Folate Cycle Research Articles

The methionine cycle and its cancer implications.

The essential amino acid methionine is a crucial regulator of sulfur metabolism in a variety of interconnected biochemical pathways. The methionine cycle is intricately linked to the folate cycle, forming the one-carbon metabolism, a crucial regulator of S-adenosylmethionine, SAM. Recent work highlights methionine's critical role in tumor growth and progression, maintaining polyamine synthesis, and playing a crucial role in the regulation of SAM both in altered chromatin states, depending on p53 status, as well as facilitating m6A methylation of NR4A2 mRNA, hence regulating proliferation in esophageal carcinoma. Accordingly, Celecoxib, a specific NR4A2 inhibitor, is a potentially powerful inhibitor of tumor growth at least in this specific model. Additionally, formaldehyde, from endogenous or exogenous sources, can directly regulate both SAM steady-state-levels and the one-carbon metabolism, with relevant implication in cancer progression. These recent scientific advancements have provided a deeper understanding of the molecular mechanisms involved in cancer development, and its potential therapeutic regulation.

Expression patterns of folate metabolism-related enzymes in the bovine oviduct: estrous cycle-dependent modulation and responsiveness to folic acid

Folate metabolism is required for important biochemical processes that regulate cell functioning, but its role in female reproductive physiology in cattle during peri- and post-conceptional periods has not been thoroughly explored. Previous studies have shown the presence of folate in bovine oviductal fluid, as well as finely regulated gene expression of folate receptors and transporters in bovine oviduct epithelial cells (BOECs). Additionally, extracellular folic acid (FA) affects the transcriptional levels of genes important for the functioning of BOECs. However, it remains unknown whether the anatomical and cyclic features inherent to the oviduct affect regulation of folate metabolism. The present study aimed to characterize the gene expression pattern of folate cycle enzymes in BOECs from different anatomical regions during the estrous cycle and to determine the transcriptional response of these genes to increasing concentrations of exogenous FA. A first PCR screening showed the presence of transcripts encoding dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase (MTR) in bovine reproductive tissues (ovary, oviduct and uterus), with expression levels in oviductal tissues comparable to, or even higher than, those detected in ovarian and uterine tissues. Moreover, expression analysis through RT-qPCR in BOECs from the ampulla and isthmus during different stages of the estrous cycle demonstrated that folate metabolism-related enzymes exhibited cycle-dependent variations. In both anatomical regions, DHFR was upregulated during the preovulatory stage, while MTHFR and MTR exhibited increased expression levels during the postovulatory stage. Under in vitro culture conditions, ampullary and isthmic cells were cultured in the presence of 10, 50, and 100 μM FA for 24 h. Under these conditions, isthmus epithelial cells exhibited a unique transcriptional response to exogenous FA, showing a pronounced increase in MTR expression levels. Our results suggest that the expression of folate metabolism-related genes in BOECs is differentially regulated during the estrous cycle and may respond to exogenous levels of folate. This offers a new perspective on the transcriptional regulation of genes associated with the folate cycle in oviductal cells and provides groundwork for future studies on their functional and epigenetic implications within the oviductal microenvironment.

Nutritional vitamin B12 regulates RAS/MAPK-mediated cell fate decisions through one-carbon metabolism

Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute one-carbon metabolism. Here, we show that dietary uptake of vitamin B12 modulates cell fate decisions controlled by the conserved RAS/MAPK signaling pathway in C. elegans. A bacterial diet rich in vitamin B12 increases vulval induction, germ cell apoptosis and oocyte differentiation. These effects are mediated by different one-carbon metabolites in a tissue-specific manner. Vitamin B12 enhances via the choline/phosphatidylcholine metabolism vulval induction by down-regulating fat biosynthesis genes and increasing H3K4 tri-methylation, which results in increased expression of RAS/MAPK target genes. Furthermore, the nucleoside metabolism and H3K4 tri-methylation positively regulate germ cell apoptosis and oocyte production. Using mammalian cells carrying different activated KRAS and BRAF alleles, we show that the effects of methionine on RAS/MAPK-regulated phenotype are conserved in mammals. Our findings suggest that the vitamin B12-dependent one-carbon metabolism is a limiting factor for diverse RAS/MAPK-induced cellular responses.

VITAMIN B2 AND ITS STATUS IN VEGETARIANS AND VEGANS

The main goal of this review was to briefly highlight the key points of today’s knowledge about the role and metabolism of vitamin B2 as well as to compare its status in vegans, vegetarians, and omnivores according to present data. Biologically active forms of water-soluble vitamin B2 (riboflavin) are represented by flavin mononucleotide (FMN) and flavin adenine diphosphate (FAD), which are coenzymes in the reactions of the electron transport chain and the pyruvate dehydrogenase complex. Riboflavin is also involved in the metabolism of fatty acids, the synthesis of cholesterol and steroid hormones. Riboflavin also participates in the folate cycle. Vitamin B2 is crucial for the metabolism of other vitamins. FMN is necessary for the for-mation of the active form of vitamin B6, while FAD is necessary for the synthesis of niacin. Severe clinical insufficiency of vitamin B2 is not common. Besides insufficient riboflavin consumption, hypothyroidism can also be a cause of vitamin B2 deficiency as thyroxine regulates the conversion of ribo-flavin to its active forms  FMN and FAD. Lack of riboflavin can cause tissue damage; especially of the epithelial, reproductive, and nervous system. The variety of its manifestations is related to the fact that riboflavin deficiency also disrupts the metabolism of vitamins B6, or PP. Similarly, riboflavin deficiency can also disrupt the folate cycle, increasing the level of homocysteine which damages vascular intima and leads to endothelial dysfunction and atherosclerosis as a result. Rapid urinary excretion of riboflavin makes it safe even if taken in a high dose, changing the urine colour into bright-yellow. This safety of riboflavin makes it unharmful to be used as an oral tracer for monitoring compliance in clinical research. Ultra-high doses of ribo-flavin (more than 400 mg/day) can cause diarrhoea or polyuria. The content of vitamin B2 in animal-derived products is higher than in plant-based ones. This also determines its lower intake in vegans and vegetarians compared to omnivores. While there is a shred of evidence that plant-based diets in-crease the production of bioavailable riboflavin by the gut microbiota, this does not appear to be sufficient to completely compensate for the vegetari-ans’/vegans’ reduced dietary intake of vitamin B2, as most of the researches point the fact that vegans and vegetarians are more prone to lack vita-min B2 than omnivores. At the same time, it should be noted that there exists no universally adopted optimal method for assessing the status of vit-amin B2 in the body. Further research and standardization of methods may ease to assess the prevalence and risks of riboflavin deficiency in various dietary groups

Genetic polymorphisms and their association with methotrexate polyglutamates during maintenance treatment in Korean children and young adults with acute lymphoblastic leukemia

The aim of this study was to investigate the impact of genetic polymorphisms on methotrexate (MTX) metabolism in Korean children and young adults with acute lymphoblastic leukemia, specifically focusing on MTX polyglutamates (MTX-PGs) in erythrocytes, which have been rarely studied. Korean children and young adult patients undergoing maintenance therapy for acute lymphoblastic leukemia, who were receiving weekly oral MTX doses of 20 mg/m²/week, were prospectively included. We investigated erythrocyte MTX-PG (PG1 to PG5) levels, MTX-PG/MTX dose ratios, and 222 genetic polymorphisms spanning 78 genes and three intergenic areas related to MTX transport, folate cycle metabolism, purine/pyrimidine pathways, and non-pathway genes (including TPMT and NUDT15 genotypes) to explore their association with MTX metabolism. MTX-PG levels were associated with MTX dose (p < 0.05), and MTX-PG3 comprised the majority of the total MTX-PGs, with a median of 39.3 %. Various polymorphisms within the same gene demonstrated differing associations with each type of MTX-PG, underscoring the complexity of MTX pharmacogenetics. Among the polymorphisms examined, 14 across 13 genes showed significant associations with MTX-PG2–5 levels, even after adjusting for the false discovery rate (ABCC5, ATG16L1, CEP72, FSTL5, GMPS, HTR3A, IMPDH1, NT5C2, SLC28A3, SLCO1B3, SUCLA2, TPMT, and TYMS). This study enhances our understanding of genetic polymorphisms in MTX metabolism and therapeutic monitoring for MTX maintenance, promoting personalized medicine in acute lymphoblastic leukemia patients.

The role of single nucleotide variants of folate cycle genes of a mother with epilepsy in the occurrence of congenital malformations of the fetus

Aim - To study the frequency of single-nucleotide variants (ONV) rs1801133 and rs1801131 of the MTHFR gene; rs1801394 of the MTRR gene, rs1805087 of the MTR gene and rs1051266 of the SLC19A1 gene in women with epilepsy and to evaluate their associations with major congenital malformations (MCM) of the fetus. Material and methods. The study included 61 women with epilepsy who have children: 20 had different fetal MCM (main group), 41 patients had children born without MCM (comparison group). DNA was extracted from blood, and the genotyping of five ONV into four genes was analyzed by polymerase chain reaction. The frequencies of genotypes and alleles in the mothers of the main and the comparison group were determined, the differences were assessed using Pearson's chi-squared criterion (χ2) and Fisher's exact criterion. Results. There were no statistically significant differences in the frequencies of genotypes and alleles for all analyzed ONV between the main group and the comparison group. There were no statistically significant differences in the frequencies of genotypes and alleles of ONV genes of the folate cycle in mothers of children with malformations (n = 14) and without malformations (n = 22), taking valproic acid. A statistically significant relationship was revealed between the carrier of a certain haplogroup of the mother and the formation of fetal MCM. Conclusion. The MCM in a child is a multifactorial phenomenon in which genetic factors with a small effect size can play a significant role only in the case of certain unfavorable combinations.

Associative study of maternal genetic variations with preeclampsia in Russian population: SNP-SNP interactions and haplotypes association

Preeclampsia is a pregnancy-associated hypertensive pathology that affects maternal and fetal quality of life. It was linked to several environmental and genetic factors including genetic polymorphisms. This study aimed to study the association, SNP-SNP interactions and haplotypes associations of thrombophilia, folate cycle and hypertension maternal genetic variations with preeclampsia risk in Russian women from Rostov region. 53 pregnant women diagnosed with preeclampsia were compared with 3108 women with relatively healthy pregnancy. DNA was extracted from blood samples and real time allele specific PCR was used for genotyping. MDR analysis was used for SNP-SNP interactions study. According to our data, F5(G1691A) and ITGB3(T1565C) mutant homozygotes were associated with higher risk of preeclampsia. MTRR (A66G) mutant allele (G) was shown as significant preeclampsia risk factor. ADD1 (G1378T) showed significantly higher frequency of mutant allele (T) and mutant homozygote genotype (TT) in preeclampsia patients comparing to control group. MDR showed that this polymorphism has the higher entropy among targeted variations which was confirmed by binary haplotypes association study. We have also examined linkage disequilibrium showing two haploblocks in between the studied genetic variations included MTHFR (C677T) and MTHFR (A1298C) block and AGT (T704C) with AGT (C521T) block. Results suggest several genetic variations and haplotypes as perspective maternal marker for preeclampsia which will contribute to improve prognosis tools and accordingly treatment and prevention possibilities.

Subcellular one carbon metabolism in cancer, aging and epigenetics.

The crosstalk between metabolism and epigenetics is an emerging field that is gaining importance in different areas such as cancer and aging, where changes in metabolism significantly impacts the cellular epigenome, in turn dictating changes in chromatin as an adaptive mechanism to bring back metabolic homeostasis. A key metabolic pathway influencing an organism's epigenetic state is one-carbon metabolism (OCM), which includes the folate and methionine cycles. Together, these cycles generate S-adenosylmethionine (SAM), the universal methyl donor essential for DNA and histone methylation. SAM serves as the sole methyl group donor for DNA and histone methyltransferases, making it a crucial metabolite for chromatin modifications. In this review, we will discuss how SAM and its byproduct, S-adenosylhomocysteine (SAH), along with the enzymes and cofactors involved in OCM, may function in the different cellular compartments, particularly in the nucleus, to directly regulate the epigenome in aging and cancer.

Analysis of the contribution of polymorphisms of hemostasis system genes and folate cycle genes to the genetic presposition to the development of thrombosis in patients with Ph-negative myeloproliferative neoplasia in the Republic of Uzbekistan

Thrombotic complications often complicate the course of the underlying disease in patients with chronic myeloproliferative neoplasia. However, a thromboembolic condition is not observed in all patients.The aim of the study was to assess the carriage frequency of polymorphic genes of the blood coagulation system and folate metabolism genes and the contribution of genetic variants to the development of thrombosis in patients with chronic Ph-negative myeloproliferative neoplasia (CMPN).Materials and methods. Molecular genetic testing for the presence of genetic variants with an assessment of their frequency of occurrence and allelic load was carried out in 142 patients with CMPN. We studied polymorphisms of the folate cycle genes – A2756G (Asp919Gly) of the MTR gene, C677T (Ala22Val) of the MTHFR gene, A66G (ILe22Met) of the MTRR gene (rs1801394), as well as mutations of the genes of blood coagulation factors – G(455)A of the FGB gene, G20210A of the F2 gene, G10976A (Arg353Gln) of the F7 gene, G1691A (Arg506Gln) of the F5 gene. The study was carried out using real-time polymerase chain reaction (PCR); The biological material for the test was whole blood.Results and discussion. The study showed that only 6 out of 50 (12%) patients with thrombotic complications had no changes in the genes studied, while 88% of patients had one or another genotypic variant, which may indicate a high probability of involvement of a hereditary genetic factor in the development of hypercoagulability and thrombotic complications in patients with chronic MPN.Conclusions. A comprehensive study of the role, interaction and operating conditions of genes that control blood coagulation processes in patients with Ph-negative chronic MPN will make it possible to understand the causes of hemostatic system disorders and develop effective measures to prevent thrombotic complications in this category of patients.

Viral communities in a pH>10 serpentinite-like environment: insight into diversity and potential roles in modulating the microbiomes by bioactive vitamin B9 synthesis.

This study presents a comprehensive investigation into the diversity, potential functionalities, and virus-microbe interactions in an artificially induced strongly alkaline environment. Functional validation of the detected viral folA genes encoding dihydrofolate reductase substantiated the synthesis of essential cofactors by viruses, which may be ubiquitous, considering the broad distribution of the viral genes associated with folate cycling.

The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity.

Dietary restriction (DR) protocols frequently employ intermittent fasting. Following a period of fasting, meal consumption increases lipogenic gene expression, including that of NADPH-generating enzymes that fuel lipogenesis in white adipose tissue (WAT) through the induction of transcriptional regulators SREBP-1c and CHREBP. SREBP-1c knockout mice, unlike controls, did not show an extended lifespan on the DR diet. WAT cytoplasmic NADPH is generated by both malic enzyme 1 (ME1) and the pentose phosphate pathway (PPP), while liver cytoplasmic NADPH is primarily synthesized by folate cycle enzymes provided one-carbon units through serine catabolism. During the daily fasting period of the DR diet, fatty acids are released from WAT and are transported to peripheral tissues, where they are used for beta-oxidation and for phospholipid and lipid droplet synthesis, where monounsaturated fatty acids (MUFAs) may activate Nrf1 and inhibit ferroptosis to promote longevity. Decreased WAT NADPH from PPP gene knockout stimulated the browning of WAT and protected from a high-fat diet, while high levels of NADPH-generating enzymes in WAT and macrophages are linked to obesity. But oscillations in WAT [NADPH]/[NADP+] from feeding and fasting cycles may play an important role in maintaining metabolic plasticity to drive longevity. Studies measuring the WAT malate/pyruvate as a proxy for the cytoplasmic [NADPH]/[NADP+], as well as studies using fluorescent biosensors expressed in the WAT of animal models to monitor the changes in cytoplasmic [NADPH]/[NADP+], are needed during ad libitum and DR diets to determine the changes that are associated with longevity.

Altered S-AdenosylMethionine availability impacts dNTP pools in Saccharomyces cerevisiae.

Saccharomyces cerevisiae has long been used as a model organism to study genome instability. The SAM1 and SAM2 genes encode AdoMet synthetases, which generate S-AdenosylMethionine (AdoMet) from Methionine (Met) and ATP. Previous work from our group has shown that deletions of the SAM1 and SAM2 genes cause changes to AdoMet levels and impact genome instability in opposite manners. AdoMet is a key product of methionine metabolism and the major methyl donor for methylation events of proteins, RNAs, small molecules, and lipids. The methyl cycle is interrelated to the folate cycle which is involved in de novo synthesis of purine and pyrimidine deoxyribonucleotides (dATP, dTTP, dCTP, and dGTP). AdoMet also plays a role in polyamine production, essential for cell growth and used in detoxification of reactive oxygen species (ROS) and maintenance of the redox status in cells. This is also impacted by the methyl cycle's role in production of glutathione, another ROS scavenger and cellular protectant. We show here that sam2∆/sam2∆ cells, previously characterized with lower levels of AdoMet and higher genome instability, have a higher level of each dNTP (except dTTP), contributing to a higher overall dNTP pool level when compared to wildtype. Unchecked, these increased levels can lead to multiple types of DNA damage which could account for the genome instability increases in these cells.

Congenital Heart Disease and Genetic Changes in Folate/Methionine Cycles.

Congenital heart disease is one of the most common congenital malformations and thus represents a considerable public health burden. Hence, the identification of individuals and families with an increased genetic predisposition to congenital heart disease (CHD) and its possible prevention is important. Even though CHD is associated with the lack of folate during early pregnancy, the genetic background of folate and methionine metabolism perturbations and their influence on CHD risk is not clear. While some genes, such as those coding for cytosolic enzymes of folate/methionine cycles, have been extensively studied, genetic studies of folate transporters (de)glutamation enzymes and mitochondrial enzymes of the folate cycle are lacking. Among genes coding for cytoplasmic enzymes of the folate cycle, MTHFR, MTHFD1, MTR, and MTRR have the strongest association with CHD, while among genes for enzymes of the methionine cycle BHMT and BHMT2 are the most prominent. Among mitochondrial folate cycle enzymes, MTHFD2 plays the most important role in CHD formation, while FPGS was identified as important in the group of (de)glutamation enzymes. Among transporters, the strongest association with CHD was demonstrated for SLC19A1.

Functional roles of folic acid in alleviating dexamethasone‐induced fatty liver syndrome in laying hens

AbstractFatty liver syndrome (FLS) poses a threat to the poultry industry due to its high occurrence and mortality rate. Folic acid (FA) is a coenzyme crucial for one‐carbon metabolism. However, the mechanism by which FA mitigates FLS in laying hens remains elusive. In this study, 60 21‐week‐old Hy‐Line Brown layers were divided into three groups: the Control (Con) group, the dexamethasone (DXM) group, and the DXM + FA group. Results showed that liver index was significantly increased in the DXM group. H&amp;E and oil red O staining showed the accumulation of lipid droplets in the liver was intensified, confirming the successful establishment of an early fatty liver model without inflammation. FA significantly reversed hepatic lipid deposition, and 57 differentially expressed genes affected by FA were identified in the transcriptome analysis. Their transcriptional and translational levels indicate that in the early FLS, insulin‐like growth factor 2/phosphatidylinositol‐3‐kinase/protein kinase B pathway related to lipid metabolism was activated; folate cycling was inhibited, while endoplasmic reticulum (ER) stress and apoptosis‐related protein abundance were elevated. Dietary FA enhanced the folate circulation, reduced lipogenesis and ER stress, and apoptosis‐related protein expression, thereby mitigating the lipid metabolism disturbance in FLS. Metabolomics identified 151 differential metabolites involved in early FLS occurrence, 34 of which were reversed by FA. Metabolites were also enriched in pathways related to lipid metabolism and hepatic damage. Collectively, these findings can be concluded that FA can alleviate early FLS by affecting lipogenesis, ER stress and apoptosis, which may be mediated by enhanced folate metabolism.

SGLT2 inhibition leads to a restoration of hepatic and circulating metabolites involved in the folate cycle and pyrimidine biosynthesis.

Inhibition of sodium-glucose cotransporter 2 (SGLT2) by empagliflozin (EMPA) and other "flozins" can improve glycemic control under conditions of diabetes and kidney disease. Though they act on the kidney, they also offer cardiovascular and liver protection. Previously, we found that EMPA decreased circulating triglycerides and hepatic lipid and cholesterol esters in male TallyHo mice fed a high-milk-fat diet (HMFD). The goal of this study was to determine whether the liver protection is associated with a change in metabolic function by characterizing the hepatic and circulating metabolic and lipidomic profiles using targeted LC-MS. In both male and female mice, HMFD feeding significantly altered the circulating and hepatic metabolome compared with low-fat diet (LFD). Addition of EMPA resulted in the restoration of circulating orotate (intermediate in pyrimidine biosynthesis) and hepatic dihydrofolate (intermediate in the folate and methionine cycles) levels in males and acylcarnitines in females. These changes were partially explained by altered expression of rate-limiting enzymes in these pathways. This metabolic signature was not detected when EMPA was incorporated into an LFD, suggesting that the restoration requires the metabolic shift that accompanies the HMFD. Notably, the HMFD increased expression of 18 of 20 circulating amino acids in males and 11 of 20 in females, and this pattern was reversed by EMPA. Finally, we confirmed that SGLT2 inhibition upregulates ketone bodies including β-hydroxybutyrate. Collectively, this study highlights the metabolic changes that occur with EMPA treatment, and sheds light on the possible mechanisms by which this drug offers liver and systemic protection.NEW & NOTEWORTHY Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin, have emerged as a new treatment option for individuals with type 2 diabetes that have positive impacts on kidney and cardiovascular disease. However, less is known about their impact on other tissues, including the liver. Here, we report that empagliflozin reduces hepatic steatosis that is associated with restoring metabolic intermediates in the folate and pyrimidine biosynthesis pathways. These changes may lead to new approaches to treat nonalcoholic fatty liver disease.

Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase

Methylenetetrahydrofolate reductase (MTHFR) is a pivotal flavoprotein connecting the folate and methionine methyl cycles, catalyzing the conversion of methylenetetrahydrofolate to methyltetrahydrofolate. Human MTHFR (hMTHFR) undergoes elaborate allosteric regulation involving protein phosphorylation and S-adenosylmethionine (AdoMet)-dependent inhibition, though other factors such as subunit orientation and FAD status remain understudied due to the lack of a functional structural model. Here, we report crystal structures of Chaetomium thermophilum MTHFR (cMTHFR) in both active (R) and inhibited (T) states. We reveal FAD occlusion by Tyr361 in the T-state, which prevents substrate interaction. Remarkably, the inhibited form of cMTHFR accommodates two AdoMet molecules per subunit. In addition, we conducted a detailed investigation of the phosphorylation sites in hMTHFR, three of which were previously unidentified. Based on the structural framework provided by our cMTHFR model, we propose a possible mechanism to explain the allosteric structural transition of MTHFR, including the impact of phosphorylation on AdoMet-dependent inhibition.

Associations of methylene tetrahydrofolate reductase (MTHFR) polymorphism with hepatocellular carcinoma in Egyptian population

Liver serves as a hub for key metabolic pathways such as folate cycle that provides one-carbon units for a network of metabolic reactions. Methylenetetrahydrofolate reductase (MTHFR) is a rate limiting enzyme in folate metabolism and thus it is vital for DNA methylation, synthesis and repair [1]. The objective of this study was to evaluate an eventual association between MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) and the susceptibility to hepatocellular carcinoma (HCC) in Egyptian population.Blood samples from patients and controls from Mansoura university hospital were used after signed consent and approval from Medical ethical committee. The two genetic loci were designed for amplification and genotyped by using PCR–RFLP.Our results clarify that, the most important predictors for HCC are T/T genotype of variant C677T and C/C genotype of variant (A1298C) with odds ratio 3.28 and 2.99 respectively. Also, MTHFR variant C677T genotype C/C or T/T combined with MTHFR variant A1298C genotype C/C were associated with an increased risk of HCC, with the OR, 2.6 and 7 respectively. CT genotype of MTHFR variant C677T showed significant difference between HCC grades and C allele of variant C677T showed significant difference in BCLC stages of HCC.Our data indicates that, the two variants (C677T and A1298C) constitute a risk factor for the development of HCC and this could be attributed to the low activities of the enzyme MTHFR that disturb one carbon metabolism and subsequently, DNA synthesis, repair and methylation, thus cellular redox state, growth, and proliferation.

FOLATES–RELATED AND BONE MARROW DISORDERS PROMOTE ATRIAL CARDIOMYOPATHY INPATIENTS AFFECTED BY PAROXYSMAL ATRIAL FIBRILLATION VIA BOTH EPCS AND ENDOTHELIAL DYSFUNCTION

Abstract Background Atrial Cardiomyopathy (AC) has been recently postulated to explain those embolic strokes not due to atrial fibrillation (AF) and paradoxical embolism. Pathogenic mechanisms underlying AC are still largely unknown. Folate cycle disorders (FD) are a yet underrated pro–thrombotic dysmetabolism. FD could hinder both endothelial and circulating endothelial progenitor cell (EPCs) functioning, therefore providing one–shot explanation to both atrial fibrosis and endothelial dysfunction (ED). Purpose This study aims to enquire for the hypothesis that: 1) atrial fibrosis (AFib) would relate to FD (intended as both: a)MTHFR C677T inherited mutations and b)bone–marrow function disorders, here referring to erythropoiesis diversions) and 2) AF patients would show dysfunctional EPCs. Methods We studied 59 consecutive patients admitted to the cardiology Unit of the General Hospital“F.Miulli”, with preserved EF, subjected to AF ablation. AFib was quantified in term of percentage of bipolar peak–to–peak voltage points below 0,5mV with respect to the wholeness of picked points. Blood count cell was evaluated at the admission. MTHFR C677T genotypes and serum folate were assessed. EPCs isolation and characterization were performed by cytometry analysis (CD45, CD34, CD133, VEGFR2 and KDR). EPCs functional wound healing assay was performed to determine the percentage of EPCs able to "fix the wound” and compared with matched–controls. Results Baseline characteristics did not differ between Sample and Control groups (Fig. 1 – Left Table). % of Afib significantly differs between C677T MTHFR homozigosis patients (n=15) with respect to non–C677TMTHFR homozygosis patients (n=44) (Fig.1 – Right graph. – p &amp;lt; 0,02). Once univariate analysis was performed, subsequent multivariate analysis highlight highest fit, once merged RBC, RDW–SD and folates values were inputed (Fig.2 – superior graph. – R2=0,39;p=0,0001). Either RBC, RDW–SD and folates coefficient reached significance (p &amp;lt; 0,0001; p &amp;lt; 0,01; p &amp;lt; 0,05 respectively). Number of EPCs signifi cantly differs between AF patients and matched controls (Fig 2 – inferior graph. –p &amp;lt; 0,001). Conclusions Our findings support the hypothesis that genetically determined folates dysmetabolism (MTHFR dysfunction) promotes AFib via a complex cardiac–bone marrow networking involving circulatingEPCs and unraveled by erythropoiesis diversions. Such results suggest a pathogenic role of folate cycle disorders in the AC development.

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.

Juvenile rheumatoid arthritis in mono-zygotic twins

Aim: To describe the rate of juvenile idiopathic arthritis progression andto determine the degree of responsiveness to methotrexate and adalimmabmanagement in mono-zygotic twins with a methylene tetrahydrofolatereductase gene mutation.Methods: The study was a 5-month, twin concordance study. Thisincludes a retrospective study of medical records, activity and severity ofthe disease, complications, which included an objective clinical examinationof the patient, based on an assessment of the severity of the diseaseusing the disease activity score calculator for rheumatoid arthritis (DAS:28), liver function test, and folate cycle enzyme.Results: Based on the study conducted, mono-zygotic twins with the sameform of arthritis, which began at the same age with the same manifestationsyndrome and joint disease, combined with the same folate cyclemutation, with similar treatment regimen had different degrees of diseaseprogression and severity. The first twin had a complication of toxic hepatitisand a concomitant autoimmune thyroiditis. The second twin had amore serious progression with small joints ankylosis.Conclusion: The study shows that monozygotic twins with juvenile idiopathicarthritis with a similar defect in the folate cycle enzyme had differentrates of disease progression of varying severity and joint damage.Consequently, this requires further study in monozygotic twins with juvenilerheumatoid arthritis.