Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-κB in human Hep G2 cells

Chern, Chi Liang; Chen, Y.-H; Cheng, Jiin‐Tsuey; Liu, T.-Z

doi:10.1016/s0753-3322(01)00095-6

Cited by 89 publications

(57 citation statements)

References 30 publications

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“…In addition to impaired thymidine and purine synthesis, folate deficiency can lead to elevated homocysteine, which can increase oxidative stress (46,47), and hypomethylation of DNA, which can affect gene expression (8,48). However, our results suggest that the growth arrest of CD8 ϩ cells was rather due to nucleotide imbalance, because normal proliferation and cell cycle of folate-deficient cells were restored with a combination of nucleosides.…”

Section: Discussionmentioning

confidence: 65%

Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro

Courtemanche

Elson-Schwab

Mashiyama

et al. 2004

The Journal of Immunology

144

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Folate is required for one-carbon transfer reactions and the formation of purines and pyrimidines for DNA and RNA synthesis. Deficiency of folate can lead to many clinical abnormalities, including macrocytic anemia, cardiovascular diseases, birth defects, and carcinogenesis. The nucleotide imbalance due to folate deficiency causes cell cycle arrest in the S phase and uracil misincorporation into DNA, which may result in DNA double-strand breaks during repair. The role of folate in the immune system has not been fully characterized. We cultured PHA-activated human T lymphocytes in varying concentrations of folate, and measured proliferation, cell cycle, apoptosis, uracil misincorporation, and proportions of Th cells (CD4+) and cytotoxic T (CD8+) cells. Folate deficiency reduced proliferation of T lymphocytes, induced cell cycle arrest in the S phase, induced apoptosis, and increased the level of uracil in DNA. Folate deficiency also increased the CD4+ to CD8+ ratio due to a marked reduction of CD8+ cell proliferation. Folate or nucleoside repletion of folate-deficient cells rapidly restored T lymphocyte proliferation and normal cell cycle, reduced the DNA uracil content, and lowered the CD4+ to CD8+ ratio. These data suggest that folate status may affect the immune system by reducing the capacity of CD8+ cells to proliferate in response to activation.

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Section: Discussionmentioning

confidence: 65%

Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro

Courtemanche

Elson-Schwab

Mashiyama

et al. 2004

The Journal of Immunology

144

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“…Of note, folic acid supplementation seems to prevent NTD in some susceptible embryos by blocking accumulation of homocysteine, a cellular oxidant [53,54,55]. Many drugs that cause neural tube, and other, defects, including thalidomide [56], phenytoin [56,57], environmental aryl hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin [58], and ionizing radiation [59] induce oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

et al. 2003

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Aims/hypothesis. Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. Methods. Maternal diabetes-induced oxidative stress was blocked with α-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Results. Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and α-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by α-tocopherol and GSHethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. Conclusion/interpretation. Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress. [Diabetologia (2003) 46:538-545]

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“…Several clinical studies, including 12 randomized and placebo-controlled intervention trials, have shown that supplementation with folic acid, vitamin B 6 , and vitamin B 12 lowers plasma homocysteine levels in most patients (61). The reduction in plasma homocysteine levels leads to normalization of endothelial function (62 -65).…”

Section: Potential Clinical Consequencesmentioning

confidence: 99%

Influence of Hyperhomocysteinemia on the Cellular Redox State – Impact on Homocysteine-Induced Endothelial Dysfunction

Weiss

Heydrick²,

Postea³

et al. 2003

Clinical Chemistry and Laboratory Medicine

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Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine's deleterious effects on the vasculature. Elevated levels of homocysteine may lead to increased generation of superoxide by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation of homocysteine and other aminothiols in the circulation. The resultant increase in superoxide levels is further amplified by homocysteinedependent alterations in the function of cellular antioxidant enzymes such as cellular glutathione peroxidase or extracellular superoxide dismutase. One direct clinical consequence of elevated vascular superoxide levels is the inactivation of the vasorelaxant messenger nitric oxide, leading to endothelial dysfunction. Scavenging of superoxide anion by either superoxide dismutase or 4,5-dihydroxybenzene 1,3-disulfonate (Tiron) reverses endothelial dysfunction in hyperhomocysteinemic animal models and in isolated aortic rings incubated with homocysteine. Similarly, homocysteine-induced endothelial dysfunction is also reversed by increasing the concentration of the endogenous antioxidant glutathione or overexpressing cellular glutathione peroxidase in animal models of mild hyperhomocysteinemia. Taken together, these findings strongly suggest that the adverse vascular effects of homocysteine are at least partly mediated by oxidative inactivation of nitric oxide.

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Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-κB in human Hep G2 cells

Cited by 89 publications

References 30 publications

Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro

Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

Influence of Hyperhomocysteinemia on the Cellular Redox State – Impact on Homocysteine-Induced Endothelial Dysfunction

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