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During the development of therapeutic microRNAs (miRNAs or miRs), it is essential to define their pharmacological actions. Rather, miRNA research and therapy mainly use miRNA mimics synthesized in vitro. After experimental screening of unique recombinant miRNAs produced in vivo, three lead antiproliferative miRNAs against human NSCLC cells, miR-22-3p, miR-9-5p, and miR-218-5p, were revealed to target folate metabolism by bioinformatic analyses. Recombinant miR-22-3p, miR-9-5p, and miR-218-5p were shown to regulate key folate metabolic enzymes to inhibit folate metabolism and subsequently alter amino acid metabolome in NSCLC A549 and H1975 cells. Isotope tracing studies further confirmed the disruption of one-carbon transfer from serine to folate metabolites by all three miRNAs, inhibition of glucose uptake by miR-22-3p, and reduction of serine biosynthesis from glucose by miR-9-5p and -218-5p in NSCLC cells. With greater activities to interrupt NSCLC cell respiration, glycolysis, and colony formation than miR-9-5p and -218-5p, recombinant miR-22-3p was effective to reduce tumor growth in two NSCLC patient-derived xenograft mouse models without causing any toxicity. These results establish a common antifolate mechanism and differential actions on glucose uptake and metabolism for three lead anticancer miRNAs as well as antitumor efficacy for miR-22-3p nanomedicine, which shall provide insight into developing antimetabolite RNA therapies.
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Objective:To investigate the association between recurrent spontaneous abortion (RSA) and methylenetetrahydrofolate reductase (MTHFR) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphism in pregnant women of appropriate age, and to observe the difference of the serum concentration of patients with different MTHFR genotypes after taking different does of folic acid.Methods:A prospective case-control study was conducted, one handred and eleven pregnant women with a history of unexplained RSA and gestation less than 12 weeks who visited the Department of Obstetrics and Gynecology of Xuancheng People's Hospital of Anhui Province from January 2019 to June 2021 were enrolled into the RSA group, and 100 normal women of childbearing age in the same area with no history of abortion were included in the control group. After venous blood was extracted, the polymorphisms of MTHFR gene C677T, A1298C PAI-1 and the serum folic acid concentration were detected.The comparison between the measurement data groups with normal distribution adopts t-test, and the counting data adopts t-test χ 2 test, Logistic regression analysis was used for multivariate analysis. Results:The genotype and allele of MTHFR C677T (CC:21.62%(24/111) and 51.00%(51/100), TT: 28.83%(32/111) and 12%(12/100)) and allele (C: 46.40%(103/222) and 69.50% (139/200), T: 53.60%(119/222) and 30.50%(61/200)) and PAI-1 (5G5G: 22.52%(25/111) and 48.00%(48/100), 4G4G: 44.14%(49/111)and 16.00%(16/100); 5G: 39.19%(87/222) and 66.00%(132/200), 4G: 60.81%(135/222) and 34.00%(68/200)) were significantly different (χ 2 values were 21.82, 22.96 and 23.51, 30.30; all P <0.001) between the RSA group and control group. Logistic analysis showed that MTHFR C677T ( OR=0.477, 95% CI 0.303-0.750) and PAI-1 genotype ( OR=0.451, 95% CI 0.306-0.665) were closely related to recurrent abortion ( P=0.001 and P<0.001). There were no significant differences in genotype and allele of MTHFR A1298C between the two groups ( P values were 0.270 and 0.149).There was no significant difference in serum concentration of folic acid between the two groups ( P=0.355 for 0.4 mg folic acid and P=0.786 for 0.8 mg or more folic acid) at the same dose of folic acid. Conclusion:The occurrence of recurrent spontaneous abortion in women of childbearing age may be related to MTHFR C677T and PAI-1 site mutation, and may not be related to MTHFR A1298C site mutation.
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Two new folate-derived analogues, named uncarophyllofolic acids A (1) and B (2), respectively, were isolated from the Uncaria rhynchophylla hook bearing stem (Gouteng in Chinese). The distinct stereochemical structures of 1 and 2 were determined by spectroscopic data analysis in combination with acidic hydrolysis and Marfey's derivatization, along with comparison of their specific rotation and Cotton effect (CE) data with those of the biogenetically related known derivatives as well as theoretical calculations of electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway of 1 and 2, associating to folate metabolism and the previously reported orychophragines A-C from Orychophragmus violaceus, is discussed.
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Folate acts as a co-factor in one carbon metabolism,playing an essential role in the synthesis and transformation of purine and pyrimidine precursors of nucleic acids simultaneously. Autism spectrum disorder ( ASD) is a neurodevelopmental disorder with unknown pathogenesis characterized by social defects and repeti-tive behaviors. The risk of ASD is associated with the functional disorders of the enzyme related to the folate me-tabolism,the disorder of folate transportation,and the genetic variation related to the folate metabolism. Several studies indicated that there might be a subtype in patients with ASD whose 5-methyltetrahydrofolate in cerebro-spinal fluid( CSF) was low,however,the level of folate outside the central nervous system was normal,which re-sulted from the exist of the folate receptor alpha autoantibodies. The children with ASD found positive for the fo-late receptor alpha autoantibodies were improved a lot when taking folinic acid or leucovorin calcium orally. This article reviewed the correlation between folate metabolism and the pathogenesis and treatment of the ASD.
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Folate involves in one-carbon metabolism pathway,which contributes to nucleotide synthesis,amino acid transformation and methylation.Early embryo development requires a number of cell proliferation and differentiation,in which folate plays a vital role.Studies revealed folate supplement lowers the incidence of congenital heart disease (CHD),and single nucleotide polymorphisms of key enzyme in folate metabolism are closely related to CHD.Folate metabolism disorder may cause hyperhomocysteinemia,which is considered as one of the independent risk factors of CHD.Mechanism in folate metabolism disorder and CHD is unclear,and studies indicate that folate metabolism disorder may lead to CHD by various ways,such as perturbing cardiac neural crest formation and migration,inhibiting DNA synthesis and interfering cell proliferation and apoptosis.Therefore,it is important to explore the role of folate metabolism disorder in CHD,which will be helpful in preventing the disease and reducing the disease burden.
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As one of important B vitamins,folate is an essential nutrient for the body and involves in various biochemical and metabolic reactions.Studies have shown that as an important methyl donor in the carbon metabolism cycle,folate has an important impact on pregnancy,pregnancy complications,and birth defects.Further studies have shown that in the folate metabolic pathway,the gene polymorphism and folic acid metabolism of a key enzyme,5,10-methylenetetetrahydrofolate reductase (MTHFR),play an important role in ovarian function.Gene polymorphism and the high homocysteine levels caused by it can lead to the damage of reproductive function and endocrine function,including follicular development,embryonic development,and hormone secretion.Gene polymorphism is also associated with the occurrence and development of ovarian disease and its response to treatment.With the deep understanding of folate metabolism,MTHFR gene polymorphism may become a new genetic marker for predicting the risk of disease and a new target for related gene therapies.
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Nonsyndromic cleft of lip with or without palate ( NSCL/P ) is one of the most common congenital birth defects in the maxillofacial region and it is related to genetic factors and environment .Folic acid deficiency , metabolic disorder and the genetic polymorphisms of key metabolic enzymes may be the important factors contributing to NSCL /P .Maternal folic acid intake may reduce the risk of non syndrome cleft lip and palate .This article will review the relationship among the metabolism of folic acid , the genetic polymorphisms of key enzymes in folate metabolism and NSCL /P .
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Chronic administration of phenytoin has been associated to have a number of adverse effects. Falling serum folate levels is one such most often reported adverse drug sequelae of long term phenytoin usage. Folates administered at pharmacological doses, on the other hand, have been blamed for a decrease in the serum concentration of phenytoin, severe enough to precipitate seizures. This review substantiated with references from various studies focuses on the folic acidphenytoin interaction and discusses the feasibility of using folate supplements to avoid such inadvertent drug sequelae in epileptic patients kept on chronic treatment with phenytoin.
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Background & objectives: Many pharmacologically-relevant polymorphisms show variability among different populations. Though limited, data from Caucasian subjects have reported several single nucleotide polymorphism (SNPs) in folate biosynthetic pathway. These SNPs may be subjected to racial and ethnic differences. We carried out a study to determine the allelic frequencies of these SNPs in an Indian ethnic population. Methods: Whole blood samples were withdrawn from 144 unrelated healthy subjects from west India. DNA was extracted and genotyping was performed using PCR-RFLP and Real-time Taqman allelic discrimination for 12 polymorphisms in 9 genes of folate-methotrexate (MTX) metabolism. Results: Allele frequencies were obtained for MTHFR 677T (10%) and 1298 C (30%), TS 3UTR 0bp (46%), MDR1 3435T and 1236T (62%), RFC1 80A (57%), GGH 401T (61%), MS 2756G (34%), ATIC 347G (52%) and SHMT1 1420T (80%) in healthy subjects (frequency of underlined SNPs were different from published study data of European and African populations). Interpretation & conclusions: The current study describes the distribution of folate biosynthetic pathway SNPs in healthy Indians and validates the previous finding of differences due to race and ethnicity. Our results pave way to study the pharmacogenomics of MTX in the Indian population.
Subject(s)
3' Untranslated Regions , Female , Folic Acid/metabolism , Gene Frequency , Humans , India , Male , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Polymorphism, Single NucleotideABSTRACT
The functional effect of the A>G transition at position 2756 on the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase), involved in folate metabolism, may be a risk factor for head and neck squamous cell carcinoma (HNSCC). The frequency of MTR A2756G (rs1805087) polymorphism was compared between HNSCC patients and individuals without history of neoplasias. The association of this polymorphism with clinical histopathological parameters was evaluated. A total of 705 individuals were included in the study. The polymerase chain reaction-restriction fragment length polymorphism technique was used to genotype the polymorphism. For statistical analysis, the chi-square test (univariate analysis) was used for comparisons between groups and multiple logistic regression (multivariate analysis) was used for interactions between the polymorphism and risk factors and clinical histopathological parameters. Using univariate analysis, the results did not show significant differences in allelic or genotypic distributions. Multivariable analysis showed that tobacco and alcohol consumption (P < 0.05), AG genotype (P = 0.019) and G allele (P = 0.028) may be predictors of the disease and a higher frequency of the G polymorphic allele was detected in men with HNSCC compared to male controls (P = 0.008). The analysis of polymorphism regarding clinical histopathological parameters did not show any association with the primary site, aggressiveness, lymph node involvement or extension of the tumor. In conclusion, our data provide evidence that supports an association between the polymorphism and the risk of HNSCC.
Subject(s)
Female , Humans , Male , Middle Aged , /genetics , Carcinoma, Squamous Cell/genetics , Head and Neck Neoplasms/genetics , Polymorphism, Genetic/genetics , Case-Control Studies , Carcinoma, Squamous Cell/enzymology , Gene Frequency , Genetic Predisposition to Disease , Genotype , Head and Neck Neoplasms/enzymology , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Risk FactorsABSTRACT
Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5 percent of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.