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Serum Homocysteine, Pyridoxine, Folate, and Vitamin B12 Levels in Migraine: Systematic Review and Meta-Analysis.
Liampas, I, Siokas, V, Mentis, AA, Aloizou, AM, Dastamani, M, Tsouris, Z, Aslanidou, P, Brotis, A, Dardiotis, E
Headache. 2020;(8):1508-1534
Abstract
BACKGROUND Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies. OBJECTIVE The present study aims to review and meta-analyze data from studies investigating the difference of serum Hcy and Hcy lowering vitamins between migraine patients and healthy controls (HC), as well as between patients with MA and migraine without aura (MO). METHODS Literature search involved MEDLINE, Embase, CENTRAL, Google Scholar, and trial registries. The Newcastle-Ottawa Scale was used to evaluate the quality of the retrieved studies. Standardized mean differences (SMDs) and 95% confidence intervals (95%CIs) were calculated. Funnel-plots were utilized for the evaluation of publication bias. RESULTS Overall, 29 (28 case-control and 1 cross-sectional) studies were retrieved. Meta-analysis was indicative of higher Hcy concentration in migraine patients vs HC overall [adults and children: 16 studies, I2 = 81%, SMD = 0.41, 95%CI = (0.20, 0.61)]. Hcy was consistently elevated in adults with migraine [adults: 12 studies, I2 = 76%, SMD = 0.35, 95%CI = (0.15, 0.54); children: 1 study, SMD = 0.37, 95%CI = (-0.05, 0.79)]. Subgroup analyses reproduced the results for both adults with MA [7 studies, I2 = 83%, SMD = 0.37, 95%CI = (0.03, 0.71)] and MO [5 studies, I2 = 84%, SMD = 0.46, 95%CI = (0.03, 0.89)]. Figures for serum folate were lower in the overall comparison of migraine patients with HC [adults and children: 11 studies, I2 = 87%, SMD = -0.36, 95%CI = (-0.68, -0.05); adults: 8 studies, I2 = 6%, SMD = -0.11, 95%CI = (-0.22, 0.01); children: 1 study, SMD = -0.71, 95%CI = (-1.14, -0.29); MA adults: 4 studies, I2 = 44%, SMD = -0.16, 95%CI = (-0.35, 0.04); MO adults: 4 studies, I2 = 47%, SMD = -0.17, 95%CI = (-0.44, 0.10)]. Serum vitamin B12 levels were not different between migraine patients and HC [adults and children: 11 studies, I2 = 88%, SMD = -0.24, 95%CI = (-0.57, 0.09); adults: 8 studies, I2 = 57%, SMD = -0.10, 95%CI = (-0.28, 0.08); children: 1 study, SMD = 0.29, 95%CI = (-0.13, 0.71); MA adults: 4 studies, I2 = 63%, SMD = -0.14, 95%CI = (-0.48, 0.20); MO adults: 4 studies, I2 = 59%, SMD = -0.15, 95%CI = (-0.45, 0.15)]. Serum Hcy was lower in MO than MA [adults and children: 10 studies, I2 = 39%, SMD = 0.30, 95%CI = (0.14, 0.46), adults: 6 studies, I2 = 29%, SMD = 0.21, 95%CI = (0.09, 0.36), children: 1 study, SMD = 0.51, 95%CI = (0.22, 0.80)]. Serum folate and vitamin B12 did not differ between MA and MO. CONCLUSIONS Our results suggest that there is a possible link between migraine, mainly MA, and elevated serum Hcy.
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Genetic, epigenetic and genomic mechanisms of methionine dependency of cancer and tumor-initiating cells: What could we learn from folate and methionine cycles.
Guéant, JL, Oussalah, A, Zgheib, R, Siblini, Y, Hsu, SB, Namour, F
Biochimie. 2020;:123-128
Abstract
Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy.
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Association of Homocysteine, Methionine, and MTHFR 677C>T Polymorphism With Rate of Cardiovascular Multimorbidity Development in Older Adults in Sweden.
Calderón-Larrañaga, A, Saadeh, M, Hooshmand, B, Refsum, H, Smith, AD, Marengoni, A, Vetrano, DL
JAMA network open. 2020;(5):e205316
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IMPORTANCE Strong evidence links high total serum homocysteine (tHcy) and low methionine (Met) levels with higher risk of ischemic disease, but other cardiovascular (CV) diseases may also be associated with their pleiotropic effects. OBJECTIVES To investigate the association of serum concentrations of tHcy and Met with the rate of CV multimorbidity development in older adults and to explore the role of methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in this association. DESIGN, SETTING, AND PARTICIPANTS The Swedish National Study on Aging and Care in Kungsholmen is a cohort study of randomly selected individuals aged 60 years or older. The present study included data on 1969 individuals with complete information and without CV diseases at baseline, collected from the baseline examination (2001-2004) to the fourth follow-up (2013-2016). Data analysis was conducted from January to May 2019. EXPOSURES Concentrations of tHcy and Met were measured from nonfasting venous blood samples. The Met:tHcy ratio was considered a possible indicator of methylation activity. MTHFR status was dichotomized as any T carriers vs noncarriers. MAIN OUTCOME AND MEASURES The number of CV diseases at each wave was ascertained based on medical interviews and records, laboratory test results, and drug data. Linear mixed models were used to study the association of baseline tHcy and Met levels and the rate of CV multimorbidity development, adjusting for sociodemographic characteristics, CV risk factors, chronic disease burden, and drug use. RESULTS Of 1969 participants, most were women (1261 [64.0%]), with a mean (SD) age of 70.9 (9.8) years; 1703 participants (86.6%) had at least a high school level of education. Baseline measurements of serum tHcy, Met, and the Met:tHcy ratio were associated with the rate of CV disease accumulation (tHcy: β = 0.023 per year; 95% CI, 0.015 to 0.030; P < .001; Met: β = -0.007 per year; 95% CI, -0.013 to -0.001; P = .02; Met:tHcy ratio: β = -0.017 per year; 95% CI, -0.023 to -0.011; P < .001). The association between low Met concentrations and the rate of CV multimorbidity development was restricted to the group with CT/TT alleles of MTHFR (β = 0.023 per year; 95% CI, 0.006 to 0.041; P = .009). Results remained largely significant when individual CV diseases were removed from the total count 1 at a time (eg, ischemic heart disease, tHcy: β = 0.023 per year; 95% CI, 0.013 to 0.027; P < .001; Met: β = -0.006 per year; 95% CI, -0.011 to -0.0003; P = .04; Met:tHcy ratio: β = -0.015 per year; 95% CI, -0.020 to -0.009; P < .001). CONCLUSIONS AND RELEVANCE In this study, high tHcy and low Met levels were associated with faster CV multimorbidity development in older age. The interactive association of Met concentrations and MTHFR polymorphism, together with the association found for the Met:tHcy ratio, point toward the relevance of impaired methylation in the pathogenesis of CV aging.
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Micronutrients in support to the one carbon cycle for the modulation of blood fasting homocysteine in PCOS women.
Schiuma, N, Costantino, A, Bartolotti, T, Dattilo, M, Bini, V, Aglietti, MC, Renga, M, Favilli, A, Falorni, A, Gerli, S
Journal of endocrinological investigation. 2020;(6):779-786
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PURPOSE Fasting blood homocysteine is increased in PCOS women and is involved in several of its co-morbidities including cardiovascular disease and infertility. Corrective interventions based on the administration of supra-physiologic doses of folic acid work to a low extent. We aimed to test an alternative approach. METHODS This was a prospective, randomized, parallel group, open label, controlled versus no treatment clinical study. PCOS women aged > 18, free from systemic diseases and from pharmacological treatments were randomized with a 2:1 ratio for treatment with activated micronutrients in support to the carbon cycle (Impryl, Parthenogen, Switzerland-n = 22) or no treatment (n = 10) and followed-up for 3 months. Fasting blood homocysteine, AMH, testosterone, SHBGs, and the resulting FTI were tested before and at the end of the follow-up. RESULTS The mean baseline fasting blood homocysteine was above the normal limit of 12 μMol/L and inversely correlated with SHBG. AMH was also increased, whereas testosterone, SHBG, and FTI were within the normal limit. The treatment achieved a significant reduction of homocysteine, that did not change in the control group, independently of the starting value. The treatment also caused an increase of AMH and a decrease of SHBGs only in the subgroup with a normal homocysteine at baseline. CONCLUSIONS In PCOS ladies, blood homocysteine is increased and inversely correlated with the SHBGs. Physiologic amounts of activated micronutrients in support to the carbon cycle achieve a reduction virtually in all exposed patients. Whether this is of clinical benefit remains to be established.
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Effects of natural polyphenol-rich pomegranate juice on the acute and delayed response of Homocysteine and steroidal hormones following weightlifting exercises: a double-blind, placebo-controlled trial.
Ammar, A, MounaTurki, , Trabelsi, K, Bragazzi, NL, Boukhris, O, Bouaziz, M, Ayadi, F, El Abed, K, Driss, T, Souissi, N, et al
Journal of the International Society of Sports Nutrition. 2020;(1):15
Abstract
BACKGROUND Maximal strength-speed exercise is a powerful stimulus to acutely increase concentrations of circulating steroid hormones and homocysteine [Hcy]. There is some evidence that antioxidant beverages rich in polyphenols can attenuate [Hcy] levels and modulate endocrine responses in favor of an anabolic environment. Polyphenols-rich pomegranate (POM) have been reported to possess one of the highest antioxidant capacities compared to other purported nutraceuticals and other food stuffs. Studies focused on proving the beneficial effect of POM consumption during maximal strength exercises have only measured physical performance, muscle damage, oxidative stress and inflammatory responses, while POM effects on [Hcy] and hormonal adaptations are lacking. The aim of the present study was to investigate the effect of consuming natural polyphenol-rich pomegranate juice (POMj) on the acute and delayed [Hcy] and steroidal hormonal responses to a weightlifting exercises session. METHODS Nine elite weightlifters (21.0 ± 1 years) performed two Olympic-weightlifting sessions after ingesting either the placebo (PLA) or POMj supplements. Venous blood samples were collected at rest and 3 min and 48 h after each session. RESULTS Compared to baseline values, circulating cortisol [C] decreased (p < 0.01) and testosterone/cortisol [T/C] ratio increased immediately following the training session in both PLA and POMj conditions (p = 0.003 for PLA and p = 0.02 for POM). During the 48 h recovery period, all tested parameters were shown to recover to baseline values in both conditions with significant increases in [C] and decreases in [T/C] (p < 0.01 for PLA and p < 0.05 for POMj) from 3 min to 48 h post-exercises. Compared to PLA, a lower level of plasma testosterone [T] was registered 3 min post exercise using POMj supplementation (p = 0.012) and a significant decrease (p = 0.04, %change = - 14%) in plasma [Hcy] was registered during the 48 h recovery period only using POMj. A moderate correlation was observed between [Hcy] and [T] responses (p = 0.002, r = - 0.50). CONCLUSION In conclusion, supplementation with POMj has the potential to attenuate the acute plasma [T] response, but did not effect 48 h recovery kinetics of [Hcy] following weightlifting exercise. Further studies investigating androgen levels in both plasma and muscular tissue are needed to resolve the functional consequences of the observed acute POMj effect on plasma [T]. TRIAL REGISTRATION Clinical Trials.gov, ID: NCT02697903. Registered 03 March 2016.
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Homocysteine and IgA nephropathy: observational and Mendelian randomization analyses.
Zhang, YM, Zhou, XJ, Shi, SF, Liu, LJ, Lyu, JC, Zhang, H
Chinese medical journal. 2020;(3):277-284
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BACKGROUND High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach. METHODS For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays. RESULTS Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 μmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 μmol/L, Z = -5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 μmol/L, Z = -8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 μmol/L, Z = -1.32, P = 0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, χ = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 μmol/L, χ = 34.06, P < 0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min·1.73 m, χ = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ = 11.47, P < 0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, χ = 17.66, P < 0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P < 0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (β = 0.76, P = 0.02), systolic blood pressure (β = 0.26, P = 0.02), diastolic blood pressure (β = 0.20, P = 0.01), and pathologic T lesion (β = 0.01, P = 0.01) in IgAN. CONCLUSIONS By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.
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Effects of consuming red furu (fermented bean curd) on serum vitamin B-12, homocysteine and other cardiometabolic risk factors in young healthy volunteers: A randomized controlled trial.
Tsheko, T, Gu, J, Tong, W, Zhou, R, Li, D
Asia Pacific journal of clinical nutrition. 2020;(2):288-298
Abstract
BACKGROUND AND OBJECTIVES The health benefits of red furu in young, healthy volunteers had not been adequately investigated. The aim of this study was to determine the effect of a single meal containing red furu on serum vitamin B-12 (B-12), homocysteine and other cardiometabolic risk factors compared with that of tofu. METHODS AND STUDY DESIGN Twenty-three healthy volunteers from Zhejiang University, China, were randomly assigned to two groups of consumption, either red furu (n=11, 5 women and 6 men) or tofu (n=12, 6 women and 6 men). Volunteers consumed one breakfast meal composed of either 50 g of red furu (intervention group) or 50 g of tofu (non-active comparison group) with two slices of bread. Fasting blood was collected at 0 h, 24 h, and 72 h. Standard methods were used to measure the volunteers' biochemical parameters. RESULTS The consumption of 50 g of red furu a day did not significantly affect serum B-12 and showed a non-significant trend to reduce serum homocysteine. In the red furu group, but not in tofu group, serum concentrations of B-12 and folate were negatively associated with homocysteine, and B-12 was positively associated with folate. CONCLUSIONS A breakfast meal with 50 g of red furu containing 0.096 μg of B-12 did not increase serum B-12 in healthy volunteers. These results suggested that one meal containing B-12 could be sufficient to reduce serum Hcy.
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Highly selective sensor for the detection of Hg2+ ions using homocysteine functionalised quartz crystal microbalance with cross-linked pyridinedicarboxylic acid.
Rotake, DR, Kumar, A, Darji, AD, Singh, J
IET nanobiotechnology. 2020;(7):563-573
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This study reports an insightful portable vector network analyser (VNA)-based measurement technique for quick and selective detection of Hg2+ ions in nanomolar (nM) range using homocysteine (HCys)-functionalised quartz-crystal-microbalance (QCM) with cross-linked-pyridinedicarboxylic acid (PDCA). The excessive exposure to mercury can cause damage to many human organs, such as the brain, lungs, stomach, and kidneys, etc. Hence, the authors have proposed a portable experimental platform capable of achieving the detection in 20-30 min with a limit of detection (LOD) 0.1 ppb (0.498 nM) and a better dynamic range (0.498 nM-6.74 mM), which perfectly describes its excellent performance over other reported techniques. The detection time for various laboratory-based techniques is generally 12-24 h. The proposed method used the benefits of thin-film, nanoparticles (NPs), and QCM-based technology to overcome the limitation of NPs-based technique and have LOD of 0.1 ppb (0.1 μg/l) for selective Hg2+ ions detection which is many times less than the World Health Organization limit of 6 μg/l. The main advantage of the proposed QCM-based platform is its portability, excellent repeatability, millilitre sample volume requirement, and easy process flow, which makes it suitable as an early warning system for selective detection of mercury ions without any costly measuring instruments.
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Serum levels of Homocysteine, Vitamin B12 and Folate in Patients with Multiple Sclerosis: an Updated Meta-Analysis.
Li, X, Yuan, J, Han, J, Hu, W
International journal of medical sciences. 2020;(6):751-761
Abstract
Background: Multiple sclerosis (MS) is a demyelinating and disabling inflammatory disease of the central nervous system. MS is triggered by complex environmental factors which mostly affect genetically the susceptible young people. Emerging data has suggested that changes of homocysteine (Hcy), Vitamin B12 and folate serum levels may be associated with MS. However, previous findings are not always consistent. Methods: In this study, we aimed to investigate the relationships between MS and Hcy, Vitamin B12 and folate with updated available data (until September, 2019). The diagnosis of MS was performed based on international criteria for the diagnosis of MS, including magnetic resonance imaging and cerebrospinal fluid tests. We searched the databases including PubMed, EMBASE, Cochrane Library and ScienceDirect. After data collection, separate analyses based on random-effect models were used to test for relationships between MS and Hcy, Vitamin B12 or folate blood levels. The effective sizes were estimated by the combined standardized mean difference (SMD) and associated 95% confidence interval (CI). Results: Based on the inclusion criteria, a total of 21 original studies with 1738 MS patients and 1424 controls were included in this study. There were 17 studies for measuring Hcy, 16 studies for measuring Vitamin B12 and 13 studies for measuring folate in patients with MS, respectively. Specifically, patients with MS had higher serum levels of Hcy (SMD: 0.64; 95% CI:0.33, 0.95; P <0.0001) compared with control groups. There were no significant differences of SMD for Vitamin B12 (SMD: -0.08; 95% CI: -0.35, 0.20; P=0.58) or folate (SMD: 0.07; 95% CI: -0.14, 0.28; P=0.52) between MS and controls. Subgroup analysis demonstrated that there was statistically significant difference for Hcy between relapsing-remitting MS (RRMS) patients and controls with a SMD of 0.67 (95% CI: 0.21, 1.13; P=0.004). However, no significant difference of Hcy serum levels between secondary progressive MS patients or primary progressive MS patients and controls was noted in this study. In addition, there was no significant difference of Hcy levels in females (SMD: 0.22; 95% CI: -0.16, 0.60; P=0.25) or males (SMD: 0.56; 95% CI: -0.13, 1.26; P=0.11) between MS patients and controls. Conclusions: Higher serum levels of Hcy were noted in patients with MS when compared with control groups. And the difference was especially significant between RRMS patients and controls. Hcy may play an important role in the pathogenesis of MS. Functional studies are required to assess the effects of Hcy on patients with MS at the molecular level.
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Homocysteine: Its Possible Emerging Role in At-Risk Population Groups.
Azzini, E, Ruggeri, S, Polito, A
International journal of molecular sciences. 2020;(4)
Abstract
Increased plasma homocysteine is a risk factor for several pathological disorders. The present review focused on the role of homocysteine (Hcy) in different population groups, especially in risk conditions (pregnancy, infancy, old age), and on its relevance as a marker or etiological factor of the diseases in these age groups, focusing on the nutritional treatment of elevated Hcy levels. In pregnancy, Hcy levels were investigated in relation to the increased risk of adverse pregnancy outcomes such as small size for gestational age at birth, preeclampsia, recurrent abortions, low birth weight, or intrauterine growth restriction. In pediatric populations, Hcy levels are important not only for cardiovascular disease, obesity, and renal disease, but the most interesting evidence concerns study of elevated levels of Hcy in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Finally, a focus on the principal pathologies of the elderly (cardiovascular and neurodegenerative disease, osteoporosis and physical function) is presented. The metabolism of Hcy is influenced by B vitamins, and Hcy-lowering vitamin treatments have been proposed. However, clinical trials have not reached a consensus about the effectiveness of vitamin supplementation on the reduction of Hcy levels and improvement of pathological condition, especially in elderly patients with overt pathologies, suggesting that other dietary and non-dietary factors are involved in high Hcy levels. The importance of novel experimental designs focusing on intra-individual variability as a complement to the typical case-control experimental designs and the study of interactions between different factors it should be emphasized.