Effects of Folate on Notch Signaling and Cell Proliferation in Neural Stem Cells of Neonatal Rats In Vitro

Zhang, Xumei; Liu, Huan; Cong, Gexin; Zhi-hong, Tian; Ren, Dunqiang; Wilson, John X.; Huang, Guowei

doi:10.3177/jnsv.54.353

Cited by 32 publications

(20 citation statements)

References 20 publications

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“…The latter data are consistent with the previous demonstrations that folic acid is able to stimulate Notch signaling, including Hes1 transcription, and promotes cell proliferation in neural stem cells [75–77]. Taken together, the positive impact observed after folic acid supplementation and following siRNA strategy, along with the associated normalization of let-7a and miR-34a, strengthen the potential role of these microRNAs and their related signaling pathways in the developmental defects consecutive to gestational methyl donor deficiency.…”

Section: Discussionsupporting

confidence: 93%

Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways

et al. 2016

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The micronutrients folate and vitamin B12 are essential for the proper development of the central nervous system, and their deficiency during pregnancy has been associated with a wide range of disorders. They act as methyl donors in the one-carbon metabolism which critically influences epigenetic mechanisms. In order to depict further underlying mechanisms, we investigated the role of let-7 and miR-34, two microRNAs regulated by methylation, on a rat model of maternal deficiency. In several countries, public health policies recommend periconceptional supplementation with folic acid. However, the question about the duration and periodicity of supplementation remains. We therefore tested maternal supply (3 mg/kg/day) during the last third of gestation from embryonic days (E) 13 to 20. Methyl donor deficiency-related developmental disorders at E20, including cerebellar and interhemispheric suture defects and atrophy of selective cerebral layers, were associated with increased brain expression (by 2.5-fold) of let-7a and miR-34a, with subsequent downregulation of their regulatory targets such as Trim71 and Notch signaling partners, respectively. These processes could be reversed by siRNA strategy in differentiating neuroprogenitors lacking folate, with improvement of their morphological characteristics. While folic acid supplementation helped restoring the levels of let-7a and miR-34a and their downstream targets, it led to a reduction of structural and functional defects taking place during the perinatal period. Our data outline the potential role of let-7 and miR-34 and their related signaling pathways in the developmental defects following gestational methyl donor deficiency and support the likely usefulness of late folate supplementation in at risk women.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-016-0035-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways

et al. 2016

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“…Many studies have demonstrated a link between folate deficiency during early pregnancy and developmental abnormalities, such as neural tube defects [10], abnormal embryonic development [11,12], and tumor formation [13]. For these reasons, dietary folate supplementation is routinely recommended during early pregnancy in human [14].…”

Section: Introductionmentioning

confidence: 99%

Folate Deficiency during Early-Mid Pregnancy Affects the Skeletal Muscle Transcriptome of Piglets from a Reciprocal Cross

Zhang

Sun³

et al. 2013

PLoS ONE

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Folate deficiency (FD) during pregnancy can cause fetal intrauterine growth restriction in pigs, of which the skeletal dysplasia is a major manifestation. Factors influencing muscle development are very important in the formation of porcine meat quality trait. However, the effect of folate deficiency on skeletal muscle development and its molecular mechanisms are unknown. The objective of this study is to determine the effect of maternal folate deficiency on the skeletal muscle transcriptome of piglets from a reciprocal cross, in which full-sibling Landrace (LR) and full-sibling Chinese local breed Laiwu (LW) pigs were used for reciprocal cross matings, and sows were fed either a folate deficient or a normal diet during early-mid gestation. In addition, the difference in the responsiveness of the piglets to folate deficiency during early-mid pregnancy between reciprocal cross groups was investigated. Longissimus dorsi (LD) muscle samples were collected from newborn piglets and a 4 × 44K Agilent porcine oligo microarray was used for transcriptome analysis of porcine LD muscle. The results showed that folate deficiency during early-mid pregnancy affected piglet body weight, LD muscle fiber number and content of intramuscular triglyceride. The microarray results indicated that 3154 genes were differentially expressed between folate deficient and normal piglets from the LR♂ × LW♀ cross, and 3885 differentially expressed genes (DEGs) in the ones from the LW♂ × LR♀ cross. From functional analyses, sow folate deficiency affected almost all biological processes in the progeny. Lipid metabolism-related genes and associated metabolic pathways were regulated extensively by folate deficiency, especially in LR♂ × LW♀ cross piglets. Most of the genes that are regulated by folate deficiency in the LD muscle of piglets were different between LR♂ × LW♀ and LW♂ × LR♀ crosses, suggesting some epigenetic effects of FD exist in genes underlying myogenesis and intramuscular fat deposition in piglets.

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“…A study done by Zhang et al on neonatal rats showed that folate altered Notch signaling, which regulates the control of proliferation and differentiation in neural stem cells. Compared to the control, folate increased the rate of cell proliferation by increasing expression of Notch1 and Hes1 , while decreasing expression of Mash1 (43). All three genes are components of the Notch signaling pathway.…”

Section: The Aldh1 Family: Enzymes Implicated In Folate and Ethanol Mmentioning

confidence: 94%

Alcohol intake and folate antagonism via CYP2E1 and ALDH1: Effects on oral carcinogenesis

2012

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The interaction of folate and alcohol consumption has been shown to have an antagonistic effect on the risk of oral cancer. Studies have demonstrated that increased intake of folate decreases the risk of oral cancer, while greater alcohol consumption has an opposite effect. However, what is poorly understood is the biological interaction of these two dietary factors in relation to carcinogenesis. We hypothesize that cytochrome P450 2E1 (CYP2E1) and the family of aldehyde dehydrogenase 1 (ALDH1) enzymes may play a causal role in the occurrence of oral cancer. Chronic and high alcohol use has been implicated in the induction of CYP2E1, which oxidizes ethanol to acetaldehyde. Acetaldehyde is a known carcinogen. As the first metabolite of ethanol, it has been shown to interfere with DNA methylation, synthesis and repair, as well as bind to protein and DNA to form stable adducts, which lead to the eventual formation of damaged DNA and cell proliferation. Studies using liver cells have demonstrated that S-adenosyl methionine (SAM), which is a product of folate metabolism, regulates the expression and catalytic activity of CYP2E1. Our first hypothesis is that as increased levels of folate lead to higher concentrations of SAM, SAM antagonizes the expression of CYP2E1, which results in decreased conversion of ethanol into acetaldehyde. Thus, the lower levels of acetaldehyde may lower risk of oral cancer. There are also two enzymes within the ALDH1 family that play an important role both in ethanol metabolism and the folate one-carbon pathway. The first, ALDH1A1, converts acetaldehyde into its non-carcinogenic byproduct, acetate, as part of the second step in the ethanol metabolism pathway. The second, ALDH1L1, also known as FDH, is required for DNA nucleotide biosynthesis, and is upregulated at high concentrations of folate. ALDH1L1 appears to be a chief regulator of cellular metabolism as it is strongly downregulated at certain physiological and pathological conditions, while its upregulation can produce drastic antiproliferative effects. ALDH1 has three known response elements that regulate gene expression (NF-Y, C/EBPβ, and RARα). Our second hypothesis is that folate interacts with one of these response elements to upregulate ALDH1A1 and ALDH1L1 expression in order to decrease acetaldehyde concentrations and promote DNA stability, thereby decreasing cancer susceptibility. Conducting future metabolic and biochemical human studies in order to understand this biological mechanism will serve to support evidence from epidemiologic studies, and ultimately promote the intake of folate to at-risk populations.

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Effects of Folate on Notch Signaling and Cell Proliferation in Neural Stem Cells of Neonatal Rats In Vitro

Cited by 32 publications

References 20 publications

Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways

Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways

Folate Deficiency during Early-Mid Pregnancy Affects the Skeletal Muscle Transcriptome of Piglets from a Reciprocal Cross

Alcohol intake and folate antagonism via CYP2E1 and ALDH1: Effects on oral carcinogenesis

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