Rice is a poor source of folate,an essential micronutrient for the body.Biofortification offers an effective way to enhance the folate content of rice and alleviate folate deficiencies in humans.In this study,we confi...Rice is a poor source of folate,an essential micronutrient for the body.Biofortification offers an effective way to enhance the folate content of rice and alleviate folate deficiencies in humans.In this study,we confirmed that OsADCS and OsGTPCHI,encoding the initial enzymes necessary for folate synthesis,positively regulate folate accumulation in knockout mutants of both japonica and indica rice backgrounds.The folate content in the low-folate japonica variety was slightly increased by the expression of the indica alleles driven by the endosperm-specific promoter.We further obtained co-expression lines by stacking OsADCS and OsGTPCHI genes;the folate accumulation in brown rice and polished rice reached 5.65μg/g and 2.95μg/g,respectively,representing 37.9-fold and 26.5-fold increases compared with the wild type.Transcriptomic analysis of rice grains from six transgenic lines showed that folate changes affected biological pathways involved in the synthesis and metabolism of rice seed storage substances,while the expression of other folate synthesis genes was weakly regulated.In addition,we identified Aus rice as a high-folate germplasm carrying superior haplotypes of OsADCS and OsGTPCHI through natural variation.This study provides an alternative and effective complementary strategy for rice biofortification,promoting the rational combination of metabolic engineering and conventional breeding to breed high-folate varieties.展开更多
Folate(FA)is an essential micronutrient of vitamin B group for growth,development,and reproduction through participating in the nucleotide synthesis and methyl donation reactions.The changes of FA level have been link...Folate(FA)is an essential micronutrient of vitamin B group for growth,development,and reproduction through participating in the nucleotide synthesis and methyl donation reactions.The changes of FA level have been linked to dietary insufficiency(e.g.,poor diet,etc.)malabsorption(e.g.,FA-associated gene mutation,etc.),increased demand(e.g.,pregnancy,etc).or medication(e.g.,antifolates drugs),or bad habits(e.g.,smoking,alcoholism,etc.).Recently,epidemiological data showed that the levels of the host FA typically changed in patients with infectious diseases.Interactions between pathogens,including bacteria,parasites and viruses,and their hosts are complex,in particular,pathogenic infection-mediated changes of the host FA levels can affect the utilization and uptake of limited FA resources of the host.Therefore,FA supplementation or the use of antifolate agents may be a potential antimicrobial strategy for managing infectious diseases.Furthermore,given that the gut microbiota is a primary source of FA in the human body,the association between gut microbiota and pathogenic infections warrants investigation.To date,little is known about how FA status and its biochemistry function affect the course of infectious diseases.In this review,we focus on the roles of FA in the interaction between the host and microbe,and briefly discuss the potential of FA and antifolates agents in the treatment of infectious diseases.展开更多
One-third of the global population is affected by micronutrient deficiency, particularly folate. Although folate synthesis has been relatively well characterized, few folate-related genes in maize have been cloned, an...One-third of the global population is affected by micronutrient deficiency, particularly folate. Although folate synthesis has been relatively well characterized, few folate-related genes in maize have been cloned, and the molecular mechanism regulating folate synthesis in maize remains unclear. In this study,transcriptome and proteome analyses of three waxy maize inbred lines with high, medium, and low folate contents were performed to identify key genes controlling folate biosynthesis. Pairwise comparisons revealed 21 differentially expressed genes and 20 differentially expressed proteins potentially associated with folate biosynthesis in the three lines. Six key folate-associated genes, Zm Mocos2, Zm GGH,Zm ADCL2, Zm CBR1, Zm SHMT, and Zm Pur H, were identified. These genes encode enzymes that potentially function in folate biosynthesis. Functional validation of one of these genes, Zm ADCL2, using an EMS mutant(Mut9264) showed that a 4-base insertion in an exon increased the folate content of fresh maize kernels 1.37-fold that of the wild type. Zm ADCL2 was considered a potential target for generating maize lines with higher folate content. KEGG enrichment analysis of differentially expressed genes and proteins showed that several pathways in addition to folate biosynthesis were likely indirectly involved in folate metabolism and content(e.g., glycine, serine, and threonine metabolism;purine metabolism;cysteine and methionine metabolism;alanine, aspartate and glutamate metabolism;glutathione metabolism;and pyruvate metabolism. The transcriptome and proteomic data generated in this study will help to clarify the mechanisms underlying folate accumulation and aid breeding efforts to biofortify maize with folate.展开更多
BACKGROUND There are conflicting results on the potential correlation between folic acid and gestational diabetes mellitus(GDM),and the correlation between genetic factors related to folic acid metabolism pathways and...BACKGROUND There are conflicting results on the potential correlation between folic acid and gestational diabetes mellitus(GDM),and the correlation between genetic factors related to folic acid metabolism pathways and GDM remains to be revealed.AIM To examine the association between single-nucleotide polymorphisms(SNPs)of enzyme genes in the folate metabolite pathway as well as that between GDM-related genes and risk for GDM.METHODS A nested case-control study was conducted with GDM cases(n=412)and healthy controls(n=412).DNA was extracted blood samples and SNPs were genotyped using Agena Bioscience’s MassARRAY gene mass spectrometry system.The associations between different SNPs of genes and the risk for GDM were estimated using logistic regression models.The generalized multi-factor dimensionality reduction(GMDR)method was used to analyze gene-gene and gene-environment interactions using the GMDR 0.9 software.RESULTS The variation allele frequency of melatonin receptor 1B(MTNR1B)rs10830963 was higher in the GDM group than in controls(P<0.05).MTNR1B rs10830963 mutant G was associated with risk for GDM[adjusted odds ratio(aOR):1.43;95%confidence interval(95%CI):1.13-1.80]in the additive model.MTNR1B rs10830963 GG+GC was significantly associated with the risk for GDM(aOR:1.65;95%CI:1.23-2.22)in the dominant model.The two-locus model of MTNR1B rs10830963 and CHEMERIN rs4721 was the best model(P<0.05)for gene-gene interactions in the GMDR results.The high-risk rs10830963×rs4721 type of interaction was a risk factor for GDM(aOR:2.09;95%CI:1.49-2.93).CONCLUSION This study does not find an association between SNPs of folate metabolic enzymes and risk for GDM.The G mutant allele of MTNR1B rs10830963 is identified as a risk factor for GDM in the additive model,and there may be gene-gene interactions between MTNR1B rs10830963 and CHEMERIN rs4721.It is conducive to studying the causes of GDM and provides a new perspective for the precise prevention of this disease.展开更多
BACKGROUND Early metastasis and recurrence are risk factors that negatively affect the prog-nosis of advanced hepatocellular carcinoma(HCC).Alpha fetoprotein(AFP)is currently the most prevalent serum biomarker for det...BACKGROUND Early metastasis and recurrence are risk factors that negatively affect the prog-nosis of advanced hepatocellular carcinoma(HCC).Alpha fetoprotein(AFP)is currently the most prevalent serum biomarker for detecting HCC and predicting tumor recurrence.However,its sensitivity and specificity are not sufficient,espe-cially in patients who are AFP negative.METHODS This work is a retrospective study that included 128 consecutive patients with benign or malignant disease of the liver from 2020 to 2021.FR+CTCs were col-lected from 3 mL of peripheral blood via immunomagnetic depletion of leuko-cytes.After ligand-target polymerase chain reaction,the number of FR+CTCs was measured.Receiver operating characteristic curves were used to determine the threshold of sensitivity and specificity of FR+CTCs.The Youden index was used to identify the optimal cutoff point and diagnostic efficiency of FR+CTCs counts.Univariate and multivariate Cox proportional hazards regression analyses were performed to evaluate the associations of biomarkers or clinical parameters with disease-free survival(DFS).RESULTS The FR+CTCs counts showed excellent diagnostic efficacy in patients with HCC,with high sensitivity(0.905)and specificity(0.773)compared with patients with benign disease.Compared with that of the AFP level,the area under the receiver operating characteristic curve of the FR+CTC count is significantly greater(0.900 compared with 0.730,P<0.05).FR+CTC levels were significantly correlated with macrovascular invasion,tumor size,tumor number,and extrahepatic tumor stage in HCC patients.FR+CTC counts were correlated with DFS in HCC patients after R0 resection.Univariate analysis of DFS revealed that the FR+CTC count,tumor number,Barcelona Clinic Liver Cancer stage and extrahepatic metastasis status were correlated with DFS.Multivariate analysis of DFS revealed that the FR+CTC count and tumor number were correlated with DFS.CONCLUSION Ligand-target polymerase chain reaction is a sensitive tool for quantifying the number of FR+CTCs in HCC patients.These findings could provide new insight for stratifying HCC patients and predicting the recurrence of HCC.展开更多
Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF). Chemotherapy drugs such as methotrexate help to slow the progression of cancer by limiting the...Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF). Chemotherapy drugs such as methotrexate help to slow the progression of cancer by limiting the ability of dividing cells to make nucleotides by competitively inhibiting DHFR. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been previously reported to exhibit competitive inhibition of DHFR, in addition to their primary action on cyclooxygenase enzymes. This interaction interferes with the enzymatic reduction of dihydrofolate to tetrahydrofolate, thereby impeding the folate metabolism pathway essential for nucleotide synthesis and cell proliferation. This activity stems from their structural resemblance to the p-aminobenzoyl-l-glutamate (pABG) moiety of folate, a substrate of DHFR. It has been established that NSAIDs containing a salicylate group (which has structural similarities to pABG), such as diflunisal, exhibit stronger DHFR-binding activity. In this study, we synthesized salicylate derivatives of naproxen with the aim of exploring their potential as inhibitors of DHFR. The interactions between these derivatives and human DHFR were characterized using a combination of biochemical, biophysical, and structural methods. Through polyacrylamide gel electrophoresis (PAGE) analysis, enzymatic assays, and quantitative ELISA, we investigated the binding affinity and inhibitory potency of the synthesized salicylate derivatives towards DHFR. The findings of this study suggest the potential of salicylate derivatives of naproxen as promising candidates for the inhibition of DHFR, thereby offering novel therapeutic opportunities for modulating the inflammatory process through multiple pathways. Further optimization of these derivatives could lead to the development of more efficacious dual-targeted analogs with enhanced therapeutic benefits.展开更多
Objective This study aimed to evaluate the associations of serum folate and/or vitamin B12 concentrations with obesity among Chinese children and adolescents.Methods A cross-sectional study was conducted including 3,0...Objective This study aimed to evaluate the associations of serum folate and/or vitamin B12 concentrations with obesity among Chinese children and adolescents.Methods A cross-sectional study was conducted including 3,079 Chinese children and adolescents,aged 6 to 17 years,from Jiangsu,China.Anthropometric indices,such as,children's body mass index(BMI),BMI z-scores,waist circumference,and waist-to-height ratio were utilized.Multivariable linear regression and generalized additive models were used to investigate the associations of serum folate and vitamin B12 levels with anthropometric indices and odds of obesity.Results We observed that serum vitamin B12 concentrations were inversely associated with all anthropometric indices and the odds of general obesity[odds ratio(OR)=0.68;95%confidence interval(CI)=0.59,0.78]and abdominal obesity(OR=0.68;95%CI=0.60,0.77).When compared to participants with both serum vitamin levels in the two middle quartiles,those with both serum folate and vitamin B12 levels in the highest quartile were less prone to general(OR=0.31,95%CI=0.19,0.50)or abdominal obesity(OR=0.46,95%CI=0.31,0.67).Conversely,participants with vitamin B12 levels in the lowest quartile alongside folate levels in the highest quartile had higher odds of abdominal obesity(OR=2.06,95%CI=1.09,3.91).Conclusion Higher serum vitamin B12 concentrations,but not serum folate concentrations,were associated with lower odds of childhood obesity.Children and adolescents with high levels of vitamin B12 and folate were less likely to be obese.展开更多
Folate deficiency has been confirmed to be related to various diseases.Unfortunately,there are few reports on the folate status of Chinese adults.This study aims to evaluate the serum folate status of blood donors in ...Folate deficiency has been confirmed to be related to various diseases.Unfortunately,there are few reports on the folate status of Chinese adults.This study aims to evaluate the serum folate status of blood donors in south-central China.In this study,248 blood donors were included.The information on subjects was collected by a brief questionnaire concerning alcohol consumption habits,smoking habits,fruit and vegetable consumption and physical activity.The serum folate concentration was measured by electrochemiluminescence immunoassay.The geometric mean serum folate concentration was 13.4 nmoll-1(95%CI,12.7-14.1).The prevalence of serum folate concentrations below 6.8 nmoll-1 was 5.2%(95%CI,2.5-8.0).There were significant differences in serum folate concentrations with respect to sex(p-values<0.05),age(p-values<0.05),fruit and vegetable consumption(p-values<0.05),and alcohol consumption habits(p-values<0.05).The concentration of serum folate increased with age(p-values<0.05)and fruit and vegetable consumption(p-values<0.05).Individuals with an age of 30 years or younger were nearly 3.5 times as likely as those aged over 30 years to have an insufficient level of serum folate(OR=3.48;95%CI:1.01-11.99).An age of 30 years or younger was a risk factor for folate deficiency.Most blood donors had sufficient serum folate concentrations in south-central China.National surveys of folate status should be implemented in China.展开更多
AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation. METHODS: Real-time ...AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation. METHODS: Real-time PCR was used to study the expression of tumor related genes in 76 mucosal tissue samples from 38 patients with gastric cancer. Samples from the gastroscopic biopsy tissues of 34 patients with chronic superficial gastritis (CSG) were used as controls. Folate concentrations in these tissues were detected by the FOL ACS: 180 automated chemiluminescence system. MTHFR polymorphisms were analyzed by PCR-RFLP, and the promoter methylation of tumor-related genes was determined by methylation-specific PCR (MSP). RESULTS: Folate concentrations were significantly higher in CSG than in cancerous tissues. Decreased expression and methylation of c-myc accompanied higher folate concentrations. Promoter hypermethylation and loss of p16INK4A in samples with MTHFR 677CC were more frequent than in samples with the 677TT or 677CT genotype. And the promoter hypermethylation and loss of p21WAF1 in samples with MTHFR 677CT were more frequent than when 677CC or 677TT was present. The 677CT genotype showed a non-significant higher risk for gastric cancer as compared with the 677CC genotype. CONCLUSION: Lower folate levels in gastric mucosal tissue may confer a higher risk of gastric carcinogenesisthrough hypomethylation and overexpression of c-myc.展开更多
AIM:To evaluate joint effects of Methylentetra-hydrofolate reductase(MTHFR) C677T genotypes,and serum folate/vitamin B12 concentrations on promoter methylation of tumor-associated genes among Iranian colorectal cancer...AIM:To evaluate joint effects of Methylentetra-hydrofolate reductase(MTHFR) C677T genotypes,and serum folate/vitamin B12 concentrations on promoter methylation of tumor-associated genes among Iranian colorectal cancer patients. METHODS:We examined the associations between MTHFR C677T genotype,and promoter methylation of P16,hMLH1,and hMSH2 tumor-related genes among151 sporadic colorectal cancer patients. The promoter methylation of tumor-related genes was determined by methylation-specific PCR. Eighty six patients from whom fresh tumor samples were obtained and 81 controls were also examined for serum folate and vitamin B12 concentrations by a commercial radioimmunoassay kit. RESULTS:We found 29.1% of cases had tumors with at least one methylated gene promoter. In case-case comparison,we did not find a significant association between methylation in tumors and any single genotype. However,in comparison to controls with the CC genotype,an increased risk of tumor methylation was associated with the CT genotype(OR = 2.5;95% CI,1.1-5.6) . In case-case comparisons,folate/vitamin B12 levels were positively associated with tumor methylation. Adjusted odds ratios for tumor methylation in cases with high(above median) versus low(below median) serum folate/vitamin B12 levels were 4.9(95% CI,1.4-17.7) ,and 3.9(95% CI,1.1-13.9) ,respectively. The frequency of methylated tumors was significantly higher in high methyl donor than low methyl donor group,especially in those with MTHFR CT(P = 0.01) ,and CT/TT(P = 0.002) genotypes,but not in those with the CC genotype(P = 1.0) . CONCLUSION:We conclude that high concentrations of serum folate/vitamin B12 levels are associated with the risk of promoter methylation in tumor-specific genes,and this relationship is modified by MTHFR C677T genotypes.展开更多
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 a...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.展开更多
Objective This study aimed to investigate the effects of N,N-dimethylglycine(DMG) on the concentration and metabolism of plasma homocysteine(pHcy) in folate-sufficient and folate-deficient rats.Methods In this study, ...Objective This study aimed to investigate the effects of N,N-dimethylglycine(DMG) on the concentration and metabolism of plasma homocysteine(pHcy) in folate-sufficient and folate-deficient rats.Methods In this study, 0.1% DMG was supplemented in 20% casein diets that were either folatesufficient(20 C) or folate-deficient(20 CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system.Results Folate deprivation significantly increased pHcy concentration in rats fed 20 C diet(from 14.19 ±0.39 μmol/L to 28.49 ± 0.50 μmol/L;P < 0.05). When supplemented with DMG, pHcy concentration was significantly decreased(12.23 ± 0.18 μmol/L) in rats fed 20 C diet but significantly increased(31.56 ±0.59 μmol/L) in rats fed 20 CFD. The hepatic methionine synthase activity in the 20 CFD group was significantly lower than that in the 20 C group;enzyme activity was unaffected by DMG supplementation regardless of folate sufficiency. The activity of hepatic cystathionine β-synthase(CBS) in the 20 CFD group was decreased but not in the 20 C group;DMG supplementation enhanced hepatic CBS activity in both groups, in which the effect was significant in the 20 C group but not in the other group.Conclusion DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.展开更多
Folate receptor alpha(FOLR1)is vital for cells ingesting folate(FA).FA plays an indispensable role in cell pro-liferation and survival.However,it is not clear whether the axis of FOLR1/FA has a similar function in vir...Folate receptor alpha(FOLR1)is vital for cells ingesting folate(FA).FA plays an indispensable role in cell pro-liferation and survival.However,it is not clear whether the axis of FOLR1/FA has a similar function in viral replication.In this study,we used vesicular stomatitis virus(VSV)to investigate the relationship between FOLR1-mediated FA deficiency and viral replication,as well as the underlying mechanisms.We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice.Meanwhile,VSV replication was notably sup-pressed by FOLR1 overexpression,and this antiviral activity was related to FA deficiency.Mechanistically,FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B(APOBEC3B)expression,which suppressed VSV replication in vitro and in vivo.In addition,methotrexate(MTX),an FA metabolism inhibitor,effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo.Overall,our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.展开更多
The Egyptian government introduced wheat-flour fortification with iron and folic acid to reduce the incidence of neural tube defects, but suspended it for technical reasons. We previously developed novel legume foods ...The Egyptian government introduced wheat-flour fortification with iron and folic acid to reduce the incidence of neural tube defects, but suspended it for technical reasons. We previously developed novel legume foods with enhanced folate content. In this study, we investigated the efficacy of 12-week intervention with folate-enhanced foods versus folic acid supplement in improving folate status in Egyptian women. A randomized, parallel intervention trial with two active groups (n = 19, n = 18) and one blinded control group (n = 20) was executed over 12 weeks. Volunteers received either germinated legume foods and orange juice (≈250 μg/d folate) or folic acid supplement (500 μg/d) or apple juice (0 μg/d folate). Folate status was assessed by erythrocyte and plasma folate and total homocysteine (tHcy) at day 0, and after 8 and 12 weeks of intervention. After 12 weeks, mean plasma folate increased by 14 (P < 0.0001) and 12 (P < 0.0001) nmoL in the folic acid and food group, respectively. Erythrocyte folate concentration increased in the folic acid group from 614 to 912 (P < 0.0001) and in the food group from 631 to 914 nmoL (P < 0.0001). After 12 weeks, 90% of subjects in the folic acid group and 70% in the food group had erythrocyte folate concentrations exceeding 906 nmol/L. tHcy concentration was decreased by 20% (P = 0.007) and 18% (P = 0.006) in the folic acid and food group, respectively, but remained unchanged in the control group during intervention. Folate-enhanced foods effectively improve folate status in women of reproductive age. These foods could be used as a complement to folic acid fortification.展开更多
Surface modification may have important influences on the penetration behavior of nanoscale drug delivery system. In the present study, we mainly focused on whether cell targeting or cell penetration could affect pene...Surface modification may have important influences on the penetration behavior of nanoscale drug delivery system. In the present study, we mainly focused on whether cell targeting or cell penetration could affect penetration abilities of nanostructured lipid carriers（NLC）. Real--time penetration of folate--or cell penetrating peptide（CPP）-modified NLC was evaluated using a multicellular tumor spheroid（MTS） established by stacking culture method as an in vitro testing platform. The results suggested that CPP modification had a better penetration behavior both on penetration depth and intensity compared with folate-modified NLC at the early stage of penetration process.展开更多
Multidrug resistance （MDR） operated by P-glycoprotein （P-gp） is one of the major causes in the treatment failure of cancers. In this work, docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-p...Multidrug resistance （MDR） operated by P-glycoprotein （P-gp） is one of the major causes in the treatment failure of cancers. In this work, docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy （polyethylene-glycol）2000 （DSPE-PEG2000）, D-α-Tocopherylpolyethylene glycol 1000 succinate （TPGSIooo） and DSPE-PEG2000-folate were developed to overcome MDR and reduce the side effect of docetaxel in cancer therapy. The diameters of micelles ranged from 13 to 26 nm and the encapsulation efficiencies were all above 85%. The influences of DSPE-PEG2000 and TPGSIooo ratios on the micellar characteristics and anti-resistant tumors effects were evaluated. Micelles with high TPGS1000 amount showed an increased cellular uptake and stronger cytotoxicity against MDR KBv cells. Moreover, the micelles modified by targeting ligand of folic acid exhibited better antitumor effect on folate receptor over-expressing KBv cells. The study provides a method for overcoming MDR in cancer therapy.展开更多
Methylenetetrahydrofolate reductase(MTHFR)is a key enzyme for the critical process of one-carbon circulation,which convert5,10-methylenetetrahydrofolate to5-methyltetrahydrofolate and participate in folate and homocys...Methylenetetrahydrofolate reductase(MTHFR)is a key enzyme for the critical process of one-carbon circulation,which convert5,10-methylenetetrahydrofolate to5-methyltetrahydrofolate and participate in folate and homocysteine conversion correlated to methyl group supply.The enzyme activity decline depends on the gene polymorphism.MTHFR impacts on the methylation process which is related to psychiatric diseases.Studies have shown association between MTHFR gene polymorphisms and mental disorders,some of which stratified by folate and cobalamin levels.In this review,we will summarize the testimony on the relationship between methylation and MTHFR polymorphism as well as the implication on psychiatric diseases by MTHFR mutation.展开更多
Objective To review the association of methylene tetrahydrofolate reductase (MTHFR) C677T mutant with coronary artery disease, as well as to highlight the results of some of these studies and to emphasize the need to ...Objective To review the association of methylene tetrahydrofolate reductase (MTHFR) C677T mutant with coronary artery disease, as well as to highlight the results of some of these studies and to emphasize the need to focus on the genetic architecture of CAD. Data SourcesData used in this article is mainly from relevant articles obtained through Pubmed, OVID and Google Scholar published from 1980 to 2008. Major studies and trials in this period were taken into account to draw accurate conclusion on the relation of those mutations in MTHFR with homocysteinemia and CAD. ResultOur analysis shows that hyperhomocysteinemia, a risk factor for occlusive arterial diseases, can be caused by disruptions of homocysteine metabolism catalyzed by MFTHR. A common alanine to valine mutation in MTHFR may contribute to mild heperhomocysteinemia in CAD. Individuals with the homozygous mutant genotype had higher plasma homocysteine, particularly when plasma folate was below the median value. ConclusionThis MTHFR mutant in the setting of insufficient folate may be a risk factor of CAD and can be regarded as a model of genetic-environmental interaction in the development of CAD.展开更多
Objective: To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), the central enzymes in folate metabolism that affects DNA meth...Objective: To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), the central enzymes in folate metabolism that affects DNA methylation and synthesis, and the risk of Down syndrome in China. Methods: Genomic DNA was isolated from the peripheral lymphocytes of 64 mothers of children with Down syndrome and 70 age matched control subjects. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFR 677C→T, MTRR 66A→G and the relationship between these genotypes and the risk of Down syndrome was analyzed. Results: The results show that the MTHFR 677C→T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 3.78 (95% confidence interval (CI), 1.78～8.47). In addition, the homozygous MTRR 66A→G polymorphism was independently associated with a 5.2-fold increase in estimated risk (95% CI, 1.90～14.22). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than the presence of either alone, with an odds ratio of 6.0 (95% CI, 2.058～17.496). The two polymorphisms appear to act without a multiplicative interaction. Conclusion: MTHFR and MTRR gene mutation alleles are related to Down syndrome, and CT, TT and GG gene mutation types increase the risk of Down syndrome.展开更多
AIM: To evaluate the associations of serum folate levelwith development, invasiveness and patient survival of gastric cancer. METHODS: In this nested case-control study, patients with newly diagnosed gastric cancer un...AIM: To evaluate the associations of serum folate levelwith development, invasiveness and patient survival of gastric cancer. METHODS: In this nested case-control study, patients with newly diagnosed gastric cancer undergoing gastrectomy were enrolled, and patients receiving chemotherapy prior to surgery, with other concurrent malignancy, or of the aboriginal and alien populations were excluded. In total, 155 gastric cancer patients and 149 healthy controls were enrolled for determination of serum folate levels and their correlation with gastric cancer. Using the median value of serum folate computed among the overall population as the cutoff value, the associations between serum folate and gastric cancer in all cases and different age and gender subgroups were analyzed by multivariate logistic regression analysis. In the patient cohort of gastric cancer, receiver-operating characteristic analyses were performed to calculate the best cutoff values of serum folate, and the associations between serum folate levels and clinicopathological features were further analyzed by multivariate regression analysis. Survival analyses were conducted using the Cox proportional hazards model.RESULTS: The mean serum folate level was significantly lower in gastric cancer patients than that in controls(3.71 ± 0.30 ng/mL vs 8.00 ± 0.54 ng/mL, P < 0.01), and folate levels were consistently lower in gastric cancer patients regardless of age and gender(all P < 0.01). Using the median serum folate value as the cutoff value, low serum folate was significantly associated with gastric cancer risk in the whole population(OR = 19.77, 95%CI: 10.54-37.06, P < 0.001) and all strata(age < 60 years OR = 17.39, 95%CI: 7.28-41.54, age ≥ 60 years(OR = 21.67, 95%CI: 8.27-56.80), males(OR = 17.95, 95%CI: 7.93-40.62), and females(OR = 20.95, 95%CI: 7.66-57.31); all P < 0.001. In the patient cohort of gastric cancer, the respective cutoff values showed that low serum folate levels were significantly associated with serosal invasion(OR = 2.54, 95%CI: 1.23-5.23), lymphatic invasion(OR = 2.23, 95%CI: 1.17-4.26), and liver metastasis(OR =6.67, 95%CI: 1.28-34.91) of gastric cancer(all P < 0.05). Serum folate level below 1.90 ng/mL was associated with poor patient survival(HR = 1.84, 95%CI: 1.04-3.27, P < 0.05) in univariate analysis.CONCLUSION: Lower serum folate levels were significantly associated with gastric cancer development and invasive phenotypes. The role of folate depletion in gastric cancer invasion warrants further study.展开更多
基金supported by the Central Public-Interest Scientific Institution Basal Research Fund,China(Grant No.CPSIBRF-CNRRI-202403)。
文摘Rice is a poor source of folate,an essential micronutrient for the body.Biofortification offers an effective way to enhance the folate content of rice and alleviate folate deficiencies in humans.In this study,we confirmed that OsADCS and OsGTPCHI,encoding the initial enzymes necessary for folate synthesis,positively regulate folate accumulation in knockout mutants of both japonica and indica rice backgrounds.The folate content in the low-folate japonica variety was slightly increased by the expression of the indica alleles driven by the endosperm-specific promoter.We further obtained co-expression lines by stacking OsADCS and OsGTPCHI genes;the folate accumulation in brown rice and polished rice reached 5.65μg/g and 2.95μg/g,respectively,representing 37.9-fold and 26.5-fold increases compared with the wild type.Transcriptomic analysis of rice grains from six transgenic lines showed that folate changes affected biological pathways involved in the synthesis and metabolism of rice seed storage substances,while the expression of other folate synthesis genes was weakly regulated.In addition,we identified Aus rice as a high-folate germplasm carrying superior haplotypes of OsADCS and OsGTPCHI through natural variation.This study provides an alternative and effective complementary strategy for rice biofortification,promoting the rational combination of metabolic engineering and conventional breeding to breed high-folate varieties.
基金supported by the Natural Science Foundation of Fujian Province,China(2025J01761 to J.W.)Open Subjects for Key Laboratory of Infection and Immunity of Anhui Higher Education Institutes,Bengbu Medical University(I&I-2024-K03 to J.W.)+2 种基金The Middle-aged and Young Teachers’Educational Research Project of Fujian Province(JAT241032 to J.W.)The Research Foundation for Advanced Talents from Bengbu Medical University(bsqd2024011 to D.C.)High-Level Hospital Construction Project of Nanjing Stomatological Hospital,Affiliated Hospital of Medical School,Institute of Stomatology,Nanjing University(0224C041 to Y.Q.).
文摘Folate(FA)is an essential micronutrient of vitamin B group for growth,development,and reproduction through participating in the nucleotide synthesis and methyl donation reactions.The changes of FA level have been linked to dietary insufficiency(e.g.,poor diet,etc.)malabsorption(e.g.,FA-associated gene mutation,etc.),increased demand(e.g.,pregnancy,etc).or medication(e.g.,antifolates drugs),or bad habits(e.g.,smoking,alcoholism,etc.).Recently,epidemiological data showed that the levels of the host FA typically changed in patients with infectious diseases.Interactions between pathogens,including bacteria,parasites and viruses,and their hosts are complex,in particular,pathogenic infection-mediated changes of the host FA levels can affect the utilization and uptake of limited FA resources of the host.Therefore,FA supplementation or the use of antifolate agents may be a potential antimicrobial strategy for managing infectious diseases.Furthermore,given that the gut microbiota is a primary source of FA in the human body,the association between gut microbiota and pathogenic infections warrants investigation.To date,little is known about how FA status and its biochemistry function affect the course of infectious diseases.In this review,we focus on the roles of FA in the interaction between the host and microbe,and briefly discuss the potential of FA and antifolates agents in the treatment of infectious diseases.
基金supported by Youth Scientific Research Foundation of Beijing Academy of Agriculture and Forestry Sciences (QNJJ202208)the Collaborative Innovation Center of Beijing Academy of Agriculture and Forestry Sciences (KJCX20240408)+1 种基金Major Scientific and Technological Achievements Cultivation Project of Beijing Academy of Agriculture and Forestry SciencesNational Natural Science Foundation of China (32201815)。
文摘One-third of the global population is affected by micronutrient deficiency, particularly folate. Although folate synthesis has been relatively well characterized, few folate-related genes in maize have been cloned, and the molecular mechanism regulating folate synthesis in maize remains unclear. In this study,transcriptome and proteome analyses of three waxy maize inbred lines with high, medium, and low folate contents were performed to identify key genes controlling folate biosynthesis. Pairwise comparisons revealed 21 differentially expressed genes and 20 differentially expressed proteins potentially associated with folate biosynthesis in the three lines. Six key folate-associated genes, Zm Mocos2, Zm GGH,Zm ADCL2, Zm CBR1, Zm SHMT, and Zm Pur H, were identified. These genes encode enzymes that potentially function in folate biosynthesis. Functional validation of one of these genes, Zm ADCL2, using an EMS mutant(Mut9264) showed that a 4-base insertion in an exon increased the folate content of fresh maize kernels 1.37-fold that of the wild type. Zm ADCL2 was considered a potential target for generating maize lines with higher folate content. KEGG enrichment analysis of differentially expressed genes and proteins showed that several pathways in addition to folate biosynthesis were likely indirectly involved in folate metabolism and content(e.g., glycine, serine, and threonine metabolism;purine metabolism;cysteine and methionine metabolism;alanine, aspartate and glutamate metabolism;glutathione metabolism;and pyruvate metabolism. The transcriptome and proteomic data generated in this study will help to clarify the mechanisms underlying folate accumulation and aid breeding efforts to biofortify maize with folate.
基金Supported by the National Key Research and Development Program of China,No.2021YFC2700700 and No.2021YFC2700704Capital’s Funds for Health Improvement and Research(CFH)in People’s Republic of China,No.2020-1-5112.
文摘BACKGROUND There are conflicting results on the potential correlation between folic acid and gestational diabetes mellitus(GDM),and the correlation between genetic factors related to folic acid metabolism pathways and GDM remains to be revealed.AIM To examine the association between single-nucleotide polymorphisms(SNPs)of enzyme genes in the folate metabolite pathway as well as that between GDM-related genes and risk for GDM.METHODS A nested case-control study was conducted with GDM cases(n=412)and healthy controls(n=412).DNA was extracted blood samples and SNPs were genotyped using Agena Bioscience’s MassARRAY gene mass spectrometry system.The associations between different SNPs of genes and the risk for GDM were estimated using logistic regression models.The generalized multi-factor dimensionality reduction(GMDR)method was used to analyze gene-gene and gene-environment interactions using the GMDR 0.9 software.RESULTS The variation allele frequency of melatonin receptor 1B(MTNR1B)rs10830963 was higher in the GDM group than in controls(P<0.05).MTNR1B rs10830963 mutant G was associated with risk for GDM[adjusted odds ratio(aOR):1.43;95%confidence interval(95%CI):1.13-1.80]in the additive model.MTNR1B rs10830963 GG+GC was significantly associated with the risk for GDM(aOR:1.65;95%CI:1.23-2.22)in the dominant model.The two-locus model of MTNR1B rs10830963 and CHEMERIN rs4721 was the best model(P<0.05)for gene-gene interactions in the GMDR results.The high-risk rs10830963×rs4721 type of interaction was a risk factor for GDM(aOR:2.09;95%CI:1.49-2.93).CONCLUSION This study does not find an association between SNPs of folate metabolic enzymes and risk for GDM.The G mutant allele of MTNR1B rs10830963 is identified as a risk factor for GDM in the additive model,and there may be gene-gene interactions between MTNR1B rs10830963 and CHEMERIN rs4721.It is conducive to studying the causes of GDM and provides a new perspective for the precise prevention of this disease.
文摘BACKGROUND Early metastasis and recurrence are risk factors that negatively affect the prog-nosis of advanced hepatocellular carcinoma(HCC).Alpha fetoprotein(AFP)is currently the most prevalent serum biomarker for detecting HCC and predicting tumor recurrence.However,its sensitivity and specificity are not sufficient,espe-cially in patients who are AFP negative.METHODS This work is a retrospective study that included 128 consecutive patients with benign or malignant disease of the liver from 2020 to 2021.FR+CTCs were col-lected from 3 mL of peripheral blood via immunomagnetic depletion of leuko-cytes.After ligand-target polymerase chain reaction,the number of FR+CTCs was measured.Receiver operating characteristic curves were used to determine the threshold of sensitivity and specificity of FR+CTCs.The Youden index was used to identify the optimal cutoff point and diagnostic efficiency of FR+CTCs counts.Univariate and multivariate Cox proportional hazards regression analyses were performed to evaluate the associations of biomarkers or clinical parameters with disease-free survival(DFS).RESULTS The FR+CTCs counts showed excellent diagnostic efficacy in patients with HCC,with high sensitivity(0.905)and specificity(0.773)compared with patients with benign disease.Compared with that of the AFP level,the area under the receiver operating characteristic curve of the FR+CTC count is significantly greater(0.900 compared with 0.730,P<0.05).FR+CTC levels were significantly correlated with macrovascular invasion,tumor size,tumor number,and extrahepatic tumor stage in HCC patients.FR+CTC counts were correlated with DFS in HCC patients after R0 resection.Univariate analysis of DFS revealed that the FR+CTC count,tumor number,Barcelona Clinic Liver Cancer stage and extrahepatic metastasis status were correlated with DFS.Multivariate analysis of DFS revealed that the FR+CTC count and tumor number were correlated with DFS.CONCLUSION Ligand-target polymerase chain reaction is a sensitive tool for quantifying the number of FR+CTCs in HCC patients.These findings could provide new insight for stratifying HCC patients and predicting the recurrence of HCC.
文摘Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF). Chemotherapy drugs such as methotrexate help to slow the progression of cancer by limiting the ability of dividing cells to make nucleotides by competitively inhibiting DHFR. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been previously reported to exhibit competitive inhibition of DHFR, in addition to their primary action on cyclooxygenase enzymes. This interaction interferes with the enzymatic reduction of dihydrofolate to tetrahydrofolate, thereby impeding the folate metabolism pathway essential for nucleotide synthesis and cell proliferation. This activity stems from their structural resemblance to the p-aminobenzoyl-l-glutamate (pABG) moiety of folate, a substrate of DHFR. It has been established that NSAIDs containing a salicylate group (which has structural similarities to pABG), such as diflunisal, exhibit stronger DHFR-binding activity. In this study, we synthesized salicylate derivatives of naproxen with the aim of exploring their potential as inhibitors of DHFR. The interactions between these derivatives and human DHFR were characterized using a combination of biochemical, biophysical, and structural methods. Through polyacrylamide gel electrophoresis (PAGE) analysis, enzymatic assays, and quantitative ELISA, we investigated the binding affinity and inhibitory potency of the synthesized salicylate derivatives towards DHFR. The findings of this study suggest the potential of salicylate derivatives of naproxen as promising candidates for the inhibition of DHFR, thereby offering novel therapeutic opportunities for modulating the inflammatory process through multiple pathways. Further optimization of these derivatives could lead to the development of more efficacious dual-targeted analogs with enhanced therapeutic benefits.
基金supported by the National Health Commission of the People’s Republic of China Medical Reform Major Program:China National Chronic Diseases and Nutrition Surveillance of Adults[2015-2017]Qianrang Zhu is funded by a China Scholarship Council PhD Scholarship[No.202109110099].
文摘Objective This study aimed to evaluate the associations of serum folate and/or vitamin B12 concentrations with obesity among Chinese children and adolescents.Methods A cross-sectional study was conducted including 3,079 Chinese children and adolescents,aged 6 to 17 years,from Jiangsu,China.Anthropometric indices,such as,children's body mass index(BMI),BMI z-scores,waist circumference,and waist-to-height ratio were utilized.Multivariable linear regression and generalized additive models were used to investigate the associations of serum folate and vitamin B12 levels with anthropometric indices and odds of obesity.Results We observed that serum vitamin B12 concentrations were inversely associated with all anthropometric indices and the odds of general obesity[odds ratio(OR)=0.68;95%confidence interval(CI)=0.59,0.78]and abdominal obesity(OR=0.68;95%CI=0.60,0.77).When compared to participants with both serum vitamin levels in the two middle quartiles,those with both serum folate and vitamin B12 levels in the highest quartile were less prone to general(OR=0.31,95%CI=0.19,0.50)or abdominal obesity(OR=0.46,95%CI=0.31,0.67).Conversely,participants with vitamin B12 levels in the lowest quartile alongside folate levels in the highest quartile had higher odds of abdominal obesity(OR=2.06,95%CI=1.09,3.91).Conclusion Higher serum vitamin B12 concentrations,but not serum folate concentrations,were associated with lower odds of childhood obesity.Children and adolescents with high levels of vitamin B12 and folate were less likely to be obese.
基金This work was supported by the Medical Research Project of Wuhan Municipal Health Commission(Grant No.WG14B13)the National Natural Science Foundation of China(Grant No.31600692)the Natural Science Foundation of Hubei Province(2017CFB406).
文摘Folate deficiency has been confirmed to be related to various diseases.Unfortunately,there are few reports on the folate status of Chinese adults.This study aims to evaluate the serum folate status of blood donors in south-central China.In this study,248 blood donors were included.The information on subjects was collected by a brief questionnaire concerning alcohol consumption habits,smoking habits,fruit and vegetable consumption and physical activity.The serum folate concentration was measured by electrochemiluminescence immunoassay.The geometric mean serum folate concentration was 13.4 nmoll-1(95%CI,12.7-14.1).The prevalence of serum folate concentrations below 6.8 nmoll-1 was 5.2%(95%CI,2.5-8.0).There were significant differences in serum folate concentrations with respect to sex(p-values<0.05),age(p-values<0.05),fruit and vegetable consumption(p-values<0.05),and alcohol consumption habits(p-values<0.05).The concentration of serum folate increased with age(p-values<0.05)and fruit and vegetable consumption(p-values<0.05).Individuals with an age of 30 years or younger were nearly 3.5 times as likely as those aged over 30 years to have an insufficient level of serum folate(OR=3.48;95%CI:1.01-11.99).An age of 30 years or younger was a risk factor for folate deficiency.Most blood donors had sufficient serum folate concentrations in south-central China.National surveys of folate status should be implemented in China.
基金Supported by the National Basic Research Funds of China 973 Project, No. 2005CB522400 grants from the National Natural Science Foundation of China, No. 30470781 grants from Shanghai Municipal Commission for Science and Technology, No. 04DZ14006 and Doctoral Funds from the Ministry of Education of China, No. 20050266013
文摘AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation. METHODS: Real-time PCR was used to study the expression of tumor related genes in 76 mucosal tissue samples from 38 patients with gastric cancer. Samples from the gastroscopic biopsy tissues of 34 patients with chronic superficial gastritis (CSG) were used as controls. Folate concentrations in these tissues were detected by the FOL ACS: 180 automated chemiluminescence system. MTHFR polymorphisms were analyzed by PCR-RFLP, and the promoter methylation of tumor-related genes was determined by methylation-specific PCR (MSP). RESULTS: Folate concentrations were significantly higher in CSG than in cancerous tissues. Decreased expression and methylation of c-myc accompanied higher folate concentrations. Promoter hypermethylation and loss of p16INK4A in samples with MTHFR 677CC were more frequent than in samples with the 677TT or 677CT genotype. And the promoter hypermethylation and loss of p21WAF1 in samples with MTHFR 677CT were more frequent than when 677CC or 677TT was present. The 677CT genotype showed a non-significant higher risk for gastric cancer as compared with the 677CC genotype. CONCLUSION: Lower folate levels in gastric mucosal tissue may confer a higher risk of gastric carcinogenesisthrough hypomethylation and overexpression of c-myc.
基金The office of the Vice Chancellor for Research, Shiraz University of Medical Sciences, No. 83-2212 Grant from the Gastroenterohepatology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
文摘AIM:To evaluate joint effects of Methylentetra-hydrofolate reductase(MTHFR) C677T genotypes,and serum folate/vitamin B12 concentrations on promoter methylation of tumor-associated genes among Iranian colorectal cancer patients. METHODS:We examined the associations between MTHFR C677T genotype,and promoter methylation of P16,hMLH1,and hMSH2 tumor-related genes among151 sporadic colorectal cancer patients. The promoter methylation of tumor-related genes was determined by methylation-specific PCR. Eighty six patients from whom fresh tumor samples were obtained and 81 controls were also examined for serum folate and vitamin B12 concentrations by a commercial radioimmunoassay kit. RESULTS:We found 29.1% of cases had tumors with at least one methylated gene promoter. In case-case comparison,we did not find a significant association between methylation in tumors and any single genotype. However,in comparison to controls with the CC genotype,an increased risk of tumor methylation was associated with the CT genotype(OR = 2.5;95% CI,1.1-5.6) . In case-case comparisons,folate/vitamin B12 levels were positively associated with tumor methylation. Adjusted odds ratios for tumor methylation in cases with high(above median) versus low(below median) serum folate/vitamin B12 levels were 4.9(95% CI,1.4-17.7) ,and 3.9(95% CI,1.1-13.9) ,respectively. The frequency of methylated tumors was significantly higher in high methyl donor than low methyl donor group,especially in those with MTHFR CT(P = 0.01) ,and CT/TT(P = 0.002) genotypes,but not in those with the CC genotype(P = 1.0) . CONCLUSION:We conclude that high concentrations of serum folate/vitamin B12 levels are associated with the risk of promoter methylation in tumor-specific genes,and this relationship is modified by MTHFR C677T genotypes.
基金supported by the National Natural Sciences Foundation of China(Nos.81630094,21732008,and 81730093)CAMS Innovation Fund for Medical Science of China(Nos.2017-I2M-3-010 and 2016-I2M-1-010)the Drug Innovation Major Project(No.2018ZX09711001-001-001)
文摘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.
基金supported by the National Natural Science Foundation of China under the Grant No. 81973048a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports and Technology of Japan [JSPS-C-21580137]。
文摘Objective This study aimed to investigate the effects of N,N-dimethylglycine(DMG) on the concentration and metabolism of plasma homocysteine(pHcy) in folate-sufficient and folate-deficient rats.Methods In this study, 0.1% DMG was supplemented in 20% casein diets that were either folatesufficient(20 C) or folate-deficient(20 CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system.Results Folate deprivation significantly increased pHcy concentration in rats fed 20 C diet(from 14.19 ±0.39 μmol/L to 28.49 ± 0.50 μmol/L;P < 0.05). When supplemented with DMG, pHcy concentration was significantly decreased(12.23 ± 0.18 μmol/L) in rats fed 20 C diet but significantly increased(31.56 ±0.59 μmol/L) in rats fed 20 CFD. The hepatic methionine synthase activity in the 20 CFD group was significantly lower than that in the 20 C group;enzyme activity was unaffected by DMG supplementation regardless of folate sufficiency. The activity of hepatic cystathionine β-synthase(CBS) in the 20 CFD group was decreased but not in the 20 C group;DMG supplementation enhanced hepatic CBS activity in both groups, in which the effect was significant in the 20 C group but not in the other group.Conclusion DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.
基金National Natural Science Foundation of China(No.31970149,81900823)The Major Research and Development Project(2018ZX10301406)Nanjing University-Ningxia University Collaborative Project(Grant#2017BN04).
文摘Folate receptor alpha(FOLR1)is vital for cells ingesting folate(FA).FA plays an indispensable role in cell pro-liferation and survival.However,it is not clear whether the axis of FOLR1/FA has a similar function in viral replication.In this study,we used vesicular stomatitis virus(VSV)to investigate the relationship between FOLR1-mediated FA deficiency and viral replication,as well as the underlying mechanisms.We discovered that FOLR1 upregulation led to the deficiency of FA in HeLa cells and mice.Meanwhile,VSV replication was notably sup-pressed by FOLR1 overexpression,and this antiviral activity was related to FA deficiency.Mechanistically,FA deficiency mainly upregulated apolipoprotein B mRNA editing enzyme catalytic subunit 3B(APOBEC3B)expression,which suppressed VSV replication in vitro and in vivo.In addition,methotrexate(MTX),an FA metabolism inhibitor,effectively inhibited VSV replication by enhancing the expression of APOBEC3B in vitro and in vivo.Overall,our present study provided a new perspective for the role of FA metabolism in viral infections and highlights the potential of MTX as a broad-spectrum antiviral agent against RNA viruses.
文摘The Egyptian government introduced wheat-flour fortification with iron and folic acid to reduce the incidence of neural tube defects, but suspended it for technical reasons. We previously developed novel legume foods with enhanced folate content. In this study, we investigated the efficacy of 12-week intervention with folate-enhanced foods versus folic acid supplement in improving folate status in Egyptian women. A randomized, parallel intervention trial with two active groups (n = 19, n = 18) and one blinded control group (n = 20) was executed over 12 weeks. Volunteers received either germinated legume foods and orange juice (≈250 μg/d folate) or folic acid supplement (500 μg/d) or apple juice (0 μg/d folate). Folate status was assessed by erythrocyte and plasma folate and total homocysteine (tHcy) at day 0, and after 8 and 12 weeks of intervention. After 12 weeks, mean plasma folate increased by 14 (P < 0.0001) and 12 (P < 0.0001) nmoL in the folic acid and food group, respectively. Erythrocyte folate concentration increased in the folic acid group from 614 to 912 (P < 0.0001) and in the food group from 631 to 914 nmoL (P < 0.0001). After 12 weeks, 90% of subjects in the folic acid group and 70% in the food group had erythrocyte folate concentrations exceeding 906 nmol/L. tHcy concentration was decreased by 20% (P = 0.007) and 18% (P = 0.006) in the folic acid and food group, respectively, but remained unchanged in the control group during intervention. Folate-enhanced foods effectively improve folate status in women of reproductive age. These foods could be used as a complement to folic acid fortification.
基金National key Basic Research Program(Grant No.2013CB932501)National Natural Science Foundation of China(Grant No.81273454 and 81473156)+1 种基金Beijing National Science Foundation(Grant No.7132113)Doctoral Foundation of the Ministry of Education(Grant No.20130001110055)
文摘Surface modification may have important influences on the penetration behavior of nanoscale drug delivery system. In the present study, we mainly focused on whether cell targeting or cell penetration could affect penetration abilities of nanostructured lipid carriers（NLC）. Real--time penetration of folate--or cell penetrating peptide（CPP）-modified NLC was evaluated using a multicellular tumor spheroid（MTS） established by stacking culture method as an in vitro testing platform. The results suggested that CPP modification had a better penetration behavior both on penetration depth and intensity compared with folate-modified NLC at the early stage of penetration process.
基金National Natural Science Foundation of China(Grant No.81273454 and 81473156)Beijing National Science Foundation(Grant No.7132113)+1 种基金National Key Basic Research Program(Grant No.2013CB932501)Doctoral Foundation of the Ministry of Education(Grant No.20130001110055)
文摘Multidrug resistance （MDR） operated by P-glycoprotein （P-gp） is one of the major causes in the treatment failure of cancers. In this work, docetaxel-loaded mixed micelles comprised of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy （polyethylene-glycol）2000 （DSPE-PEG2000）, D-α-Tocopherylpolyethylene glycol 1000 succinate （TPGSIooo） and DSPE-PEG2000-folate were developed to overcome MDR and reduce the side effect of docetaxel in cancer therapy. The diameters of micelles ranged from 13 to 26 nm and the encapsulation efficiencies were all above 85%. The influences of DSPE-PEG2000 and TPGSIooo ratios on the micellar characteristics and anti-resistant tumors effects were evaluated. Micelles with high TPGS1000 amount showed an increased cellular uptake and stronger cytotoxicity against MDR KBv cells. Moreover, the micelles modified by targeting ligand of folic acid exhibited better antitumor effect on folate receptor over-expressing KBv cells. The study provides a method for overcoming MDR in cancer therapy.
文摘Methylenetetrahydrofolate reductase(MTHFR)is a key enzyme for the critical process of one-carbon circulation,which convert5,10-methylenetetrahydrofolate to5-methyltetrahydrofolate and participate in folate and homocysteine conversion correlated to methyl group supply.The enzyme activity decline depends on the gene polymorphism.MTHFR impacts on the methylation process which is related to psychiatric diseases.Studies have shown association between MTHFR gene polymorphisms and mental disorders,some of which stratified by folate and cobalamin levels.In this review,we will summarize the testimony on the relationship between methylation and MTHFR polymorphism as well as the implication on psychiatric diseases by MTHFR mutation.
文摘Objective To review the association of methylene tetrahydrofolate reductase (MTHFR) C677T mutant with coronary artery disease, as well as to highlight the results of some of these studies and to emphasize the need to focus on the genetic architecture of CAD. Data SourcesData used in this article is mainly from relevant articles obtained through Pubmed, OVID and Google Scholar published from 1980 to 2008. Major studies and trials in this period were taken into account to draw accurate conclusion on the relation of those mutations in MTHFR with homocysteinemia and CAD. ResultOur analysis shows that hyperhomocysteinemia, a risk factor for occlusive arterial diseases, can be caused by disruptions of homocysteine metabolism catalyzed by MFTHR. A common alanine to valine mutation in MTHFR may contribute to mild heperhomocysteinemia in CAD. Individuals with the homozygous mutant genotype had higher plasma homocysteine, particularly when plasma folate was below the median value. ConclusionThis MTHFR mutant in the setting of insufficient folate may be a risk factor of CAD and can be regarded as a model of genetic-environmental interaction in the development of CAD.
基金Project (No. 2003ABA148) supported by the Science Foundation of Hubei Province, China
文摘Objective: To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), the central enzymes in folate metabolism that affects DNA methylation and synthesis, and the risk of Down syndrome in China. Methods: Genomic DNA was isolated from the peripheral lymphocytes of 64 mothers of children with Down syndrome and 70 age matched control subjects. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFR 677C→T, MTRR 66A→G and the relationship between these genotypes and the risk of Down syndrome was analyzed. Results: The results show that the MTHFR 677C→T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 3.78 (95% confidence interval (CI), 1.78～8.47). In addition, the homozygous MTRR 66A→G polymorphism was independently associated with a 5.2-fold increase in estimated risk (95% CI, 1.90～14.22). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than the presence of either alone, with an odds ratio of 6.0 (95% CI, 2.058～17.496). The two polymorphisms appear to act without a multiplicative interaction. Conclusion: MTHFR and MTRR gene mutation alleles are related to Down syndrome, and CT, TT and GG gene mutation types increase the risk of Down syndrome.
基金Supported by National Science Council,Executive YuanNo.NSC-96-2314-B-075A-007,No.NSC100-2628-B005002MY4,No.NSC101-2320-B-005-006-MY3 and No.NSC101-2911-I-005-301the ATU plan of the Ministry of Education,Taiwan
文摘AIM: To evaluate the associations of serum folate levelwith development, invasiveness and patient survival of gastric cancer. METHODS: In this nested case-control study, patients with newly diagnosed gastric cancer undergoing gastrectomy were enrolled, and patients receiving chemotherapy prior to surgery, with other concurrent malignancy, or of the aboriginal and alien populations were excluded. In total, 155 gastric cancer patients and 149 healthy controls were enrolled for determination of serum folate levels and their correlation with gastric cancer. Using the median value of serum folate computed among the overall population as the cutoff value, the associations between serum folate and gastric cancer in all cases and different age and gender subgroups were analyzed by multivariate logistic regression analysis. In the patient cohort of gastric cancer, receiver-operating characteristic analyses were performed to calculate the best cutoff values of serum folate, and the associations between serum folate levels and clinicopathological features were further analyzed by multivariate regression analysis. Survival analyses were conducted using the Cox proportional hazards model.RESULTS: The mean serum folate level was significantly lower in gastric cancer patients than that in controls(3.71 ± 0.30 ng/mL vs 8.00 ± 0.54 ng/mL, P < 0.01), and folate levels were consistently lower in gastric cancer patients regardless of age and gender(all P < 0.01). Using the median serum folate value as the cutoff value, low serum folate was significantly associated with gastric cancer risk in the whole population(OR = 19.77, 95%CI: 10.54-37.06, P < 0.001) and all strata(age < 60 years OR = 17.39, 95%CI: 7.28-41.54, age ≥ 60 years(OR = 21.67, 95%CI: 8.27-56.80), males(OR = 17.95, 95%CI: 7.93-40.62), and females(OR = 20.95, 95%CI: 7.66-57.31); all P < 0.001. In the patient cohort of gastric cancer, the respective cutoff values showed that low serum folate levels were significantly associated with serosal invasion(OR = 2.54, 95%CI: 1.23-5.23), lymphatic invasion(OR = 2.23, 95%CI: 1.17-4.26), and liver metastasis(OR =6.67, 95%CI: 1.28-34.91) of gastric cancer(all P < 0.05). Serum folate level below 1.90 ng/mL was associated with poor patient survival(HR = 1.84, 95%CI: 1.04-3.27, P < 0.05) in univariate analysis.CONCLUSION: Lower serum folate levels were significantly associated with gastric cancer development and invasive phenotypes. The role of folate depletion in gastric cancer invasion warrants further study.
