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Folic acid supplementation normalizes the endothelial progenitor cell transcriptome of patients with type 1 diabetes: a case-control pilot study.

ABSTRACT: BACKGROUND: Endothelial progenitor cells play an important role in vascular wall repair. Patients with type 1 diabetes have reduced levels of endothelial progenitor cells of which their functional capacity is impaired. Reduced nitric oxide bioavailability and increased oxidative stress play a role in endothelial progenitor cell dysfunction in these patients. Folic acid, a B-vitamin with anti-oxidant properties, may be able to improve endothelial progenitor cell function. In this study, we investigated the gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes compared to endothelial progenitor cells from healthy subjects. Furthermore, we studied the effect of folic acid on gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes. METHODS: We used microarray analysis to investigate the gene expression profiles of endothelial progenitor cells from type 1 diabetes patients before (n = 11) and after a four week period of folic acid supplementation (n = 10) compared to the gene expression profiles of endothelial progenitor cells from healthy subjects (n = 11). The probability of genes being differentially expressed among the classes was computed using a random-variance t-test. A multivariate permutation test was used to identify genes that were differentially expressed among the two classes. Functional classification of differentially expressed genes was performed using the biological process ontology in the Gene Ontology database. RESULTS: Type 1 diabetes significantly modulated the expression of 1591 genes compared to healthy controls. These genes were found to be involved in processes regulating development, cell communication, cell adhesion and localization. After folic acid treatment, endothelial progenitor cell gene expression profiles from diabetic patients were similar to those from healthy controls. Genes that were normalized by folic acid played a prominent role in development, such as the transcription factors ID1 and MAFF. Few oxidative-stress related genes were affected by folic acid. CONCLUSION: Folic acid normalizes endothelial progenitor cell gene expression profiles of patients with type 1 diabetes. Signaling pathways modulated by folic acid may be potential therapeutic targets to improve endothelial progenitor cell function.

SUBMITTER: van Oostrom O

PROVIDER: S-EPMC2739843 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Folic acid supplementation normalizes the endothelial progenitor cell transcriptome of patients with type 1 diabetes: a case-control pilot study.

van Oostrom Olivia O de Kleijn Dominique P V DP Fledderus Joost O JO Pescatori Mario M Stubbs Andrew A Tuinenburg Attie A Lim Sai Kiang SK Verhaar Marianne C MC

Cardiovascular diabetology 20090825

<h4>Background</h4>Endothelial progenitor cells play an important role in vascular wall repair. Patients with type 1 diabetes have reduced levels of endothelial progenitor cells of which their functional capacity is impaired. Reduced nitric oxide bioavailability and increased oxidative stress play a role in endothelial progenitor cell dysfunction in these patients. Folic acid, a B-vitamin with anti-oxidant properties, may be able to improve endothelial progenitor cell function. In this study, we ...[more]

PMID: 19706161

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Project description:Background: Endothelial progenitor cells play an important role in vascular wall repair. Patients with type 1 diabetes have reduced levels of endothelial progenitor cells of which their functional capacity is impaired. Reduced nitric oxide bioavailability and increased oxidative stress play a role in endothelial progenitor cell dysfunction in these patients. Folic acid, a B-vitamin with anti-oxidant properties, may be able to improve endothelial progenitor cell function. In this study, we investigated the gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes compared to endothelial progenitor cells from healthy subjects. Furthermore, we studied the effect of folic acid on gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes. Methods: We used microarray analysis to investigate the gene expression profiles of endothelial progenitor cells from type 1 diabetes patients before (n=11) and after a four week period of folic acid supplementation (n=10) compared to the gene expression profiles of endothelial progenitor cells from healthy subjects (n=11). The probability of genes being differentially expressed among the classes was computed using a random-variance t-test. A multivariate permutation test was used to identify genes that were differentially expressed among the two classes. Functional classification of differentially expressed genes was performed using the biological process ontology in the Gene Ontology database. Results: Type 1 diabetes significantly modulated the expression of 1591 genes compared to healthy controls. These genes were found to be involved in processes regulating development, cell communication, cell adhesion and localization. After folic acid treatment, endothelial progenitor cell gene expression profiles from diabetic patients were similar to those from healthy controls. Genes that were normalized by folic acid played a prominent role in development, such as the transcription factors ID1 and MAFF. Few oxidative-stress related genes were affected by folic acid. Conclusion: Folic acid normalizes endothelial progenitor cell gene expression profiles of patients with type 1 diabetes. Signaling pathways modulated by folic acid may be potential therapeutic targets to improve endothelial progenitor cell function.

Project description:Background:Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. Objective:This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. Design:In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 ?g per day), 3 g creatine per day, 400 ?g FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo. Results:Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation. Conclusions:The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.

Project description:BackgroundTo prevent folate deficiencies, many countries supplement various foodstuffs with folic acid. This compound is a synthetic oxidised folate that differs from naturally occurring reduced folates in its metabolism and uptake. Notably, safety reviews of folic acid supplementation have not considered interactions with gut bacteria. Here, we use the Caenorhabditis elegans - Escherichia coli animal- microbe model to examine a possible bacterial route for folic acid uptake. It has been assumed that supplements are taken up directly by the worm, especially because E. coli is unable to take up folates. However, E. coli, like many other bacteria, can transport the folate breakdown product, para-aminobenzoate-glutamate (PABA-glu), via AbgT and use it for bacterial folate synthesis. This pathway may impact host health because inhibition of bacterial folate synthesis increases C. elegans lifespan.ResultsFolic acid supplementation was found to rescue a C. elegans developmental folate-deficient mutant; however, a much higher concentration was required compared to folinic acid, a reduced folate. Unlike folinic acid, the effectiveness of folic acid supplementation was dependent on the E. coli gene, abgT, suggesting a bacterial route with PABA-glu uptake by E. coli as a first step. Surprisingly, we found up to 4% PABA-glu in folic acid preparations, including in a commercial supplement. Via breakdown to PABA-glu, folic acid increases E. coli folate synthesis. This pathway restores folate synthesis in a bacterial mutant defective in PABA synthesis, reversing the ability of this mutant to increase C. elegans lifespan.ConclusionsFolic acid supplementation in C. elegans occurs chiefly indirectly via bacterial uptake of breakdown products via E. coli AbgT, and can impact C. elegans development and longevity. Examining how folic acid supplementation affects bacterial folate synthesis in the human gut may help us to better understand the safety of folic acid supplementation.

Project description:Ischemic stroke is a devastating, life altering event which can severely reduce patient quality of life. Despite years of research there have been minimal therapeutic advances. Endothelial progenitor cells (EPCs), stem cells involved in both vasculogenesis and angiogenesis, may be a potential therapeutic target. After a stroke, EPCs migrate to the site of ischemic injury to repair cerebrovascular damage, and their numbers and functional capacity may determine patients' outcome. This study aims to determine whether the number of circulating EPCs and their functional aspects may be used as biomarkers to identify the type (cortical or lacunar) and/or severity of ischemic stroke. The study will also investigate if there are any differences in these characteristics between healthy volunteers over and under 65 years of age. 100 stroke patients (50 lacunar and 50 cortical strokes) will be recruited in this prospective, observational case-controlled study. Blood samples will be taken from stroke patients at baseline (within 48 hours of stroke) and days 7, 30 and 90. EPCs will be counted with flow cytometry. The plasma levels of pro- and anti-angiogenic factors and inflammatory cytokines will also be determined. Outgrowth endothelial cells will be cultured to be used in tube formation, migration and proliferation functional assays. Primary outcome is disability or dependence on day 90 after stroke, assessed by the modified Rankin Scale. Secondary outcomes are changes in circulating EPC numbers and/or functional capacity between patient and healthy volunteers, between patient subgroups and between elderly and young healthy volunteers. Recruitment started in February 2017, 167 participants have been recruited. Recruitment will end in November 2019. West Midlands - Coventry & Warwickshire Research Ethics Committee approved this study (REC number: 16/WM/0304) on September 8, 2016. Protocol version: 2.0. The Bayraktutan Dunhill Medical Trust EPC Study was registered in ClinicalTrials.gov (NCT02980354) on November 15, 2016. This study will determine whether the number of EPCs can be used as a prognostic or diagnostic marker for ischemic strokes and is a step towards discovering if transplantation of EPCs may aid patient recovery.

Dataset Information

Folic acid supplementation normalizes the endothelial progenitor cell transcriptome of patients with type 1 diabetes: a case-control pilot study.

Publications

Folic acid supplementation normalizes the endothelial progenitor cell transcriptome of patients with type 1 diabetes: a case-control pilot study.

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