Folate-engineered chitosan nanoparticles: next-generation anticancer nanocarriers.

Chitosan nanoparticles (NPs) are well-recognized as promising vehicles for delivering anticancer drugs due to their distinctive characteristics. They have the potential to enclose hydrophobic anticancer molecules, thereby enhancing their solubilities, permeabilities, and bioavailabilities; without the use of surfactant, i.e., through surfactant-free solubilization. This allows for higher drug concentrations at the tumor sites, prevents excessive toxicity imparted by surfactants, and could circumvent drug resistance. Moreover, biomedical engineers and formulation scientists can also fabricate chitosan NPs to slowly release anticancer agents. This keeps the drugs at the tumor site longer, makes therapy more effective, and lowers the frequency of dosing. Notably, some types of cancer cells (fallopian tube, epithelial tumors of the ovary, and primary peritoneum; lung, kidney, ependymal brain, uterus, breast, colon, and malignant pleural mesothelioma) have overexpression of folate receptors (FRs) on their outer surface, which lets folate-drug conjugate-incorporated NPs to target and kill them more effectively. Strikingly, there is evidence suggesting that the excessively produced FR&αgr (isoforms of the FR) stays consistent throughout treatment in ovarian and endometrial cancer, indicating resistance to conventional treatment; and in this regard, folate-anchored chitosan NPs can overcome it and improve the therapeutic outcomes. Interestingly, overly expressed FRs are present only in certain tumor types, which makes them a promising biomarker for predicting the effectiveness of FR-targeted therapy. On the other hand, the folate-modified chitosan NPs can also enhance the oral absorption of medicines, especially anticancer drugs, and pave the way for effective and long-term low-dose oral metronomic scheduling of poorly soluble and permeable drugs. In this review, we talked briefly about the techniques used to create, characterize, and tailor chitosan-based NPs; and delved deeper into the potential applications of folate-engineered chitosan NPs in treating various cancer types.

Over-expression of SiADCL1 in Arabidopsis modulates folate and amino acid metabolism to impact on flowering time.

Foxtail millet is a C4 crop rich in folate (FA). This study explores the roles of the 4-amino-4-deoxychorismate lyase (ADCL) - a member of the transaminase IV group of enzymes - in FA metabolism and conferred phenotypes. Phylogenetic comparisons identified diversity in the transaminase IV/ADCL gene family in the foxtail millet genome which was associated with genomic duplications. Molecular docking studies suggested that SiADCL1 bound most strongly to aminodeoxychorismate (ADC) and most likely had the highest catalytic activities. SiADCL1 which was highly expressed in roots, peduncles and flag leaves. Over-expression of SiADCL1 in Arabidopsis significantly increased total FA content (1.14-1.84 fold) and this was linked to a delayed flowering time. Metabolomic and transcriptomic characterization of the derived over-expression lines, found that FA promotes the change of methylation-related genes, ethylene synthesis, amino acid metabolism and flowering-related genes. This study revealed a potential gene coexpression network linked with FA and targeted key genes that could be exploited in foxtail millet breeding programs.

Concentrations and predictors of select nutrients in Canadian human milk samples from the Maternal-Infant Research on Environmental Chemicals pregnancy cohort.

BACKGROUND: Human milk (HM) composition data are widely used in clinical, regulatory, and public health initiatives. The existing HM profiles in United States and Canadian nutrient databanks are outdated and now considered inappropriate to estimate current nutrient intakes. Recent reviews have underscored the limited North American data available to generate a new profile. OBJECTIVES: To describe concentrations and sources of variability of nutrients in HM from a large cohort collected in Canada. METHODS: The Maternal-Infant Research on Environmental Chemicals (MIREC) study recruited participants in the first trimester of pregnancy from 10 Canadian cities between 2008 and 2011. HM samples (n = 559-835, depending on nutrient) were collected 3-10 wk postpartum and analyzed for minerals (calcium, magnesium, phosphorus, potassium, sodium, manganese, molybdenum, zinc, copper, iodine, selenium), vitamin D [vitamin D3, 25-hydroxyvitamin D3], folate vitamers (folic acid, 5-methyltetrahydrofolate, total folates), and fatty acids (panel). We examined associations between participant characteristics and log-transformed nutrient concentrations using linear regression. RESULTS: Concentrations of HM components in MIREC samples were within the range observed in literature except for manganese, which was >100-fold lower than the value in the existing Canadian nutrient databank profile [2.43 (standard deviation 2.84) compared with 260 ng/g]. In multivariable models, concentrations of folate vitamers, vitamin D, and fatty acids demonstrated greater variability with maternal and sample characteristics than minerals. Factors such as relevant supplement use, body mass index, and for vitamin D, skin color and season, had a larger impact on nutrient concentrations than characteristics typically standardized in HM research, such as maternal or infant health, and method of collection. CONCLUSIONS: HM mineral concentrations from this study meet the methodological inclusion criteria for updating nutrient databank values and dietary reference intakes. Consideration of factors such as diet, skin color, and BMI will be important for selecting studies for developing representative reference values based on HM.

Detrimental impact of solar and geomagnetic activity on plasma B-complex vitamins in the VA normative aging study cohort.

It has been hypothesized that ultraviolet (UV) radiation can lead to depletion of plasma folate and B12 vitamin, but few studies have investigated effects of other parameters of solar and geomagnetic activity (SGA). We investigated the association between four SGA parameters-interplanetary magnetic field (IMF), sunspot number (SSN), Kp index, and ground shortwave solar radiation (SWR)-and three plasma B-complex vitamins-folate, B6, and B12-in 910 participants from the Normative Aging Study (NAS) between 1998 and 2017. Mixed-effects regression models were used for 1- to 28-moving day averages of SGA exposure, adjusted for covariates. We compared the impact of SGA in individuals under higher and lower B-complex supplementation (> or < 50th quartile). Our findings show that increases in solar activity variables IMF and SSN were found to be significantly associated with decreases in B12 vitamin. IMF and SSN were associated with decrease in folate levels, especially in individuals under higher levels of B-complex supplementation. No associations were found for SWR and Kp index. To our knowledge, this is the first study that demonstrated the detrimental impact of solar activity on plasma B12 and folate in a large cohort. These findings have clinical implications during periods of high solar activity.

Lactobacillus Eats Amyloid Plaque and Post-Biotically Attenuates Senescence Due to Repeat Expansion Disorder and Alzheimer's Disease.

Patients with Alzheimer's disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive clinical outcomes. The chronic high-fat diet (HFD), or gut dysbiosis, is one of the major contributors of ADRD in part by disrupted transport, epigenetic DNMT1 and the folate 1-carbon metabolism (FOCM) cycle, i.e., rhythmic methylation/de-methylation on DNA, an active part of epigenetic memory during genes turning off and on by the gene writer (DNMT1) and eraser (TET2/FTO) and the transsulfuration pathway by mitochondrial 3-mercaptopyruvate sulfur transferase (3MST)-producing H2S. The repeat CAG expansion and m6A disorder causes senescence and AD. We aim to target the paradigm-shift pathway of the gut-brain microbiome axis that selectively inhibits amyloid deposits and increases mitochondrial transsulfuration and H2S. We have observed an increase in DNMT1 and decreased FTO levels in the cortex of the brain of AD mice. Interestingly, we also observed that probiotic lactobacillus-producing post-biotic folate and lactone/ketone effectively prevented FOCM-associated gut dysbiosis and amyloid deposits. The s-adenosine-methionine (SAM) transporter (SLC25A) was increased by hyperhomocysteinemia (HHcy). Thus, we hypothesize that chronic gut dysbiosis induces SLC25A, the gene writer, and HHcy, and decreases the gene eraser, leading to a decrease in SLC7A and mitochondrial transsulfuration H2S production and bioenergetics. Lactobacillus engulfs lipids/cholesterol and a tri-directional post-biotic, folic acid (an antioxidant and inhibitor of beta amyloid deposits; reduces Hcy levels), and the lactate ketone body (fuel for mitochondria) producer increases SLC7A and H2S (an antioxidant, potent vasodilator and neurotransmitter gas) production and inhibits amyloid deposits. Therefore, it is important to discuss whether lactobacillus downregulates SLC25A and DNMT1 and upregulates TET2/FTO, inhibiting ß-amyloid deposits by lowering homocysteine. It is also important to discuss whether lactobacillus upregulates SLC7A and inhibits ß-amyloid deposits by increasing the mitochondrial transsulfuration of H2S production.

Serum Concentrations of Folate Forms Following Supplementation of Multimicronutrients with 400 µg or 800 µg Mix of (6S)-5-Methyltetrahydrofolate and Folic Acid (1:1) in Women of Childbearing Age.

SCOPE: A mixture of (6S)-5-methyltetrahydrofolate-calcium salt ((6S)-5-MTHF-Ca) and folic acid (FA) from multimicronutrient supplements may show a dose-dependent effect on serum folate concentrations. METHODS AND RESULTS: The study compares fasting concentrations of serum folate spices after 8 weeks of either 400 or 800 µg day-1 of 1:1 folate mixture in 172 nonpregnant women. Serum (6S)-5-MTHF concentrations raise from a mean (SD) of 19.1 (13.4) to 73.9 (19.6) nmol L-1 in the 800 µg group and from 17.5 (9.4) to 54.5 (21.1) nmol L-1 in the 400 µg group (p < 0.001 within-group changes). The raise in serum (6S)-5-MTHF is stronger in the 800 µg compared to the 400 µg group (p < 0.001 between-group). The prevalence of FA concentrations ≥0.20 nmol L-1 increases between baseline and week 8 in both groups, but is not different between the groups (p = 0.116). The mean percentage of (6S)-5-MTHF of total serum folate increases in both intervention groups, but is not different between the groups at 8 weeks (95.5 (4.1)% versus 94.4 (5.7)%, p = 0.309). CONCLUSIONS: Supplementation of multimicronutrients with 800 µg folate mix for 8 weeks causes higher serum (6S)-5-MTHF concentrations, but not a higher prevalence of detectable FA compares to 400 µg folate.

Safety and tolerability of mirvetuximab soravtansine monotherapy for folate receptor alpha-expressing recurrent ovarian cancer: An integrated safety summary.

OBJECTIVE: Mirvetuximab soravtansine-gynx (MIRV) is a novel antibody-drug conjugate targeting folate receptor alpha (FRα), which is overexpressed in epithelial ovarian cancer (EOC), with limited expression on normal tissues. This integrated safety summary sought to characterize the safety profile of MIRV monotherapy in participants with FRα-expressing recurrent EOC. METHODS: Safety data were retrospectively analyzed from 4 clinical studies (phase 1 trial [NCT01609556], phase 3 FORWARD I [NCT02631876], phase 2 SORAYA [NCT04296890], phase 3 MIRASOL [NCT04209855]) that evaluated participants with FRα-expressing recurrent EOC who received ≥1 dose of MIRV 6 mg/kg adjusted ideal body weight every 3 weeks. RESULTS: In this analysis of 682 participants, 94 % had platinum-resistant ovarian cancer (PROC). Blurred vision (43 %), nausea (41 %), diarrhea (39 %), and fatigue (35 %) were the most common treatment-emergent adverse events (TEAEs) and were primarily grade 1-2 in severity. Grade ≥ 3 TEAEs occurred in 48 % of participants, with the most common being keratopathy and blurred vision (5 % each). Most TEAEs were managed with supportive care and dose modifications, and only 12 % of participants experienced a TEAE leading to discontinuation (1 % due to ocular events). No corneal ulcerations or perforations have been reported. Median time to onset of blurred vision and keratopathy was 5.9 and 6.7 weeks, respectively. Most blurred vision events and keratopathy events resolved completely (71 % and 66 %, respectively) or partially (15 % and 14 %, respectively). CONCLUSIONS: As demonstrated among 682 participants, the safety profile of MIRV is well tolerated and consists primarily of low-grade gastrointestinal, fatigue, headache, peripheral neuropathy, and resolvable ocular adverse events.

The Imbalance of Homocysteine, Vitamin B12 and Folic Acid in Parkinson Plus Syndromes: A Review beyond Parkinson Disease.

While there is a link between homocysteine (Hcy), B12 and folic acid and neurodegeneration, especially in disorders like Parkinson's and Alzheimer's diseases, its role in Parkinson plus syndromes (PPS) has only been partially investigated. It appears that elevated Hcy, along with an imbalance of its essential vitamin cofactors, are both implicated in the development and progression of parkinsonian syndromes, which represent different disease pathologies, namely alpha-synucleinopathies and tauopathies. Attributing a potential pathogenetic role in hyperhomocysteinemia would be crucial in terms of improving the diagnostic and prognostic accuracy of these syndromes and also for providing a new target for possible therapeutic intervention. The scope of this review is to focus on vitamin imbalance in PPS, with a special emphasis on the role of Hcy, B12 and folic acid in the neurodegenerative process and their implication in the therapeutic approach of these disorders.

Parental arsenic exposure and tissue-specific DNA methylation in Bangladeshi infants with spina bifida.

An emerging hypothesis linking arsenic toxicity involves altered epigenetic mechanisms, such as DNA methylation. In this study, we examined the relationship between parents' arsenic exposure and DNA methylation in tissues obtained from 28 infants with spina bifida from Bangladesh. We analyzed arsenic in parents' toenails using inductively coupled plasma mass spectrometry (ICP-MS). DNA methylation was measured in infants' dural tissue, buccal swabs, and whole blood using the Illumina Infinium MethylationEPIC BeadChip. We performed epigenome-wide association analyses (EWAS) and tested differentially methylated regions (DMRs). In EWAS, DNA methylation at cg24039697 in dural tissue was positively associated (ß = 0.59, p = 7.6 × 10-9) with father's toenail arsenic concentrations, adjusting for covariates. We did not identify any CpG sites related to father's arsenic exposure in the other tissues, or any CpG sites related to mother's arsenic exposure. Gene ontology analysis identified many biological pathways of interest, including the Wnt signaling pathways. We identified several DMRs across the tissues related to arsenic exposure that included probes mapping to genes that have previously been identified in studies of neural tube defects. This study emphasizes the potential impact of arsenic exposure in fathers, often understudied in epidemiological studies, on DNA methylation in a unique neurological tissue specific to spina bifida.

Genome-Wide Association Study Identifies Genetic Polymorphisms for Folate-Related Biomarkers in Chinese Preconception Women.

BACKGROUND: Single-nucleotide polymorphism (SNP) allele frequencies, dietary habits, and folate status and their associations vary across ethnic populations. Little is known about the SNPs accounting for variations of folate-related biomarkers for Chinese preparing-for-pregnant females. OBJECTIVES: We aimed to identify SNPs contributing to RBC and serum folate, vitamin B-12, and homocysteine concentrations in Chinese female preconception population. METHODS: A genome-wide association study was conducted on 1000 randomly selected preconception Chinese women from the Shanghai Preconception Cohort. SNPs were genotyped using Illumina chips, and associations with biomarkers were assessed using simple linear regression models under the assumption of an additive genetic model. Genome-wide significance was considered at P < 10-7. RESULTS: The MTHFR rs1801133 was the major genetic coding variant contributing to RBC folate, serum folate, and homocysteine concentrations (P = 2.28 × 10-16; P = 8.85 × 10-8, and P = 2.46 × 10-13, repsectively). It is associated with increased RBC folate (ß: 0.154 per additional risk allele after log transform), decreased serum folate (ß: -0.951 per additional risk allele), and increased serum homocysteine concentrations (ß: 1.153 per additional risk allele). The predominant SNP associated with serum folate was rs147162222 in NTRK2 (P = 2.55 × 10-8), although that associated with homocysteine was rs77025184 located between PDE7B and LINC00271 (P = 4.91 × 10-17). For vitamin B-12, FUT2 rs1047781 was the dominant genetic variant (P = 1.59 × 10-10). The numbers of signals with a P value of <10-7 for RBC folate, serum folate, vitamin B-12, and homocysteine were 12, 18, 8, and 614, respectively. CONCLUSIONS: This study represents the first genome-wide association study focusing on folate-related biomarkers in a Chinese preparing-for-pregnant female population. The contributions of dominent SNPs to each biomarker are partly different from other populations. The rs1801133 (C677T) in MTHFR is the predominant genetic variant contributing to RBC folate and rs1047781 (A385T) in FUT2 as the primary one explaining vitamin B-12. Notably, the intronic rs147162222 and noncoding rs77025184 are the predominant SNPs for serum folate and homocysteine, respectively.

Association between methylenetetrahydrofolate reductase C677T polymorphisms and male oligozoospermia, asthenozoospermia or oligoasthenozoospermia: a case-control study.

Mutation of methylenetetrahydrofolate reductase (MTHFR) C677T leads to the decrease of folate utilization and the impairment of spermatogenesis. This study attempts to investigate the association between MTHFR C677T polymorphisms and nonobstructive oligozoospermia, asthenozoospermia or oligoasthenozoospermia in the Chinese population. The study cohort comprised 189 patients diagnosed with oligozoospermia, asthenozoospermia or oligoasthenozoospermia, and 626 controls based on clinical examinations. The MTHFR c.677 genotype of all subjects was determined by fluorescence staining in situ hybridization and the significance of different genotype frequencies was further analyzed by Chi-square test. The results showed that the frequency of MTHFR 677 CT genotype in the oligozoospermia, asthenozoospermia and oligoasthenozoospermia group was 33.3%, 38.3% and 44.0% respectively, whereas it was 47.3% in the control group. The P value of Chi-square test was 0.070, 0.103 and 0.654, respectively. The frequency of MTHFR 677 TT genotype in the oligozoospermia, asthenozoospermia and oligoasthenozoospermia group was 31.1%, 11.7% and 18.0% respectively, while that in the control group was 19.5%. The P value of Chi-square test was 0.061, 0.070 and 0.066, respectively. Collectively, there is a weak association between MTHFR C677T polymorphisms and oligozoospermia, asthenozoospermia or oligoasthenozoospermia within the current Chinese population cohort.

Higher Incidence of Common Polymorphisms in the Genes of Folate and Methionine Cycles in Children With Orofacial Clefs and Congenital Heart Defects Compared to their Unaffected Siblings.

BACKGROUND: Uninterrupted folate metabolism plays a vital role in embryonic development, ensuring a supply of one-carbon-activated folate cofactors for essential processes. Folate deficiency has been implicated in the development of orofacial clefts (OFC) and congenital heart disease (CHD). Although both malformations have been extensively studied in lieu of folate deficiency, the results of corresponding studies are ambiguous due to the interplay of maternal and fetal genomes controlling folate metabolism in the developing fetus. METHODS: We used the innovative study design to compare affected and unaffected siblings from the same mother, thus minimizing the effect of the maternal genome. Thus, it might be possible to identify genetic markers of congenital malformations that pertain exclusively to the child. This study compared demographic and environmental factors between OFC or CHD-affected and unaffected pregnancies as well as the presence of polymorphisms in genes of folate metabolism between OFC or CHD-affected and unaffected siblings. RESULTS: Only the maternal fever in the first trimester was a risk factor for OFC, whereas the maternal advanced age, medication administration, and common polymorphism in the FPGS gene increased the risk of CHD formation. Both OFC and CHD formation were associated with a higher number of variant loci in genes of folate-methionine cycles. CONCLUSIONS: Both OFC and CHD formation were associated with a higher number of mutated loci in genes of folate-methionine cycles, indicating polygenic and possibly multifactorial inheritance.

Synergistic effect of folic acid and hypericin administration to improve the efficacy of photodynamic therapy via folate receptors.

Transport systems are developed to improve the solubility of the transported drug, increase its stability, enhance its pharmacological activity and target cancer while minimising side effects. In this work, nanoporous silica particles that can be functionalized and loaded with a large number of hydrophobic molecules are proposed. The designed system was modified with folic acid to target the folic acid receptors of cancer cells. This modification enabled a higher uptake of the drug by the cells. Hypericin was selected as a hydrophobic molecule/drug with photodynamic properties suitable for diagnosis and therapy. Fluorescence microscopy and flow cytometry were used to detect the targeting and distribution of hypericin in the cancer cells. Furthermore, the combination of folic acid and hypericin has been shown to form singlet oxygen and to have a synergistic effect in improving the efficacy of photodynamic therapy. The functionalisation of the particles proposed in this work holds great potential for the delivery of hydrophobic drugs to other types of cancer cells with increased expression of the folic acid receptor to which the particles can be attached.

Milk Fat Globules: 2024 Updates.

Milk fat globules (MFGs) are a remarkable example of nature's ingenuity. Human milk (HM) carries contains 3-5% fat, 0.8-0.9% protein, 6.9-7.2% carbohydrate calculated as lactose, and 0.2% mineral constituents. Most of these nutrients are carried in these MFGs, which are composed of an energy-rich triacylglycerol (TAG) core surrounded by a triple membrane structure. The membrane contains polar lipids, specialized proteins, glycoproteins, and cholesterol. Each of these bioactive components serves important nutritional, immunological, neurological, and digestive functions. These MFGs are designed to release energy rapidly in the upper gastrointestinal tract and then persist for some time in the gut lumen so that the protective bioactive molecules are conveyed to the colon. These properties may shape the microbial colonization and innate immune properties of the developing gastrointestinal tract. Milk fat globules in milk from humans and ruminants may resemble in structure but there are considerable differences in size, profile, composition, and specific constituents. There are possibilities to not only enhance the nutritional composition in a goal-oriented fashion to correct specific deficiencies in the infant but also to use these fat globules as a nutraceutical in infants who require specific treatments. To mention a few, there might be possibilities in enhancing neurodevelopment, in defense against gastrointestinal and respiratory tract infections, improving insulin sensitivity, treating chronic inflammation, and altering plasma lipids. This review provides an overview of the composition, structure, and biological activities of the various components of the MFGs. We have assimilated research findings from our own laboratory with an extensive review of the literature utilizing key terms in multiple databases including PubMed, EMBASE, and Science Direct. To avoid bias in the identification of studies, keywords were short-listed a priori from anecdotal experience and PubMed's Medical Subject Heading (MeSH) thesaurus.

Comparison of Vitamin D, B12, and Folic Acid Levels According to Attack Frequency in Familial Mediterranean Fever Cases.

Objectives: Familial Mediterranean fever (FMF) is an autoinflammatory disease more commonly observed in the Eastern Mediterranean region. Studies have shown that inflammatory processes may decrease vitamin D, vitamin B12 and folate levels, but there is no clear data on the effect of attack frequency on these levels. Our study aimed to evaluate the effect of FMF attack frequency on vitamin levels. Methods: FMF patients aged between 4-18 years were considered as the study group, while healthy children who had vitamin levels during the same period were considered as the control group. The study group was further subgrouped according to the number of attacks. Those experiencing 2 or fewer attacks per year are classified as the attack group, while those experiencing 6 or more attacks per year are classified as the frequent attack group. Results: A total of 494 subjects were included. The study group was composed of 333 FMF patients, 108 of them in the attack group and 225 in the frequent attack group. Control group included 161 children. The median and interquartile range (IQR: P25-75) in the frequent attack, attack, and control groups for 25(OH)D levels were 14.3 (9.57-18.9), 14.85 (10.12-21.77), and 14.95 (9.92-20.12) ng/ml, for B12 levels were 320 (238-415), 328 (250.25-439.25), and 373 (273.75-519.25) pg/ml, and for folate levels were 6 (5.13-8.12), 6.8 (5.36-8.9), and 7 (5.3-9.9) ng/ml, respectively. There is no significant difference between groups for 25(OH)D and folate (p=0.436 and p=0.25, respectively). Vitamin B12 levels are significantly lower in study group (p=0.001) but there is no difference according to attack frequency (p=0.92). Conclusion: There is no effect of attack frequency on 25(OH)D, vitamin B12 and folate levels. The fact that vitamin B12 levels are within normal limits in patients with FMF may be explained by the adequate dietary habits of these patients.

Association between RBC folate and diabetic nephropathy in Type2 diabetes mellitus patients: a cross-sectional study.

Folates play a crucial role as cofactors in metabolic pathways, influencing biological methylation and nucleotide synthesis, which has a significant impact on overall health and disease susceptibility. Diabetic nephropathy (DN) is a prevalent and severe complication of diabetes mellitus (DM). The correlation between RBC folate and DN remains unclear currently. This study aims to assess whether RBC folate is associated with DN. Based on data from the NHANES (2011-2018), we conducted a cross-sectional study involving 3070 adults with type 2 DM (T2DM). Demographic factors, levels of folate and vitamin B12, dietary folate intakes, and relevant laboratory data were obtained from all participants. Logistic regression, fitting smooth curves, interaction effects were utilized to support the research objectives. Regression analyses demonstrated a positive relation between RBC folate and DN. (P < 0.001). A positive association between levels of RBC folate and the risk of DN was observed after full adjustment for all the confounding variables (odds ratio: 1.38, 95% confidence interval: 1.27-1.49, P < 0.001). Similar patterns of association were observed for subgroup analysis (all P values for interaction > 0.05). In addition, curve fitting after adjusting for all the confounding variables demonstrated that there was a linear relationship between RBC folate and DN (P for non-linearity = 0.147). Increased RBC folate levels were linked to a higher risk of DN in type 2 diabetes. RBC folate should be considered as a crucial indicator for folate status in DN.

Causal Association of Folic Acid Supplementary Therapy and Gastric Ulcer: A Mendelian Randomization Study.

Previous research has suggested a potential link between folic acid supplementary therapy and gastric ulcers. To investigate this relationship further, we conducted a Mendelian randomization (MR) analysis using data from the UK Biobank. Our analysis primarily employed inverse variance-weighted (IVW) methods, including both fixed-effect and random-effect models. To ensure the robustness of our findings, additional methods such as the simple median, the weighted median, and the penalized weighted median were also applied. The MR analysis aimed to explore the causal effect of FA supplementary therapy on gastric ulcers. Seven single nucleotide polymorphisms (SNPs) at genetic loci associated with FA supplementary therapy were identified. Both the random-effect and fixed-effect IVW models indicated that genetically predicted FA supplementary therapy significantly reduced the risk of gastric ulcers (OR, 0.870; 95% CI, 0.826-0.917, p<0.001). This result was consistent across other methods, with similar outcomes observed using the simple median (OR, 0.835; 95% CI, 0.773-0.901, p<0.001), the weighted median (OR, 0.854; 95% CI, 0.794-0.919, p<0.001), and the penalized weighted median (OR, 0.849; 95% CI, 0.789-0.914, p<0.001). Leave-one-out sensitivity analysis confirmed that no individual SNP significantly drove the association between FA supplementary therapy and gastric ulcers. This MR study provides genetic evidence that FA supplementary therapy may decrease the risk of gastric ulcers.

Improvement of serum folate status in the US women of reproductive age with fortified iodised salt with folic acid (FISFA study).

OBJECTIVE: Mandatory folic acid fortification of enriched grains has reduced neural tube defect prevalence in several countries. We examined salt as an additional vehicle for folic acid fortification. The primary objective was to examine the change in serum folate concentration after 1 month of consumption of fortified iodised salt with folic acid (FISFA) among women of reproductive age. The secondary objectives were to examine (1) the feasibility of implementing FISFA intervention and (2) the acceptability of FISFA. DESIGN: We conducted a pre­post intervention study (January­April 2023). Participants received a FISFA saltshaker with the study salt (1 g of sodium chloride salt fortified with 100 mcg of folic acid) to use instead of regular table salt for 1 month. Serum folate was measured using the Elecsys Folate-III immunoassay method at baseline and 1-month endpoint. Change in serum folate was assessed using a two-tailed Wilcoxon signed rank test for paired samples. SETTING: Metropolitan city, Southern USA. PARTICIPANTS: Non-pregnant, 18­40-year-old women who lived alone/with a partner. RESULTS: Thirty-two eligible women consented to participate, including eleven non-Hispanic-White, eleven non-Hispanic-Black and ten Hispanic. Post-intervention, there was a significant increase in median serum folate concentration of 1·40 nmol/l (IQR 0·74­2·05; P < 0·001) from 24·08 nmol/l to 25·96 nmol/l in an analytical sample of n 29. An increase was seen in 28/29 (93 %) participants. Feasibility: 100 % study consent and compliance. FISFA acceptability: 25 d average use; 1·28 g average daily intake; 96·7 % and 90 % reported taste and colour of FISFA as highly acceptable, respectively. CONCLUSIONS: FISFA is an effective approach to increasing serum folate concentrations among women of reproductive age. Findings should be replicated in a larger study.

Vitamin B12 is correlated with insulin resistance and metabolism disorder markers in women with recurrent pregnancy loss.

OBJECTIVES: Recurrent pregnancy loss (RPL) seriously affects women's reproductive and mental health, and the incidence has increased in recent years. Insulin resistance (IR) acts as a significant contributing factor to RPL. Studies suggest that vitamin B12, folate intake, and homocysteine are correlated with IR, but the exact nature remains controversial and requires further investigation. In this study, we aimed to assess the levels and correlations between vitamin B12-folate-homocysteine and insulin resistance in RPL patients. STUDY DESIGN: 73 control subjects and 256 RPL patients (144 RPL patients without IR and 112 RPL patients with IR) were included in this observational retrospective cross-sectional study. The differences in vitamin B12, folate, and homocysteine levels between RPL patients with and without IR were analyzed using a Student's t-test. Pearson correlations were utilized to examine the correlation between vitamin B12-folate-homocysteine and glucose and lipid metabolism parameters. Multivariable linear regressions were used to assess the independent correlation of each factor with HOMA-IR. RESULTS: Compared to the control subjects, RPL patients exhibited lower vitamin B12 (p < 0.001) and folate (p < 0.001), and higher homocysteine (p = 0.001). RPL patients with IR described decreases in vitamin B12 (p = 0.003) and folate (p = 0.028), and increases in homocysteine (p = 0.033) as RPL patients without IR. Vitamin B12 in RPL patients was significantly negatively correlated with homocysteine (r = -0.348, p < 0.001), HOMA-IR (r = -0.214, p < 0.001), BMI (r = -0.160, p = 0.017), TG (r = -0.148, p = 0.039) and CHO (r = -0.149, p = 0.038) and positively correlated with folate (r = 0.217, p < 0.001). In multivariable linear regressions, after adjusting for age, strong correlations were observed between vitamin B12 (ß = -0.197, p = 0.010), BMI (ß = 0.466, p < 0.001), and HOMA-IR in RPL patients. CONCLUSION: Vitamin B12 is significantly correlated with IR in RPL patients. Circulating vitamin B12-folate-homocysteine metabolism could be a window of the pathological process of IR, obesity, and lipid metabolism disorders in RPL patients.

MTHFR C677T、MTHFR A1298C、MTRR A66G and MTR A2756G polymorphisms and male infertility risk: a systematic review and meta-analysis.

BACKGROUND: Epidemiological studies have reported that polymorphisms of folate-metabolizing genes have a significant impact on male infertility. However, the results of published studies have come to different conclusions. OBJECTIVE: To determine an association between folate-metabolizing gene polymorphisms and the risk of male infertility. METHODS: The meta-analysis was conducted according to the PRISMA 2020 statement. The protocol was registered with PROSPERO (CRD42023412251). Studies were searched from PubMed, Google Scholar, Embase, Scopus, and the Cochrane Library up to 24st October2023. Articles that satisfied the inclusion criteria were evaluated for their quality using the Newcastle-Ottawa Scale. Data were extracted from the eligible studies and were analyzed for pooled up odds ratio (OR) with 95% confidence interval (CI). Meta-analysis was conducted using STATA 12. RESULTS: Forty-six case-control studies were included in the meta-analysis which comprised 20,639 participants. The pooled analysis revealed that the MTHFR C677T polymorphism was significantly associated with male infertility and abnormospermia.Three-fifths of the model showed there was a significant association between the MTR A2756G polymorphism and male infertility. Both MTHFR A1298C and MTRR A66G polymorphisms were not significantly associated with male fertility. Furthermore, subgroup analysis revealed a significant association between the MTHFR C677T polymorphism and male fertility in Asian countries. CONCLUSION: This meta-analysis suggests that the MTHFR C677T and MTR A2756G polymorphisms may be a potential risk factor for male infertility.