaemic effects in a mouse model of insulin resistance, which suggests potential applications in insulin-resistance and glucose haemostasis.
Publisher: Frontiers Media SA
Date: 06-05-2020
Publisher: Future Science Ltd
Date: 10-2017
Abstract: Aim: A semisynthetic primary bile acid (PBA) has exerted hypoglycemic effects in Type 1 diabetic animals, which were hypothesized to be due to its anti-inflammatory and cellular glucose-regulatory effects. Thus, the research purpose aimed to examine antidiabetic effects of a PBA, in terms of cellular inflammation and survival and insulin release, in the context of supporting β-cell delivery and Type 1 diabetic treatment. Materials & methods: 10 formulations were prepared, five without PBA (control) and five with PBA (test). Formulations were used to microencapsulate pancreatic β cells and the microcapsules were examined for morphology, cell viability, insulin release and inflammation. Results & conclusion: PBA improved cell viability, insulin release and reduced inflammation in a formulation-dependent manner, which suggests potential use in cell delivery and diabetes treatment. [Formula: see text]
Publisher: Cold Spring Harbor Laboratory
Date: 23-02-2022
DOI: 10.1101/2022.02.21.481384
Abstract: Despite its critical role in neurodevelopment and brain function, vitamin-D (vit-D) homeostasis, metabolism and kinetics within the central nervous system remain largely undetermined. Thus, it is of critical importance to establish an accurate, highly sensitive and reproducible method to quantitate vit-D in brain tissue. Here, we present a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method and for the first time, demonstrate detection of seven major vit-D metabolites in brain tissues of C57BL/6J wild-type mice, namely: 1,25(OH) 2 D 3 , 3-epi-1,25(OH) 2 D 3, 1,25(OH) 2 D 2 , 25(OH)D 3 , 25(OH)D 2 , 24,25(OH) 2 D 3 , and 24,25(OH) 2 D 2 . Chromatographic separation was achieved on a pentaflurophenyol column 3 mM ammonium formate with water/methanol [A] and methanol/isopropanol [B] phases. Detection was by positive-ion electrospray tandem mass spectrometry. We used calibration standards of each metabolite prepared in brain matrices to validate the detection range, precision, accuracy and recovery. Isotopically labelled analogues, 1,25(OH) 2 D 3 -d 3 , 25(OH)D 3 -C 5 and 24,25(OH) 2 D 3 -d 6 , served as the internal standards for the closest molecular related metabolite in all measurements. The calibration range was between 1 fg/mL to 10 ng/mL with an LLOD and LLOQ of 10 fg/mL and 3 fg/mL, respectively. The intra-/inter-day precision and accuracy for measuring brain vit-D metabolites ranged between 0.12-11.53% and 0.28-9.11%, respectively. Recovery ranged between 99.06% and 106.9% for all metabolites. Collectively, the sensitivity and efficiency of our method supersedes previously reported protocols used to measure vit-D and to our knowledge, the first protocol to reveal the abundance of 25(OH)D 2 , 1,25(OH)D 2 and 24,25(OH) 2 D 2 , in brain tissue of any species. This technique may be important in supporting the future advancement of pre-clinical research into the function of vit-D in neurophysiological, neuropsychiatric, and neurodegeneration.
Publisher: Cold Spring Harbor Laboratory
Date: 04-11-2022
DOI: 10.1101/2022.11.02.22281863
Abstract: Migraine is a common and distressing neurological condition characterised by recurrent throbbing headaches, nausea and heightened sensitivity to light and sound. Accumulating evidence suggests that cerebral arteries dilate during migraine, causing distal microvessels to constrict, which could activate nociceptors and cause onset of headache pain. If so, preventing or attenuating chronic microvascular constriction, and promoting a dilatory phenotype, may reduce frequency and/or severity of migraines. The primary aim of the L-Arginine and Aged Garlic Extract (LARGE) trial is to investigate whether oral treatment with dietary nutraceuticals, L-arginine and aged garlic extract (AGE), both systemic vasodilatory agents, will alleviate migraine frequency, duration and severity in adults with chronic frequent episodic migraines. The study is a randomised double-blind placebo-controlled phase-II single-site clinical trial conducted in Perth, Australia. The target s le is to recruit 240 participants diagnosed with chronic frequent episodic migraines between 18 and 80 years of age. Participants will be randomised to one of four treatment groups for 14 weeks (placebo induction for 2 weeks, followed by 12 weeks on one of the respective treatment arms): placebo, L-arginine, AGE, or a combination of L-arginine and AGE. The doses of L-arginine and AGE are 1.5 g and 1 g daily, respectively. The primary outcome is to assess migraine response using change in migraine frequency and intensity between baseline and 12 weeks. Secondary outcomes include the impact of L-arginine and/or AGE on photosensitivity, retinal vessel changes, and blood biomarker concentrations of vascular tone, following a 12-week intervention. The Curtin University Human Research Ethics Committee (HREC) has approved this study (Approval number: HRE2020-0466 Version 4 16 th August 2021). Written consent will be obtained from all participants prior to commencing their participation in the trial. The results of the study will be disseminated in peer-reviewed publications and presented at key national and international conferences and local stakeholder events. The trial is registered with the Australian New Zealand Clinical Trials Registry ACTRN12621001476820 (Universal Trial Number: U1111-1268-1117). This is the first in-human randomised double-blind placebo-controlled phase-II clinical trial examining the efficacy, safety and tolerability of L-arginine and AGE, in preventing chronic frequent episodic migraines by assessing participant-reported pain-related outcomes, and changes in photosensitivity and retinal vessels. The double-blinded nature of the study, and the placebo run-in for 2 weeks at the beginning of the study, are strengths in trial methodology. The protocol describes the oral administration of 2 nutraceutical-based interventions as possible prophylactic treatments for chronic frequent episodic migraines, with potential for direct clinical translation of outcomes. Potential limitations of the study include the fixed-dose design of each treatment arm and that in vivo neuroimaging methods, such as magnetic resonance imaging (MRI), will not be conducted to determine putative cerebro-vasodilatory changes to coincide with the outcome measures. Dose-response studies may be indicated.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2021
DOI: 10.1038/S41430-021-00962-X
Abstract: A 74-year-old female subject with suboptimal management of episodic tension headache was treated with a daily dose of 1.5 g L-arginine and 1.2 g aged garlic extract (AGE). The aim of the intervention was to promote vasodilation of parenchymal cerebral blood vessels. Within 6 weeks of commencing treatment, her self-reported symptoms improved markedly and were sustained at 2 years following commencement. We propose that the putative beneficial effect of L-arginine and AGE in this patient is because of the well-established systemic vasodilatory effects of L-arginine and aged garlic extract. On the hypothesis that migraine is precipitated by cerebral microvascular constriction, we recommend a double-blind randomised controlled trial to clinically test this hypothesis in migraine patients.
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/647689
Publisher: MDPI AG
Date: 08-08-2021
DOI: 10.3390/PHARMACEUTICS13081223
Abstract: Probucol (PB) is a highly lipophilic drug with potential protective effects on pancreatic β-cells from inflammation and oxidation. PB has poor bioavailability and solubility, and despite many attempts, significant improvement in antidiabetic effects or absorption has yet to be discovered. Recently, the role of bile acids has been established in significant drug formulation stabilisation effects and as cell-penetrating agents. Promising results in pharmaceutical formulation studies on drug stability and release patterns when lithocholic acid (LCA) is conjugated with PB and sodium alginate (SA) have been demonstrated. Thus, this study aimed to develop and characterise PB microcapsules incorporating LCA and examine the biological effects of the microcapsules in vitro and in vivo. PB/LCA microcapsules were prepared using an encapsulation method, ionic gelation vibrational jet flow technology. LCA incorporation in PB microcapsules showed positive effects on β-cells with improved insulin release, antioxidant activity, and PB intracellular uptake. Diabetic mice gavaged LCA-PB microcapsules showed a significant reduction in diabetes signs and symptoms, better survival rate, reduced blood glucose levels, and pro-inflammatory cytokines, with an increase PB level in blood and tissues suggesting a potential therapy for treating diabetes mellitus.
Publisher: Public Library of Science (PLoS)
Date: 04-04-2019
Publisher: Oxford University Press (OUP)
Date: 2019
DOI: 10.1039/C8MT00230D
Abstract: X-ray fluorescence microscopy reveals unique elemental signatures within sub-populations of hippoc al pyramidal neurons.
Publisher: Wiley
Date: 31-07-2011
DOI: 10.1007/S11745-011-3595-4
Abstract: Amyloid-β (Aβ) is secreted from lipogenic organs such as intestine and liver as an apolipoprotein of nascent triacylglycerol rich lipoproteins. Chronically elevated plasma Aβ may compromise cerebrovascular integrity and exacerbate amyloidosis--a hallmark feature of Alzheimer's disease (AD). Probucol is a hypocholesterolemic agent that reduces amyloid burden in transgenic amyloid mice, but the mechanisms for this effect are presently unclear. In this study, the effect of Probucol on intestinal lipoprotein-Aβ homeostasis was explored. Wild-type mice were fed a control low-fat diet and enterocytic Aβ was stimulated by high-fat (HF) diet enriched in 10% (w/w) saturated fat and 1% (w/w) cholesterol for the duration of 1 month. Mice treated with Probucol had the drug incorporated into the chow at 1% (w/w). Quantitative immunofluorescence was utilised to determine intestinal apolipoprotein B (apo B) and Aβ abundance. We found apo B in both the perinuclear region of the enterocytes and the lacteals in all groups. However, HF feeding and Probucol treatment increased secretion of apo B into the lacteals without any change in net villi abundance. On the other hand, HF-induced enterocytic perinuclear Aβ was significantly attenuated by Probucol. No significant changes in Aβ were observed within the lacteals. The findings of this study support the notion that Probucol suppresses dietary fat induced stimulation of Aβ biosynthesis and attenuate availability of apo B lipoprotein-Aβ for secretion.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2013
Abstract: Emerging evidence suggests that disturbances in the blood–brain barrier (BBB) may be pivotal to the pathogenesis and pathology of vascular-based neurodegenerative disorders. Studies suggest that heightened systemic and central inflammations are associated with BBB dysfunction. This study investigated the effect of the anti-inflammatory nutraceuticals garlic extract-aged (GEA), alpha lipoic acid (ALA), niacin, and nicotinamide (NA) in a murine dietary-induced model of BBB dysfunction. C57BL/6 mice were fed a diet enriched in saturated fatty acids (SFA, 40% fat of total energy) for nine months to induce systemic inflammation and BBB disturbances. Nutraceutical treatment groups included the provision of either GEA, ALA, niacin or NA in the positive control SFA-group and in low-fat fed controls. Brain parenchymal extravasation of plasma derived immunoglobulin G (IgG) and large macromolecules (apolipoprotein (apo) B lipoproteins) measured by quantitative immunofluorescent microscopy, were used as markers of disturbed BBB integrity. Parenchymal glial fibrillar acidic protein (GFAP) and cyclooxygenase-2 (COX-2) were considered in the context of surrogate markers of neurovascular inflammation and oxidative stress. Total anti-oxidant status and glutathione reductase activity were determined in plasma. Brain parenchymal abundance of IgG and apoB lipoproteins was markedly exaggerated in mice maintained on the SFA diet concomitant with significantly increased GFAP and COX-2, and reduced systemic anti-oxidative status. The nutraceutical GEA, ALA, niacin, and NA completely prevented the SFA-induced disturbances of BBB and normalized the measures of neurovascular inflammation and oxidative stress. The anti-inflammatory nutraceutical agents GEA, ALA, niacin, or NA are potent inhibitors of dietary fat-induced disturbances of BBB induced by systemic inflammations.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2017
DOI: 10.1007/S11095-017-2138-Y
Abstract: Recently we demonstrated that microencapsulation of a murine pancreatic β-cell line using an alginate-ursodeoxycholic acid (UDCA) matrix produced microcapsules with good stability and cell viability. In this study, we investigated if translation of this formulation to microencapsulation of primary β-cells harvested from mature double-transgenic healthy mice would also generate stable microcapsules with good cell viability. Islets of Langerhans were isolated from Ngn3-GFP/RIP-DsRED mice by intraductal collagenase P digestion and density gradient centrifugation, dissociated into single cells and the β-cell population purified by Fluorescence Activated Cell Sorting. β-cells were microencapsulated using either alginate-poly-l-ornithine (F1 control) or alginate-poly-l-ornithine-UDCA (F2 test) formulations. Microcapsules were microscopically examined and microencapsulated cells were analyzed for viability, insulin and cytokine release, 2 days post-microencapsulation. Microcapsules showed good uniformity and morphological characteristics and even cell distribution within microcapsules with or without UDCA. Two days post microencapsulation cell viability, mitochondrial ATP and insulin production were shown to be optimized in the presence of UDCA whilst production of the proinflammatory cytokine IL-1β was reduced. Contradictory to our previous studies, UDCA did not reduce production of any other pro-inflammatory biomarkers. These results suggest that UDCA incorporation improves microcapsules' physical and morphological characteristics and improves the viability and function of encapsulated mature primary pancreatic β-cells.
Publisher: SAGE Publications
Date: 29-08-2018
Abstract: An emerging body of evidence consistently suggests that compromised blood-brain barrier integrity may be causally associated with cognitive decline induced by type-2 diabetes. Our previous studies demonstrated that selected anti-inflammatory/anti-oxidative agents can preserve the integrity of blood-brain barrier and prevent neuroinflammation in mouse models of dysfunctional blood-brain barrier. Therefore, we have tested whether the previously proven blood-brain barrier protective agent, probucol, can prevent blood-brain barrier breakdown and cognitive decline in a dietary-induced murine model of diabetic insulin resistance. After 6-month chronic ingestion of a diet high in fat and fructose, the mice became insulin resistant. The high-fat and high-fructose-fed mice showed significant cognitive decline assessed by Morris water maze, concomitant with significant elevations in cortical and hippoc al glial acidic fibrillary protein and Fluoro Jade-C staining, indicating heightened neuroinflammation and neurodegeneration, respectively. The integrity of blood-brain barrier in high-fat and high-fructose-fed mice was substantially compromised, and this showed a significant association with heightened neurodegeneration. Co-provision of probucol with high-fat and high-fructose diet completely prevented the cognitive decline and blood-brain barrier dysfunction. Similarly, metformin was able to restore the cognitive function in high-fat and high-fructose-fed mice, while its blood-brain barrier protective effects were modest. These data suggest that probucol may prevent cognitive decline induced by insulin resistance by preserving the integrity of blood-brain barrier, whereas metformin's neuroprotective effects may be mediated through a separate pathway.
Publisher: Public Library of Science (PLoS)
Date: 17-06-2202
DOI: 10.1371/JOURNAL.PONE.0243858
Abstract: Cannabidiol (CBD) confers therapeutic effects in some neurological disorders via modulation of inflammatory, oxidative and cell-signalling pathways. However, CBD is lipophilic and highly photooxidative with low oral bioavailability in plasma and brain. In this study, we aimed to design and test a CBD microencapsulation method as a drug delivery strategy to improve the absorption of CBD. Additionally, we evaluated the brain uptake of CBD capsules when administered alongside capsules containing a permeation-modifying bile acid, deoxycholic acid (DCA). Microcapsules containing either CBD or DCA were formed using the ionic gelation method with 1.5% sodium alginate formulations and 100 mM calcium chloride. C57BL/6J wild type mice randomly assigned to three treatment groups (3–4 mice per group) were administered CBD in the following preparations: 1) CBD capsules, 2) CBD capsules + DCA capsules and 3) naked CBD oil (control). To assess the short-term bioavailability of CBD, plasma and brain s les were collected at 0.3, 1 and 3 hours post administration and CBD levels were analysed with liquid chromatography mass spectrometer. We produced spherical capsules at 400 ± 50 μm in size. The CBD capsules were calculated to have a drug loading of 2% and an encapsulation efficiency of 23%. Mice that received CBD capsules + DCA capsules showed a 40% and 47% increase in CBD plasma concentration compared to mice on CBD capsules and naked CBD oil, respectively. Furthermore, the CBD capsules + DCA capsules group showed a 48% and 25% increase in CBD brain concentration compared to mice on CBD capsules and naked CBD oil, respectively. In mice treated with CBD capsules + DCA capsules, the brain CBD concentration peaked at 0.3 hours with a 300% increased availability compared to CBD capsules and naked CBD oil groups, which peaked at 1 hour after administration. The microencapsulation method combined with a permeation enhancer, DCA increased the short-term bioavailability of CBD in plasma and brain.
Publisher: Cambridge University Press (CUP)
Date: 23-10-2019
DOI: 10.1017/S000711451900268X
Abstract: Studies show that vitamin D (vit-D) (25(OH)D), the bioactive metabolite (1,25(OH) 2 D 3 ) and vit-D receptors (vit-D receptor protein disulphide isomerase, family A member 3) are expressed throughout the brain, particularly in regions pivotal to learning and memory. This has led to the paradigm that avoiding vit-D deficiency is important to preserve cognitive function. However, presently, it is not clear if the common clinical measure of serum 25(OH)D serves as a robust surrogate marker for central nervous system (CNS) homeostasis or function. Indeed, recent studies report CNS biosynthesis of endogenous 25(OH)D, the CNS expression of the CYP group of enzymes which catalyse conversion to 1,25(OH) 2 D 3 and thereafter, deactivation. Moreover, in the periphery, there is significant ethnic/genetic heterogeneity in vit-D conversion to 1,25(OH) 2 D 3 and there is a paucity of studies which have actually investigated vit-D kinetics across the cerebrovasculature. Compared with peripheral organs, the CNS also has differential expression of receptors that trigger cellular response to 1,25(OH) 2 D 3 metabolites. To holistically consider the putative association of peripheral (blood) abundance of 25(OH)D on cognitive function, herein, we have reviewed population and genetic studies, pre-clinical and clinical intervention studies and moreover have considered potential confounders of vit-D analysis.
Publisher: American Chemical Society (ACS)
Date: 03-2019
DOI: 10.1021/ACSCHEMNEURO.9B00039
Abstract: Non-insulin-dependent diabetes mellitus (NIDDM) is reported to increase the risk of cognitive impairment and dementia. However, the underlying mechanisms are not fully understood. While the brain homeostasis of metals and lipids is pivotal to maintaining energy metabolism and redox homeostasis for healthy brain function, no studies have reported hippoc al metal and biochemical changes in NIDDM. Therefore, we here utilized direct spectroscopic imaging to reveal the elemental distribution within the hippoc al subregions of an established murine model of NIDDM, db/db mice. In 26-week-old insulin resistant db/db mice, X-ray fluorescence microscopy revealed that the Cu content within the dentate gyrus and CA3 was significantly greater than that of the age-matched nondiabetic control mice. In addition, Fourier transform infrared (FTIR) spectroscopy analysis indicated a significant increase in the abundance of lactate within the corpus callosum (CC), dentate gyrus, CA1, and CA3 regions of diabetic db/db mice compared to that of the control, indicating altered energy metabolism. FTIR analysis also showed a significant decrease in the level of lipid methylene and ester within the CC of db/db mice. Furthermore, immunomicroscopy analyses demonstrated the increase in the level of glial fibrillary acidic protein expression and peri-vascular extravasation of IgG, indicating astrogliosis and blood-brain barrier dysfunction, respectively. These data suggest that astrogliosis-induced alterations in the supply of Cu, lipids, and energy substrates may be involved in the mechanisms of NIDDM-associated cognitive decline.
Publisher: SPIE
Date: 29-04-2017
DOI: 10.1117/12.2272365
Publisher: Future Science Ltd
Date: 10-2018
Abstract: Aim: To enhance the bioavailability and brain uptake of probucol and examine whether it attenuates neuroinflammation and neurodegeneration by utilizing a sodium alginate nanoencapsulation technique. Materials & methods: Wild-type mice were given either low-fat standard chow, high-fat (HF) diet to induce neuroinflammation and neurodegeneration, HF diet supplemented with nanocapsuled probucol at a concentration of 0.1% (w/w), HF diet supplemented with noncapsulated probucol at the same concentration of 0.1%, or HF diet supplemented with noncapsulated probucol at higher concentration (1%) for 24 weeks. Results & conclusion: The nanoencapsulation increased the plasma and brain concentration of probucol significantly compared with the mice that was given the same dosage of probucol without capsulation, and significantly suppressed the neuroinflammation and neurodegeneration.
Publisher: Bentham Science Publishers Ltd.
Date: 11-09-2020
DOI: 10.2174/1389450121666200204115121
Abstract: Recent studies have suggested that hyperglycaemia influences the bile acid profile and concentrations of secondary bile acids in the gut. This study aimed to measure changes in the bile acid profile in the gut, tissues, and faeces in type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). T1D and T2D were established in a mouse model. Twenty-one seven-weeks old balb/c mice were randomly ided into three equal groups, healthy, T1D and T2D. Blood, tissue, urine and faeces s les were collected for bile acid measurements. Compared with healthy mice, T1D and T2D mice showed lower levels of the primary bile acid, chenodeoxycholic acid, in the plasma, intestine, and brain, and higher levels of the secondary bile acid, lithocholic acid, in the plasma and pancreas. Levels of the bile acid ursodeoxycholic acid were undetected in healthy mice but were found to be elevated in T1D and T2D mice. Bile acid profiles in other organs were variably influenced by T1D and T2D development, which suggests similarity in effects of T1D and T2D on the bile acid profile, but these effects were not always consistent among all organs, possibly since feedback mechanisms controlling enterohepatic recirculation and bile acid profiles and biotransformation are different in T1D and T2D.
Publisher: Japanese Society of Nutrition and Food Science
Date: 2008
DOI: 10.4327/JSNFS.61.27
Publisher: Wiley
Date: 2004
Abstract: Epidemiological studies suggest that the red wine consumption may reduce the risk factor of cardiovascular disease. However, the mechanisms of how the red wine phenolic components reduce the risk of cardiovascular disease is currently unknown. Our previous study demonstrated that red wine polyphenolics suppress the secretion of pro‐atherogenic lipoproteins (very low density lipoproteins) from human hepatic HepG2 cells. Therefore, in this study we hypothesize that red wine polyphenolics will also attenuate the production and secretion of another pro‐atherogenic lipoprotein (chylomicrons) from human intestinal Caco‐2 cells. Cultured Caco‐2 cells were incubated in the presence of dealcoholized red wine, alcoholized red wine and atorvastatin for 24 h. The apo B48 protein (marker of intestinal chylomicrons) was quantified on Western blotting and the enhanced chemiluminescence. Apo B48 levels in the cells and that secreted into the media were significantly reduced by 29% in the cells incubated with dealcoholized red wine compared with control cells. Also the similar effect was shown in the cells incubated with alcoholized red wine. The cells incubated with atorvastatin shown the significant reduction of apo B48 production compared to control cells. Collectively, this study suggests that red wine polyphenolics down regulate the production of chylomicron in intestinal Caco‐2 cells.
Publisher: S. Karger AG
Date: 2020
DOI: 10.1159/000509109
Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, few pharmacological treatments exist to alleviate these socio-behavioural impairments. Prenatal administration of valproic acid (VPA) has become an accepted animal model of ASD and has been extensively used to explore new pharmacotherapies in rodents. We conducted a systematic review of the behavioural impairments induced by the VPA model in rodents, with specific reference to 3 core socio-behavioural alterations associated with ASD: repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. We systematically reviewed studies attempting to alleviate these core behavioural alterations using pharmacological means. We include 132 studies exploring the prenatal effects of VPA in rodents. Gestational exposure to VPA in rodents has significant effects on rodent-equivalent measures of the 3 core behavioural traits characteristic of ASD in humans, inducing social impairments, repetitive behaviour, and cognitive rigidity/inflexibility after birth. This model’s validity has seen it used to test potential drug treatments for ASD and is likely to continue doing so. We conclude the rodent VPA model may be suitable to examine future therapeutic interventions for ASD, providing an overview of the progress made so far.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2020
DOI: 10.1038/S41598-019-53999-1
Abstract: The antilipidemic drug, probucol (PB), has demonstrated potential applications in Type 2 diabetes (T2D) through its protective effects on pancreatic β-cells. PB has poor solubility and bioavailability, and despite attempts to improve its oral delivery, none has shown dramatic improvements in absorption or antidiabetic effects. Preliminary data has shown potential benefits from bile acid co-encapsulation with PB. One bile acid has shown best potential improvement of PB oral delivery (ursodeoxycholic acid, UDCA). This study aimed to examine PB and UDCA microcapsules (with UDCA microcapsules serving as control) in terms of the microcapsules’ morphology, biological effects ex vivo , and their hypoglycemic and antilipidemic and anti-inflammatory effects in vivo . PBUDCA and UDCA microcapsules were examined in vitro (formulation studies), ex vivo and in vivo . PBUDCA microcapsules exerted positive effects on β-cells viability at hyperglycemic state, and brought about hypoglycemic and anti-inflammatory effects on the prediabetic mice. In conclusion, PBUDCA co-encapsulation have showed beneficial therapeutic impact of dual antioxidant-bile acid effects in diabetes treatment.
Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1007/S00394-015-0968-0
Abstract: There is increasing evidence supporting an association of higher serum vitamin D concentration with better cognitive performance in older in iduals. However, to date, consideration of the putative association between vitamin D and cognition has been based principally on studies investigating clinical participant s les manifesting vitamin D deficiency, particularly in older people. Moreover, relationships between vitamin D and cognition are typically not considered in the context of counter-regulatory calcium-modulating hormones or calcium homeostasis. Serum vitamin D/bioactive (ionised) calcium arathyroid hormone homeostasis was considered in the context of cognitive performance in healthy, middle-aged and older in iduals. A cross-sectional s le of 179 participants between the ages of 47-84 years was recruited for this study (114 females, 65 males). Participants provided fasting blood s les for analysis of serum 25-hydroxyvitamin D levels, ionised calcium (iCa) and parathyroid hormone (PTH) and completed cognitive measures of verbal episodic learning and memory. Serum 25-hydroxyvitamin D concentrations were negatively associated (with and without covariates of age, gender, depression and NART scores, iCa, and PTH) with measures of verbal episodic learning and memory, in particular with trial 5 of the Rey Auditory Verbal Learning Test (RAVLT) and long-delay free recall on the RAVLT. Overall, the findings from this study suggest an association between higher vitamin D status and poorer performance on verbal episodic memory in middle-aged and older in iduals with normal vitamin D-calcium-PTH homeostasis. Despite requiring replication in other participant s les, this is a potentially important finding as it indicates that it may not be beneficial from a cognitive perspective to provide vitamin D supplements in in iduals with already adequate vitamin D status.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.ATHEROSCLEROSIS.2006.03.013
Abstract: Postprandial lipaemia is a significant contributor to the development of dyslipidaemia and cardiovascular disease, which has more recently been shown as a potential risk factor for obesity and pre-diabetes. Clinically however, the diagnosis of early insulin-resistance remains confounded due to the fact that aberrations in lipid metabolism are not often readily identified using classic indicators of hypercholesterolemia (i.e. LDL). In this study, we assessed the metabolism of apolipoprotein-B48 (apoB48)-containing lipoproteins in an animal model of obesity and insulin-resistance, the JCR:LA-cp rat. The contribution of lipoproteins from the intestine was assessed by measuring plasma apoB48 concentration in the postprandial period following an oral fat load. Plasma apoB48 was measured by improved enhanced chemiluminescent detection and other biochemical parameters measured by established analysis. Fasting concentrations of plasma apoB48, postprandial apoB48 area under the curve (AUC), as well as incremental-AUC (iAUC), were all significantly greater in the obese phenotype compared to lean controls. Fasting apoB48 correlated significantly with apoB48-iAUC, triglyceride (TG)-iAUC and insulin-iAUC. In addition, there was a highly significant association with fasting insulin and the postprandial ratio of TG:apoB48, a relationship not often detected in humans during insulin-resistance. We conclude that the JCR:LA-cp rat can be used as a model of postprandial lipemia to explore chylomicron metabolism during the onset and development of insulin-resistance, including the increased cardiovascular complications of the metabolic syndrome.
Start Date: 2014
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded Activity