<i>In vitro</i>folate supplementation alleviates oxidative stress, mitochondria-associated death signalling and apoptosis induced by 7-ketocholesterol

Huang, Rong; Yaong, H.-C.; Chen, S.-C.; Lu, Yasong

doi:10.1079/bjn20041259

Cited by 42 publications

(30 citation statements)

References 45 publications

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“…The oxidative stress protective eVect of PABA may originate in its precursor function in folic acid biosynthesis. Folic acid plays a pivotal role in the prevention of mitochondria-associated oxidative injuries (Huang et al 2004;Chang et al 2007), which are intensiWed in tBOOH-exposed fungal cultures (Fekete et al 2007). Relying on the outcomes of these studies, we argue here for the use of prototrophic strains to promote interlaboratory standardization of future stress assays.…”

Section: Discussionmentioning

confidence: 99%

AtfA bZIP-type transcription factor regulates oxidative and osmotic stress responses in Aspergillus nidulans

et al. 2010

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The aim of the study was to demonstrate that the bZIP-type transcription factor AtfA regulates different types of stress responses in Aspergillus nidulans similarly to Atf1, the orthologous 'all-purpose' transcription factor of Schizosaccharomyces pombe. Heterologous expression of atfA in a S. pombe Deltaatf1 mutant restored the osmotic stress tolerance of fission yeast in surface cultures to the same level as recorded in complementation studies with the atf1 gene, and a partial complementation of the osmotic and oxidative-stress-sensitive phenotypes was also achieved in submerged cultures. AtfA is therefore a true functional ortholog of fission yeast's Atf1. As demonstrated by RT-PCR experiments, elements of both oxidative (e.g. catalase B) and osmotic (e.g. glycerol-3-phosphate dehydrogenase B) stress defense systems were transcriptionally regulated by AtfA in a stress-type-specific manner. Deletion of atfA resulted in oxidative-stress-sensitive phenotypes while the high-osmolarity stress sensitivity of the fungus was not affected significantly. In A. nidulans, the glutathione/glutathione disulfide redox status of the cells as well as apoptotic cell death and autolysis seemed to be controlled by regulatory elements other than AtfA. In conclusion, the orchestrations of stress responses in the aspergilli and in fission yeast share several common features, but further studies are needed to answer the important question of whether a fission yeast-like core environmental stress response also operates in the euascomycete genus Aspergillus.

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Section: Discussionmentioning

confidence: 99%

AtfA bZIP-type transcription factor regulates oxidative and osmotic stress responses in Aspergillus nidulans

et al. 2010

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“…Several tRNA synthetase genes contain CAREs in their promoters that were cobound by ATF4 and C/EBP␥ (see Table S1 in the supplemental material). Moreover, folate is known to be a free radical scavenger that displays antioxidant properties (33,34). Cross-comparison of the ATF4 and C/EBP␥ peaks with the 248 common stress-induced genes revealed an intersection of 15 genes that are coregulated and cobound by ATF4 and C/EBP␥ (Fig.…”

Section: Resultsmentioning

confidence: 99%

C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4

Huggins

Mayekar

Martín

et al. 2016

Molecular and Cellular Biology

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eThe integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances, and endoplasmic reticulum (ER) stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here, we show that C/EBP␥:ATF4 heterodimers, but not C/EBP␤:ATF4 dimers, are the predominant CARE-binding species in stressed cells. C/EBP␥ and ATF4 associate with genomic CAREs in a mutually dependent manner and coregulate many ISR genes. In contrast, the C/EBP family members C/EBP␤ and C/EBP homologous protein (CHOP) were largely dispensable for induction of stress genes. Cebpg ؊/؊ mouse embryonic fibroblasts (MEFs) proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg ؊/؊ mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBP␥-deficient newborns die from atelectasis and respiratory failure, which can be mitigated by in utero exposure to the antioxidant N-acetylcysteine. Cebpg ؊/؊ mice on a mixed strain background showed improved viability but, upon aging, developed significantly fewer malignant solid tumors than WT animals. Our findings identify C/EBP␥ as a novel antioxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells.A variety of stresses, such as amino acid limitation, protein misfolding in the endoplasmic reticulum (ER), oxidative stress, hypoxia, and intracellular pathogens, activate gene expression programs collectively known as the integrated stress response (ISR) (1). Stress-induced genes are involved in multiple cellular processes that include nutrient uptake, amino acid synthesis, metabolic changes, antioxidant defenses, and cell survival, leading to cell recovery and alleviation of stress. However, prolonged or irresolvable stress can trigger cell death (2).Protein misfolding and ER stress are associated with several diseases, including diabetes and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Huntington's disease (3). The ISR also plays an important role in cancer as tumor cells frequently experience nutrient deprivation, hypoxia, and oxidative stress and require stress response regulators such as the transcription factor (TF) ATF4 to thrive under adverse conditions (4, 5). Elevated levels of reactive oxygen species (ROS) can initiate oncogenesis by causing DNA mutations and genome instability (6). However, recent studies have shown that, once established, tumor cells are reliant on antioxidant pathways for growth and survival (7,8). Moreover, radio-and chemotherapies induce death or senescence of cancer cells partly by increasing ROS. Thus, acquiring a detailed understanding of the pathways and mechanisms that regulate stress response genes may le...

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“…21 Alternatively, folate may be protective, because it can also act as an antioxidant. 11 However, this argument assumes that the protein-restricted dams rapidly become folate deficient, and we do not know this.…”

Section: Torrens Et Al Folate Prevents Offspring Vascular Defectsmentioning

confidence: 99%

“…Folate has been specifically shown to enhance NO production 9,10 through mechanisms possibly involving the enhanced regeneration of the eNOS cofactor tetrahydrobiopterin (BH 4 ) or through its antioxidant properties. 10,11 This could be of particular importance, because we have demonstrated previously a decreased release of NO in proteinrestricted pregnant dams. 7 We, therefore, hypothesized that folate supplementation would prevent the adverse effects of dietary imbalance during pregnancy on cardiovascular function in both the mother and also in her offspring.…”

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confidence: 99%

Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction

et al. 2006

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Abstract-Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet Ϯ5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (PϽ0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (PϽ0.01), impaired acetylcholine-induced vasodilatation (PϽ0.01), and reduced levels of endothelial NO synthase mRNA (PϽ0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function. Key Words: diet Ⅲ endothelium Ⅲ hypertension, experimental Ⅲ nitric oxide Ⅲ pregnancy C ardiovascular disease arises from complex interactions between genetic susceptibility and adverse environmental influences. Increasing evidence suggests that environmental, particularly nutritional, factors operate from the earliest stages of development. 1,2 The concept of developmental origins of adult disease 3 has been strengthened by observations in animals that an unbalanced diet in pregnancy leads to cardiovascular and metabolic dysfunction in the offspring. 4 The offspring phenotype induced by such dietary manipulation has similarities with the human metabolic syndrome, providing further evidence for a developmental component to the etiology of this syndrome and giving models for investigating the underlying mechanisms. 5 In the rat, we have demonstrated previously that maternal protein restriction during pregnancy leads to impaired endothelial function in the uterine and mesenteric arteries of the dam in late pregnancy 6 and that supplementation of the maternal diet with glycine ...

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In vitrofolate supplementation alleviates oxidative stress, mitochondria-associated death signalling and apoptosis induced by 7-ketocholesterol

Cited by 42 publications

References 45 publications

AtfA bZIP-type transcription factor regulates oxidative and osmotic stress responses in Aspergillus nidulans

AtfA bZIP-type transcription factor regulates oxidative and osmotic stress responses in Aspergillus nidulans

C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4

Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction

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