ORCID Profile
0000-0002-4782-3608
Current Organisations
University of New South Wales
,
University of Queensland
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Publisher: JMIR Publications Inc.
Date: 22-09-2021
DOI: 10.2196/28766
Abstract: Despite recent and potent technological advances, the real-world implementation of remote digital health technology in the care and monitoring of patients with motor neuron disease has not yet been realized. Digital health technology may increase the accessibility to and personalization of care, whereas remote biosensors could optimize the collection of vital clinical parameters, irrespective of patients’ ability to visit the clinic. To facilitate the wide-scale adoption of digital health care technology and to align current initiatives, we outline a road map that will identify clinically relevant digital parameters mediate the development of benefit-to-burden criteria for innovative technology and direct the validation, harmonization, and adoption of digital health care technology in real-world settings. We define two key end products of the road map: (1) a set of reliable digital parameters to capture data collected under free-living conditions that reflect patient-centric measures and facilitate clinical decision making and (2) an integrated, open-source system that provides personalized feedback to patients, health care providers, clinical researchers, and caregivers and is linked to a flexible and adaptable platform that integrates patient data in real time. Given the ever-changing care needs of patients and the relentless progression rate of motor neuron disease, the adoption of digital health care technology will significantly benefit the delivery of care and accelerate the development of effective treatments.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2022
DOI: 10.1186/S13073-021-01006-6
Abstract: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1 / GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data ( N cases = 20,806, N controls = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain ( N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). SMR analyses implicated both TNIP1 and GPX3 ( p 1.15 × 10 −6 ), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1 . In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10 −3 , adjusted R 2 = 0.042, B effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1 . This has implications for understanding disease mechanisms ( GPX3 acts in the same pathway as SOD1 , a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous ex les of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings.
Publisher: The Endocrine Society
Date: 25-10-2019
Abstract: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.
Publisher: Wiley
Date: 13-01-2022
DOI: 10.1111/BPH.15738
Abstract: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi‐target drug used to treatment of coronary artery disease, trimetazidine, in SOD1 G93A mice. As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti‐inflammatory and antioxidant effect. We orally treated SOD1 G93A mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg −1 , from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord. Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1 G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves. In SOD1 G93A mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-02-2022
DOI: 10.1126/SCITRANSLMED.ABJ0264
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 s les passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
Publisher: Wiley
Date: 09-08-2021
DOI: 10.1111/ENE.15003
Abstract: To establish the utility of venous creatinine as a biomarker to monitor loss of fat‐free mass in patients with amyotrophic lateral sclerosis (ALS). In this multicenter natural history study, body composition and venous creatinine were assessed in 107 patients with ALS and 52 healthy controls. Longitudinal patterns of venous creatinine and its association with the risk of death during follow‐up were determined in a cohort of patients with ALS from Australia ( n = 69) and the Netherlands ( n = 38). The mean levels of venous creatinine were 75.78 ± 11.15 μmol/L for controls, 70.25 ± 12.81 μmol/L for Australian patients, and 59.95 ± 14.62 μmol/L for Dutch patients with ALS. The relationship between measures of venous creatinine and fat‐free mass was similar between all groups ( r = 0.36, p 0.001). Within patients, fat‐free mass declined by 0.31 (95% confidence interval [CI]: 0.22–0.40) kg/month, and venous creatinine declined by 0.52 (95% CI: 0.38–0.66) μmol/L/month, with a longitudinal correlation of 0.57 (95% CI: 0.35–0.76, p 0.001). Lower levels of venous creatinine were associated with increased risk for earlier death in patients with ALS (hazard ratio = 0.94, 95% CI: 0.90–0.98, p = 0.007). Venous creatinine is decreased in ALS and declines alongside a decline in fat‐free mass over the course of the disease, and may serve as a practical marker to monitor the change of fat‐free mass in patients with ALS. This could inform clinical care and provide an alternative endpoint for the evaluation of therapeutic interventions that focus on slowing the loss of fat‐free mass and disease progression in ALS.
Publisher: Wiley
Date: 22-06-2015
DOI: 10.1111/JNE.12278
Abstract: Pharmacological studies reveal that interactions between hypothalamic inhibitory somatostatin and stimulatory growth hormone-releasing hormone (GHRH) govern pulsatile GH release. However, in vivo analysis of somatostatin and GHRH release into the pituitary portal vasculature and peripheral GH output demonstrates that the withdrawal of somatostatin or the appearance of GHRH into pituitary portal blood does not reliably dictate GH release. Consequently, additional intermediates acting at the level of the hypothalamus and within the anterior pituitary gland are likely to contribute to the release of GH, entraining GH secretory patterns to meet physiological demand. The identification and validation of the actions of such intermediates is particularly important, given that the pattern of GH release defines several of the physiological actions of GH. This review highlights the actions of neuropeptide Y in regulating GH release. It is acknowledged that pulsatile GH release may not occur selectively in response to hypothalamic control of pituitary function. As such, interactions between somatotroph networks, the median eminence and pituitary microvasculature and blood flow, and the emerging role of tanycytes and pericytes as critical regulators of pulsatility are considered. It is argued that collective interactions between the hypothalamus, the median eminence and pituitary vasculature, and structural components within the pituitary gland dictate somatotroph function and thereby pulsatile GH release. These interactions may override hypothalamic somatostatin and GHRH-mediated GH release, and modify pulsatile GH release relative to the peripheral glucose supply, and thereby physiological demand.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Informa UK Limited
Date: 29-05-2019
Publisher: eLife Sciences Publications, Ltd
Date: 23-12-2021
DOI: 10.7554/ELIFE.72937
Abstract: Gonadotropin-releasing hormone (GnRH) is the primary neuropeptide controlling reproduction in vertebrates. GnRH stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis via a G-protein-coupled receptor, GnRHR, in the pituitary gland. In mammals, GnRHR lacks a C-terminal cytosolic tail (Ctail) and does not exhibit homologous desensitization. This might be an evolutionary adaptation that enables LH surge generation and ovulation. To test this idea, we fused the chicken GnRHR Ctail to the endogenous murine GnRHR in a transgenic model. The LH surge was blunted, but not blocked in these mice. In contrast, they showed reductions in FSH production, ovarian follicle development, and fertility. Addition of the Ctail altered the nature of agonist-induced calcium signaling required for normal FSH production. The loss of the GnRHR Ctail during mammalian evolution is unlikely to have conferred a selective advantage by enabling the LH surge. The adaptive significance of this specialization remains to be determined.
Publisher: Wiley
Date: 12-09-2013
DOI: 10.1111/JNE.12078
Abstract: The age-associated decline in growth hormone (GH) secretion may be a consequence of the reduction in the number of GH-releasing hormone (GHRH) positive neurones. However, it remains unclear whether an alteration in the number or distribution of somatostatin (SST) neurones contributes to this change. In the present study, we characterised the role of SST in modulating the change in pulsatile GH secretion in male C57Bl/6J mice throughout puberty and into early adulthood. We assessed pulsatile GH secretion in mice at 4, 8 and 16 weeks of age. These ages correspond to early pubertal, early adulthood and adulthood, respectively. We show an elevation in peak, total and pulsatile GH secretion coinciding with periods of rapid linear growth. Using in situ hybridisation and morphometric methods, we mapped the distribution of Sst mRNA expression within the mouse brain relative to this change in pulsatile GH secretion. The results obtained show that altered pulsatile GH secretion in male mice from 4-16 weeks of age does not coincide with a significant change in the number of Sst mRNA expressing neurones or an abundance of Sst mRNA expression throughout the arcuate nucleus (ARC) and periventricular nucleus (PeV). Rather, we observed a progressive decline in Sst mRNA expressing neurones within subnuclei of the paraventricular nucleus at this time. We conclude that structural changes in Sst expression within the PeV and ARC may not reflect the observed decline in pulsatile GH secretion in mice from puberty into early adulthood.
Publisher: Wiley
Date: 05-09-2023
DOI: 10.1111/ENE.16052
Publisher: Springer Science and Business Media LLC
Date: 27-02-2020
DOI: 10.1038/S41525-020-0118-3
Abstract: We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands s le (area under the curve, AUC = 0.65, CI 95% = [0.62–0.68], p = 8.3 × 10 −22 ). The maximum AUC achieved was 0.69 (CI 95% = [0.66–0.71], p = 4.3 × 10 −34 ) when cell-type proportion was included in the predictor.
Publisher: Informa UK Limited
Date: 07-2017
DOI: 10.2147/DNND.S120607
Publisher: JMIR Publications Inc.
Date: 14-03-2021
Abstract: espite recent and potent technological advances, the real-world implementation of remote digital health technology in the care and monitoring of patients with motor neuron disease has not yet been realized. Digital health technology may increase the accessibility to and personalization of care, whereas remote biosensors could optimize the collection of vital clinical parameters, irrespective of patients’ ability to visit the clinic. To facilitate the wide-scale adoption of digital health care technology and to align current initiatives, we outline a road map that will identify clinically relevant digital parameters mediate the development of benefit-to-burden criteria for innovative technology and direct the validation, harmonization, and adoption of digital health care technology in real-world settings. We define two key end products of the road map: (1) a set of reliable digital parameters to capture data collected under free-living conditions that reflect patient-centric measures and facilitate clinical decision making and (2) an integrated, open-source system that provides personalized feedback to patients, health care providers, clinical researchers, and caregivers and is linked to a flexible and adaptable platform that integrates patient data in real time. Given the ever-changing care needs of patients and the relentless progression rate of motor neuron disease, the adoption of digital health care technology will significantly benefit the delivery of care and accelerate the development of effective treatments.
Publisher: The Endocrine Society
Date: 17-05-2011
DOI: 10.1210/EN.2011-0253
Abstract: Measures of pulsatile GH secretion require frequent collection and analysis of blood s les at regular intervals. Due to blood volume constraints, repeat measures of circulating levels of GH in mice remain challenging. Consequently, few observations exist in which the pulsatile pattern of GH secretion in mice have been characterized. To address this, we developed a technique for the collection and analysis of circulating levels of GH at regular and frequent intervals in freely moving mice. This was achieved through the development of a sensitive assay for the detection of GH in small (2 μl) quantities of whole blood. The specificity and accuracy of this assay was validated following guidelines established for single-laboratory validation as specified by the International Union of Pure and Applied Chemistry. We incorporated an established method for tail-clip blood s le collection to determine circulating levels of GH secretion in 36 whole blood s les collected consecutively over a period of 6 h. Resulting measures were characterized by peak secretion periods and interpulse stable baseline secretion periods. Periods characterized by elevated whole blood GH levels consisted of multicomponent peaks. Deconvolution analysis of resulting measures confirmed key parameters associated with pulsatile GH secretion. We show a striking decrease in pulsatile GH secretion in mice after 12-18 h of fasting. This model is necessary to characterize the pulsatile profile of GH secretion in mice and will significantly contribute to current attempts to clarify mechanisms that contribute to the regulation of GH secretion.
Publisher: The Endocrine Society
Date: 09-2014
DOI: 10.1210/EN.2014-1126
Abstract: Ghrelin is a gut hormone processed from the proghrelin peptide acting as the endogenous ligand of the GH secretagogue receptor 1a. The regulatory role of endogenous ghrelin on pulsatile GH secretion and linear growth had to be established. The aim of the present study was to delineate the endogenous actions of preproghrelin on peripheral and central components of the GH axis. Accordingly, the ultradian pattern of GH secretion was measured in young and old preproghrelin-deficient males. Blood s les were collected by tail bleeding every 10 minutes over a period of 6 hours. Analysis of the GH pulsatile pattern by deconvolution showed that GH was secreted in an ultradian manner in all genotypes, with major secretory peaks occurring at about 3-hour intervals. In older mice, the peak number was reduced and secretion was less irregular compared with younger animals. Remarkably, in young Ghrl−/− mice, the litude of GH secretory bursts was significantly reduced. In older mice, however, genotype differences were less significant. Changes in GH pulsatility in young Ghrl−/− mice were associated with a tendency for reduced GH pituitary contents and plasma IGF-I concentrations, but with only a minor impact on linear growth. In Ghrl+/− mice, despite reduced Acyl ghrelin to des-acyl ghrelin ratio, GH secretion was not impaired. Ghrelin deficiency was not associated with a reduction in hypothalamic GHRH content or altered response to GHRH stimulation. Therefore, reduction in GHRH production and/or sensitivity do not primarily account for the altered GH pulsatile secretion of young Ghrl−/− mice. Instead, GHRH expression was elevated in young but not old Ghrl−/− mice, suggesting that differential compensatory responses resulting from the absence of endogenous ghrelin is occurring according to age. These results show that endogenous ghrelin is a regulator of GH pulse litude in growing mice but does not significantly modulate linear growth.
Publisher: BMJ
Date: 08-09-2018
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 07-02-2008
DOI: 10.1111/J.1365-2826.2008.01661.X
Abstract: During pregnancy, neuroendocrine control of prolactin secretion is markedly altered to allow a state of hyperprolactinaemia to develop. Prolactin secretion is normally tightly regulated by a short-loop negative-feedback mechanism, whereby prolactin stimulates activity of tuberoinfundibular dopamine (TIDA) neurones to increase dopamine secretion into the pituitary portal blood. Dopamine inhibits prolactin secretion, thus reducing prolactin concentrations in the circulation back to the normal low level. Activation of this feedback secretion by placental lactogen during pregnancy maintains relatively low levels of prolactin secretion during early and mid-pregnancy. Despite the continued presence of placental lactogen, however, dopamine secretion from TIDA neurones is reduced during late pregnancy. Moreover, the neurones become completely unresponsive to endogenous or exogenous prolactin at this time, allowing a large nocturnal surge of prolactin to occur from the maternal pituitary gland during the night before parturition. In this review, we describe the changing patterns of prolactin secretion during pregnancy in the rat, and discuss the neuroendocrine mechanisms controlling these changes. The loss of response to prolactin is an important maternal adaptation to pregnancy, allowing the prolonged period of hyperprolactinaemia required for mammary gland development and function and for maternal behaviour immediately after parturition, and possibly also contributing to a range of other adaptive responses in the mother.
Publisher: Wiley
Date: 15-03-2016
DOI: 10.1002/CPHY.C150002
Abstract: This article reviews the main findings that emerged in the intervening years since the previous volume on hormonal control of growth in the section on the endocrine system of the Handbook of Physiology concerning the intra‐ and extrahypothalamic neuronal networks connecting growth hormone releasing hormone (GHRH) and somatostatin hypophysiotropic neurons and the integration between regulators of food intake/metabolism and GH release. Among these findings, the discovery of ghrelin still raises many unanswered questions. One important event was the application of deconvolution analysis to the pulsatile patterns of GH secretion in different mammalian species, including Man, according to gender, hormonal environment and ageing. Concerning this last phenomenon, a great body of evidence now supports the role of an attenuation of the GHRH/GH/Insulin‐like growth factor‐1 (IGF‐1) axis in the control of mammalian aging. © 2016 American Physiological Society. Compr Physiol 6:687‐735, 2016.
Publisher: Cold Spring Harbor Laboratory
Date: 19-03-2023
DOI: 10.1101/2023.03.13.23287229
Abstract: Amyotrophic lateral sclerosis (ALS), the most predominant form of Motor Neuron Disease (MND), is a progressive and fatal neurodegenerative condition that spreads throughout the neuromotor system by afflicting upper and lower motor neurons. Lower motor neurons project from the central nervous system and innervate muscle fibres at motor endplates, which degrade over the course of the disease leading to muscle weakness. The direction of neurodegeration from or to the point of neuromuscular junctions and the role of muscle itself in pathogenesis has continued to be a topic of debate in ALS research. To assess the variation in gene expression between affected and nonaffected muscle tissue that might lead to this local degeneration of motor units, we generated RNA-seq skeletal muscle transcriptomes from 28 MND cases and 18 healthy controls and conducted differential expression analyses on gene-level counts, as well as an isoform switching analysis on isoform-level counts. We identified 52 differentially-expressed genes (Benjamini-Hochberg-adjusted p 0.05) within this comparison, including 38 protein coding, 9 long non-coding RNA, and 5 pseudogenes. Of protein-coding genes, 31 were upregulated in cases including with notable genes including the collagenic COL25A1 ( p = 3.1 × 10 −10 ), SAA1 which is released in response to tissue injury ( p = 3.6 × 10 −5 ) as well as others of the SAA family, and the actin-encoding ACTC1 ( p = 2.3 × 10 −5 ). Additionally, we identified 17 genes which exhibited a functional isoform switch with likely functional consequences between cases and controls. Our analyses provide evidence of increased tissue generation in MND cases, which likely serve to compensate for the degeneration of motor units and skeletal muscle.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.NUTRES.2014.04.001
Abstract: Dysregulation of adipose hormones in obesity has been associated with the hastened development of metabolic syndrome and associated chronic disease sequalae including cardiovascular disease and type 2 diabetes mellitus. This study aims to identify common biochemical and anthropometric markers that impact adipose hormones, including adiponectin and leptin. Based on previous literature, it was hypothesized that these would be adversely impacted by liver function parameters, and adiponectin levels would be positively correlated with phospholipid Ω-3 fatty acids. Forty nondiabetic adult subjects (body mass index, ≥ 25.0 kg/m(2)) were recruited. Fasting plasma s les were taken to assess adipokine levels, glucose metabolism, electrolytes, liver enzymes, and blood lipids. Basic anthropometric measurements were also recorded. Adiponectin levels were positively correlated with high-density lipoprotein cholesterol and negatively correlated with anthropometric measures, insulin, liver enzymes, triglycerides, and very low-density lipoprotein cholesterol but not body mass index. Conversely, plasma leptin levels were positively correlated with anthropometric measures, C-reactive protein, high-density lipoprotein cholesterol, and plasma phospholipid proportions of Ω-3 α linoleic acid but inversely correlated with creatinine levels. These results support other data regarding correlations between adiponectin and relative adipose distribution. Correlations with specific liver enzymes may indicate that adiponectin levels are tied to fatty acid deposition in the liver however, liver/kidney damage though further mechanistic clarification is required. Leptin levels were associated with measures of adiposity but not liver enzymes. Each of these variables, along with blood lipids, may serve as potential future therapeutic targets for the prevention and management of obesity and related comorbidities.
Publisher: SAGE Publications
Date: 19-02-2014
Abstract: Intermittent fasting (IF) is neuroprotective across a range of insults, but the question of whether extending the interval between meals alters neurogenesis after ischemia remains unexplored. We therefore measured cell proliferation, cell death, and neurogenesis after transient middle cerebral artery occlusion (MCAO) or sham surgery (SHAM) in mice fed ad libitum (AL) or maintained on IF for 3 months. IF was associated with twofold reductions in circulating levels of the adipocyte cytokine leptin in intact mice, but also prevented further reductions in leptin after MCAO. IF/MCAO mice also exhibit infarct volumes that were less than half those of AL/MCAO mice. We observed a 30% increase in basal cell proliferation in the hippoc us and subventricular zone (SVZ) in IF/SHAM, relative to AL/SHAM mice. However, cell proliferation after MCAO was limited in IF mice, which showed twofold increases in cell proliferation relative to IF/SHAM, whereas AL/MCAO mice exhibit fivefold increases relative to AL/SHAM. Attenuation of stroke-induced neurogenesis was correlated with reductions in cell death, with AL/MCAO mice exhibiting twice the number of dying cells relative to IF/MCAO mice. These observations indicate that IF protects against neurological damage in ischemic stroke, with circulating leptin as one possible mediator.
Publisher: Springer International Publishing
Date: 2018
Publisher: Informa UK Limited
Date: 09-07-2020
Publisher: Wiley
Date: 14-07-2009
DOI: 10.1111/J.1365-2826.2009.01887.X
Abstract: Obesity is associated with reduced levels of growth hormone (GH) and the disruption of pulsatile GH secretion. This results in relative GH deficiency. It is likely that a regulatory relationship between GH secretion and adipose tissue exists as the secretion of GH recovers to normal levels after a reduction in body weight. This report characterise the expression and interaction of adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) and adiponectin, respectively, in regulating the activity of GH secreting cells. Polymerase chain reaction analysis of the GH3 cell line, rat anterior pituitary gland and isolated somatotroph cells from transgenic GFP expressing mice confirmed the expression of both AdipoR1 and AdipoR2 in GH secretory cells. Because GH cells expressed both receptors, it is likely that the measured increase in GH secretion, observed in primary cultured rat pituitary cells after 30 min of incubation with full-length murine adiponectin, was mediated by a direct receptor regulated process. Adiponectin induced an increase in intracellular Ca(2+) through both the influx of extracellular Ca(2+) and the release of intracellular Ca(2+) stores resulting in the secretion of GH. Furthermore, results confirm that this increase in GH secretion depended mainly on an increase in Ca(2+) influx through L-type Ca(2+) channels. It is concluded that adiponectin directly regulates GH secretion from somatotrophs by binding to either adiponectin receptor, and that this is mediated via a similar process observed after the stimulation of GH secretion by GH-releasing hormone.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 16-10-2013
Abstract: An increase in adiposity is associated with altered levels of biologically active proteins. These include the hormones adiponectin and leptin. The marked change in circulating concentrations of these hormones in obesity has been associated with the development of insulin resistance and metabolic syndrome. Variations in dietary lipid consumption have also been shown to impact obesity. Specifically, omega-3 fatty acids have been correlated with the prevention of obesity and subsequent development of chronic disease sequalae. This review explores animal and human data relating to the effects of omega-3 fatty acids (marine lipids) on adiponectin and leptin, considering plausible mechanisms and potential implications for obesity management. Current evidence suggests a positive, dose-dependent relationship between omega-3 fatty acid intake and circulating levels of adiponectin. In obese subjects, this may translate into a reduced risk of developing cardiovascular disease, metabolic syndrome and diabetes. In non-obese subjects, omega-3 is observed to decrease circulating levels of leptin however, omega-3-associated increases in leptin levels have been observed in obese subjects. This may pose benefits in the prevention of weight regain in these subjects following calorie restriction.
Publisher: Elsevier BV
Date: 2019
DOI: 10.2139/SSRN.3482152
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41588-021-00973-1
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 in iduals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2022
DOI: 10.1007/S00415-022-11273-X
Abstract: To capture the patient’s attitude toward remote monitoring of motor neuron disease (MND) in care and clinical trials, and their concerns and preferences regarding the use of digital technology. We performed an international multi-centre survey study in three MND clinics in The Netherlands, the United Kingdom, and Australia. The survey was co-developed by investigators and patients with MND, and sent to patients by e-mail or postal-mail. The main topics included: patients’ attitude towards remote care, participating in decentralized clinical trials, and preferences for and concerns with digital technology use. In total, 332 patients with MND participated. A majority of patients indicated they would be happy to self-monitor their health from home (69%), be remotely monitored by a multidisciplinary care team (75%), and would be willing to participate in clinical trials from home (65%). Patients considered respiratory function and muscle strength most valuable for home-monitoring. The majority of patients considered the use of at least three devices/apps (75%) once a week (61%) to be acceptable for home-monitoring. Fifteen percent of patients indicated they would not wish to perform home-measurements reporting concerns about the burden and distress of home-monitoring, privacy and data security. Most patients with MND exhibited a positive attitude toward the use of digital technology in both care and clinical trial settings. A subgroup of patients reported concerns with home-monitoring, which should be addressed in order to improve widespread adoption of remote digital technology in clinical MND care.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Wiley
Date: 25-11-2015
DOI: 10.1111/JNE.12327
Abstract: Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/-) mice.
Publisher: The Endocrine Society
Date: 24-03-2020
Publisher: Society for Neuroscience
Date: 03-12-2014
DOI: 10.1523/JNEUROSCI.4622-13.2014
Abstract: The hypothalamic NPY system plays an important role in regulating food intake and energy expenditure. Different biological actions of NPY are assigned to NPY receptor subtypes. Recent studies demonstrated a close relationship between food intake and growth hormone (GH) secretion however, the mechanism through which endogenous NPY modulates GH release remains unknown. Moreover, conclusive evidence demonstrating a role for NPY and Y-receptors in regulating the endogenous pulsatile release of GH does not exist. We used genetically modified mice (germline Npy , Y1 , and Y2 receptor knock-out mice) to assess pulsatile GH secretion under both fed and fasting conditions. Deletion of NPY did not impact fed GH release however, it reversed the fasting-induced suppression of pulsatile GH secretion. The recovery of GH secretion was associated with a reduction in hypothalamic somatotropin release inhibiting factor ( Srif somatostatin ) mRNA expression. Moreover, observations revealed a differential role for Y1 and Y2 receptors, wherein the postsynaptic Y1 receptor suppresses GH secretion in fasting. In contrast, the presynaptic Y2 receptor maintains normal GH output under long-term ad libitum -fed conditions. These data demonstrate an integrated neural circuit that modulates GH release relative to food intake, and provide essential information to address the differential roles of Y1 and Y2 receptors in regulating the release of GH under fed and fasting states.
Publisher: Wiley
Date: 04-07-2007
DOI: 10.1111/J.1365-2826.2007.01590.X
Abstract: During late-pregnancy, tuberoinfundibular dopaminergic (TIDA) neurones, a critical component of the negative-feedback loop regulating prolactin secretion, become unresponsive to the stimulatory effects of prolactin. The change in TIDA responsiveness to prolactin at this time results in a decrease in dopamine secretion and a prolactin surge. As the onset of parturition and the antepartum prolactin surge depend on the withdrawal of progesterone in the presence of oestrogen, it is likely that ovarian steroid hormones mediate this change in TIDA responsiveness. To determine whether ovarian steroids can directly modulate TIDA activity, and whether changes of receptor numbers might contribute to overall steroid-regulation of these neurones, we investigated the level of oestrogen receptor alpha (ERalpha) and progesterone receptor (PR) expression within TIDA neurones during pregnancy and lactation. Animals were sacrificed on dioestrous, days 12, 19 and 21 of pregnancy and day 5 of lactation, and the proportion of TIDA neurones expressing ERalpha or PR, as well as the total number of PR expressing cells within the arcuate nucleus, was determined. Approximately 75% and 55% of tyrosine hydroxylase neurones expressed ERalpha and PR, respectively. Levels of steroid receptor expression within TIDA neurones remained fairly constant, except for an increase in ERalpha on days 12 and 19 of pregnancy compared to dioestrous and lactation day 5. The presence of steroid receptors on TIDA neurones during pregnancy and lactation supports the concept of a direct effect of steroid hormones on these neurones at this time. Thus, steroid hormones may directly act on TIDA neurones to regulate maternal prolactin secretion. The relatively stable level of expression during late pregnancy suggests that a shift in steroid receptor expression during late pregnancy does not contribute to the change in TIDA responsiveness to prolactin at this time.
Publisher: The Endocrine Society
Date: 12-2013
DOI: 10.1210/EN.2013-1570
Abstract: GH deficiency is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, therapy with GH and/or IGF-I has not shown benefit. To gain a better understanding of the role of GH secretion in ALS pathogenesis, we assessed endogenous GH secretion in wild-type and hSOD1G93A mice throughout the course of ALS disease. Male wild-type and hSOD1G93A mice were studied at the presymptomatic, onset, and end stages of disease. To assess the pathological features of disease, we measured motor neuron number and neuromuscular innervation. We report that GH secretion profile varies at different stages of disease progression in hSOD1G93A mice compared with age-matched controls, GH secretion is unchanged prior to the onset of disease symptoms, elevated at the onset of disease symptoms, and reduced at the end stage of disease. In hSOD1G93A mice at the onset of disease, GH secretion is positively correlated with the percentage of neuromuscular innervation but not with motor neuron number. Moreover, this occurs in parallel with an elevation in the expression of muscle IGF-I relative to controls. Our data imply that increased GH secretion at symptom onset may be an endogenous endocrine response to increase the local production of muscle IGF-I to stimulate reinnervation of muscle, but that in the latter stages of disease this response no longer occurs.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
Publisher: Elsevier
Date: 2021
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.JNS.2014.02.035
Abstract: Amyotrophic lateral sclerosis (ALS) is an adult onset, neurodegenerative disease that is characterized by the loss of upper (corticospinal) and lower motor neurons. ALS is a multifactorial disease whereby a combination of genetic and environmental factors may contribute to disease pathogenesis. While the majority of studies indicate that the underlying causes for ALS pathology may be due to multiple defects at the cellular level, factors that have recently been identified to be associated with survival could lead to the development of beneficial interventions. In ALS, a higher pre-morbid body mass index (BMI) and the maintenance of BMI and nutritional state is associated with improved outcome. This review will focus on the associations between body composition and adiposity relative to disease duration and risk, and will discuss current evidence that supports the benefits of improving energy balance, and the maintenance of body mass through nutritional intervention in ALS.
Publisher: Oxford University Press (OUP)
Date: 24-09-2020
DOI: 10.1093/BRAINCOMMS/FCAA154
Abstract: Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the SOD1G93A mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, within the patient cohort there was considerable heterogeneity in whole-body metabolism and fuel oxidation profiles. Thus, future studies that decipher specific metabolic changes at an in idual patient level are essential for the development of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.YFRNE.2014.04.004
Abstract: Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby females are generally more frequently affected than males. In this review, we consider gender differences in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the prevalence of common autoimmune diseases specific to adult males and females in countries commonly surveyed. We discuss possible mechanisms for sex specific differences including gender differences in immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones, genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a significant influence on the development of autoimmune disease. Thus, considerations of gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease.
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3741233
Publisher: Wiley
Date: 08-11-2023
DOI: 10.1111/ENE.15589
Abstract: Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS. We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS ( n = 42), patients with AD ( n = 167) and non‐neurodegenerative disease controls ( n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes. Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite ( p = 0.58) or hypermetabolism ( p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight ( p = 0.08) and fat mass ( p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07). These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death.
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000446502
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research.
Publisher: Wiley
Date: 03-11-2016
DOI: 10.1113/JP272988
Publisher: Cold Spring Harbor Laboratory
Date: 24-03-2021
DOI: 10.1101/2021.03.12.21253115
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study (EWAS) meta-analysis in 10,462 s les (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.
Publisher: Cold Spring Harbor Laboratory
Date: 15-03-2021
DOI: 10.1101/2021.03.12.21253159
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced in iduals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: The Endocrine Society
Date: 21-01-2021
Abstract: Follicle-stimulating hormone (FSH) regulates gonadal function and fertility. Measurement of FSH in bodily fluids and tissues is possible with radioimmunoassays and enzyme-linked immunosorbent assays (ELISAs). Recently, several novel assays were developed to measure pituitary hormones including growth hormone, prolactin, and luteinizing hormone in mice from small s le volumes. Here, we describe a novel and sensitive ELISA that enables the accurate measurement of FSH in serum, plasma, and whole blood from female and male mice. The assay can also be used to measure FSH in murine pituitary lysates and cell culture media. In summary, the new methodology described here will enable investigators to measure FSH from a variety of biological s les in mice accurately, at low cost, and in their own laboratories.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2FD90004A
Publisher: BMJ
Date: 23-06-2020
Publisher: The American Association of Immunologists
Date: 06-2016
Abstract: The complement peptide C3a is a key component of the innate immune system and a major fragment produced following complement activation. We used a murine model of melanoma (B16-F0) to identify a hitherto unknown role for C3a-C3aR signaling in promoting tumor growth. The results show that the development and growth of B16-F0 melanomas is retarded in mice lacking C3aR, whereas growth of established melanomas can be arrested by C3aR antagonism. Flow cytometric analysis showed alterations in tumor-infiltrating leukocytes in the absence of C3aR. Specifically, neutrophils and CD4(+) T lymphocyte subpopulations were increased, whereas macrophages were reduced. The central role of neutrophils was confirmed by depletion experiments that reversed the tumor inhibitory effects observed in C3aR-deficient mice and returned tumor-infiltrating CD4(+) T cells to control levels. Analysis of the tumor microenvironment showed upregulation of inflammatory genes that may contribute to the enhanced antitumor response observed in C3aR-deficient mice. C3aR deficiency/inhibition was also protective in murine models of BRAF(V600E) mutant melanoma and colon and breast cancer, suggesting a tumor-promoting role for C3aR signaling in a range of tumor types. We propose that C3aR activation alters the tumor inflammatory milieu, thereby promoting tumor growth. Therapeutic inhibition of C3aR may therefore be an effective means to trigger an antitumor response in melanoma and other cancers.
Publisher: Cold Spring Harbor Laboratory
Date: 03-04-2020
DOI: 10.1101/2020.04.02.021238
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS. Here, using the SOD1 G93A mouse model of ALS, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an in idual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.
Publisher: Informa UK Limited
Date: 16-08-2021
Publisher: Informa UK Limited
Date: 27-04-2017
DOI: 10.1080/21678421.2017.1317811
Abstract: Anthropometric measurements including body mass index (BMI) and body adiposity index (BAI) are widely employed as indicators of fat mass (FM). Metabolic abnormalities in amyotrophic lateral sclerosis (ALS) impact disease progression, therefore assessment of FM informs care. The aim of this study was to determine whether BMI and BAI are accurate predictors of FM in ALS. Methodology and main findings: BMI, BAI and percentage FM (determined by air displacement plethysmography FM-ADP) were measured in control (n = 35) and ALS (n = 44) participants. While BMI and BAI correlated significantly with FM-ADP, neither index provided an accurate estimate of FM. In longitudinally assessed ALS participants (n = 29 ∼six-month repeat assessment interval), although a change in BMI (r Using FM-ADP as the standard, this study suggests that BMI and BAI are not accurate measures of FM in ALS. Furthermore, longitudinal assessments indicate that changes in BMI and BAI do not consistently reflect true changes of FM in ALS.
Publisher: Springer Science and Business Media LLC
Date: 06-02-2023
DOI: 10.1007/S00415-023-11584-7
Abstract: Actigraphy has been proposed as a measure for tracking functional decline and disease progression in patients with Motor Neuron Disease (MND). There is, however, little evidence to show that wrist-based actigraphy measures correlate with functional decline, and no consensus on how best to implement actigraphy. We report on the use of wrist actigraphy to show decreased activity in patients compared to controls, and compared the utility of wrist- and hip-based actigraphy for assessing functional decline in patients with MND. In this multi-cohort, multi-centre, natural history study, wrist- and hip-based actigraphy were assessed in 139 patients with MND (wrist, n = 97 hip, n = 42) and 56 non-neurological control participants (wrist, n = 56). For patients with MND, longitudinal measures were contrasted with clinical outcomes commonly used to define functional decline. Patients with MND have reduced wrist-based actigraphy scores when compared to controls (median differences: prop. active = − 0.053 [− 0.075, − 0.026], variation axis 1 = − 0.073 [− 0.112, − 0.021]). When comparing wrist- and hip-based measures, hip-based accelerometery had stronger correlations with disease progression (prop. active: τ = 0.20 vs 0.12 variation axis 1: τ = 0.33 vs 0.23), whereas baseline wrist-based accelerometery was better related with future decline in fine-motor function (τ = 0.14–0.23 vs 0.06–0.16). Actigraphy outcomes measured from the wrist are more variable than from the hip and present differing sensitivity to specific functional outcomes. Outcomes and analysis should be carefully constructed to maximise benefit, should wrist-worn devices be used for at-home monitoring of disease progression in patients with MND.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1FD00088H
Abstract: After introducing nanoelectrochemistry, this introductory lecture focuses on recent developments in two major application areas of nanoelectrochemistry electrocatalysis and using single entities in sensing.
Publisher: Research Square Platform LLC
Date: 18-03-2021
DOI: 10.21203/RS.3.RS-322430/V1
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced in iduals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: Bioscientifica
Date: 24-05-2013
DOI: 10.1530/JOE-13-0084
Abstract: Pathological changes associated with obesity are thought to contribute to GH deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contributes to progressive weight gain and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight epididymal fat mass and circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs), and glucose. Data were obtained from male mice maintained on a standard or high-fat diet. We confirm the suppression of pulsatile GH secretion following dietary-induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight, and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain and thus precedes the development of obesity. Moreover, data illustrate key interactions between GH secretion and circulating levels of insulin and reflect the potential physiological role of GH in modulation of insulin-induced lipogenesis throughout positive energy balance.
Publisher: Elsevier
Date: 2015
Publisher: Informa UK Limited
Date: 02-01-2017
DOI: 10.1080/10253890.2016.1276898
Abstract: In the laboratory setting, typical endocrine and targeted behavioral tests are limited in their ability to provide a direct assessment of stress in animals housed in undisturbed conditions. We hypothesized that an automated phenotyping system would allow the detection of subtle stress-related behavioral changes well beyond the time-frames examined using conventional methods. In this study, we have utilized the TSE PhenoMaster system to continuously record basal behaviors and physiological parameters including activity, body weight, food intake and oxygen consumption in undisturbed and stressed C57Bl/6J male mice (n = 12/group), with a pharmacological intervention using the conventional anxiolytic, diazepam (5 mg kg
Publisher: Wiley
Date: 23-11-2017
DOI: 10.1111/ACEL.12703
Publisher: The Endocrine Society
Date: 2012
DOI: 10.1210/EN.2011-1681
Abstract: Fasting results in the mobilization of adipose stores and the elevation of levels of free fatty acids (FFA). In humans, this process is driven by a release in GH. Little is known regarding the role of GH in modulating this process during early stages of fasting in the mouse. Confirmation of the role of GH in modulating FFA release in the fasting mouse is of particular importance given the frequent use of mouse models to study metabolic mechanisms. Here, we correlate the initial release of FFA throughout fasting in mice with pulsatile GH secretion. Observations illustrate the rapid release of FFA in response to food withdrawal. This does not correlate with a rise in GH secretion. Rather, we observed a striking loss in pulsatile secretion of GH throughout the first 6 h of fasting, suggesting that GH does not modulate the initial release of FFA in the mouse in response to fasting. This was confirmed in GH receptor knockout mice, in which we observed a robust fasting-induced rise in FFA. We further illustrate the dynamic relationship between the orexigenic and anorexigenic hormones ghrelin and leptin during fasting in the mouse. Our findings show an initial suppression of leptin and the eventual rise in circulating levels of acyl-ghrelin with fasting. However, altered acyl-ghrelin and leptin secretion occurs well after the rise in FFA and the suppression of GH secretion. Consequently, we conclude that although acyl-ghrelin and leptin may modulate the physiological response to drive food intake, these changes do not contribute to the initial loss of pulsatile GH secretion. Rather, it appears that the suppression of GH secretion in fasting may occur in response to an elevation in fasting levels of FFA or physiological stress. Observations highlight a ergent role for GH in modulating FFA release between man and mouse.
Publisher: Wiley
Date: 12-07-2019
Publisher: The Endocrine Society
Date: 27-12-2007
DOI: 10.1210/EN.2007-0867
Abstract: Hyperprolactinemia can reduce fertility and libido. Although central prolactin actions are thought to contribute to this, the mechanisms are poorly understood. We first tested whether chronic hyperprolactinemia inhibited two neuroendocrine parameters necessary for female fertility: pulsatile LH secretion and the estrogen-induced LH surge. Chronic hyperprolactinemia induced by the dopamine antagonist sulpiride caused a 40% reduction LH pulse frequency in ovariectomized rats, but only in the presence of chronic low levels of estradiol. Sulpiride did not affect the magnitude of a steroid-induced LH surge or the percentage of GnRH neurons activated during the surge. Estradiol is known to influence expression of the long form of prolactin receptors (PRL-R) and components of prolactin’s signaling pathway. To test the hypothesis that estrogen increases PRL-R expression and sensitivity to prolactin, we next demonstrated that estradiol greatly augments prolactin-induced STAT5 activation. Lastly, we measured PRL-R and suppressor of cytokine signaling (SOCS-1 and -3 and CIS, which reflect the level of prolactin signaling) mRNAs in response to sulpiride and estradiol. Sulpiride induced only SOCS-1 in the medial preoptic area, where GnRH neurons are regulated, but in the arcuate nucleus and choroid plexus, PRL-R, SOCS-3, and CIS mRNA levels were also induced. Estradiol enhanced these effects on SOCS-3 and CIS. Interestingly, estradiol also induced PRL-R, SOCS-3, and CIS mRNA levels independently. These data show that GnRH pulse frequency is inhibited by chronic hyperprolactinemia in a steroid-dependent manner. They also provide evidence for estradiol-dependent and brain region-specific regulation of PRL-R expression and signaling responses by prolactin.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.IJPHARM.2015.08.095
Abstract: In the current study, the efficacy and pharmacokinetic profile of lactose-conjugated luteinizing hormone releasing hormone (LHRH) was examined following oral administration in male rats. A rapid and sensitive liquid chromatography/mass spectrometry technique was developed and applied for measuring the concentration of lactose[Q(1)][w(6)]LHRH (compound 1) in rat plasma in order to allow measurement of pharmacokinetic parameters. LH release was evaluated using a sandwich ELISA. Maximum serum concentration (Cmax = 0.11 μg/ml) was reached at 2h (Tmax) following oral administration of the compound at 10mg/kg. The half-life was determined to be 2.6h. The absolute bioavailability of the orally administered compound was found to be 14%, which was a remarkable improvement compared to zero-to-low oral bioavailability of the native peptide. Compound 1 was effective in stimulating LH release at 20mg/kg after oral administration. The method was validated at a linear range of 0.01-20.0 μg/ml and a correlation coefficient of r(2) ≥ 0.999. The accuracy and precision values showed the reliability and reproducibility of the method for evaluation of the pharmacokinetic parameters. These findings showed that the lactose derivative of LHRH has a therapeutic potential to be further developed as an orally active therapeutics for the treatment of hormone-dependent diseases.
Publisher: Oxford University Press (OUP)
Date: 24-01-2016
Publisher: Informa UK Limited
Date: 30-05-2019
Publisher: Informa UK Limited
Date: 03-06-2022
DOI: 10.1080/07448481.2022.2061861
Abstract: The purposes of this study were to (1) longitudinally examine US college and university COVID-19 dashboard content and (2) explore county-level population health and COVID-19 community indicators where colleges with large undergraduate enrollments were located. We identified 10 colleges with the largest undergraduate enrollments. Next, we located all public and private two- and four-year nonprofit colleges ( In 2021 and 2022, two-thirds ( Overall quality, content, and features of COVID-19 dashboards varied greatly across colleges. Future COVID-19 dashboard designs should focus on providing evidence-based information with the goal of promoting and supporting informed decision making.
Publisher: The Endocrine Society
Date: 09-2012
DOI: 10.1210/EN.2012-1178
Abstract: The transition between puberty and adulthood is accompanied by a slowing in linear growth. Although GH is a key factor that drives somatic development into adulthood, early adulthood coincides with a reduction in circulating levels of GH. To this extent, a pathological decline in postpubertal GH secretion is detrimental to attainment of peak lean muscle mass and bone mass and promotes adiposity and increases susceptibility to the development of obesity in adulthood. Here we characterized pulsatile GH secretion in C57BL/6J mice at 12 and 16 wk of age. Deconvolution analysis of these measures reveals a reduction in pulsatile GH secretion between 12 and 16 wk of age. Dietary intervention with high-fat feeding at 8 wk of age results in a significant increase in adiposity, the development of glucose intolerance, and hyperinsulinemia. We show the exacerbation of the age-associated decline in pulsatile GH secretion in high-fat-fed mice after 4 wk of dietary intervention (at 12 wk of age), and a further suppression of pulsatile GH secretion by 8 wk of dietary intervention (at 16 wk of age). Suppressed pulsatile secretion of GH did not coincide with an elevation in circulating free fatty acids. Rather, we observed increased hepatic triglyceride content and an eventual decrease in circulating levels of IGF-I. Given the established role of GH in maintaining healthy aging, we anticipate that an advancing of the age-associated decline in pulsatile GH secretion as a consequence of dietary-induced weight gain may have long-term ramifications on adult health.
Publisher: Wiley
Date: 29-01-2021
DOI: 10.1111/JNE.12938
Abstract: Ghrelin is a gut hormone best known for its role in regulating appetite and stimulating the secretion of the anabolic hormone growth hormone (GH). However, there is considerable evidence to show wider‐ranging biological actions of ghrelin that favour improvements in cellular and systemic metabolism, as well as neuroprotection. Activation of these ghrelin‐mediated pathways may alleviate pathogenic processes that are assumed to contribute to accelerated progression of disease in patients with neurodegenerative disease. Here, we provide a brief overview on the history of discoveries that led to the identification of ghrelin. Focussing on the neurodegenerative disease amyotrophic lateral sclerosis (ALS), we also present an overview of emerging evidence that suggests that ghrelin and ghrelin mimetics may serve as potential therapies for the treatment of ALS. Given that ALS is a highly heterogeneous disease, where multiple disease mechanisms contribute to variability in disease onset and rate of disease progression, we speculate that the wide‐ranging biological actions of ghrelin might offer therapeutic benefit through modulating multiple disease‐relevant processes observed in ALS. Expanding on the well‐known actions of ghrelin in regulating food intake and GH secretion, we consider the potential of ghrelin‐mediated pathways in improving body weight regulation, metabolism and the anabolic and neuroprotective actions of GH and insulin‐like growth factor‐1 (IGF‐1). This is of clinical significance because loss of body weight, impairments in systemic and cellular metabolism, and reductions in IGF‐1 are associated with faster disease progression and worse disease outcome in patients with ALS.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 11-2006
DOI: 10.1111/J.1365-2826.2006.01499.X
Abstract: Oestrogen actions within the hypothalamus are essential for a range of reproductive functions. In this study, we sought to develop a method for suppressing central oestrogen action without affecting peripheral oestrogenic effects. We administered the oestrogen receptor antagonist ICI-182,780 (ICI) via crystalline implants into the left lateral ventricle or the arcuate nucleus and measured the effectiveness of this drug on three endpoints known to be regulated by oestrogen: gonadotrophin-releasing hormone (GnRH) pulse frequency, progesterone receptor expression and the generation of a sustained prolactin surge during late pregnancy. To confirm that central ICI administration had no effect on peripheral actions of oestrogen, we monitored changes in uterine weight. Intracerebroventricular ICI treatment reversed the inhibitory effects of oestrogen on GnRH pulse frequency, as measured by plasma luteinising hormone pulse frequency. No effect on the oestrogenic induction of progesterone receptors within the arcuate nucleus or ventromedial hypothalamus was observed however, a small yet significant reduction in progesterone receptor expression within dopaminergic neurones in the arcuate nucleus was observed. Intracerebroventricular or direct crystalline ICI administration to the arcuate nucleus did not change the serum prolactin level during late pregnancy. Central administration of ICI did not affect uterine weight, and thus did not have a peripheral effect. These data suggest that central administration of ICI can overcome some actions of oestrogen in the brain, such as GnRH pulse frequency, but does not affect other oestrogen mediated actions, including the induction of progesterone receptors or the antepartum prolactin surge. Thus, it appears that there is a differential sensitivity to the inhibition of central oestrogen actions by ICI.
Publisher: The Endocrine Society
Date: 23-05-2012
DOI: 10.1210/EN.2011-2171
Abstract: GH deficiency has been found in subjects with amyotrophic lateral sclerosis (ALS). Disrupted endocrine function could contribute to the progressive muscle loss and hypermetabolism seen in ALS. It is not possible to study all the elements of the GH-IGF-I axis in ALS patients. Consequently, it remains unclear whether dysfunctional GH secretion contributes to disease pathogenesis and why GH and IGF-I directed treatment strategies are ineffective in human ALS. The hSOD1G93A transgenic mouse model is useful for the detailed investigation of the pathogenesis of ALS. We report that symptomatic male hSOD1G93A transgenic mice exhibit a deficiency in GH secretion similar to that seen in human ALS. Further characterization of the GH-IGF-I axis in hSOD1G93A mice reveals central and peripheral abnormalities that are not found in wild-type age-matched controls. Specifically, we observe aberrant endogenous pulsatile GH secretion, reduced pituitary GH content, and decreased circulating levels of IGF-I, indicating global GH deficiency in hSOD1G93A mice. Furthermore, a reduction in the expression of the IGF-I receptor α-subunit in skeletal muscle and lumbar spinal cords of hSOD1G93A mice suggests impaired IGF-I signaling within these tissues. This is the first account of disrupted GH secretion in a transgenic mouse model of ALS. These observations are essential for the development of effective GH and IGF-I targeted therapies in ALS.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2021
DOI: 10.1186/S13578-020-00511-2
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.
Publisher: Informa UK Limited
Date: 27-09-2022
Publisher: Frontiers Media SA
Date: 23-01-2018
Publisher: Cold Spring Harbor Laboratory
Date: 16-09-2021
DOI: 10.1101/2021.09.13.460073
Abstract: Gonadotropin-releasing hormone (GnRH) is the primary neuropeptide controlling reproduction in vertebrates. GnRH stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis via a G protein-coupled receptor, GnRHR, in the pituitary gland. In mammals, GnRHR lacks a C-terminal cytosolic tail (Ctail) and does not exhibit homologous desensitization. This might be an evolutionary adaptation that enables LH surge generation and ovulation. To test this idea, we fused the chicken GnRHR Ctail to the endogenous murine GnRHR in a transgenic model. The LH surge was blunted, but not blocked in these mice. In contrast, they showed reductions in FSH production, ovarian follicle development, and fertility. Addition of the Ctail altered the nature of agonist-induced calcium signaling required for normal FSH production. The loss of the GnRHR Ctail during mammalian evolution is unlikely to have conferred a selective advantage by enabling the LH surge. The adaptive significance of this specialization remains to be determined.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.CECA.2011.12.005
Abstract: The secretion of growth hormone (GH) from somatotrophs located within the anterior pituitary gland is stimulated by endogenous hypothalamic growth hormone-releasing hormone (GHRH) and the GH secretagogue (GHS) ghrelin, and inhibited by somatotropin-releasing inhibitory factor (SRIF, also known as somatostatin). These factors bind to specific G-protein-coupled receptors on the cell membrane, and directly or indirectly modify the properties of ion channels and second messenger systems. Ultimately this results in a change in intracellular free Ca(2+) concentration ([Ca(2+)](i)) and the secretion of GH. Somatotrophs possess a variety of ion channels on their membranes, and modification of these ion channels, especially Ca(2+), K(+), and Na(+) channels, is tightly linked to intracellular Ca(2+) levels and therefore hormone secretion. Various issues regarding receptor distribution, role of ion channels, alteration of membrane potential, and involvement of intracellular signaling system in the control of GH secretion are discussed in this review. In particular, this work will focus on ion channels and [Ca(2+)](i) in somatotrophs.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.BEEM.2017.10.009
Abstract: Growth hormone (GH) secretory patterns emerge following birth, and changes in patterning occur throughout life. These secretory patterns are coupled to growth, reproduction and metabolism. Comparing human and animal studies, this review will highlight ultradian patterning of GH release and the mechanisms that contribute to this. Discussions will focus on the emergence in variations in the number and frequency of GH secretory events, and the amounts of GH released (peak and basal). Animal studies have contributed significantly to our understanding of the processes that regulate GH release. However, translation of knowledge from animal models to benefit our understanding of human physiology is sometimes limited. To overcome these limitations, it is critical that we reconcile the cause and consequences of differences in GH release between humans and model organisms. In doing so, we can embrace emerging technologies that will rapidly advance our knowledge of endogenous process that control GH release.
Publisher: Oxford University Press (OUP)
Date: 16-06-2023
Abstract: Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other MN diseases and draw perspectives for future research and treatment.
Publisher: Springer Science and Business Media LLC
Date: 2015
Publisher: The Open Journal
Date: 05-08-2022
DOI: 10.21105/JOSS.04368
Publisher: Springer Science and Business Media LLC
Date: 25-04-2022
DOI: 10.1186/S40478-022-01360-5
Abstract: A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin ( n -agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n -agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n -agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n -agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND.
Publisher: Wiley
Date: 02-10-2016
DOI: 10.1113/JP272770
Publisher: Springer Science and Business Media LLC
Date: 26-03-2021
DOI: 10.1186/S13059-021-02275-5
Abstract: People with neurodegenerative disorders show erse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
Publisher: American Chemical Society (ACS)
Date: 11-10-2017
DOI: 10.1021/ACS.JMEDCHEM.6B01771
Abstract: Gonadotropin-releasing hormone (GnRH) agonists (e.g., triptorelin) are used for androgen suppression therapy. They possess improved stability as compared to the natural GnRH, yet they suffer from a poor pharmacokinetic profile. To address this, we used a GnRH peptide-modified dendrimer platform with and without lipidation strategy. Dendrimers were synthesized on a polylysine core and bore either native GnRH (1, 2, and 5) or lipid-modified GnRH (3 and 4). Compound 3, which bore a lipidic moiety in a branched tetramer structure, showed approximately 10-fold higher permeability and metabolic stability and 39 times higher antitumor activity against hormone-resistant prostate cancer cells (DU145) relative to triptorelin. In gonadotropin-release experiments, dendrimer 3 was shown to be the most potent construct. Dendrimer 3 showed similar luteinizing hormone (LH)-release activity to triptorelin in mice. Our findings indicate that dendrimer 3 is a promising analog with higher potency for the treatment of hormone-resistant prostate cancer than the currently available GnRH agonists.
Publisher: The Endocrine Society
Date: 11-2012
DOI: 10.1210/EN.2012-1622
Abstract: Ghrelin is the endogenous ligand for the GH secretagogue receptor (GHSR) and robustly stimulates GH release from the anterior pituitary gland. Ghrelin also regulates the secretion of anterior pituitary hormones including TSH, LH, prolactin (PRL), and ACTH. However, the relative contribution of a direct action at the GHSR in the anterior pituitary gland vs. an indirect action at the GHSR in the hypothalamus remains undefined. We used a novel GHSR-enhanced green fluorescent protein (eGFP) reporter mouse to quantify GHSR coexpression with GH, TSH, LH, PRL, and ACTH anterior pituitary cells in males vs. females and in chow-fed or calorie-restricted (CR) mice. GHSR-eGFP-expressing cells were only observed in anterior pituitary. The number of GHSR-eGFP-expressing cells was higher in male compared with females, and CR did not affect the GHSR-eGFP cell number. Double staining revealed 77% of somatotrophs expressed GHSR-eGFP in both males and females. Nineteen percent and 12.6% of corticotrophs, 21% and 9% of lactotrophs, 18% and 19% of gonadotrophs, and 3% and 9% of males and females, respectively, expressed GHSR-eGFP. CR increased the number of TSH cells, but suppressed the number of lactotrophs and gonadotrophs, expressing GHSR-eGFP compared with controls. These studies support a robust stimulatory action of ghrelin via the GHSR on GH secretion and identify a previously unknown sexual dimorphism in the GHSR expression in the anterior pituitary. CR affects GHSR-eGFP expression on lactotrophs, gonadotrophs, and thyrotrophs, which may mediate reproductive function and energy metabolism during periods of negative energy balance. The low to moderate expression of GHSR-eGFP suggests that ghrelin plays a minor direct role on remaining anterior pituitary cells.
Publisher: The Endocrine Society
Date: 02-02-2015
DOI: 10.1210/EN.2014-1571
Abstract: The pattern of prolactin (PRL) secretion depends on the physiological state. Due to insufficient detection sensitivity of existing assays, the precise description of these patterns in mice is lacking. We described an ultrasensitive ELISA assay that can detect mouse PRL in small fractions of whole blood, allowing longitudinal studies of PRL secretion profiles in freely moving mice. Over a 24-hour period, males displayed no oscillation in PRL levels, whereas virgin and lactating females showed large pulses. Peaks of PRL secretion reached 30–40 ng/mL in lactating female mice and rarely exceeded 10 ng/mL in virgin females. These pulses of PRL in lactating females were associated with suckling. The return of pups after an experimental 12-hour weaning induced a pulse of PRL release, reaching 100 ng/mL. This approach also enabled us to assess the inhibitory tone from hypothalamic dopamine neurons on PRL secretion. We used a dopamine D2 receptor antagonist to relieve pituitary lactotrophs from the tuberoinfundibular dopaminergic inhibitory tone and demonstrate a D2-induced PRL rise that can be used to evaluate both the secretory capacity of lactotrophs and the magnitude of the inhibitory tone on pituitary PRL release. We demonstrate that, although lactotroph function is altered to enhance chronic PRL output, their secretory response to acute stimulus is not modified during lactation and that chronic hyperprolactinemia is linked to a lower inhibitory tone. The combination of a sensitive PRL ELISA and administration of D2 receptor antagonist provide a unique opportunity to investigate the function and plasticity of the lactotroph axis in freely moving mice.
Publisher: Springer US
Date: 16-10-2022
Publisher: The Endocrine Society
Date: 06-03-2008
DOI: 10.1210/EN.2007-1623
Abstract: Prolactin stimulates tuberoinfundibular dopamine neurons in the arcuate nucleus of the hypothalamus, mediated by signal transducer and activator of transcription 5b (STAT5b). During late pregnancy, these neurons become unresponsive to prolactin, with a loss of prolactin-induced activation of STAT5b and decreased dopamine secretion. Suppressors of cytokine signaling (SOCS) proteins inhibit STAT-mediated signaling, and SOCS mRNAs are specifically elevated in the arcuate nucleus during late pregnancy. We hypothesized that changes in circulating ovarian steroids during late pregnancy might induce expression of SOCS mRNAs, thus disrupting STAT5b-mediated prolactin signaling. Rats were ovariectomized on d 18 of pregnancy and treated with ovarian steroids to simulate an advanced, normal, or delayed decline in progesterone. Early progesterone withdrawal caused an early increase in prolactin secretion, and increased SOCS-1 and -3 and cytokine-inducible SH2-containing protein (CIS) mRNA levels in the arcuate nucleus. Prolonged progesterone treatment prevented these changes. To determine whether ovarian steroids directly alter SOCS mRNA levels, estrogen- and/or progesterone-treated ovariectomized nonpregnant rats were acutely injected with prolactin (300 μg sc) or vehicle. SOCS-1 and -3 and CIS mRNA levels in the arcuate nucleus were significantly increased by estrogen or prolactin, whereas progesterone treatment reversed the effect of estrogen. Results demonstrate that estrogen and prolactin can independently induce SOCS mRNA in the arcuate nucleus and that this effect is negatively regulated by progesterone. This is consistent with the hypothesis that declining progesterone and high levels of estrogen during late pregnancy induce SOCS in the tuberoinfundibular dopamine neurons, thus contributing to their insensitivity to prolactin at this time.
Publisher: BMJ
Date: 29-04-2018
Abstract: To determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival. Fifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment. Hypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4 p .01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7) p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (−0.68 points/month vs −0.39 points/month p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03). Hypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS.
No related grants have been discovered for Frederik Steyn.