المؤلفون: Zongye Cai, Siyu Tian, Theo Klein, Ly Tu, Laurie W. Geenen, Thomas Koudstaal, Annemien E. van den Bosch, Yolanda B. de Rijke, Irwin K. M. Reiss, Eric Boersma, Claude van der Ley, Martijn Van Faassen, Ido Kema, Dirk J. Duncker, Karin A. Boomars, Karin Tran-Lundmark, Christophe Guignabert, Daphne Merkus

المصدر: Scientific Reports, Vol 12, Iss 1, Pp 1-14 (2022)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/79f725107d30412dac03fd519e49b69dTest

المؤلفون: Annelies Heylen, Yannick Vermeiren, Ido P. Kema, Martijn van Faassen, Claude van der Ley, Debby Van Dam, Peter P. De Deyn

المصدر: Pharmaceuticals, Vol 16, Iss 4, p 615 (2023)

مصطلحات موضوعية: amyotrophic lateral sclerosis, frontotemporal dementia, early onset Alzheimer’s disease, anthranilic acid, kynurenic acid, quinolinic acid, Medicine, Pharmacy and materia medica, RS1-441

الوصف: Objectives: Despite distinct clinical profiles, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients share a remarkable portion of pathological features, with a substantial percentage of patients displaying a mixed disease phenotype. Kynurenine metabolism seems to play a role in dementia-associated neuroinflammation and has been linked to both diseases. We aimed to explore dissimilarities in kynurenine pathway metabolites in these early onset neurodegenerative disorders in a brain-region-specific manner. Methods: Using liquid chromatography mass spectrometry (LC-MS/MS), kynurenine metabolite levels were determined in the brain samples of 98 healthy control subjects (n = 20) and patients with early onset Alzheimer’s disease (EOAD) (n = 23), ALS (n = 20), FTD (n = 24) or a mixed FTD–ALS (n = 11) disease profile. Results: Overall, the kynurenine pathway metabolite levels were significantly lower in patients with ALS compared to FTD, EOAD and control subjects in the frontal cortex, substantia nigra, hippocampus and neostriatum. Anthranilic acid levels and kynurenine-to-tryptophan ratios were consistently lower in all investigated brain regions in ALS compared to the other diagnostic groups. Conclusions: These results suggest that the contribution of kynurenine metabolism in neuroinflammation is lower in ALS than in FTD or EOAD and may also be traced back to differences in the age of onset between these disorders. Further research is necessary to confirm the potential of the kynurenine system as a therapeutic target in these early onset neurodegenerative disorders.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1424-8247/16/4/615Test; https://doaj.org/toc/1424-8247Test

الوصول الحر: https://doaj.org/article/f1641d36fab848f7a537b7c648a30fe7Test

المؤلفون: Lianmin Chen, Inge C.L. van den Munckhof, Kiki Schraa, Rob ter Horst, Martijn Koehorst, Martijn van Faassen, Claude van der Ley, Marwah Doestzada, Daria V. Zhernakova, Alexander Kurilshikov, Vincent W. Bloks, Albert K. Groen, Niels P. Riksen, Joost H.W. Rutten, Leo A.B. Joosten, Cisca Wijmenga, Alexandra Zhernakova, Mihai G. Netea, Jingyuan Fu, Folkert Kuipers

المصدر: Cell Reports, Vol 33, Iss 1, Pp 108212- (2020)

مصطلحات موضوعية: bile acids, genetics, gut microbiome, liver, enterohepatic circulation, obesity, Biology (General), QH301-705.5

الوصف: Summary: Bile acids (BAs) are implicated in the etiology of obesity-related conditions such as non-alcoholic fatty liver disease. Differently structured BA species display variable signaling activities via farnesoid X receptor (FXR) and Takeda G protein-coupled BA receptor 1 (TGR5). This study profiles plasma and fecal BAs and plasma 7α-hydroxy-4-cholesten-3-one (C4) in 297 persons with obesity, identifies underlying genetic and microbial determinants, and establishes BA correlations with liver fat and plasma lipid parameters. We identify 27 genetic associations (p < 5 × 10−8) and 439 microbial correlations (FDR < 0.05) for 50 BA entities. Additionally, we report 111 correlations between BA and 88 lipid parameters (FDR < 0.05), mainly for C4 reflecting hepatic BA synthesis. Inter-individual variability in the plasma BA profile does not reflect hepatic BA synthetic pathways, but rather transport and metabolism within the enterohepatic circulation. Our study reveals genetic and microbial determinants of BAs in obesity and their relationship to disease-relevant lipid parameters that are important for the design of personalized therapies targeting BA-signaling pathways.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211124720312018Test; https://doaj.org/toc/2211-1247Test

الوصول الحر: https://doaj.org/article/f5c4cfa383074f0b833a8d715bdad341Test

المؤلفون: Martijn van Faassen, Claude van der Ley, Ido P. Kema, Karin Eijkelenkamp, Rainer Bischoff, Wilhelmina H. A. de Jong

المساهمون: Analytical Biochemistry, Medicinal Chemistry and Bioanalysis (MCB), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM)

المصدر: Analytical Chemistry, 92(13), 9072-9078. AMER CHEMICAL SOC INC
Analytical Chemistry

مصطلحات موضوعية: Analyte, Dopamine, 010402 general chemistry, Tandem mass spectrometry, 01 natural sciences, Article, Analytical Chemistry, Levodopa, chemistry.chemical_compound, Catecholamines, Propionic anhydride, Limit of Detection, Reference Values, Tandem Mass Spectrometry, Humans, Solid phase extraction, Derivatization, Chromatography, High Pressure Liquid, Metanephrine, Detection limit, Chromatography, 010401 analytical chemistry, Solid Phase Extraction, Metanephrines, Plasma, 0104 chemical sciences, chemistry

الوصف: Plasma-free metanephrines and catecholamines are essential markers in the biochemical diagnosis and follow-up of neuroendocrine tumors and inborn errors of metabolism. However, their low circulating concentrations (in the nanomolar range) and poor fragmentation characteristics hinder facile simultaneous quantification by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Here, we present a sensitive and simple matrix derivatization procedure using propionic anhydride that enables simultaneous quantification of unconjugated l-DOPA, catecholamines, and metanephrines in plasma by LC-MS/MS. Dilution of propionic anhydride 1:4 (v/v) in acetonitrile in combination with 50 μL of plasma resulted in the highest mass spectrometric response. In plasma, derivatization resulted in stable derivatives and increased sensitivity by a factor of 4-30 compared with a previous LC-MS/MS method for measuring plasma metanephrines in our laboratory. Furthermore, propionylation increased specificity, especially for 3-methoxytyramine, by preventing interference from antihypertensive medication (β-blockers). The method was validated according to international guidelines and correlated with a hydrophilic interaction LC-MS/MS method for measuring plasma metanephrines (R2 > 0.99) and high-performance liquid chromatography with an electrochemical detection method for measuring plasma catecholamines (R2 > 0.85). Reference intervals for l-DOPA, catecholamines, and metanephrines in n = 115 healthy individuals were established. Our work shows that analytes in the subnanomolar range in plasma can be derivatized in situ without any preceding sample extraction. The developed method shows improved sensitivity and selectivity over existing methods and enables simultaneous quantification of several classes of amines.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d905b6f62987e2b8154b01de4efdbd7eTest
https://hdl.handle.net/11370/6cc708af-ebac-4c8c-a160-78099dfac8ecTest

المؤلفون: Ido P. Kema, Peter Paul De Deyn, Claude van der Ley, Jana Janssens, Martijn van Faassen, Yannick Vermeiren

المساهمون: Lifestyle Medicine (LM), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Molecular Neuroscience and Ageing Research (MOLAR)

المصدر: Neurochemical Research, 45(5), 1191-1201
Neurochemical Research 45 (2020) 5
Neurochemical research
NEUROCHEMICAL RESEARCH, 45(5), 1191-1201. SPRINGER/PLENUM PUBLISHERS
Neurochemical Research

مصطلحات موضوعية: 0301 basic medicine, Male, SYMPTOMS, L-DOPA, Biochemistry, METABOLITES, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, PARKINSONS-DISEASE, Monoaminergic, Medicine, Amyotrophic lateral sclerosis, Kynurenine, Neuropathology, Dopaminergic, General Medicine, EXPANSION, Middle Aged, Ventral tegmental area, Chemistry, medicine.anatomical_structure, QUINOLINIC ACID, Frontotemporal Dementia, Female, Frontotemporal dementia, medicine.medical_specialty, Neurophysiology, Substantia nigra, 03 medical and health sciences, Cellular and Molecular Neuroscience, KYNURENINE PATHWAY, Internal medicine, mental disorders, Humans, Biogenic Monoamines, LOBAR DEGENERATION, Biology, Aged, Retrospective Studies, Original Paper, business.industry, Amyotrophic Lateral Sclerosis, Biomarker, medicine.disease, COGNITIVE IMPAIRMENT, nervous system diseases, 030104 developmental biology, Endocrinology, chemistry, Dementia, Human medicine, ALS, business, 030217 neurology & neurosurgery, Biomarkers, Quinolinic acid

الوصف: Exploring the neurochemical continuum between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) with respect to monoamines and kynurenines in cerebrospinal fluid (CSF) and serum, may be useful to identify possible new research/therapeutic targets. Hence, we analysed monoamines and kynurenines in CSF and serum derived from patients with FTD (n = 39), ALS (n = 23), FTD-ALS (n = 4) and age-matched control subjects (n = 26), using reversed-phase ultra-high performance liquid chromatography (RP-UHPLC) with electrochemical detection (ECD) and liquid chromatography tandem mass spectrometry, respectively. We noted a shared dopaminergic disturbance in FTD and ALS when compared to CONTR, with significantly increased serum DA levels and decreased DOPAC concentrations, as well as decreased DOPAC/DA ratios in both disease groups. In CSF, significantly reduced DOPAC concentrations in FTD and ALS were observed as well. Here, a significant increase in DA levels and decrease in DOPAC/DA ratios was only found in FTD relative to CONTR. With respect to the kynurenine pathway (KP), we only found decreased HK/XA ratios, indicative for vitamin B6 status, in serum of ALS subjects compared to FTD. The dopaminergic commonalities observed in FTD and ALS might relate to a disturbance of dopaminergic nerve terminals in projection areas of the substantia nigra and/or ventral tegmental area, although these findings should first be confirmed in brain tissue. Lastly, based on the results of this work, the KP does not hold promise as a research/therapeutic target in FTD and ALS. Electronic supplementary material The online version of this article (10.1007/s11064-020-03002-5) contains supplementary material, which is available to authorized users.

وصف الملف: application/octet-stream; text/html; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::86ec2c877a5a0a14538da3ca9a4ddd79Test
https://doi.org/10.1007/s11064-020-03002-5Test

المؤلفون: Ido P. Kema, Rayoun Ramendra, André Marette, Darakhshan Sohail Ahmed, Laurence Raymond Marchand, Jing Ouyang, Malcolm Finkelman, Jonathan B. Angel, Brandon Fombuena, Claude van der Ley, Jean-Pierre Routy, Yonglong Zhang, John Lin, Petronela Ancuta, Stéphane Isnard, Bertrand Routy, Delphine Planas, Meriem Messaoudene, Thibault V. Varin, Corentin Richard

المساهمون: Lifestyle Medicine (LM), Guided Treatment in Optimal Selected Cancer Patients (GUTS)

المصدر: Open Forum Infectious Diseases
Open Forum Infectious Diseases, 7(9):338. Oxford University Press

مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, Gut flora, Gastroenterology, DISEASE, Major Articles, 03 medical and health sciences, 0302 clinical medicine, BUTYRATE, Weight loss, Diabetes mellitus, Internal medicine, INFECTION, medicine, microbiota, 030212 general & internal medicine, RISK, biology, business.industry, INFLAMMATORY RESPONSE, HIV, weight, nondiabetic, AKKERMANSIA-MUCINIPHILA, biology.organism_classification, medicine.disease, Polycystic ovary, CANCER, 3. Good health, Metformin, TRANSLOCATION, 030104 developmental biology, Infectious Diseases, AcademicSubjects/MED00290, Oncology, SYSTEMIC IMMUNE ACTIVATION, medicine.symptom, GAIN, business, metformin, Weight gain, Dyslipidemia, Akkermansia muciniphila, medicine.drug

الوصف: Background People with HIV (PWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities, and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PWH. The antidiabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PWH receiving ART, especially those with a low CD4/CD8 ratio. Methods In the Lilac pilot trial, we recruited 23 nondiabetic PWH receiving ART for more than 2 years with a low CD4/CD8 ratio (
The ability to keep an HIV elite controller status is not permanent. We showed that, independently to protective MHC-I HLA alleles, elevated level of anti-CMV IgG is linked to CD4 T-cell decay in a Canadian cohort of elite controllers.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0545f9c8a7c483de3124537391714380Test
http://europepmc.org/articles/PMC7489545Test

المؤلفون: Ido P. Kema, Claude van der Ley, Zongye Cai, Daphne Merkus, Martijn van Faassen, Dirk J. Duncker

المساهمون: Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM)

المصدر: European Respiratory Journal, 54. EUROPEAN RESPIRATORY SOC JOURNALS LTD

مصطلحات موضوعية: NAD synthesis, Lung, medicine.anatomical_structure, business.industry, medicine, Experimental approaches, Pharmacology, medicine.disease, business, Pulmonary hypertension, Animal models

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::383f9531f055d49e8afce03cd5bb4851Test
https://research.rug.nl/en/publications/f7338b1d-8245-4f33-990b-de247aa40d2bTest

المؤلفون: Ido P. Kema, Johanna M. Geleijnse, Stephan J. L. Bakker, Gerjan Navis, Else van den Berg, Ineke J. Riphagen, Anna van der Veen, Isidor Minović, António W Gomes-Neto, Claude van der Ley, Martijn van Faassen, Manfred Eggersdorfer

المساهمون: Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Organ Transplantation (GIOT), Value, Affordability and Sustainability (VALUE)

المصدر: American Journal of Clinical Nutrition, 106(6), 1366-1374. Oxford University Press
The American journal of clinical nutrition 106 (2017) 6
The American journal of clinical nutrition, 106(6), 1366-1374

مصطلحات موضوعية: Male, 0301 basic medicine, Vitamin b, Xanthurenates, Nutrition and Disease, Medicine (miscellaneous), Kidney, Gastroenterology, SERUM, Cohort Studies, chemistry.chemical_compound, Risk Factors, Voeding en Ziekte, Cause of Death, Neoplasms, Medicine, Longitudinal cohort, RISK, Nutrition and Dietetics, PLASMA, Middle Aged, renal transplantation, DEFICIENCY, Renal transplant, Pyridoxal Phosphate, Vitamin B Complex, Plasma concentration, Female, Kidney Diseases, Vitamin B 6 Deficiency, Adult, Vitamin, medicine.medical_specialty, infectious disease, Nutritional Status, Infections, MULTIPLE IMPUTATION, 03 medical and health sciences, Internal medicine, KYNURENINE, Humans, cancer, Xanthurenic acid, Pyridoxal, VLAG, Aged, 030109 nutrition & dietetics, business.industry, MASS-SPECTROMETRY, Kidney Transplantation, Vitamin B 6, chemistry, long-term mortality, functional vitamin B-6 status, Long term mortality, business, Biomarkers

الوصف: Background: Low plasma concentrations of pyridoxal 5'-phosphate (PLP) are common in renal transplant recipients (RTRs) and confer increased risk of long-term mortality. To our knowledge, it is not known whether low plasma PLP concentrations have functional (i.e., intracellular) consequences and, if so, whether such consequences are associated with increased risk of mortality.Objectives: We assessed the association of plasma PLP with functional vitamin B-6 status and explored the potential association of functional vitamin B-6 status with long-term mortality in RTRs.Design: In a longitudinal cohort of 678 stable RTRs with a median follow-up of 5.3 y (IQR: 4.8-6.1 y) and 297 healthy controls, PLP, plasma 3-hydroxykynurenine (3-HK), and xanthurenic acid (XA) were analyzed via validated assays. PLP was used as direct biomarker for vitamin B-6 status, and the 3-HK:XA ratio was used as functional biomarker of vitamin B-6 status with a higher ratio reflecting worse functional vitamin B-6 status.Results: Median PLP, 3-HK, and XA concentrations were 41 nmol/L (IQR: 29-60 nmol/L), 40.1 nmol/L (IQR: 33.0-48.0 nmol/L), and 19.1 nmol/L (IQR: 14.5-24.9 nmol/L), respectively, in healthy controls compared with 29 nmol/L (IQR: 17-50 nmol/L), 61.5 nmol/L (IQR: 45.6-86.5 nmol/L), and 25.5 nmol/L (IQR: 17.2-40.0 nmol/L), respectively, in RTRs (all P < 0.001). RTRs had a higher median 3-HK:XA ratio (2.38; IQR: 1.68-3.49) than did healthy controls (2.13; IQR: 1.63-2.71) (P < 0.05). In RTRs, the 3-HK:XA ratio was inversely associated with plasma PLP (β = -0.21, P < 0.001). Moreover, a higher 3-HK:XA ratio was independently associated with increased risk of all-cause mortality (HR per SD increment: 1.30; 95% CI: 1.13, 1.49), cancer mortality (HR per SD increment: 1.47; 95% CI: 1.12, 1.95), and infectious disease mortality (HR per SD increment: 1.50; 95% CI: 1.21, 1.86) in RTRs.Conclusions: Vitamin B-6-deficient RTRs have a worse functional vitamin B-6 status than do healthy controls and vitamin B-6-sufficient RTRs. Worse functional vitamin B-6 status in RTRs is independently associated with an increased risk of mortality particularly because of cancer and infectious disease. This trial was registered at clinicaltrials.gov as NCT02811835.

وصف الملف: application/pdf; application/octet-stream

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::38ca316cee62db31b67b4f43683a6836Test
https://doi.org/10.3945/ajcn.117.164012Test

المؤلفون: Ido P. Kema, Yannick Vermeiren, Ellen A. A. Nollen, Peter Paul De Deyn, Freek J. H. Sorgdrager, Claude van der Ley, Martijn van Faassen

المساهمون: Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM)

المصدر: Journal of Neurochemistry 151 (2019) 5
Journal of Neurochemistry, 151(5), 656-668. Blackwell Publishing Ltd
Journal of Neurochemistry
Journal of neurochemistry
Journal of Neurochemistry, 151(5), 656-668

مصطلحات موضوعية: 0301 basic medicine, Male, medicine.medical_specialty, Aging, Kynurenine pathway, Parkinson's disease, Excitotoxicity, medicine.disease_cause, Biochemistry, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, Kynurenic acid, Alzheimer Disease, kynurenic acid, Internal medicine, Medicine, Humans, Biology, Aged, business.industry, Clinical Studies, Biomakers & Imaging, Neurodegeneration, neurodegeneration, Parkinson Disease, Middle Aged, medicine.disease, kynurenine, Chemistry, 030104 developmental biology, Endocrinology, chemistry, ageing, Parkinson’s disease, Original Article, Female, Human medicine, ORIGINAL ARTICLES, business, Alzheimer’s disease, 030217 neurology & neurosurgery, Kynurenine, Quinolinic acid

الوصف: The kynurenine (Kyn) pathway, which regulates neuroinflammation and N‐methyl‐d‐aspartate receptor activation, is implicated in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Age‐related changes in Kyn metabolism and altered cerebral Kyn uptake along large neutral amino acid transporters, could contribute to these diseases. To gain further insight into the role and prognostic potential of the Kyn pathway in PD and AD, we investigated systemic and cerebral Kyn metabolite production and estimations of their transporter‐mediated uptake in the brain. Kyn metabolites and large neutral amino acids were retrospectively measured in serum and cerebrospinal fluid (CSF) of clinically well‐characterized PD patients (n = 33), AD patients (n = 33), and age‐matched controls (n = 39) using solid‐phase extraction‐liquid chromatographic‐tandem mass spectrometry. Aging was disease independently associated with increased Kyn, kynurenic acid and quinolinic acid in serum and CSF. Concentrations of kynurenic acid were reduced in CSF of PD and AD patients (p = 0.001; p = 0.002) but estimations of Kyn brain uptake did not differ between diseased and controls. Furthermore, serum Kyn and quinolinic acid levels strongly correlated with their respective content in CSF and Kyn in serum negatively correlated with AD disease severity (p = 0.002). Kyn metabolites accumulated with aging in serum and CSF similarly in PD patients, AD patients, and control subjects. In contrast, kynurenic acid was strongly reduced in CSF of PD and AD patients. Differential transporter‐mediated Kyn uptake is unlikely to majorly contribute to these cerebral Kyn pathway disturbances. We hypothesize that the combination of age‐ and disease‐specific changes in cerebral Kyn pathway activity could contribute to reduced neurogenesis and increased excitotoxicity in neurodegenerative disease.
To study the role and diagnostic potential of the kynurenine (Kyn) pathway in age‐related neurodegenerative disease, time‐linked serum, and cerebrospinal fluid (CSF) samples from Alzheimer’s disease (AD) patients, Parkinson’s disease (PD) patients and age‐matched cognitively healthy controls were retrospectively selected. Kyn metabolites and large neutral amino acids (LNAAs), which compete with Kyn metabolites to cross the blood–brain barrier, were analyzed by mass spectrometry. Age‐related increases of several Kyn metabolites were similar in controls, AD, and PD. Concentrations of kynurenic acid (KA), which plays a role in glutamate toxicity and neuronal development, were strongly reduced in CSF of PD and AD patients.

وصف الملف: text/html; application/pdf; pdf; application/octet-stream

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::069147d6e5d34efbad985448ca4b5613Test
https://research.wur.nl/en/publications/age-and-disease-specific-changes-of-the-kynurenine-pathway-in-parTest

المؤلفون: Ido P. Kema, André Marette, Claude van der Ley, Brandon Frombuena, Thibaut Varin, John Lin, Jean-Pierre Routy, Jonathan B. Angel, Meriem Messaoudene, Bertrand Routy, Petronela Ancuta, Delphine Planas, Stéphane Isnard

المصدر: Cancer Research. 80:PR04-PR04

مصطلحات موضوعية: Cancer Research, education.field_of_study, biology, business.industry, Population, Lachnospiraceae, Inflammation, Butyrate, Gut flora, biology.organism_classification, Polycystic ovary, Metformin, Oncology, Immunology, Medicine, Microbiome, medicine.symptom, business, education, medicine.drug

الوصف: Background: Persisting inflammation is associated with increased risk of comorbidities and cancer development in people living with HIV (PLWH) under antiretroviral therapy (ART). Indeed, our observations show that a low CD4/CD8 ratio is predictive of the number of polyps in the colon in those people. Mechanistically, we and other have shown that coinfection with viruses such as cytomegalovirus and gut damage inducing microbial translocation induce inflammation in ART-treated PLWH. Metformin, an antidiabetic drug with antiaging effect, was shown to decrease inflammation by improving glucose metabolism and changing gut microbiota composition in diabetic people and in nondiabetic women with polycystic ovary syndrome. In healthy men, metformin was also associated with modification of the gut microbiota. In PLWH, the gut microbiota is different than the general population, and its composition was associated with inflammatory profiles. Herein, we report results from the LILAC (CIHR/CTN PT027) pilot clinical trial evaluating the effect of 12 weeks of metformin on blood/gut inflammation and gut microbial composition in nondiabetic PLWH on ART. Methods: A total of 22 nondiabetic (HbA1c Results: CD4 T-cell count, CD4/CD8, and HbA1c levels did not vary between visits; however, plasma sCD14 levels decreased at V2 and V3 compared to V1. Bacterial alpha diversity tended to increase at V2 and V3. However, we observed a significant increase of Escherichia/Shigella and Lachnoclostridium and a decrease of Collinsella abundances at V2 compared to V1. A. muciniphila abundance was increased at V2. Abundance of Lachnospiraceae, specialized in butyrate production, was increased at V3 compared to V1. Accordingly, we found increased serum butyrate/isobutyrate levels at V2 and V3 compared to V1. No differences were observed for other SCFA propionate, succinate, and methylmalonate. Conclusion: A 12-week metformin therapy in nondiabetic PLWH on ART was safe and decreased plasma levels of the inflammatory marker sCD14 in association with an enrichment of butyrate-producing bacteria in stools and increased serum butyrate levels. As microbiota composition was associated with response to cancer therapy (especially immunotherapy), metformin use should be tested before immunotherapy. This abstract is also being presented as Poster A15. Citation Format: Stéphane Isnard, John Lin, Brandon Frombuena, Thibaut V. Varin, André Marette, Delphine Planas, Meriem Messaoudene, Bertrand Routy, Claude Van Der Ley, Ido Kema, Petronela Ancuta, Jonathan Angel, Jean-Pierre Routy. Potential of metformin to modify the gut microbiota and prevent inflammation in nondiabetic people with HIV [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR04.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1f4b8d4a68fcb5162b033ae6702fcb8aTest
https://doi.org/10.1158/1538-7445.mvc2020-pr04Test