Folic Acid Treatment Research Articles

Folic acid and vitamin B12 treatment for children with nutritional anemia

From 1958 * to the beginning of 1960, we used vitamin B12 and folic acid treatment in children for alimentary anemia in 48 patients and folic acid alone in 20 patients.

Folic Acid Treatment for Patients with Vascular Cognitive Impairment: A Systematic Review and Meta-Analysis.

BackgroundAs the life expectancy of elderly people has drastically increased, the incidence of cardiovascular and cerebrovascular diseases in this population has proportionally grown. Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease. Homocysteine has recently been recognized as a contributor to the pathomechanisms involved in cognitive impairment. B vitamins, such as folic acid, are known to be effective in lowering homocysteine levels.MethodsWe conducted a systematic review and meta-analysis of research on folic acid treatments for vascular cognitive impairment. Only randomized controlled trials studies that compared the efficacy of folic acid with placebo or other interventions were considered, irrespective of publication status, year of publication, and languages. Two independent reviewers searched the Medline via Ovid, EMBASE, and Cochrane Central Register of Controlled Trials (Central) journal databases up to July 2021 and independently appraised the included studies. We used mean difference outcome with 95% confidence intervals (CI) to calculate the change of Mini-Mental State Examination, cognitive function domain, and concentration of homocysteine.ResultsWe found 3 studies comparing folic acid with placebo and 1 study comparing folic acid with other interventions. There is only slight evidence that the Mini-Mental State Examination score in patients who received folic acid increased 0.3 point higher compared with the placebo group after 24 months (95% CI = −0.12 to 0.37; P = .31). There is very strong evidence that the concentration of homocysteine in the folic acid group became 6.16 μmol/L lower compared with the placebo group after 6 months (95% CI = 2.32 to 8.21 lower; P < .001).ConclusionsOur review shows the effectiveness of folic acid in lowering the plasma homocysteine concentration after 6 months compared with placebo. However, this effect was not accompanied by improvement in cognitive function.Study registration: CRD42020199433 https://www.crd.york.ac.uk/prospero/export_details_pdf.php)

Point-of-care Hb measurement in pooled capillary blood by a portable autoanalyser: comparison with venous blood Hb measured by reference methods in cross-sectional and longitudinal studies.

Population-based surveys commonly use point-of-care (POC) methods with capillary blood samples for estimating Hb concentrations; these estimates need to be validated by comparison with reference methods using venous blood. In a cross-sectional study in 748 participants (17-86 years, 708 women, Hb: 5·1 to 18·2 g/dl) from Hyderabad, India, we validated Hb measured from a pooled capillary blood sample by a POC autoanalyser (Horiba ABX Micros 60OT, Hb-C-AA) by comparison with venous blood Hb measured by two reference methods: POC autoanalyser (Hb-V-AA) and cyanmethemoglobin method (Hb-V-CM). These comparisons also allowed estimation of blood sample-related and equipment-related differences in the Hb estimates. We also conducted a longitudinal study in 426 participants (17-21 years) to measure differences in the Hb response to iron folate (IFA) treatment by the capillary blood POC method compared with the reference methods. In the cross-sectional study, Bland-Altman analyses showed trivial differences between source of blood (Hb-C-AA and Hb-V-AA; mean difference, limits of agreement: 0·1, -0·8 to 1·0 g/dl) and between analytical methods (Hb-V-AA and Hb-V-CM; mean difference, limits of agreement: < 0·1, -1·8 to 1·8 g/dl). Cross-sectional anaemia prevalence estimated using Hb-C-AA did not differ significantly from Hb-V-CM or Hb-V-AA. In the longitudinal study, the Hb increment in response to IFA intervention was not different when using Hb-C-AA (1·6 ± 1·7 g/dl) compared with Hb-V-AA (1·7 ± 1·7 g/dl) and Hb-V-CM (1·7 ± 1·7 g/dl). The pooled capillary blood-autoanalyzer method (Hb-C-AA) offers a practical and accurate way forward for POC screening of anaemia.

Combining genetic risk score with artificial neural network to predict the efficacy of folic acid therapy to hyperhomocysteinemia

Artificial neural network (ANN) is the main tool to dig data and was inspired by the human brain and nervous system. Several studies clarified its application in medicine. However, none has applied ANN to predict the efficacy of folic acid treatment to Hyperhomocysteinemia (HHcy). The efficacy has been proved to associate with both genetic and environmental factors while previous studies just focused on the latter one. The explained variance genetic risk score (EV-GRS) had better power and could represent the effect of genetic architectures. Our aim was to add EV-GRS into environmental factors to establish ANN to predict the efficacy of folic acid therapy to HHcy. We performed the prospective cohort research enrolling 638 HHcy patients. The multilayer perception algorithm was applied to construct ANN. To evaluate the effect of ANN, we also established logistic regression (LR) model to compare with ANN. According to our results, EV-GRS was statistically associated with the efficacy no matter analyzed as a continuous variable (OR = 3.301, 95%CI 1.954–5.576, P < 0.001) or category variable (OR = 3.870, 95%CI 2.092–7.159, P < 0.001). In our ANN model, the accuracy was 84.78%, the Youden’s index was 0.7073 and the AUC was 0.938. These indexes above indicated higher power. When compared with LR, the AUC, accuracy, and Youden’s index of the ANN model (84.78%, 0.938, 0.7073) were all slightly higher than the LR model (83.33% 0.910, 0.6687). Therefore, clinical application of the ANN model may be able to better predict the folic acid efficacy to HHcy than the traditional LR model. When testing two models in the validation set, we got the same conclusion. This study appears to be the first one to establish the ANN model which added EV-GRS into environmental factors to predict the efficacy of folic acid to HHcy. This model would be able to offer clinicians a new method to make decisions and individual therapeutic plans.

Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells.

Diabetic cardiomyopathy (DCM) is the leading cause of death in diabetic patients. Folic acid has a protective effect on diabetes-induced cardiomyocyte damage. The aim of this study was to explore the effects of folic acid on cardiomyocytes cultured under high glucose and fat (HGF) conditions and type 2 diabetes mellitus (T2DM) mice, and elucidate the underlying mechanisms. Bioinformatics analysis was used to identify the potential drugs through the Drug-Gene Interaction database. H9C2 cardiomyocytes were cultured with 30 mM glucose and 500 nM palmitic acid in the presence or absence of folic acid or YAP1 inhibitor (verteporfin) or YAP1 siRNA. The cell viability and lactate dehydrogenase (LDH) release were measured using specific assay kits. Pyroptosis was detected by flow cytometry. The concentrations of IL-1β and IL-18 in the supernatants were measured by ELISA. The NLRP3, ASC and caspase-1 mRNA levels were detected by qRT-PCR and that the proteins expression of NLRP3, ASC, cleaved caspase-1 (p10), caspase-1, YAP1, p-YAP1, LATS1 and P-LATS1 were detected by Western blotting. C57BL/6 mice were fed with high fat diet (HFD) combined with streptozotocin (STZ) intraperitoneally to establish a T2DM model, folic acid or PBS treatment for 8 weeks by oral gavage, blood glucose and body weight were measured every 4 weeks, mouse heart tissue was used to detect pyroptosis and hippo signaling pathway related protein expression. We identified 427 differentially expressed genes in the cardiac tissues of high fat diet + streptozotocin mice, among the 30 most significantly DEGs, folic acid was predicted to be the most likely therapeutic drug. Folic acid alleviated HGF-induced cell damage in vitro and in vivo by decreasing activation of the Hippo pathway, as indicated by lower LDH release and increased cell viability, and decreased expression of NLRP3, ASC, cleaved caspase-1, IL-1β, IL-18, p-YAP and p-LATS. Verteporfin or YAP1 siRNA neutralized the protective effect of folic acid by reversing YAP1-induced pyroptosis. Folic acid reduced NLRP3 inflammasome-mediated pyroptosis by down-regulating the Hippo signaling pathway, thereby effectively reducing T2DM-induced damage in H9C2 cells and animals.

MHC class II in renal tubules plays an essential role in renal fibrosis.

Immunomodulation is considered a potential therapeutic approach for chronic kidney disease (CKD). Although it has been previously reported that CD4+ T cells contribute to the development of renal fibrosis, the role of MHC class II (MHCII) in the development of renal fibrosis remains largely unknown. The present study reports that the expression of MHCII molecules in renal cortical tubules is upregulated in mouse renal fibrosis models generated by unilateral ureter obstruction (UUO) and folic acid (FA). Proximal tubule epithelial cells (PTECs) are functional antigen-presenting cells that promote the proliferation of CD4+ T cells in an MHCII-dependent manner. PTECs from mice with renal fibrosis had a stronger ability to induce T cell proliferation and cytokine production than control cells. Global or renal tubule-specific ablation of H2-Ab1 significantly alleviated renal fibrosis following UUO or FA treatment. Renal expression of profibrotic genes showed a consistent reduction in H2-Ab1 gene-deficient mouse lines. Moreover, there was a marked increase in renal tissue CD4+ T cells after UUO or FA treatment and a significant decrease following renal tubule-specific ablation of H2-Ab1. Furthermore, renal tubule-specific H2-Ab1 gene knockout mice exhibited higher proportions of regulatory T cells (Tregs) and lower proportions of Th2 cells in the UUO- or FA-treated kidneys. Finally, Immunohistochemistry (IHC) studies showed increased renal expression of MHCII and the profibrotic gene α smooth muscle actin (α-SMA) in CKD patients. Together, our human and mouse data demonstrate that renal tubular MHCII plays an important role in the pathogenesis of renal fibrosis.

IRF-4 deficiency reduces inflammation and kidney fibrosis after folic acid-induced acute kidney injury

The chronic phase following toxin-induced acute kidney injury (AKI) is characterized by robust inflammation and progressive kidney fibrosis. Interferon regulatory factor 4 (IRF-4) is a type of multifunctional transcription factor that has been deeply linked to inflammation and fibrotic diseases. However, the role of IRF-4 in kidney damage and renal fibrosis after toxin-induced AKI remain to be explored. In this work, we examined the effect of IRF-4 deficiency on inflammation and kidney fibrosis in an AKI-chronic kidney disease (CKD) transition model induced by folic acid (FA) injury. We showed that FA treatment resulted in severe acute tubular injury followed by inflammatory reaction and interstitial fibrosis in wild-type mice. A sharp elevation of IRF-4 levels was observed in FA-injured kidneys. IRF-4 knockout led to a substantial reduction of extracellular matrix (ECM) proteins deposition and inhibited myofibroblasts transformation in the kidneys of mice subjected to FA treatment. In addition, IRF-4 ablation impaired F4/80+ macrophages and CD3+ T lymphocytes infiltration into the FA-injured kidneys. Loss of IRF-4 reduced the production of inflammatory molecules such as CXCL16, IL-18, IL-6, and TGF-β1 in the kidneys in response to FA stress. Following FA injury, the kidneys of IRF-4 knockout mice had fewer bone marrow-derived myofibroblasts than wild-type controls. Moreover, IRF-4 disruption inhibited macrophages to myofibroblasts differentiation in the kidneys in response to FA stimuli. In vitro, IL-4 stimulated expression of α-smooth muscle actin and ECM proteins and promoted M2 macrophages to myofibroblasts transition in mouse bone marrow-derived monocytes, which was abolished in the absence of IRF-4. Thus, we identified an important role of IRF-4 in the pathogenesis of progressive CKD following FA-induced AKI.

Folic acid Supplementation on placental Interleukin-6 and offspring growth in prenatal stress mice model

Introduction: Stress during pregnancy affects physical and psychological change, resulting in wide range of mild to severe abnormalities including inflammation, abberant placentation, fetal growth defect, and the decrease quality of life in the fetus’ adulthood. Previous study showed that Folic Acid (FA) has the potential effect in the pregnant and fetus’ prosperities due to the protective properties in the embryogenesis. To that end, we created the stress mice model and treated with FA, assessment was obtained by the expression of IL-6 in placenta and birth weight observation to reflect the fetus quality. Methods: subjects were 21 pregnant mice (Mus musculus) that divided into three groups (n=7) comprised of normal pregnant mice, stress mice model, and stress mice model treated with FA groups. Stress induction started from gestational day (gd) 10 to gd-15 by chronic restrain stress and 379 lux bright light exposure each twice-a-day within 30 minutes to induce depressive and anxiety-like behaviours. Folic acid treatment was begun with the similar time with the stress induction by dose dependent 3 mg/kg bw/day once a day prior the stress induction. On gd-16, mice were euthanized and fetal weight was examined followed by placental tissue collection for immunochemistry staining. Results: Placental IL-6 expression were not statistically different in stressed pregnant-mice treated by folic acid (p=0.077). There was a significant difference in fetal weight (p= 0.0001). In addition, the expression of placental IL-6 was associated with fetal weight (p= 0.021). Conclusions: The FA treatment has the ability to increase the fetal birth weight but unable to decrease the IL-6 as the pro-inflammatory cytokine in stress-induced mice.

P–686 &amp;lt;span&amp;gt;safety &amp;amp; efficacy of the combination therapy of inositols, antioxidants and vitamins in polycystic ovarian syndrome (PCOS): A multicentric, retrospective observational study (Trazer study)&amp;lt;/span&amp;gt;

Abstract Study question Does combinations therapy of insulin sensitizing agents, antioxidants and vitamins are safe and efficacious in PCOS patients. Summary answer Combination therapy of inositols, antioxidants and vitamins is safe and effective non-hormonal treatment option to manage PCOS. What is known already Monotherapy of insulin sensitising agents, antioxidants and vitamins is beneficial in the treatment of PCOS. Nutritional supplement containing inositols, N-acetylcysteine (NAC), lycopene, chromium picolinate, vitamin D3, biotin and folic acid treatment resulted in a significant improvement in menstrual cyclicity, acne and hirsutism. But there is no evidence pertaining to the hormonal parameters and ovarian morphology. Therefore, the present investigation was planned to evaluate the effects of combination therapy of inositols, antioxidants and vitamins on sign and symptoms, metabolic and hormonal parameters in women with PCOS. Study design, size, duration Multicentric, retrospective, observational cohort study was planned for the first time at thirty-six fertility clinics in different states of India from April 2019 to November 2020. Both lean and obese patients (16–39 years; n = 180) with confirmed diagnosis of PCOS as per the Rotterdam/ESHRE criteria were included in study. Participants/materials, setting, methods Patients were received a combination therapy of insulin sensitizers, antioxidants and vitamins in a marketed formulation (Trazer F ForteTM) twice daily as a tablet for 3 months and thereafter ovulation induction was done using letrozole (2.5–5 mg). Primary outcomes were improvements in signs of PCOS (menstrual cyclicity or ovulation restoration, acne and hirsutism), body weight, body mass index, waist circumference, ovarian cysts, pregnancy rate and hormonal balance. Secondary outcome was the evaluation of side effects. Main results and the role of chance Combination therapy of Trazer F ForteTM containing insulin sensitising agents (inositols, NAC and chromium), antioxidants (NAC and lycopene), and vitamins (vitamin D, biotin and folic acid) showed significant improvement in menstrual cyclicity by 54.3% and 88.2% in obese PCOS cases, and 48.7% and 79.5% in lean PCOS cases after 3- and 6-month of intervention respectively. Significant improvement was observed in acne, hirsutism and ovarian cysts post-intervention in both obese and lean PCOS women. After successful completion of the treatment, significant corrections were observed in metabolic (fasting glucose, fasting insulin and HOMA-IR) and hormonal profile (free testosterone, LH:FSH ratio, AMH and progesterone) in obese as well as lean PCOS cases. The clinical pregnancy rate was 16.2% and 34.1% in obese women, and 9.9% and 22.1% in lean cases after 3- and 6-month of intervention respectively. Limitations, reasons for caution Prevalent of PCOS is different in different population in India with diverse ethnic background. Hence, community-based intervention studies on larger population are needed to assess the efficacy and safety of such combinations amongst different age groups of women with PCOS. Wider implications of the findings: Since, PCOS is a multifactorial disorder, combined use of inositols, antioxidants and vitamins can be used as a promising and clinically relevant non-hormonal treatment option for the management of PCOS. Trial registration number NA

Effect of folic acid combined with pravastatin on arteriosclerosis in elderly hypertensive patients with lacunar infarction.

This study aimed to assess the effect of folic acid combined with pravastatin on atherosclerosis-related indexes in elderly patients with hypertension complicated with lacunar cerebral infarction.A total of 134 elderly hypertensive patients with lacunar cerebral infarction were randomly divided into 3 groups using the random number table method. Group A, the folic acid group, had 45 cases and received low-dose folic acid (0.8 mg/d) treatment on the basis of antihypertensive treatment. Group B, the pravastatin group, had 45 cases and received pravastatin (20 mg/d) treatment on the basis of antihypertensive treatment. Group C, the folic acid combined with the pravastatin group, had 44 cases. Members of this group received pravastatin (20 mg/d) and low-dose folic acid (0.8 mg/d) based on antihypertensive treatment. Levels of folic acid, homocysteine (Hcy), tumor necrosis factor alpha (TNF-a), matrix metallopeptidase 9 (MMP-9), cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were measured by ELISA before treatment in all 3 groups. Carotid intima-media thickness (IMT) was measured using ultrasound, and systolic and diastolic blood pressure were measured with a mercury column. After 8 weeks of treatment, the levels of folic acid, Hcy, TNF-a, MMP-9, TC, LDL-C, and systolic and diastolic blood pressure were compared among the 3 groups. IMT levels were measured at 12 weeks of treatment.After 8 weeks of treatment, compared with group B, patients in groups A and C had folic acid levels significantly higher than baseline levels, with significantly lower Hcy levels (both P < .05). Patients in group C presented significantly decreased TNF-a, MMP-9, TC, and LDL-C levels and systolic and diastolic blood pressure after 8 weeks of treatment, compared with those in groups A and B (both P < .05). These patients also showed significantly decreased IMT levels compared with those in the other groups (P < .05).Low-dose folic acid combined with pravastatin in elderly patients with lacunar cerebral infarction can reduce the level of homocysteine, improve the degree of carotid atherosclerosis, protect vascular endothelium, and reduce blood lipids and blood pressure, presenting better benefits than pravastatin alone.

Electrochemical Sensing of Folic Acid in Presence of Ascorbic acid Using Carbon Paste Nano Composite Modified Electrode

In the present work, combination of unique properties of two nano material compounds, MgO nano paricles (MgO NPs) and multi-wall carbon nanotubes (MWCNT), and electrocatalytic activity of an oxadiazole derivative, 3-(5-(pyridine-4-yl)-1,3,4-oxadiazole-2-ylthio)-4- methylcyclohexa-1,3-diene-1,2-diol; POM, was used to fabricate a sensitive electrode (POM-MgO NPs-MWCNT-CPE) for electrochemical determination of folic acid. The electrochemical treatment of folic acid was studied in phosphate buffer solution (0.1 M, pH 7) by means of common electrochemical techniques such as cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The sensitive fabricated electrode displayed good operating characteristics such as wide linear range and low detection limit for the determination of folic acid. Using the fabricated electrode, a wide linear dynamic range in concentration range 0.08-650.0 μM, and a limit of detection of 0.02 μM were found. Using the modified electrode, the two well distinguished peaks were recorded at 110.0 and 209 mV for ascorbic acid and folic acid, respectively. Reliability and accuracy of the introduced electrode were studied in pharmaceutical and biological samples.

The Effects of Salicylic, Folic and Ascorbic Acid Treatment on Shelf Life Quality of Broccoli Florets

This study aims to investigate the effect of Salicylic acid (2 mM), Folic acid (5 mg L−1) and Ascorbic acid (2 mM) treatments on the shelf life and quality of 'Belstar F1' broccoli variety. Treated broccoli heads were stored at 21±2˚C for 4 days in plastic containers with lids. It is determined that at the end of the storage period, the lowest weight loss (2.74%), total soluble solids (8.07%), pH value (7.14) and the highest amount of titratable acidity (0.12%) were found in the group treated with ascorbic acid and the least change in color parameters (L*; 29.41, a*; -4.59, b*; 10.78) and the highest total chlorophyll content (0.32 mg/g) in the group treated with folic acid. It is thought that the effects of ascorbic acid, salicylic acid and folic acid treatment at postharvest storage period should be investigated in detail in molecular and biochemical studies for more concrete data.

Effects of a Folic Acid 5 Mg Daily Intervention on Markers of Vitamin B Status and Kynurenine Pathway

BackgroundIn Brazil, most folic acid (FA) containing supplements contain 5 mg FA. This dose is usually prescribed for patients with chronic hemolytic anemia and for women planning pregnancy. The effects of high FA doses on vitamin B1, B2 and B6 status including the kynurenine pathway are still unclear.AimsTo assess the effects of a daily intervention with 5 mg FA in healthy subjects on vitamins B1, B2 and B6 serum marker status and serum concentration ok kynurenines.Material and MethodsThirty health subjects participated in a 5 mg/day FA intervention. Blood samples were obtained at baseline (D0) and after 45 (D45) and 90 days (D90) of intervention. We assessed serum concentrations of vitamin B6 (pyridoxal-5'-phosphate (PLP), pyridoxal (PL) and 4-pyridoxic acid (PA)), vitamin B2 (riboflavin and flavin mononucleotide (FMN)) and vitamin B1 vitamers (thiamine and thiamine monophosphate (TMP)), as well as tryptophan, kynurenine and several metabolites of tryptophan catabolism in the kynurenine pathway (3-hydroxykynurenine (HK), kynurenic acid (KA), anthranilic acid (AA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), picolinic acid (Pic) and quinolinic acid (QA)) using LC-MS/MS. PA ratio (PAr) was calculated by PA/(PLP + PL). All variables were normalized by Box-Cox transformation. Comparisons were performed by repeated-measures ANOVA.ResultsConcentrations of all vitamin B6 vitamers (PLP, PL and PA), as well as PAr, were similar at baseline and D45 and D90 of FA intervention. No differences were found among serum vitamin B2 vitamers (riboflavin and FMN) after FA intervention. However, a trend for a decrease in serum TMP concentrations was observed at D90 (P = 0.054). No changes in serum tryptophan and all serum kynurenine pathway metabolites were observed after intervention with FA compared with baseline, except for AA, which was higher at D45 and D90 than baseline (P < 0.001).ConclusionOur data suggest that daily use of 5 mg FA by healthy subjects may interfere with vitamin B1 status markers. In addition, serum AA increased with FA intervention, which suggest that the use of high dose FA supplements might affect the kynurenine pathway.Financing: FAPESP (2016/18854-4) and CNPq (401586/2014-6) DisclosuresNo relevant conflicts of interest to declare.

High gestational folic acid supplementation prevents hypoxia-ischemia-induced caspase-3 augmenting without changing synapsin and H3 methylation levels in the rat hippocampus.

Perinatal asphyxia is a peripartum event that can cause permanent sequelae to the newborns, affecting the brain development. Recently, it has been demonstrated that epigenetics mechanisms play an important role in this injury and that folic acid (FA) supplementation during pregnancy can affect these epigenetics modifications as well as gene expression. We have identified both positive and negative effects of FA treatment in rats submitted to a model of neonatal hypoxia-ischemia (HI). Considering that FA supplementation is already used in pregnant women and that HI occurs in the peripartum period, this study was designated to evaluate how gestational FA supplementation and neonatal HI affect: apoptosis (caspase-3) and expression of synaptic proteins (synapsin and PSD-95) and the methylation of histone H3 lysine (K) 4 and 27 in the rat hippocampus. Pregnant Wistar rats were divided according to the diets: standard (SD), supplemented with 2mg/kg of FA or with 20mg/kg of FA. HI procedure was performed at the 7th PND. Protein expression and H3 methylation were evaluated at the 60th PND in the rats' hippocampus. Neonatal HI increased caspase-3 expression decreased synapsin expression and reduced H3K4me2, -me3 and H3K27me2, -me3 in the ipsilateral hippocampus. FA only prevented the augment in caspase-3 expression. In conclusion, neonatal HI caused lasting effects on caspase-3-mediated cell death (prevented by the FA) and synaptic proteins in the rats' hippocampus. This is the first study to show that histone modifications may contribute to these pathological findings in the hippocampus of HI animals.

The Effect Of Vitamin B12 and Folic Acid on Multiple Sclerosis in Mice

Background: Multiple sclerosis (MS) is an autoimmune disease in which a deficiency of vitamin B12 along with folic acid can contribute to its progression. The aim of this study was to investigate the role of these two vitamins in altering myelin base protein (MBP) in the MS model of rats and also to measure some ionic parameters in serum. Methods: Brain histology was followed by analysis of the relationship between vitamin B12 treatment or folic acid and MBP as well as changes in total protein concentration (TPC). MBP expression was assessed by SDS-PAGE and serum levels of iron. Copper and zinc were also assessed by Duncan test. Results: MBP expression in cortical extract was increased by simultaneous treatment with vitamin B12 and folic acid compared with the groups treated individually. Histological examinations showed that the highest level of tissue repair was in the same group. There was a significant difference between cortical TPC in the control and treatment of vitamin B12 and folic acid, but serum levels of Fe, Zn and Cu were not significantly different between the groups. Conclusion: It can be concluded that the combination of these vitamins increases the expression of MBP protein.

Folic acid supplementation rescues valproic acid-induced developmental neurotoxicity and behavioral alterations in zebrafish embryos.

Fetal exposure to the anticonvulsant drug valproic acid (VPA), used to treat certain types of epilepsy, increases the risk for birth defects, including neural tube defects, as well as learning difficulties and behavioral problems. Here, we investigated neurotoxic effects of VPA exposure using zebrafish as a model organism. The capacity of folic acid (FA) supplementation to rescue the VPA-induced neuronal and behavioral perturbations was also examined. Zebrafish embryos of different transgenic lines with neuronal green fluorescent protein expression were exposed to increasing concentrations of VPA with or without FA supplementation. Fluorescence microscopy was used to visualize alterations in brain structures and neural progenitor cells, as well as motor neurons and neurite sprouting. A twitching behavioral assay was used to examine the functional consequences of VPA and FA treatment. In zebrafish embryos, VPA exposure caused a decrease in the midbrain size, an increase in the midline gap of the hindbrain, and perturbed neurite sprouting of secondary motor neurons, in a concentration-dependent manner. VPA exposure also decreased the fluorescence intensity of neuronal progenitor cells in early developmental stages, indicating fewer cells. Furthermore, VPA exposure significantly altered embryonic twitching activity, causing hyperactivity in dark and hypoactivity in light. Supplementation of FA rescued the VPA-induced smaller midbrain size and hindbrain midline gap defects. FA treatment also increased the number of neuronal progenitor cells in VPA-treated embryos and salvaged neurite sprouting of the secondary motor neurons. FA rescued the VPA-induced alterations in twitching activity in light but not in dark. We conclude that VPA exposure induces specific neurotoxic perturbations in developing zebrafish embryos, and that FA reversed most of the identified defects. The results demonstrate that zebrafish is a promising model to study VPA-induced teratogenesis and to screen for countermeasures.

Do platelet rich plasma and folic acid reverse experimental induced ovarian failure: Emphasis on folliculogenesis, and ovarian steroidogenesis

Background: Valproic acid (VPA) is a commonly prescribed antiepileptic drug. VPA could mediate endocrinal reproductive dysfunction on a long-term use. This study was designed to evaluatethe possible protective effects of platelet rich plasma (PRP) alone and PRP in combination with folic acid (FA) in a rat model of VPA induced ovarian failure. Materials and Methods: Thirty-five adult rats were randomly divided into five equal groups and 14 female rats were used for PRP preparation as control, VPA, co-treated VPA with FA, co-treated VPA with PRP and co-treated VPA with FA and PRP groups. All treatments were administered for 90 days. The effects of PRP and/or FA against VPA were evaluated through assessment of ovarian oxidant/antioxidant biomarkers, hormonal assay of reproductive hormones, quantification of mRNA gene expression for ovarian steroidogenesis pathway-encoding genes. Histopathological examination of the ovarian tissues was implemented. Results: Revealed that VPA exposure caused ovarian failure as documented by the decreased ovarian superoxide dismutase and catalase activities, increased ovarian malondialdehyde levels, diminished serum reproductive hormones concentrations and repressed the ovarian steroidogenesis pathway-encoding genes. In addition, VPA-induced marked ovarian histopathological alterations and impaired folliculogenesis. PRP and/or FA treatment improved ovarian function after VPA exposure. Adding FA to PRP produced less ovarian collagen fibers accumulation and more ovarian estrogen receptors immunoexpression than those produced by PRP alone. While other protective effects against VPA induced ovarian failure are equal between the two agents. Conclusion: PRP exhibited a protective role against VPA-induced ovarian failure in adult rats. A combined PRP and FA therapy is superior to PRP alone to some extent.

Hyperhomocysteinemia-related serum metabolome alterations not normalized by short-term folic acid treatment.

Hyperhomocysteinemia (HHCys) is an independent risk factor for various diseases such as cardiovascular diseases, Alzheimer's, and cancers. Folate deficiency is one of the significant reasons for HHCys. However, it is not known whether folate deficiency with HHCys is associated with any serum metabolites. Our objective was to identify the metabolic alterations in people having folate deficiency with HHCys and check whether a short-term folic acid therapy could reverse those metabolic changes. The study enrolled 34 participants aged between 18 and 40 years having folate deficiency (< 4.6 ng/mL) with HHCys (> 15 μmol/L) and 21 normal healthy individuals. A short-term intervention of oral folic acid (5 mg/day) was done in the HHCys group for 30 days. Untargeted metabolomics analysis of serum was performed in all study subjects before and after the folic acid treatment. Different univariate methods and the multivariable-adjusted linear regression models were employed to determine an association between homocysteine level and metabolite profile. Metabolomics analysis data showed that many metabolites involved in the biochemical pathways of lipid metabolisms such as polyunsaturated fatty acids, glycerolipids, and phospholipids were downregulated in the HHCys group. Short-term oral folic acid therapy significantly reduced their serum homocysteine level. However, the metabolic pathway alterations observed in folate-deficient HHCys-condition were unaltered even after the folic acid treatment. Our study revealed that people who have a folic acid deficiency with HHCys have an altered metabolite profile related to lipid metabolism, which cannot be reversed by short-term folic acid therapy.

Pharmacological inhibition of SETD7 by PFI-2 attenuates renal fibrosis following folic acid and obstruction injury

Renal fibrosis is the common pathological hallmark of chronic kidney disease, and SET domain containing lysine methyltransferase 7 (SETD7) promote considerably renal fibrosis. However, the signaling mechanisms underlying SETD7 driving renal fibrosis are not fully understood. Here, we investigated the role of SETD7 in M2 macrophages-myofibroblasts transition and the myeloid fibroblasts activation in folic acid and obstruction-induced renal fibrosis. Mice treated with PFI-2, an inhibitor of SETD7, presented less bone marrow-derived myofibroblasts, fewer CD206+/α-smooth muscle actin + cells and developed less renal fibrosis (P＜0.01). Furthermore, SETD7 inhibition reduced the infiltration of inflammatory cells and decreased the production of pro-inflammatory cytokines and chemokines in the kidneys after folic acid treatment (P＜0.01). Finally, SETD7 inhibition suppressed the accumulation of NF-κB p65+ cells in folic acid nephropathy (P＜0.01). Taken together, SETD7 mediates M2 macrophages-myofibroblasts transition, bone marrow-derived myofibroblasts activation, and inflammation response in the development of renal fibrosis.

Positive effects of folic acid supplementation on cognitive aging are dependent on ω-3 fatty acid status: a post hoc analysis of the FACIT trial

Although epidemiological studies suggest a protective role of B vitamins and omega-3 (ω-3) fatty acids in cognitive decline, findings from intervention studies are conflicting. Mechanistic studies suggest that the ω-3 (n-3) fatty acid status can modulate the effects of B vitamins on cognitive decline. We investigated the interaction between baseline ω-3 fatty acid statuses and folic acid treatment on cognitive decline in a placebo-controlled trial [FACIT (Folic Acid and Carotid Intima-media Thickness)]. This post hoc analysis included 791 older adults aged 50-70 y with plasma total homocysteine≥13 µmol/L and≤26 µmol/L and serum vitamin B12≥200 pmol/L. Participants received 800 µg folic acid or placebo daily for 3 y. Global cognitive functioning and domain-specific functioning (episodic memory, information processing speed, executive functioning) were assessed at baseline and after 3 y. The effect of the folic acid supplementation was analyzed according to tertiles of baseline ω-3 fatty acid concentrations using linear multiple regression. The mean ± SD age of the study population was 60.2±5.6 y, and the mean ± SD Mini-Mental State Examination score was 28.6±1.5. The treatment effect of folic acid was significantly larger in participants in the low compared to high ω-3 fatty acid tertile for global cognition (difference in z-score: mean ± SE = 0.16 ± 0.059; P<0.01). Regarding domain-specific functioning, similar results were observed for information processing speed (mean ± SE = 0.167 ± 0.068; P=0.01). There were no overall interactions between folic acid treatment and ω-3 fatty acid tertiles for episodic memory (P=0.14) and executive functioning (P=0.21). This post hoc analysis revealed that the efficacy of folic acid treatment on cognitive functioning is dependent on the ω-3 fatty acid status. Individuals with a lower ω-3 fatty acid status at baseline benefited from folic acid treatment, while individuals with a higher ω-3 fatty acid status did not. The results potentially explain the inconsistency in outcomes of B-vitamin supplementation trials and emphasize the importance of a personalized approach. This trial was registered at clinicaltrials.gov as NCT00110604.