scholarly journals Folic Acid Exerts Dose-Dependent Biphasic Effects on Cardiac Development of Zebrafish Embryos

2021 ◽  
Author(s):  
Xuhui Han ◽  
Bingqi Wang ◽  
Hongjie Wang ◽  
Yao Zu
Keyword(s):  
Folic Acid ◽  
Methylenetetrahydrofolate Reductase ◽  
Cardiac Development ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Marker Genes ◽  
Zebrafish Embryos ◽  
Cardiovascular Development ◽  
Knock Out ◽  
Dose Dependent

Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is significantly associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. And we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid, and mthfr-/- mutant all gave rise to early pericardial edema and cardiac defect at 3 days after fertilization(dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5dpf. The expression levels of cardiac marker genes hand2, gata4 and nppa changed in the abnormality of folate metabolism embryos and mthfr-/- mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. And our results reveal that folic acid has a dose-dependent biphasic effect on early cardiac development.

scholarly journals Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish

Biology ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 28
Author(s):  
Xuhui Han ◽  
Bingqi Wang ◽  
Dongxu Jin ◽  
Kuang Liu ◽  
Hongjie Wang ◽  
...  
Keyword(s):  
Folic Acid ◽  
Heart Development ◽  
Cardiac Development ◽  
Folic Acid Supplementation ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Marker Genes ◽  
Zebrafish Embryos ◽  
Cardiovascular Development ◽  
Acid Supplementation

Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. Moreover, we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid and mthfr−/− mutant all gave rise to early pericardial edema and cardiac defect at 3 days post fertilization (dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5 dpf. The expression levels of cardiac marker genes hand2, gata4, and nppa changed in the abnormality of folate metabolism embryos and mthfr−/− mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. Furthermore, our results reveal that folic acid has a dose-dependent effect on early cardiac development. Precise dosage of folic acid supplementation is crucial for the embryonic development of organisms.

scholarly journals A Novel Review of Homocysteine and Pregnancy Complications

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Chuce Dai ◽  
Yiming Fei ◽  
Jianming Li ◽  
Yang Shi ◽  
Xiuhua Yang
Keyword(s):  
Folic Acid ◽  
Pregnancy Complications ◽  
Methylenetetrahydrofolate Reductase ◽  
Normal Pregnancy ◽  
Positive Outcome ◽  
Mthfr Gene ◽  
Folate Intake ◽  
Daily Diet ◽  
B12 Deficiency ◽  
Work Done

Homocysteine (Hct) is a substance produced in the metabolism of methionine. It is an essential type of amino acid gained from the daily diet. Methylenetetrahydrofolate reductase (MTHFR) gene mutation is related to elevated total homocysteine (tHct) expressions, in particular, among women with low folate intake. Hyperhomocysteinemia (HHct) is caused by numerous factors, such as genetic defects, lack of folic acid, vitamin B6 and B12 deficiency, hypothyroidism, drugs, aging, and renal dysfunction. Increased Hct in peripheral blood may lead to vascular illnesses, coronary artery dysfunction, atherosclerotic changes, and embolic diseases. Compared to nonpregnant women, the Hct level is lower in normal pregnancies. Recent studies have reported that HHct was associated with numerous pregnancy complications, including recurrent pregnancy loss (RPL), preeclampsia (PE), preterm delivery, placental abruption, fetal growth restriction (FGR), and gestational diabetes mellitus (GDM). Besides, it was discovered that neonatal birth weight and maternal Hct levels were negatively correlated. However, a number of these findings lack consistency. In this review, we summarized the metabolic process of Hct in the human body, the levels of Hct in different stages of normal pregnancy reported in previous studies, and the relationship between Hct and pregnancy complications. The work done is helpful for obstetricians to improve the likelihood of a positive outcome during pregnancy complications. Reducing the Hct level with a high dosage of folic acid supplements during the next pregnancy could be helpful for females who have suffered pregnancy complications due to HHct.

scholarly journals The assessment of the efficiency of 5-methyltethydrofolate according to level by homocysteine, methionine and betaine in pregnant women with polymorphism rs 1801133 (677 C> T) of the MTHFR gene

2020 ◽  
Vol 24 (4) ◽  
pp. 618-623
Author(s):  
O. B. Lastovetska ◽  
O. V. Bulavenko
Keyword(s):  
Folic Acid ◽  
Pregnant Women ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Reproductive Age ◽  
Third Trimester ◽  
The Third ◽  
Serum Homocysteine ◽  
Significant Difference

Annotation. The prevention of early pregnancy loss, taking into account the polymorphism of the genes of enzymes that controlling folate metabolism, have become the goal of clinical studies in recent years, and the determination of risk factors for patients of late reproductive age and embryonic losses in history becomes critical for the development of effective measures to prevent miscarriage. The use of medical prevention of perinatal pathology using a biologically active form of folate in the form of 5-methyltetrahydrofolate in women with anamnestic loss of pregnancy looks promising. The aim of the study was to evaluate the effectiveness of drug prevention in patients with anamnestic embryonic losses, taking into account the role of the rs1801133 (677 C>T) polymorphism of the MTHFR gene based on the results of the dynamics of serum levels of homocysteine, betaine, and methionine. The patients were divided into the main group (polymorphism rs1801133 (677 C>T) of the MTHFR gene and anamnestic embryonic loss), which was divided into 2 subgroups: I subgroup included 20 women who received folic acid preparations (400 μg per day), II subgroup – 20 patients who received a complex preparation containing 5-methyltetrahydrofolate and control groups (practically healthy women) (n=20). Prescribing drugs began at the pre-gravid stage 8–10 weeks before pregnancy planning, and the administration ended up to 26 weeks of pregnancy. Determination of serum homocysteine levels and markers of folate metabolism - methionine and betaine – were performed at the end of the 1st – beginning of the 2nd trimester of pregnancy and in the third trimester. In the study of the effectiveness of preventive therapy on the dynamics of markers of folate metabolism functionality in pregnant women of late reproductive age with anamnestic embryonic losses and polymorphism rs1801133 (677 C>T) of the MTHFR gene when using a combined drug containing folic acid and 5-methyltetrahydrofolate, at the first end – at the beginning In the second trimester, there was a significant increase in betaine and methionine (p<0.05), while in the third trimester, a positive statistically significant difference (p<0.05) was diagnosed in an increase in methionine, betaine and a decrease in serum homocysteine levels.

scholarly journals Enhanced canonical Wnt signaling during early zebrafish development perturbs the interaction of cardiac mesoderm and pharyngeal endoderm and causes thyroid specification defects

2019 ◽  
Author(s):  
Isabelle Vandernoot ◽  
Benoît Haerlingen ◽  
Achim Trubiroha ◽  
Pierre Gillotay ◽  
Véronique Janssens ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Wnt Signaling Pathway ◽  
Bmp Signaling ◽  
Thyroid Cell ◽  
Zebrafish Embryos ◽  
Cardiovascular Development ◽  
Fluorescent Reporter ◽  
Cardiac Mesoderm

AbstractBackgroundCongenital hypothyroidism (CH) due to thyroid dysgenesis is a frequent congenital endocrine disorder for which the molecular mechanisms remain unresolved in the far majority of cases. This situation reflects in part our still limited knowledge about the mechanisms involved in the early steps of thyroid specification from the endoderm, in particular the extrinsic signaling cues that regulate foregut endoderm patterning. In this study, we used small molecules and genetic zebrafish models to characterize the role of various signaling pathways in thyroid specification.MethodsWe treated zebrafish embryos during different developmental periods with small molecule compounds known to modulate the activity of Wnt signaling pathway and observed effects in thyroid, endoderm and cardiovascular development using whole mount in situ hybridization and transgenic fluorescent reporter models. We used an antisense morpholino to create a zebrafish acardiac model. For thyroid rescue experiments, BMP pathway induction in zebrafish embryos was obtained by using heatshock inducible transgenic lines.ResultsInterestingly, combined analyses of thyroid and cardiovascular development revealed that overactivation of Wnt signaling during early development leads to impaired thyroid specification concurrent with severe defects in the cardiac specification. When using a model of morpholino-induced blockage of cardiomyocyte differentiation, a similar correlation was observed, suggesting that defective signaling between cardiac mesoderm and endodermal thyroid precursors contributes to thyroid specification impairment. Rescue experiments through transient overactivation of BMP signaling could partially restore thyroid specification in models with defective cardiac development.ConclusionCollectively, our results indicate that BMP signaling is critically required for thyroid cell specification and identify cardiac mesoderm as a likely source of BMP signals.

scholarly journals Genetic variation in genes of folate metabolism and neural-tube defect risk

2006 ◽  
Vol 65 (2) ◽  
pp. 204-215 ◽  
Author(s):  
Ivon J. M. van der Linden ◽  
Lydia A. Afman ◽  
Sandra G. Heil ◽  
Henk J. Blom
Keyword(s):  
Genetic Variation ◽  
Neural Tube ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Nucleotide Polymorphism ◽  
Folate Transport ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
B Vitamin

Neural-tube defects (NTD) are common congenital malformations that can lead to severe disability or even death. Periconceptional supplementation with the B-vitamin folic acid has been demonstrated to prevent 50–70% of NTD cases. Since the identification of the first genetic risk factor of NTD, the C677T single-nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase (MTHFR) gene, and the observation that elevated plasma homocysteine levels are associated with NTD, research has focused on genetic variation in genes encoding for enzymes of folate metabolism and the closely-related homocysteine metabolism. In the present review relevant SNP in genes that code for enzymes involved in folate transport and uptake, the folate cycles and homocysteine metabolism are summarised and the importance of these SNP discussed in relation to NTD risk.

scholarly journals The Relationship Between Methylation Defects and Different Genetic Disorders: Two Case Reports

2016 ◽  
Author(s):  
Emine Aydın ◽  
Ahmet Cevdet Ceylan ◽  
Mehmet Sinan Beksaç
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Chromosomal Abnormalities ◽  
Case Reports ◽  
Genetic Disorders ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Key Enzyme ◽  
Gene Switching ◽  
Methylation Defects ◽  
The Relationship

<p>5, 10-methylenetetrahydrofolate reductase (MTHFR) is a coding gene, for a key enzyme in methionine-homocysteine and folate metabolism. This pathway has been associated with gene specific DNA hypo and hypermethylation as a result of gene switching on or off.<br />Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms are associated with folate metabolism disorders; such as, it results in an impaired DNA methylation and chromosomal abnormalities, gene deficiencies and structural anomalies. Here, we reported two cases of compound heterozygote and homozygote MTHFR gene mutation association with genetical disorders during the pregnancies.</p>

Schizophrenia and folate pharmacogenetics: Review of the literature regarding folic acid and its pharmacogenetically regulated metabolism in relation to schizophrenia treatments

2012 ◽  
Vol 1 (9) ◽  
pp. 225-229 ◽  
Author(s):  
Andrew Wechter ◽  
Kristen N. Gardner ◽  
Tyler B. Grove ◽  
Vicki L. Ellingrod
Keyword(s):  
Metabolic Syndrome ◽  
Folic Acid ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Gene Variants ◽  
Cognitive Symptoms ◽  
Review Of The Literature ◽  
Dietary Folate ◽  
The Relationship

Folic acid and its metabolism and utilization has become of increasing importance within the field of schizophrenia. Methylenetetrahydrofolate reductase (MTHFR) is the enzyme responsible for the formation of methyltetrahydrofolate (5-methyl THF) from dietary folate. Multiple studies have demonstrated relationships between MTHFR gene variants and schizophrenia. This review discusses these studies, and their findings regarding the relationship between different variants of the MTHFR gene and risk of antipsychotic-related metabolic syndrome, and the relationship between the pharmacogenetics of folate and the negative/cognitive symptoms of schizophrenia.

scholarly journals Effect of in ovo feeding of folic acid on the folate metabolism, immune function and epigenetic modification of immune effector molecules of broiler

2015 ◽  
Vol 115 (3) ◽  
pp. 411-421 ◽  
Author(s):  
Shizhao Li ◽  
Lihui Zhi ◽  
Yanli Liu ◽  
Jing Shen ◽  
Lei Liu ◽  
...  
Keyword(s):  
Folic Acid ◽  
Immune Function ◽  
Histone Methylation ◽  
Methylenetetrahydrofolate Reductase ◽  
Epigenetic Modification ◽  
Average Daily Gain ◽  
Folate Metabolism ◽  
Feed Conversion ◽  
In Ovo ◽  
Methionine Synthase Reductase

AbstractThis study was conducted to investigate the effect of in ovo feeding (IOF) of folic acid on the folate metabolism, immune function and the involved epigenetic modification of broilers. A total of 400 (Cobb) hatching eggs were randomly divided into four groups (0, 50, 100 and 150 µg injection of folic acid at embryonic age 11 d), and chicks hatched from each treatment were randomly divided into six replicates with 12 broilers/replicate after incubation. The results indicated that, in ovo, 100- and 150-µg folic acid injections improved the hatchability. The average daily gain and feed conversion ratio increased in the 150-µg group during the late growth stage. Simultaneously, in the 100- and 150-µg groups, an increase was observed in hepatic folate content and the expression of methylenetetrahydrofolate reductase (d1 and 42) and methionine synthase reductase (d21). IgG and IgM concentrations, as well as plasma lysozyme activity of broilers, showed a marked increase along with increasing folic acid levels. The splenic expression levels of IL-2 and IL-4 were up-regulated, whereas that of IL-6 was down-regulated, in the 100- and 150-µg folic acid treatment groups. In addition, histone methylation in IL-2 and IL-4 promoters exhibited an enrichment of H3K4m2 but a loss of H3K9me2 with the increased amount of folic acid additive. In contrast, a decrease in H3K4m2 and an increase in H3K9me2 were observed in the IL-6 promoter in folic acid treatments. Furthermore, in ovo, the 150-µg folic acid injection improved the chromatin tightness of the IL-2 and IL-4 promoter regions. Our findings suggest that IOF of 150 µg of folic acid can improve the growth performance and folate metabolism of broilers, and enhance the relationship between immune function and epigenetic regulation of immune genes, which are involved with the alterations in chromatin conformation and histone methylation in their promoters.

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