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One-carbon metabolism (1CM), a metabolic network centered around the folate and methionine cycles, is intricately linked to T cell immune function in the progression of various diseases. Metabolites originating from 1CM have the ability to regulate signaling pathways within T cell and tumor cells. Tumor cells reshape 1CM within the tumor microenvironment (TME) to modulate the activation, survival, and differentiation of T cells through epigenetic modifications. Combining dietary interventions for 1CM with adoptive T cell therapy and immune checkpoint blockade could synergistically improve tumor control by bolstering T cell function within the TME. One-carbon metabolism (1CM), comprising folate metabolism and methionine metabolism, serves as an important mechanism for cellular energy provision and the production of vital signaling molecules, including single-carbon moieties. Its regulation is instrumental in sustaining the proliferation of cancer cells and facilitating metastasis; in addition, recent research has shed light on its impact on the efficacy of T cell-mediated immunotherapy. In this review, we consolidate current insights into how 1CM affects T cell activation, differentiation, and functionality. Furthermore, we delve into the strategies for modulating 1CM in both T cells and tumor cells to enhance the efficacy of adoptively transferred T cells, overcome metabolic challenges in the tumor microenvironment (TME), and maximize the benefits of T cell-mediated immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Serine is a major source of one‐carbon units needed for the synthesis of nucleotides and the production of intramitochondrial nicotinamide adenine dinucleotide phosphate (NADPH), and it plays an important role in cancer cell proliferation. The aim of this study was to develop a deuterium (2H) MRS imaging method for imaging tumor serine metabolism. Methods: Sequential (2H) spectra and spectroscopic images were used to monitor the metabolism of [2,3,3‐2H3]serine in patient‐derived glioblastoma cells in vitro and in tumors obtained by their orthotopic implantation in mouse brain. Results: [14,14‐2H2] 5,10‐methylene‐tetrahydrofolate, [2H]glycine, [2H]formate, and labeled water were detected in cell suspensions and water labeling in spectroscopic images of tumors. Studies in cells and tumors with variable mitochondrial content and inhibitor studies in cells demonstrated that most of the labeled serine was metabolized in the mitochondria. Water labeling in the cell suspensions was correlated with formate labeling; therefore, water labeling observed in tumors could be used to provide a surrogate measure of flux in the pathway of one‐carbon metabolism in vivo. Conclusion: The method has the potential to be used clinically to select patients for treatment with inhibitors of one‐carbon metabolism and subsequently to detect their early responses to such treatment. [ABSTRACT FROM AUTHOR]

Objective·To explore the regulatory mechanism of folate cycle metabolism in the immunosuppressive effect of myeloid derived suppressor cells (MDSCs). Methods·Bone marrow cells were isolated from C57BL/6 mice and cultured in RPMI 1640 medium supplemented with GM-CSF, G-CSF, and IL-6 to induce MDSCs in vitro. PD-L1 expression level and ROS production level of induced MDSCs were detected by flow cytometry. CD8+ T cells were enriched from the spleen by MACS with anti-CD8a-conjugated microbeads, labeled with Celltrace violet, and then co-cultured with MDSCs. After 72 h, proliferation was assessed by flow cytometry. Folate cycle-related metabolic enzymes in MDSCs were detected by real-time quantitative PCR. MDSCs were treated with folate cycle metabolic enzyme MTHFD2 inhibitor DS18561882 (DS18) and folic acid antagonist Pemetrexed. ROS and mitoROS production in MDSCs were assessed by flow cytometry. CD8+ T cells were enriched from the spleen by MACS with anti-CD8a-conjugated microbeads, labeled with Celltrace violet, and then co-cultured with Pemetrexed or DS18-treated MDSCs. After 72 h, proliferation was assessed by flow cytometry. Transcript levels of folate cycle-related metabolic enzymes in pemetrexed or DS18-treated MDSCs were detected by RNAseq. A subcutaneous tumor mouse model of colon cancer was established. From the tenth day post-implantation, tumor-bearing mice were intraperitoneally injected with Pemetrexed (200 mg/kg) and tumor size was recorded for tumor growth curve. On the fourteenth day, mice were sacrificed, and tumors were harvested. MC38 tumor-bearing mice were treated with isotype antibody, anti-CD8 monoclonal antibody (1 mg/kg, deplete CD8+ T cells), Pemetrexed (200 mg/kg), and combination of Pemetrexed with anti-CD8 antibody. MC38 tumor-bearing mice were treated with isotype antibody, anti-Gr1 monoclonal antibody (1.25 mg/kg, clearing MDSCs), combination of Pemetrexed with anti-Gr1 antibody. On the tenth day after implantation, tumor-bearing mice were treated with Pemetrexed (50 mg/kg), anti-PD-1 monoclonal antibody (250 μg/kg), Pemetrexed, and combination of Pemetrexed with anti-PD-1 antibody. Results·Flow cytometry data showed that PD-L1 level and ROS production were increased in induced MDSCs, and CD8+ T cell proliferation was also suppressed significantly. qPCR data revealed the expression of folate cycle-related metabolic enzymes MTHFD2 and others was increased in MDSCs. The accumulation of MDSCs was affected by DS18 or Pemetrexed, ROS production in MDSCs was reduced, and the immunosuppression of CD8+ T cells was relieved. RNA-seq results showed that genes related to MDSCs differentiation, such as S100 calc-binding protein A8, and genes related to MDSCs inhibition, such as cytochrome b-245β chain, which is related to ROS production, were also down-regulated after treatment with two folic acid cycling inhibitors. Tumor growth was suppressed by Pemetrexed. Tumor progression was promoted by combination of Pemetrexed with anti-CD8 antibody, compared with Pemetrexed monotherapy. However, tumor growth delay was inhibited by combination of Pemetrexed and anti-CD8, compared with anti-CD8 monotherapy. Tumor growth delay was caused by MDSCs depletion. But tumor growth was promoted by combination of pemetrexed and anti-Gr1, compared with pemetrexed monotherapy. Tumor growth was restricted by combination of pemetrexed and anti-PD-1 antibody, compared with anti-PD-1 monotherapy. Conclusion·Pemetrexed relies on CD8+ T cells for anti-tumor effects and further retards tumor growth by reprogramming MDSCs to an anti-tumor phenotype. Modulating MDSCs by targeting folate cycle could impair their immunosuppressive ability and enhance the efficacy of immune checkpoint blockade in cancer treatment.

By means of visiting folic acid processing plant, this article introduces the structure, metabolism and mechanism of folic acid, and the recommendations for folic acid supplementation are given. In order to help those who need to take folic acid supplements, this article also provides a deep understanding of the functions of folic acid in the body by combining scientific and entertaining ways. [ABSTRACT FROM AUTHOR]

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments. [ABSTRACT FROM AUTHOR]

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Funicular myelosis (sub­acute combined degeneration) is a disease characterized by the development of degeneration of the posterior and lateral cords of the spinal cord. Funicular myelosis is a neurological complication of vitamin B12 deficiency, which occurs as a result of reduced intake of vitamin B12 with food, malabsorption, in connection with taking some drugs (metformin, proton pump inhibitors, and nitrous oxide), with invasion by Diphyllobothrium latum. The disease is usually characterized by the presence of paresthesias, the development of sensitive ataxia, and impaired gait. The aim of the work was to demon­strate a clinical case of funicular myelosis in a young patient in order to improve the diagnostic process, paying attention to the genetic profile and identifying a concomitant predisposition to folate cycle disorder. A clinical case of funicular myelosis in a 39-year-old woman is described. The patient came to the neurology department with complaints of numbness in the upper and lower limbs, periodic shooting pains along the spine when the head is tilted forward. During the neurological examination, the following was observed: a decrease in vibrational, muscle-joint, discrimination sensitivity in the upper limbs, paresthesias in the distal parts of the limbs, and sensitive ataxia. According to the results of the magnetic resonance imaging (MRI) of the spinal cord, a lesion of the posterior cords on the long segment (C2-Th1) was found, which corresponds to the subacute degeneration of the spinal cord, which arose due to the deficiency of holotranscobalamin (active B12). The patient received appropriate treatment and was discharged home. Subsequently, the patient was found to have a concomitant genetic predisposition to folate cycle disorder and the development of thrombophilia. A year later, the woman again came to the neurological department. We carried out a repeated examination, evaluation of the results of the MRI of the cervical spine and other examinations in dynamics. According to the results of the literature analysis, additional markers for the diagnosis of funicular myelosis (in particular, homocysteine), the causes of hyper­homocysteinemia and its effects on the body were described. Timely detection and treatment of vitamin B12 deficiency is quite important, since in severe cases the development of spastic paraplegia is possible. Recovery of lost functions depends on the extent of spinal cord damage and the duration of the disease. If anemia is observed together with neurological symptoms, it is necessary to be especially attentive to possible funicular myelosis and to carry out appropriate diagnostic searches. And when detecting hyperhomocysteinemia, it is advisable to take into account other factors that can cause an increase in the level of homocysteine, in addition to a deficiency of vitamins B6, B12 and folic acid.

Abstract Background The folate cycle of one-carbon (C1) metabolism, which plays a central role in the biosynthesis of nucleotides and amino acids, demonstrates the significance of metabolic adaptation. We investigated the evolutionary history of the methylenetetrahydrofolate dehydrogenase (mTHF) gene family, one of the main drivers of the folate cycle, across life. Results Through comparative genomic and phylogenetic analyses, we found that several lineages of Archaea lacked domains vital for folate cycle function such as the mTHF catalytic and NAD(P)-binding domains of FolD. Within eukaryotes, the mTHF gene family diversified rapidly. For example, several duplications have been observed in lineages including the Amoebozoa, Opisthokonta, and Viridiplantae. In a common ancestor of Opisthokonta, FolD and FTHFS underwent fusion giving rise to the gene MTHFD1, possessing the domains of both genes. Conclusions Our evolutionary reconstruction of the mTHF gene family associated with a primary metabolic pathway reveals dynamic evolution, including gene birth-and-death, gene fusion, and potential horizontal gene transfer events and/or amino acid convergence.

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.

Background: The folate cycle of one-carbon (C1) metabolism, which plays a central role in the biosynthesis of nucleotides and amino acids, demonstrates the significance of metabolic adaptation. We investigated the evolutionary history of the methylenetetrahydrofolate dehydrogenase (mTHF) gene family, one of the main drivers of the folate cycle, across life. Results: Through comparative genomic and phylogenetic analyses, we found that several lineages of Archaea lacked domains vital for folate cycle function such as the mTHF catalytic and NAD(P)-binding domains of FolD. Within eukaryotes, the mTHF gene family diversified rapidly. For example, several duplications have been observed in lineages including the Amoebozoa, Opisthokonta, and Viridiplantae. In a common ancestor of Opisthokonta, FolD and FTHFS underwent fusion giving rise to the gene MTHFD1, possessing the domains of both genes. Conclusions: Our evolutionary reconstruction of the mTHF gene family associated with a primary metabolic pathway reveals dynamic evolution, including gene birth-and-death, gene fusion, and potential horizontal gene transfer events and/or amino acid convergence. [ABSTRACT FROM AUTHOR]

Folate, also known as vitamin B9, plays a crucial role in the one-carbon (1C) metabolism, a conserved pathway from microbes to humans. The 1C metabolism, consisting of the folate and methionine cycles, is essential in many biological processes such as nucleotide and protein biosynthesis, cell proliferation, and embryonic development. Despite its functional role, little is known about the 1C metabolism in crustaceans. As part of an ongoing effort to characterize important pathways in Calanus finmarchicus, the biomass-dominant zooplankton in much of the North Atlantic Ocean, we identified transcripts encoding the 1C metabolism enzymes. Using an in silico workflow consisting of a transcriptome mining, reciprocal blasts, and structural analyses of the deduced proteins, we identified the entire set of enzymes in both cycles. The majority encoded for full-length proteins and clustered with homologs from other species. Stage-specific expression was reported, with several transcripts showing high expression in the naupliar stage (e.g., 10-FTHFD, SHMT2) while some methyltransferases (e.g., BHMT, SHMT, DNMT) were more expressed in adults. Overall, this study provides a set of genes which can be used as potential biomarkers of development and reproduction and can be tested in other zooplankters to assess ocean health status monitoring. [ABSTRACT FROM AUTHOR]

Aim: to assess associations between folate cycle gene polymorphism and neonatal birth weight in pregnant women with fetal growth retardation (FGR) and related functional effects in population of the Central Black Earth Region.Materials and Methods. 98 cases of women with FGR were enrolled to a retrospective molecular and genetic screening to assess prevalence 5 SNPs (single nucleotide polymorphisms) in genes involved in folic acid cycle and methionine metabolism (rs699517 TYMS, rs2790 TYMS, rs1979277 SHMT1, rs1805087 MTR, rs1801394 MTRR).Results. It was found out that allele A of the rs1801394 MTRR was associated with a lower neonatal birth weight (recessive model: β = –0.34 ± 0.13; p = 0.009). This polymorphic locus exerts crucial functional effects by determining the amino acid substitution in methionine synthase reductase (Ile22Met) localized in the region of modified histones, which mark enhancers and promoters in ectoderm, endoderm and mesoderm cell cultures, primary osteoblast cells, brain, fat nuclei, skeletal muscles, etc. In addition, rs1801394 MTRR is found DNA sites (motifs) responsible for sensitivity to transcription factors STAT and TBX5 being also related to MTRR gene mRNA expression level in subcutaneous and visceral adipose tissue, thyroid gland, fibroblast cell culture as well as various brain regions.Conclusion. Thus, the allele A of the rs1801394 polymorphism in MTRR gene is a risk factor for a lower neonatal birth weight.

Funicular myelosis (subacute combined degeneration) is a disease characterized by the development of degeneration of the posterior and lateral cords of the spinal cord. Funicular myelosis is a neurological complication of vitamin B12 deficiency, which occurs as a result of reduced intake of vitamin B12 with food, malabsorption, in connection with taking some drugs (metformin, proton pump inhibitors, and nitrous oxide), with invasion by Diphyllobothrium latum. The disease is usually characterized by the presence of paresthesias, the development of sensitive ataxia, and impaired gait. The aim of the work was to demonstrate a clinical case of funicular myelosis in a young patient in order to improve the diagnostic process, paying attention to the genetic profile and identifying a concomitant predisposition to folate cycle disorder. A clinical case of funicular myelosis in a 39-year-old woman is described. The patient came to the neurology department with complaints of numbness in the upper and lower limbs, periodic shooting pains along the spine when the head is tilted forward. During the neurological examination, the following was observed: a decrease in vibrational, muscle-joint, discrimination sensitivity in the upper limbs, paresthesias in the distal parts of the limbs, and sensitive ataxia. According to the results of the magnetic resonance imaging (MRI) of the spinal cord, a lesion of the posterior cords on the long segment (C2-Th1) was found, which corresponds to the subacute degeneration of the spinal cord, which arose due to the deficiency of holotranscobalamin (active B12). The patient received appropriate treatment and was discharged home. Subsequently, the patient was found to have a concomitant genetic predisposition to folate cycle disorder and the development of thrombophilia. A year later, the woman again came to the neurological department. We carried out a repeated examination, evaluation of the results of the MRI of the cervical spine and other examinations in dynamics. According to the results of the literature analysis, additional markers for the diagnosis of funicular myelosis (in particular, homocysteine), the causes of hyper-homocysteinemia and its effects on the body were described. Timely detection and treatment of vitamin B12 deficiency is quite important, since in severe cases the development of spastic paraplegia is possible. Recovery of lost functions depends on the extent of spinal cord damage and the duration of the disease. If anemia is observed together with neurological symptoms, it is necessary to be especially attentive to possible funicular myelosis and to carry out appropriate diagnostic searches. And when detecting hyper-homocysteinemia, it is advisable to take into account other factors that can cause an increase in the level of homocysteine, in addition to a deficiency of vitamins B6, B12 and folic acid. [ABSTRACT FROM AUTHOR]

Several maternal genetic variations are known to play an important role during pregnancy since they can affect mother health and/or fetal growth. The frequency of these variants is variable among different populations. This study aimed to investigate thrombophilia, folate metabolism and hypertension genetic variants in reproductive age women of Rostov region (Russia) and then assess their linkage disequilibrium (LD) and heterogeneity among populations. A total of 3108 reproductive age women were included (33.75 ± 5.13 years). Twenty‐one genetic variants were detected with RT‐PCR. LD was tested according to (D′) coefficient and p value. The highest frequency of mutant allele in studied population was as follows: PAI‐1 rs1799768, MTRR rs1801394, AGT rs699, and AGTR2 rs1403543. We showed a high possibility of coinheritance of MTHFR rs1801133 with rs1801131 and AGT rs699 with rs4762 (D′=0.992 and 0.999, respectively). In addition, comparative analysis showed F7 rs6046, FGB rs1800790, MTR rs1805087, and AGT rs699 significantly more frequent among Rostov females by 1.3–1.5 times than European. MTHFR rs1801133, ADD1 rs4961, AGTR2 rs1403543, NOS3 rs2070744, and rs1799983 were with higher frequencies in Europeans than those in the studied group. Our data could be used as a reference for further associative studies of targeted genetic variations in different pregnancy complications specifically in this population. [ABSTRACT FROM AUTHOR]

Introduction. Hyperhomocysteinemia (HHC) is one of the arms in the pathogenesis of thrombotic complications in female cancer patients.Aim: to assess an HHC-related impact to developing thrombotic complications in patients with malignant neoplasms of the female genital organs and breast cancer.Materials and Methods. There were retrospectively evaluated the data collected from 236 patients: with ovarian tumors (n = 63), cervical cancer (n = 51), breast tumors (n = 64), malignant neoplasms of the uterine body (n = 58). The control group consisted of 50 women without malignant neoplasms. The analysis of homocysteine (HC) concentration, the frequency of polymorphisms of the genes encoding folate cycle enzymes MTHFR C677T, MTHFR A1298C, MTRR A66G, MTR A2756G as well as the rate of thrombotic complications was carried out. A risk of blood HC level-related thrombotic complications was assessed.Results. Plasma HC concentration comprised ≥ 22 μmol/l in 30.5 % of patients. Thrombotic complications within one year after discharge from the hospital were developed in 15.3 % cases. The risk of thrombotic complications turned out to be higher in patients with elevated plasma HC level (≥ 22 μmol/l) (odds ratio = 2.99; 95 % confidence interval = 1.11–8.08). No significantly increased prevalence of polymorphisms in the genes encoding folate cycle enzymes among female cancer patients was detected.Conclusion. Monitoring HC level in female cancer patients contributes separately to predict a likelihood of thrombotic complications. Prescribing drugs that reduce HC level (folic acid) and monitoring its concentration in female cancer patients during therapy, including chemotherapy, can potentially lower an incidence of thrombotic complications.

Folate, also known as vitamin B9, plays a crucial role in the one-carbon (1C) metabolism, a conserved pathway from microbes to humans. The 1C metabolism, consisting of the folate and methionine cycles, is essential in many biological processes such as nucleotide and protein biosynthesis, cell proliferation, and embryonic development. Despite its functional role, little is known about the 1C metabolism in crustaceans. As part of an ongoing effort to characterize important pathways in Calanus finmarchicus, the biomass-dominant zooplankton in much of the North Atlantic Ocean, we identified transcripts encoding the 1C metabolism enzymes. Using an in silico workflow consisting of a transcriptome mining, reciprocal blasts, and structural analyses of the deduced proteins, we identified the entire set of enzymes in both cycles. The majority encoded for full-length proteins and clustered with homologs from other species. Stage-specific expression was reported, with several transcripts showing high expression in the naupliar stage (e.g., 10-FTHFD, SHMT2) while some methyltransferases (e.g., BHMT, SHMT, DNMT) were more expressed in adults. Overall, this study provides a set of genes which can be used as potential biomarkers of development and reproduction and can be tested in other zooplankters to assess ocean health status monitoring.

Non-alcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform (GLS1) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse primary hepatocytes, in human hepatocyte cell lines, and in NASH mouse livers. We suggest that under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprogramming of serine metabolism, wherein serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. The restored methionine cycle can induce phosphatidylcholine synthesis from the phosphatidylethanolamine N-methyltransferase-mediated and CDP-choline pathways as well as by base-exchange reactions between phospholipids, thereby restoring hepatic phosphatidylcholine content and very-low-density lipoprotein export. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.

Methylenetetrahydrofolate reductase (MTHFR) is a key metabolic enzyme in colonization and virulence of Neisseria meningitidis, a causative agent of meningococcal diseases. Here, the biochemical and structural properties of MTHFR from a virulent strain of N. meningitidis serogroup B (NmMTHFR) were characterized. Unlike other orthologs, NmMTHFR functions as a unique homohexamer, composed of three homo‐dimerization partners, as shown in our 2.7 Å resolution crystal structure. Six active sites were formed solely within monomers and located away from the oligomerization interfaces. Flavin adenine dinucleotide cofactor formed hydrogen bonds with conserved sidechains, positioning its isoalloxazine ring adjacent to the overlapping binding sites of nicotinamide adenine dinucleotide (NADH) coenzyme and CH2‐H4folate substrate. NmMTHFR utilized NADH (Km = 44 μM) as an electron donor in the NAD(P)H‐CH2‐H4folate oxidoreductase assay, but not nicotinamide adenine dinucleotide phosphate (NADPH) which is the donor required in human MTHFR. In silico analysis and mutagenesis studies highlighted the significant difference in orientation of helix α7A (Phe215–Thr225) with that in the human enzyme. The extended sidechain of Met221 on helix α7A plays a role in stabilizing the folded structure of NADH in the hydrophobic box. This supports the NADH specificity by restricting the phosphate group of NADPH that causes steric clashes with Glu26. The movement of Met221 sidechain allows the CH2‐H4folate substrate to bind. The unique topology of its NADH and CH2‐H4folate binding pockets makes NmMTHFR a promising drug target for the development of new antimicrobial agents that may possess reduced off‐target side effects. PDB Code(s): 7RML; [ABSTRACT FROM AUTHOR]

Background: Hyperhomocysteinemia is important in the development of endothelial dysfunction, a pathogenetic component of diabetic retinopathy (DR) in type 2 diabetes mellitus (DM2). The major cause of homocysteine accumulation is missing or dysfunctional enzymes and cofactors that are needed to perform homocystein metabolic processes. This is, for the most part, the deficiency of folate cycle enzymes determined by methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, and methionine synthase (MTR) A2756G polymorphisms. Purpose: To assess the role of polymorphisms of folate cycle enzymes (MTHFR C677T, MTHFR A1298C, MTR A2756G) in DR progression in patients with DM2. Material and Methods: The study included 83 DM2 patients (83 eyes) in whom DR met the criteria of non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) according to the Early Treatment of Diabetic Retinopathy Study (ETDRS). The control group was composed of 35 non-diabetics comparable to patients with respect to gender, age and body mass index. Real-time PCR was conducted on a Gene Amp® PCR System 7500 to determine polymorphisms. Plasma L-homocysteine levels were determined using an enzyme-linked immunosorbent assay (ELISA) microplate reader and Axis® Homocysteine Enzyme Immunoassay Kit (AXIS-SHIELD Diagnostics Ltd). Conclusion: We found no association of rs1801133, rs1805087, and rs1801131, folate-cycle polymorphisms, with the development of DR in DM2, compared with non-diabetics. In NPDR patients having the minor homozygous GG genotype of MTR 2756А/G and/or the minor homozygous CC genotype of MTHFR 1298A/C, plasma L-homocysteine levels were significantly increased. This requires further elucidation of the role of hyperhomocysteinemia as a factor of DR progression or as a marker of the severity of tissue injury. The duration of DM2 is an important factor of DR progression in carriers of the most common CC and CT genotypes of rs1801133, AG genotype of rs1805087, and АА genotype of rs1801131.

Hyperhomocysteinemia (HHcy) is an autosomal recessive inherited metabolic disease caused by variations in folate metabolism genes, characterized by impaired methionine metabolism and accumulation of homocysteine (Hcy) in the blood serum. It was shown that men usually have higher plasma Hcy levels than women, but have not yet assessed the leading factors of these differences, which is important for the development of personalized protocols for the prevention of folate metabolism disorders in couples with reproductive disorders. This study aimed to analyze the effect of intergenic and gene-factor interactions on the risk of developing HHcy in men and women of married couples with reproductive disorders. In our study were involved 206 married Caucasian couples (206 males and 206 females) from central regions of Ukraine with early pregnancy losses in the anamnesis. We found that the incidence of HHcy in men was significantly higher than in women. Gender differences in folic acid and vitamin B12 levels were identified. The best predictors of HHcy in men (MTRR (A66G), MTHFR (C677T), MTR (A2756G), vitamin B12 level) and in women (MTHFR (C677T), MTR (A2756G), vitamin B12 level) were selected by binary logistic regression. There was no significant difference in the distribution of genotypes by the studied gene variants when comparing men and women with HHcy. Our findings demonstrate that there is a gender difference in the development of HHcy. This difference is caused by intergenic interaction and by environmental factors, in particular, nutrition and vitamins consumption. [ABSTRACT FROM AUTHOR]

Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, transcriptomic, and metabolomic techniques. Genotypes of 3 SNPs in a case-control cohort were initially correlated to clinical and serum MAFLD markers. Subsequently, the expression of 84 key genes in response to the loss of SLC19A1 was evaluated with the aid of an RT2 profiler-array. After shRNA-silencing of SLC19A1 in THLE2 cells, folate and lipid levels were measured by ELISA and staining techniques, respectively. In addition, up to 482 amino acids and lipid metabolites were semi-quantified in SLC19A1-knockdown (KD) cells through ultra-high-performance liquid chromatography coupled with mass spectrometry. SNPs, rs1051266 and rs3788200, were significantly associated with the development of fatty liver for the single-marker allelic test. The minor alleles of these SNPs were associated with a 0.6/−1.67-fold decreased risk of developing MAFLD. When SLC19A1 was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional SLC19A1 provoked significant changes in the regulation of genes associated with lipid droplet accumulation within the cell and the onset of NAFLD. Metabolomic analyses showed a highly altered profile, where most of the species that accumulated in SLC19A1-KD-cells belong to the chemical groups of triacylglycerols, diacylglycerols, polyunsaturated fatty acids, and long chain, highly unsaturated cholesterol esters. In conclusion, the lack of SLC19A1 gene expression in hepatocytes affects the regulation of key genes for normal liver function, reduces intracellular folate levels, and impairs lipid metabolism, which entails lipid droplet accumulation in hepatocytes. [ABSTRACT FROM AUTHOR]

Cancer cells are characterized by accelerated proliferation and an outstanding adaptation of their metabolic pathways to meet energy demands. The folate cycle, also known as folate metabolism or one-carbon metabolism, through enzymatic interconversions, provides metabolites necessary for nucleotide synthesis, methylation, and reduction power, helping to maintain the high rate of proliferation; therefore, the study of this metabolic pathway is of great importance in the study of cancer. Moreover, multiple enzymes involved in this cycle have been implicated in different types of cancer, corroborating the cell's adaptations under this pathology. During the last decade, nonalcoholic fatty liver disease has emerged as the leading etiology related to the rise in the incidence and deaths of hepatocellular carcinoma. Specifically, cholesterol accumulation has been a determinant promoter of tumor formation, with solid evidence that an enriched-cholesterol diet plays a crucial role in accelerating the development of an aggressive subtype of hepatocellular carcinoma compared to other models. In this review, we will discuss the most recent findings to understand the contribution of folate metabolism to cancer cells and tumor microenvironment while creating a link between the dynamics given by cholesterol and methylenetetrahydrofolate dehydrogenase 1-like, a key enzyme of the cycle located in the mitochondrial compartment. [ABSTRACT FROM AUTHOR]

Study background objectives: Cancer poses a significant health concern as it is incurable. Every year, research on how to treat and eradicate this chronic condition is done. This systematic review will unmask the recent developments concerning highly active 1C metabolism with regard to cancer diagnosis, treatment, and drug resistance. The significance of this study is rolling out evidence-based evidence on the importance of one-carbon metabolism in cancer diagnosis and treatment. Methods: Eight randomized controlled trials (RCTs) were reviewed from five electronic databases - EMBASE, Scopus Review, Google Scholar, Web of Science, and PubMed. Outcomes from the eight studies were analyzed to paint a picture of the topic in question. While the Preferred Reporting Items for Systematic Reviews and Meta-Analysis' (PRISMA) protocol guided the initial literature search, The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach informed quality assessments of the eligible studies. Conclusion: Since its emergence in the 1980s, 1C metabolism has been investigated and broadened to capture essential aspects of cancer treatment, diagnosis, and drug resistance. The review found that metabolites like folic acid could be used to detect different types of cancer. The metabolic pathways could induce tumorigenesis and DNA methylation, hence drug resistance. [ABSTRACT FROM AUTHOR]

Background: Hyperhomocysteinemia is important in the development of endothelial dysfunction, a pathogenetic component of diabetic retinopathy (DR) in type 2 diabetes mellitus (DM2). The major cause of homocysteine accumulation is missing or dysfunctional enzymes and cofactors that are needed to perform homocystein metabolic processes. This is, for the most part, the deficiency of folate cycle enzymes determined by methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, and methionine synthase (MTR) A2756G polymorphisms. Purpose: To assess the role of polymorphisms of folate cycle enzymes (MTHFR C677T, MTHFR A1298C, MTR A2756G) in DR progression in patients with DM2. Material and Methods: The study included 83 DM2 patients (83 eyes) in whom DR met the criteria of non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) according to the Early Treatment of Diabetic Retinopathy Study (ETDRS). The control group was composed of 35 non-diabetics comparable to patients with respect to gender, age and body mass index. Real-time PCR was conducted on a Gene Amp® PCR System 7500 to determine polymorphisms. Plasma L-homocysteine levels were determined using an enzyme-linked immunosorbent assay (ELISA) microplate reader and Axis® Homocysteine Enzyme Immunoassay Kit (AXIS-SHIELD Diagnostics Ltd). Conclusion: We found no association of rs1801133, rs1805087, and rs1801131, folate-cycle polymorphisms, with the development of DR in DM2, compared with non-diabetics. In NPDR patients having the minor homozygous GG genotype of MTR 2756A/G and/or the minor homozygous CC genotype of MTHFR 1298A/C, plasma L-homocysteine levels were significantly increased. This requires further elucidation of the role of hyperhomocysteinemia as a factor of DR progression or as a marker of the severity of tissue injury. The duration of DM2 is an important factor of DR progression in carriers of the most common CC and CT genotypes of rs1801133, AG genotype of rs1805087, and AA genotype of rs1801131. [ABSTRACT FROM AUTHOR]

BACKGROUND: Summary data indicate that it has increased attention to the study of the role of the folate cycle and the genes encoding its key components in the complicated course of the neonatal period in premature infants. Therefore, the aim of our study was to investigate the relationship of folate cycle gene variants with the features of the neonatal course in premature infants with severe intraventricular hemorrhages (IVH). METHODS: The study included 24 preterm infants with with IVHs of 3d and 4th degree that received standard clinical, laboratory and instrumental examination. RESULTS: Apgar scores at 1 and 5 minutes were significantly lower in patients with AA genotype according to variant A1298C of the MTHFR gene. The concentration of total protein on 6th day after birth was negatively correlated with the A66G variant of the MTRR gene. The mean concentration of ionized calcium in the first day after birth was higher in the subgroup of patients with the AA genotype (according to variant A1298C of the MTHFR gene). In the subgroup of patients requiring mechanical ventilation, the frequency of AA genotype according to variant A2756G of the MTR gene was significantly increased. The presence of respiratory disorders and oxygen dependence was negatively correlated with variant A1298C MTHFR. The day of surfactant administration was positively correlated with variant A1298C of the MTHFR gene. CONCLUSION: The results of this study indicate that gene variants MTHFR (C677T, A1298C), MTRR (A66G), MTR (A2756G), RFC1 (G80A) may affect the neonatal course in premature infants with severe IVH. [ABSTRACT FROM AUTHOR]

Congenital malformations are pathology with a multifactorial etiology. Among their many endogenous, exogenous factors and hereditary predisposition are important. In particular a decrease in follicular enzymes (MTHFR, MTR, MTRR) activity at the genetic level, as well as a deficiency of vitamins and vitamin-like compounds of group B. Objective: to provide a pathogenetic justification for personified correction of disorders in the folate cycle in biological parents preparing for pregnancy to prevent congenital malformations in their children by using folates containing metafolin (5-MTHF). Materials and methods. The study involved 75 women and 75 men (biological parents) who had children/fetuses with congenital malformations in previous pregnancies, and 75 newborn children of these couples. All of them used the proposed preconceptional preparation. Alleles of folate cycle enzyme genes (MTHFR, MTR, MTRR) were determined by polymerase chain reaction in blood and saliva. Results. A high frequency of polymorphism of the folate cycle enzyme genes was observed in men among subjects (father, mother, child). The indicator was 77.7% compared with 68.7% in mothers and 60.7% in their children. The frequency of homozygous alleles was highest in parents (men) – 19.6%, lower in mothers – 13.1% and in children – 12.7%. Result of heterozygous alleles decreased from children indicator (87.3%) to their mothers (86.7%) and parents (80.4%). Conclusions. Obtained results emphasize the practical importance for determining the alleles of the folate cycle enzyme genes (MTHFR, MTR, MTRR) at the stage of preconception preparation for pregnancy in biological parents and then in their newborn children from the standpoint of preventive medicine. Reduced activity of the corresponding enzymes pathogenetically explains the feasibility of using folate complexes containing active folate metafolin (5-MTHF) in order to prevent congenital malformations.

Methotrexate (MTX) is the immunosuppressive anti-inflammatory drug and the antagonist of the enzyme dihydrofolate reductase. Pharmacogenomic studies and clinical evidences suggest that altered response to MTX in patients with different diseases is associated with polymorphisms of genes that regulate folate metabolism. The purpose of the article was to analyze the methotrexate effect on the biochemical indices of psoriasis patients depending on methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms. Effects of two single-nucleotide polymorphisms, C677T and A1298C, were studied. An increase of alanine aminotransferase and aspartate aminotransferase activity above the normal level in the patients with both MTHFR gene polymorphisms after methotrexate intake was observed. In patients with CC, TT, CT genotypes for C677T polymorphism and AA genotype for A1298C polymorphism of MTHFR gene, significant differen­ces in alpha-amylase activity before and after treatment with methotrexate were detected. Analysis of the biochemical indices of patients with arthropathic and vulgaris psoriasis showed that the positive effect of MTX treatment could be associated with wild-type alleles in both polymorphisms of MTHFR gene, while the ineffectiveness of methotrexate was associated with the dihеterozygous genotype. The largest number of smokers was found within the CTAA genotype group (37.5%), while no smokers were observed within TTAA patients and most of CCAA patients. The data obtained testify the utility of the individual approach to the psoriasis patients therapy taking into account genetic background.

Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, transcriptomic, and metabolomic techniques. Genotypes of 3 SNPs in a case-control cohort were initially correlated to clinical and serum MAFLD markers. Subsequently, the expression of 84 key genes in response to the loss of SLC19A1 was evaluated with the aid of an RT2 profiler-array. After shRNA-silencing of SLC19A1 in THLE2 cells, folate and lipid levels were measured by ELISA and staining techniques, respectively. In addition, up to 482 amino acids and lipid metabolites were semi-quantified in SLC19A1-knockdown (KD) cells through ultra-high-performance liquid chromatography coupled with mass spectrometry. SNPs, rs1051266 and rs3788200, were significantly associated with the development of fatty liver for the single-marker allelic test. The minor alleles of these SNPs were associated with a 0.6/−1.67-fold decreased risk of developing MAFLD. When SLC19A1 was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional SLC19A1 provoked significant changes in the regulation of genes associated with lipid droplet accumulation within the cell and the onset of NAFLD. Metabolomic analyses showed a highly altered profile, where most of the species that accumulated in SLC19A1-KD-cells belong to the chemical groups of triacylglycerols, diacylglycerols, polyunsaturated fatty acids, and long chain, highly unsaturated cholesterol esters. In conclusion, the lack of SLC19A1 gene expression in hepatocytes affects the regulation of key genes for normal liver function, reduces intracellular folate levels, and impairs lipid metabolism, which entails lipid droplet accumulation in hepatocytes.

Background. A variety of biological processes regulated by differential gene expression are required to maintain a normal gestation and accordingly, the mutations and polymorphisms in such genes may cause miscellaneous biological disorders that eventually result in early pregnancy loss. Many studies reported that aberrant fetal DNA methylation as well as embryonic chromosome abnormalities may lead to impairment of fetal early growth and development. Therefore, we have aimed to genotype several gene polymorphisms might be involved in the above-mentioned biological disorders to screen their prevalence in Russian population. Materials and methods. 81 Russian women without previous history of normal pregnancy or early abortion were recruited into this population study to determine the genotype and allele frequencies through genotyping using RFLP-PCR method for DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, and DNMT3L rs2070565, allele-specific PCR for SYCP3 T657C, and real-time PCR for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, and MTRR rs1801394. Results. Minor homozygous genotypes and minor alleles of the polymorphisms DNMT3B rs2424913 (TT: 11.1%, T: 37.05%), DNMT1 rs2228611 (GG: 18.5%, G: 40.75%), and DNMT1 rs8101626 (GG: 16.0%, G: 40.1%) were quite prevalent in Russian women and as frequent as those of the well-studied polymorphisms: MTRR rs1801394 (GG: 27.2%, G: 50.65%), MTHFR rs1801131 (CC: 17.3%, C: 40.15%), and MTHFR rs1801133 (TT: 11.1%, T: 29.0%).The heterozygous genotype of SYCP3 T657C (CT: 12.3%, T: 6.15%) was also quite frequent. Conclusion. Based on our study and literature data, we suggest that DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 T657C polymorphisms along with the common folate cycle gene polymorphisms can be potential genetic predictors for early pregnancy loss in Russian women.

Cystathionine beta-synthase deficient homocystinuria (HCU) is a life-threatening disorder of sulfur metabolism. Our knowledge of the metabolic changes induced in HCU are based almost exclusively on data derived from plasma. In the present study, we present a comprehensive analysis on the effects of HCU upon the hepatic metabolites and enzyme expression levels of the methionine-folate cycles in a mouse model of HCU. HCU induced a 10-fold increase in hepatic total homocysteine and in contrast to plasma, this metabolite was only lowered by approximately 20% by betaine treatment indicating that this toxic metabolite remains unacceptably elevated. Hepatic methionine, S -adenosylmethionine, S -adenosylhomocysteine, N -acetlymethionine, N -formylmethionine, methionine sulfoxide, S -methylcysteine, serine, N -acetylserine, taurocyamine and N -acetyltaurine levels were also significantly increased by HCU while cysteine, N -acetylcysteine and hypotaurine were all significantly decreased. In terms of polyamine metabolism, HCU significantly decreased spermine and spermidine levels while increasing 5′-methylthioadenosine. Betaine treatment restored normal spermine and spermidine levels but further increased 5′-methylthioadenosine. HCU induced a 2-fold induction in expression of both S -adenosylhomocysteine hydrolase and methylenetetrahydrofolate reductase. Induction of this latter enzyme was accompanied by a 10-fold accumulation of its product, 5-methyl-tetrahydrofolate, with the potential to significantly perturb one‑carbon metabolism. Expression of the cytoplasmic isoform of serine hydroxymethyltransferase was unaffected by HCU but the mitochondrial isoform was repressed indicating differential regulation of one‑carbon metabolism in different sub-cellular compartments. All HCU-induced changes in enzyme expression were completely reversed by either betaine or taurine treatment. Collectively, our data show significant alterations of polyamine, folate and methionine cycle metabolism in HCU hepatic tissues that in some cases, differ significantly from those observed in plasma, and have the potential to contribute to multiple aspects of pathogenesis. [ABSTRACT FROM AUTHOR]

Background: In recent years, the interest in genetic predisposition studies for coronary artery disease and restenosis has increased. Studies show that polymorphisms of genes encoding folate cycle and homocysteine metabolism enzymes significantly contribute to atherogenesis and endothelial dysfunction. The purpose of this study was to examine some SNPs of genes coding for folate cycle enzymes and DNA methyltransferases as risk factors for in-stent restenosis. Methods: The study included 113 patients after stent implantation and 62 patients without signs of coronary artery disease at coronary angiography as the control group. Real-time PCR and RFLP-PCR were applied to genotype all participants for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, MTRR rs1801394, DNMT1 rs8101626, DNMT3B rs1569686, and DNMT3B rs2424913 gene polymorphisms. Statistical data processing was carried out using the R language and the SPSS Statistics 20 software. Results: Statistically significant differences in the DNMT3B gene polymorphisms were found between patients with and without in-stent restenosis. An association of TT rs1569686 and TT rs2424913 genotypes with the development of restenosis was revealed. The TT rs1569686 genotype was more frequent in the patients under the age of 65 years and in the subgroup of patients with post-12-month restenosis, as was the minor GG genotype for MTR rs1805087. The homozygous TT genotype for MTHFR rs1801133 was significantly more frequent in the subgroup over 65 years old. The frequencies of the heterozygous genotype for the MTRR gene and the minor GG homozygotes for the DNMT1 gene were significantly higher in the subgroup with in-stent restenosis under 65 years old. Conclusions: The results of this study could be used for a comprehensive risk assessment of ISR development, determining the optimal tactics and an individual approach in the treatment of patients with coronary artery disease before or after percutaneous coronary interventions, including homocysteine-lowering treatment in patients with hyperhomocysteinemia and a high risk of in-stent restenosis.

Low provision of cells with vitamin B2 and magnesium leads to a decrease in the activity of the sirtuin-1 deacetylase and an increase in the activity of the pro-inflammatory factor NF-kB, a decrease in the levels of glutathione, an increase in the levels of homocysteine, thrombus formation, the activity of mitochondria, the development of migraine, convulsions and miscarriage. The role of riboflavin in the regulation of the folate cycle in the genotype MTHFR 677TT for the prevention of folatresistant fetal malformations, the advantages of an aqueous solution of riboflavin and magnesium citrate is considered. The data on titanium dioxide, which increases the level of pro-inflammatory cytokines IL-1b, IL-4, IL-5, IL-6, G-CSF, CCL-2, CCL-3, CCL-4, are presented.

Purpose: Reduction in methylenetetrahydrofolate reductase (MTHFR) activity due to genetic variations in the MTHFR gene has been controversially implicated in subfertility in human in vitro fertilization. However, there is no direct gene-knockdown study of embryonic MTHFR to assess its involvement in mammalian preimplantation development. The purpose of this study is to investigate expression profiles and functional roles of MTHFR in bovine preimplantation development. Methods: Reverse transcription-quantitative PCR (RT-qPCR) and analysis of publicly available RNA-seq data were performed to reveal expression levels of MTHFR during bovine preimplantation development. We knocked down MTHFR by siRNA-mediated RNA interference from the 8- to 16-cell stage and assessed the effects on preimplantation development. Results: The RT-qPCR analysis showed relatively high MTHFR expression at the GV oocyte stage, which was decreased toward the 8- to 16-cell stage and then slightly restored at the blastocyst stage. Public data–based analysis also showed the similar pattern of expression with substantial embryonic expression at the blastocyst stage. MTHFR knockdown reduced the blastocyst rate (P < 0.01) and the numbers of total (P < 0.0001), trophectoderm (P < 0.0001), and inner cell mass (P < 0.001) cells. Conclusion: The results indicate that embryonic MTHFR is indispensable for normal blastocyst development. The findings provide insight into the debatable roles of MTHFR in fertility and may be applicable for the improvement of care for early embryos via modulation of surrounding folate-related nutritional conditions in vitro and/or in utero, depending on the parental and embryonic MTHFR genotype. [ABSTRACT FROM AUTHOR]

Aim: to show the effect of genetically determined folate cycle deficiency in children with autism spectrum disorders (ASD).Participants: 89 children (57 boys; 32 girls, Ukraine, 2-10 years old); participants were diagnosed with ASD. The control group consisted of 34 children with ASD.Diagnostic methods:polymerase chain reaction (PCR), complex immunological research, diagnosis of infection, determination of biomarkers.Results and discussion:Hyperhomocysteinemia was revealed in 87% of cases (p <0.05; Z

The folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Such one-carbon unit production plays a critical role in development, the immune system, and cancer. Using rodent models, here we show that the whole-body SHMT flux acts to net consume rather than produce glycine. Pharmacological inhibition of whole-body SHMT1/2 and genetic knockout of liver SHMT2 elevated circulating glycine levels up to eight-fold. Stable-isotope tracing revealed that the liver converts glycine to serine, which is then converted by serine dehydratase into pyruvate and burned in the tricarboxylic acid cycle. In response to diets deficient in serine and glycine, de novo biosynthetic flux was unaltered, but SHMT2- and serine-dehydratase-mediated catabolic flux was lower. Thus, glucose-derived serine synthesis is largely insensitive to systemic demand. Instead, circulating serine and glycine homeostasis is maintained through variable consumption, with liver SHMT2 a major glycine-consuming enzyme. [Display omitted] • Serine and glycine de novo synthesis is insensitive to dietary level • Homeostasis is maintained by variable hepatic consumption • Folate metabolism runs "in reverse" in the liver, net converting glycine to serine • Blocking the key folate enzyme SHMT2 causes systemic glycine buildup The amino acid glycine is obtained from diet or by folate-mediated enzymatic production from serine. McBride et al. report that the folate pathway in the liver operates in the reverse direction and is in fact a major glycine clearance pathway. [ABSTRACT FROM AUTHOR]

Aging and age-related diseases in humans are mainly caused by oxidative stress through over-production of reactive oxygen species (ROS). In our previous study, multi-micronutrient supplement containing antioxidants and phytochemicals (MP) resulted in higher antioxidative activity by increasing plasma folate with resistance to DNA damage and LDL oxidation to subjects. In this study, plasma samples were analysed for metabolomics study using 1H NMR. The metabolic profiles before MP supplementation and after 8-week MP supplementation were clearly separated based on multivariant analyses of principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA). Twenty-seven metabolites from variable importance plots were screened before MP supplementation and after 8-week MP supplementation. The 27 metabolites had significantly increased levels of betaine but significantly decreased levels of choline, serine, and threonine after MP supplementation. These results suggested that MP supplementation could activate folate cycle to increase resistance to DNA damages.

Altered metabolism in cancer cells is critical for tumor growth. One of the most notable aspects of this metabolic reprogramming lies in one-carbon metabolism. Cells require one-carbon units for nucleotide synthesis, methylation reactions, and for the generation of reducing cofactors. Therefore, the ability to rewire and fine-tune one-carbon metabolism is essential for the maintenance of cellular homeostasis. In this review, we describe how the major nutrient, energy, and redox sensors of the cell play a significant role in the regulation of flux through one-carbon metabolism to enable cell fate decisions. We will also discuss how dysregulated oncogenic signaling hijacks these regulatory mechanisms to support and sustain high rates of proliferation and cell survival essential for tumor growth.

The methionine and folate cycles play a fundamental role in cell physiology and their alteration is involved in liver injury and hepatocarcinogenesis. Glycine N-methyltransferase is implicated in methyl group supply, DNA methylation, and nucleotide biosynthesis. It regulates the cellular S-adenosylmethionine/S-adenosylhomocysteine ratio and S-adenosylmethioninedependent methyl transfer reactions. Glycine N-methyltransferase is absent in fast-growing hepatocellular carcinomas and present at a low level in slower growing HCC ones. The mechanism of tumor suppression by glycine N-methyltransferase is not completely known. Glycine N-methyltransferase inhibits hepatocellular carcinoma growth through interaction with Dep domain-containing mechanistic target of rapamycin (mTor)-interacting protein, a binding protein overexpressed in hepatocellular carcinoma. The interaction of the phosphatase and tensin homolog inhibitor, phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger, with glycine N-methyltransferase enhances proteasomal degradation of this exchanger by the E3 ubiquitin ligase HectH. Glycine N-methyltransferase also regulates genes related to detoxification and antioxidation pathways. It supports pyrimidine and purine syntheses and minimizes uracil incorporation into DNA as consequence of folate depletion. However, recent evidence indicates that glycine N-methyltransferase targeted into nucleus still exerts strong anti-proliferative effects independent of its catalytic activity, while its restriction to cytoplasm prevents these effects. Our current knowledge suggest that glycine N-methyltransferase plays a fundamental, even if not yet completely known, role in cellular physiology and highlights the need to further investigate this role in normal and cancer cells. [ABSTRACT FROM AUTHOR]

Copyright of Mezdunarodnyj Nevrologiceskij Zurnal is the property of Zaslavsky O.Yu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: The lack of novel therapeutic targets poses the major challenge to prolong survival and improve the quality of life for esophageal squamous cell carcinoma (ESCC). Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) plays critical roles in folate cycle maintenance. However, little information is available concerning the role of MTHFD1L in cancer cells, and no studies have addressed such issues in esophageal cancer. Materials and method: Surgical cancer and adjacent normal esophageal tissues were obtained from patients with esophagectomy and esophagogastrostomy for ESCC. Western blot, immunohistochemistry and Quantitative RT-PCR were performed to evaluate protein and RNA expression levels of MTHFD1L. Knockdown of MTHFD1L expression was achieved by using short hairpin RNA. The effects of MTHFD1L silencing on ESCC cell proliferation and apoptosis were assessed by the MTT assay, Celigo assays, Annexin V FACS assay and Caspase-3/7 array in vitro. Results: Twenty-three paired cancer and adjacent normal esophageal tissues from patients with ESCC were included in this study. MTHFD1L protein and RNA expression levels were significantly upregulated in ESCC tissue as compared with normal tissue. High expression of MTHFD1 was also detected in two esophageal cancer cell lines (TE-1 and EC109). Knockdown of MTHFD1L expression inhibited the proliferation of TE-1 cells, and the apoptosis was distinctly increased following shMTHFD1L infection. Conclusions: Our preliminary study highlighted for the first time that MTHFD1L might be involved in the development of ESCC, which may provide a new potential tumor-specific therapeutic targeting for anti-folate agents. [ABSTRACT FROM AUTHOR]

The folate pathway is critical to proper cellular function and metabolism. It is responsible for multiple functions, including energy (ATP) production, methylation reactions for DNA and protein synthesis and the production of immunomodulatory molecules, inosine and adenosine. These play an important role in immune signaling and cytotoxicity. Herein, we hypothesize that defects in the folate pathway in genetically susceptible individuals could lead to immune dysfunction, permissive environments for chronic cyclical latent/lytic viral infection, and, ultimately, the development of unchecked autoimmune responses to infected tissue, in this case islet beta cells. In the context of type 1 diabetes (T1D), there has been a recent increase in newly diagnosed cases of T1D in the past 20 years that has exceeded previous epidemiological predictions with yet unidentified factor(s). This speaks to a potential environmental trigger that adversely affects immune responses. Most research into the immune dysfunction of T1D has focused on downstream adaptive responses of T and B cells neglecting the role of the upstream innate players such as natural killer (NK) cells. Constantly, surveilling the blood and tissues for pathogens, NK cells remove threats through direct cytotoxic responses and recruitment of adaptive responses using cytokines, such as IL-1β and IFN-γ. One long-standing hypothesis suggests viral infection as a potential trigger for the autoimmune response in T1D. Recent data suggest multiple viruses as potential causal agents. Intertwined with this is an observed reduced NK cell enumeration, cytotoxicity, and cytokine signaling in T1D patients. Many of the viruses implicated in T1D are chronic latent/lysogenic infections with demonstrated capacity to reduce NK cell response and number through mechanisms that resemble those of pregnancy tolerance. Defects in the folate pathway in T1D patients could result in decreased immune response to viral infection or viral reactivation. Dampened NK responses to infections result in improper signaling, improper antigen presentation, and amplified CD8+ lymphocyte proliferation and cytotoxicity, a hallmark of beta cell infiltrates in patients with T1D onset. This would suggest a critical role for NK cells in T1D development linked to viral infection and the importance of the folate pathway in maintaining proper NK response.

Cancer cells harness nutrients to support its rapid proliferation through metabolic reprogramming. Our report identified folate cycle as a metabolic target in hepatocellular carcinoma. Folate cycle stagnation via inhibition of its mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) greatly induced oxidative stress improving HCC cells' response to sorafenib.

Copyright of Likarska Sprava is the property of J. Likarska Sprava and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The folate pathway is critical to proper cellular function and metabolism. It is responsible for multiple functions, including energy (ATP) production, methylation reactions for DNA and protein synthesis and the production of immunomodulatory molecules, inosine and adenosine. These play an important role in immune signaling and cytotoxicity. Herein, we hypothesize that defects in the folate pathway in genetically susceptible individuals could lead to immune dysfunction, permissive environments for chronic cyclical latent/lytic viral infection, and, ultimately, the development of unchecked autoimmune responses to infected tissue, in this case islet beta cells. In the context of type 1 diabetes (T1D), there has been a recent increase in newly diagnosed cases of T1D in the past 20 years that has exceeded previous epidemiological predictions with yet unidentified factor(s). This speaks to a potential environmental trigger that adversely affects immune responses. Most research into the immune dysfunction of T1D has focused on downstream adaptive responses of T and B cells neglecting the role of the upstream innate players such as natural killer (NK) cells. Constantly, surveilling the blood and tissues for pathogens, NK cells remove threats through direct cytotoxic responses and recruitment of adaptive responses using cytokines, such as IL-1β and IFN-γ. One long-standing hypothesis suggests viral infection as a potential trigger for the autoimmune response in T1D. Recent data suggest multiple viruses as potential causal agents. Intertwined with this is an observed reduced NK cell enumeration, cytotoxicity, and cytokine signaling in T1D patients. Many of the viruses implicated in T1D are chronic latent/lysogenic infections with demonstrated capacity to reduce NK cell response and number through mechanisms that resemble those of pregnancy tolerance. Defects in the folate pathway in T1D patients could result in decreased immune response to viral infection or viral reactivation. Dampened NK responses to infections result in improper signaling, improper antigen presentation, and amplified CD8+ lymphocyte proliferation and cytotoxicity, a hallmark of beta cell infiltrates in patients with T1D onset. This would suggest a critical role for NK cells in T1D development linked to viral infection and the importance of the folate pathway in maintaining proper NK response. [ABSTRACT FROM AUTHOR]

Aims: Folate metabolism plays a critical role in DNA methylation and synthesis. Polymorphisms in folate metabolism may affect enzyme activities and thereby affect the cancer risk. Methionine synthase (MTR) and methionine synthase reductase (MTRR) are critical enzymes for the folate cycle. In this study, possible associations between genetic variabilities in MTR and MTRR and susceptibility to lung cancer (LC) were investigated in a Turkish population. Methods: A case-control study with 193 LC cases and 199 noncancerous controls was conducted. DNA was extracted from leukocytes using the high pure polymerase chain reaction (PCR) template preparation kit. The MTR 2756 A>G (rs1805087), MTRR 524 C > T (rs1532268), and MTRR 66 A>G (rs1801394) genotypes were determined using PCR-restriction fragment length polymorphism (PCR-RFLP) assays. The genotype and haplotype analyses of these polymorphisms were performed using SPSS 21 and Haploview 4.2, respectively. Results: An association between the MTRR A66G polymorphism and LC ( p = 0.042) was found. In addition, this allele was observed more frequently in smokers compared to nonsmokers ( p = 0.030). In contrast, the distribution of the MTR 2756 A>G and the MTRR 524 C > T allele frequencies were similar in the subject cases and controls. Conclusions: In conclusion, the present study suggests an association between the MTRR 66 A>G gene polymorphisms and LC risk in a Turkish population. [ABSTRACT FROM AUTHOR]

This aim of the study was to research the prevalence of genotypes and alleles of2756A>G polymorphism of gene of methionine synthase (MTR) gene in Russian and Buryat populations of Eastern Siberia. We used DNA blood database of children and teenagers of the Russian and Buryat nationality living in Eastern Siberia. Genotyping was carried out using standard PCR method. Prevalence of minor G-allele in Russian population was 25,7 %, in Buryat population - 13,2 %. We revealed differences in prevalence of genotypes and alleles between studied groups (p = 0,051; p = 0,032).