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Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
McCann, KJ, Yadav, M, Alishahedani, ME, Freeman, AF, Myles, IA
PloS one. 2021;(3):e0248011
Abstract
Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.
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The potential role of folate metabolism in interstitial cystitis.
Keagy, CD
International urogynecology journal. 2019;(3):363-370
Abstract
The topic of interstitial cystitis (IC), also known as painful bladder syndrome (PBS), and folate/one carbon metabolism has previously been unaddressed in research. This narrative review highlights a potential connection for those with mast cell-related IC and histamine-mediated pain that is explored through four conceptual sections. The first section focuses on the nature of mast cell involvement and histamine-mediated pain in some interstitial cystitis patients. The second section reviews the literature on folate status in wider allergic conditions. The third section addresses the role of folate and methylation in general in histamine excretion. Finally, folate metabolism and vascular function are addressed because of the vascular abnormalities present in some IC bladders.
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The effects of folate supplementation on lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials.
Tabrizi, R, Lankarani, KB, Akbari, M, Naghibzadeh-Tahami, A, Alizadeh, H, Honarvar, B, Sharifi, N, Mazoochi, M, Ostadmohammadi, V, Fatholahpour, A, et al
Diabetes & metabolic syndrome. 2018;(3):423-430
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Abstract
BACKGROUND AND OBJECTIVE Although several studies have assessed the effect of folate supplementation on lipid profiles among patients with metabolic diseases, findings are inconsistent. This review of randomized controlled trials (RCTs) was conducted to summarize the evidence on the effects of folate supplementation on lipid profiles among patients with metabolic diseases. METHODS Randomized-controlled trials (RCTs) published in PubMed, EMBASE, Web of Science and Cochrane Library databases up to until 20 August 2017 were searched. Two review authors independently assessed study eligibility, extracted data, and evaluated risk of bias of included studies. Heterogeneity was measured with a Q-test and with I2 statistics. Data were pooled by using the fix or random-effect model based on the heterogeneity test results and expressed as standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS A total of thirteen randomized controlled trials were included. Folate supplementation did not affect systolic blood pressure (SMD -0.87; 95% CI, -1.83, 0.09) and diastolic blood pressure (SMD -0.59; 95% CI, -1.55, 0.37), and lipid profiles including triglycerides (SMD 0.10; 95% CI, -0.42, 0.63), total- (SMD 0.06; 95% CI, -0.31, 0.43), HDL- (SMD 0.04; 95% CI, -0.36, 0.44), VLDL- (SMD 0.08; 95% CI, -0.24, 0.41), and LDL-cholesterol (SMD -0.14; 95% CI, -0.55, 0.28). CONCLUSIONS Folate supplementation did not affect blood pressures and lipid profiles among patients with metabolic diseases. Additional prospective studies regarding the impact of folate supplementation on blood pressures and lipid profiles in patients with metabolic diseases are necessary.
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Implication of homocysteine in diabetes and impact of folate and vitamin B12 in diabetic population.
Mursleen, MT, Riaz, S
Diabetes & metabolic syndrome. 2017;:S141-S146
Abstract
Diabetes mellitus is an acutely debilitating ailment affecting a large population of the world. At present, over 415 million people around the world including 7 million people in Pakistan suffering from diabetes. Homocysteine is an amino acid that is inversely related to vitamin B12 and folate, and raised level of homocysteine is implicated in many adverse health conditions. In this study, the potential role of homocysteine in diabetes and the epidemiology of hyperhomocysteinaemia, and vitamin B12 and folate deficiency is reviewed along with the impact of folate and vitamin B12 in regulation of homocysteine level. Deficiency of vitamin B12 and folate is rare in developed countries and the countries which adopted fortification programs, but deficiency of these vitamins is found to be highly prevalent in developing world, particularly in Pakistan. Several studies have found an association of high homocysteine levels and diabetes, but a few studies found contrary results. Hence, further epidemiological studies are recommended for homocysteine involvement in diabetes and vitamin B12 and folate deficiency, so that an urgent action can be taken to control the hyperhomocysteinaemia and consequently the ever increasing burden of disease and specifically diabetes.
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Nutritional factors and metabolic variables in relation to the risk of coronary heart disease: A case control study in Armenian adults.
Fazeli Moghadam, E, Tadevosyan, A, Fallahi, E, Goodarzi, R
Diabetes & metabolic syndrome. 2017;(1):7-11
Abstract
INTRODUCTION Dietary factors can affect the coronary heart disease (CHD). Results of previous studies on the association between the diet and CHD are not consistent in different countries. There were no data on this association in Armenia. OBJECTIVE Aims of this case-control study were to evaluate the association between nutritional factors and CHD among Armenians in Yerevan. METHODS During 2010 and 2011, we randomly selected 320 CHD patients with a diagnosis of CHD less than 6 months and 320 subjects without CHD (≥30years old) from the hospitals and polyclinics in Yerevan. Dietary intakes with 135 food items over the previous 12 months were evaluated using a semi-quantitative food frequency questionnaire. RESULTS After adjusting for some CHD risk factors higher intakes of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) were associated with a reduced risk of CHD, while this association was not witnessed for saturated fatty acids (SFA). In addition, findings indicated an inverse relation between vitamins (E, B6 and B12, folic acid) and fiber with CHD. In this population, smoking, hypertension, and metabolic syndrome (MetS) were significantly more common among patients with CHD. CONCLUSION The intake of vitamins E, B6 and B12, folic acid, PUFA, MUFA and fiber appeared to be predictors of CHD, independently of other risk factors.
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Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.
Burda, P, Kuster, A, Hjalmarson, O, Suormala, T, Bürer, C, Lutz, S, Roussey, G, Christa, L, Asin-Cayuela, J, Kollberg, G, et al
Journal of inherited metabolic disease. 2015;(5):863-72
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Abstract
In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.
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Folate: metabolism, genes, polymorphisms and the associated diseases.
Nazki, FH, Sameer, AS, Ganaie, BA
Gene. 2014;(1):11-20
Abstract
Folate being an important vitamin of B Complex group in our diet plays an important role not only in the synthesis of DNA but also in the maintenance of methylation reactions in the cells. Folate metabolism is influenced by several processes especially its dietary intake and the polymorphisms of the associated genes involved. Aberrant folate metabolism, therefore, affects both methylation as well as the DNA synthesis processes, both of which have been implicated in the development of various diseases. This paper reviews the current knowledge of the processes involved in folate metabolism and consequences of deviant folate metabolism, particular emphasis is given to the polymorphic genes which have been implicated in the development of various diseases in humans, like vascular diseases, Down's syndrome, neural tube defects, psychiatric disorders and cancers.
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Metabolic response to folate supplementation in overweight women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial.
Asemi, Z, Karamali, M, Esmaillzadeh, A
Molecular nutrition & food research. 2014;(7):1465-73
Abstract
SCOPE This study was conducted to determine the effects of folate supplementation on metabolic profiles in obese women with polycystic ovary syndrome (PCOS). METHODS AND RESULTS This randomized double-blind placebo-controlled clinical trial was conducted among 81 obese women (weight range: 65-110 kg) aged 18-40 year old diagnosed with PCOS. Participants were randomly assigned to three groups receiving: (1) Folate-1: 1 mg/day folate supplements (n = 27); (2) Folate-5: 5 mg/day folate supplements (n = 27), and (3) placebo (n = 27) for 8 weeks. Fasting blood samples were taken at baseline and after 8 weeks' intervention to quantify glucose metabolism and lipid concentrations. Folate supplementation (5 mg), compared with folate-1 and placebo, resulted in reduced plasma homocysteine (p-interaction = 0.009), homeostasis model of assessment-insulin resistance score (p-interaction = 0.01), and total cholesterol/HDL-C ratio (p-interaction = 0.01). Furthermore, we found a significant difference in mean change of serum total cholesterol (p-interaction = 0.01), LDL- (p-interaction = 0.007), and non-HDL-cholesterol levels (p = 0.01) in the folate-5 group compared with folate-1 and placebo. CONCLUSION 5 mg/day folate supplementation for 8 weeks among women with PCOS had beneficial effects on metabolic profiles.
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Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia.
Roffman, JL, Lamberti, JS, Achtyes, E, Macklin, EA, Galendez, GC, Raeke, LH, Silverstein, NJ, Smoller, JW, Hill, M, Goff, DC
JAMA psychiatry. 2013;(5):481-9
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Abstract
IMPORTANCE More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation. OBJECTIVES To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response. DESIGN Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12. SETTING Three community mental health centers affiliated with academic medical centers in the United States. PARTICIPANTS Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale. INTERVENTION One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo. MAIN OUTCOME MEASURES Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale). RESULTS Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups. CONCLUSIONS Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00611806.
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Maternal gene polymorphisms involved in folate metabolism and the risk of having a Down syndrome offspring: a meta-analysis.
Yang, M, Gong, T, Lin, X, Qi, L, Guo, Y, Cao, Z, Shen, M, Du, Y
Mutagenesis. 2013;(6):661-71
Abstract
Down syndrome (DS) is the most common chromosomal abnormality. Many studies have assessed the association between maternal gene polymorphisms involved in folate metabolism and the risk of having a DS offspring, but data are conflicting. Our study aimed to arrive at a more accurate estimation. Therefore, we carried out a meta-analysis of 26, 17, 9, 15, 9 and 6 case-control studies on the relationship between maternal methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, methionine synthase reductase (MTRR) A66G, reduced folate carrier 1 A80G and cystathionine β-synthase 844ins68 polymorphisms and the risk of having a DS offspring. The allele contrast and model-free approach were used. Results showed marginal significant associations for MTHFR C677T, overall [odds ratio (OR) = 1.28 (1.22, 1.46) and generalised odds ratio (ORG) = 1.35 (1.16, 1.57)] and in Caucasian [OR = 1.15 (1.03, 1.29) and ORG = 1.20 (1.04, 1.38)], Asian [OR = 1.68 (1.08, 2.63) and ORG = 1.74 (1.08, 2.80)] and Brazilian [OR = 1.22 (1.04, 1.43) and ORG = 1.28 (1.06, 1.55)] populations; for MTRR A66G, overall [OR = 1.22 (1.02, 1.46) and ORG = 1.31 (1.06, 1.62)]; and for RFC1 A80G, overall [OR = 1.16 (1.02, 1.31) and ORG = 1.18 (1.01, 1.37)]. MTHFR A1298C, MTR 12756G and CBS 844ins68 polymorphisms produced non-significant results. Since potential confounders could not be ruled out completely in this meta-analysis, further studies are needed to confirm these results.