Retracted: Proanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathway.
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ABSTRACT:
SUBMITTER: Oxidative Medicine and Cellular Longevity
PROVIDER: S-EPMC7846395 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
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Retracted: Proanthocyanidins Antagonize Arsenic-Induced Oxidative Damage and Promote Arsenic Methylation through Activation of the Nrf2 Signaling Pathway.
Oxidative medicine and cellular longevity 20210122
[This retracts the article DOI: 10.1155/2019/8549035.]. ...[more]
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Project description:PurposeTo investigate the effects of grape seed proanthocyanidin extract (GSPE) on oxidative damage and arsenic (As) methylation and to clarify the role of Nrf2 in the process.MethodsL-02 cells were treated with arsenic (25 μM) and GSPE (10, 25, and 50 mg/L) for 24 h. Cell viability was analyzed by MTT assay. Cell apoptosis and ROS fluorescence were detected by flow cytometry. Oxidative stress marker levels were measured using commercial kits. mRNA and protein expression were detected by qRT-PCR and western blotting. The cellular concentrations of methylation products were measured by HPLC-HGAFS. Arsenic methylation ability of cells was determined.ResultsCell survival rate was significantly lower in the As group than in the control group (P < 0.05), while cell apoptosis increased and the number of apoptotic cells decreased gradually after GSPE intervention. Superoxide dismutase, glutathione, and sulfhydryl levels in the intervention group were significantly higher (P < 0.05), while MDA and ROS levels were significantly lower (P < 0.05) than those in the As group. The mRNA and protein expression of Nrf2, HO-1, NQO1, and glutathione-S-transferase increased in the As + GSPE group compared with that in the As group (P < 0.05). GSPE significantly increased methylated As level, primary methylation index, secondary methylation index, average growth rate of methylation, and average methylation speed compared with the GSPE untreated group (P < 0.05). After Nrf2 inhibition, the effect of GSPE decreased significantly.ConclusionGSPE activates the Nrf2 signaling pathway to antagonize As-induced oxidative damage and to promote As methylation metabolism. Therefore, GSPE may be a potential agent for relieving As-induced hepatotoxicity.
| S-EPMC6360624 | biostudies-literature
Project description:The widespread use of therapeutic glucocorticoids has increased the frequency of glucocorticoid-induced osteoporosis (GIOP). One of the potential pathological processes of GIOP is an increased level of oxidative stress and mitochondrial dysfunction, which eventually leads to osteoblast apoptosis. Proanthocyanidins (PAC) are plant-derived antioxidants that have therapeutic potential against GIOP. In our study, a low dose of PAC was nontoxic to healthy osteoblasts and restored osteogenic function in dexamethasone- (Dex-) treated osteoblasts by suppressing oxidative stress, mitochondrial dysfunction, and apoptosis. Mechanistically, PAC neutralized Dex-induced damage in the osteoblasts by activating the Nrf2 pathway, since silencing Nrf2 partly eliminated the protective effects of PAC. Furthermore, PAC injection restored bone mass and promoted the expression of Nrf2 in the distal femur of Dex-treated osteoporotic rats. In summary, PAC protect osteoblasts against Dex-induced oxidative stress and mitochondrial dysfunction via the Nrf2 pathway activation and may be a promising drug for treating GIOP.
| S-EPMC7533007 | biostudies-literature
Project description:Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg) in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL)-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER) stress-related genes and protein (GRP78 and CHOP). Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress and apoptosis of liver tissue.
| S-EPMC5084042 | biostudies-literature
Project description:Metabolic diseases, such as ketosis, are closely associated with decreased reproductive performance (such as delayed estrus and decreased pregnancy rate) in dairy cows. The change of ?-hydroxybutyrate (BHBA) concentration in dairy cattle is an important mechanism leading to ketosis, and its blood concentration in ketotic cows is always significantly higher than in nonketotic cows. Many studies indicated that BHBA can induce oxidative damage in liver and other organs. Proanthocyanidins (PCs) have gained substantial attention in the last decade as strong antioxidative substances. This study aimed to demonstrate a protective effect of PCs against BHBA-induced oxidative stress damage in bovine endometrial (BEND) cells by activating the nuclear erythroid2-related factor2 (Nrf2) signaling pathway. Our research show that PCs could significantly increase activities of catalase (CAT) and glutathione peroxidase (GSH-PX), glutathione (GSH) content, and antioxidant capacity (T-AOC), while significantly decreasing malondialdehyde (MDA) content in BEND cells. Both mRNA and protein expression levels of Nrf2 were significantly increased in BEND cells, and glutamate?cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1), manganese superoxide dismutase (Mn-SOD), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were also significantly increased. These results indicate that PCs can antagonize BHBA-induced oxidative damage by activating the Nrf2 signaling pathway to exert an antioxidant effect.
| S-EPMC6384621 | biostudies-literature
Project description:BackgroundInorganic arsenic is an environmental carcinogen that may act through multiple mechanisms including formation of methylated derivatives in vivo. Sodium arsenite (up to 5.0 microM) renders arsenic methylation-competent TRL1215 rat liver epithelial cells tumorigenic in nude mice at 18 weeks of exposure and arsenic methylation-deficient RWPE-1 human prostate epithelial cells tumorigenic at 30 weeks of exposure. We assessed the role of arsenic biomethylation in oxidative DNA damage (ODD) using a recently developed immuno-spin trapping method.MethodsImmuno-spin trapping was used to measure ODD after chronic exposure of cultured TRL1215 vs RWPE-1 cells, or of methylation-competent UROtsa/F35 vs methylation-deficient UROtsa human urothelial cells, to sodium arsenite. Secreted matrix metalloproteinase (MMP)-2 and -9 activity, as analyzed by zymography, cellular invasiveness by using a transwell assay, and colony formation by using soft agar assay were compared in cells exposed to arsenite with and without selenite, an arsenic biomethylation inhibitor, to assess the role of ODD in the transition to an in vitro cancer phenotype.ResultsExposure of methylation-competent TRL1215 cells to up to 1.0 microM sodium arsenite was followed by a substantial increase in ODD at 5-18 weeks (eg, at 16 weeks with 1.0 microM arsenite, 1138% of control, 95% confidence interval [CI] = 797% to 1481%), whereas exposure of methylation-deficient RWPE-1 cells to up to 5.0 microM arsenite did not increase ODD for a 30-week period. Inhibition of arsenic biomethylation with sodium selenite abolished arsenic-induced ODD and invasiveness, colony formation, and MMP-2 and -9 hypersecretion in TRL1215 cells. Arsenic induced ODD in methylation-competent UROtsa/F35 cells (eg, at 16 weeks, with 1.0 microM arsenite 225% of control, 95% CI = 188% to 262%) but not in arsenic methylation-deficient UROtsa cells, and ODD levels corresponded to the levels of increased invasiveness, colony formation, and hypersecretion of active MMP-2 and -9 seen after transformation to an in vitro cancer phenotype.ConclusionArsenic biomethylation appears to be obligatory for arsenic-induced ODD and appears linked in some cells with the accelerated transition to an in vitro cancer phenotype.
| S-EPMC2794302 | biostudies-literature
Project description:The in situ control of redox insult in human organs is of major clinical relevance, yet remains incompletely understood. Activation of Nrf2, the “master regulator” of genes controlling cellular redox homeostasis, is advocated as a therapeutic strategy for diseases with severely impaired redox balance. Yet it remains to be shown whether this strategy is effective in human organs, rather than isolated human cell types. We have therefore explored the role of Nrf2 in a uniquely accessible human (mini-) organ, human scalp hair follicles (HFs), by Microarray analysis of human HFs treated with 20uM sulforaphane for 24hr.
2017-06-29 | GSE83911 | GEO
Project description:Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.
| S-EPMC7215459 | biostudies-literature
Project description:Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2-mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria-targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2-mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial-specific interventions as a key aspect of antioxidant and antiaging therapies.
| S-EPMC6156351 | biostudies-literature
Project description:BackgroundMounting evidence points to a crucial role of amyloid-? (A?) in the pathophysiology of Alzheimer's disease (AD), a disorder in which brain glucose hypometabolism, downregulation of central elements of phosphorylation pathways, reduced ATP levels, and enhanced oxidative damage coexist, and sometimes precede, synaptic alterations and clinical manifestations. Since the brain has limited energy storage capacity, mitochondria play essential roles in maintaining the high levels of energy demand, but, as major consumers of oxygen, these organelles are also the most important generators of reactive oxygen species (ROS). Thus, it is not surprising that mitochondrial dysfunction is tightly linked to synaptic loss and AD pathophysiology. In spite of their relevance, the mechanistic links among ROS homeostasis, metabolic alterations, and cell bioenergetics, particularly in relation to A?, still remain elusive.MethodsWe have used classic biochemical and immunocytochemical approaches together with the evaluation of real-time changes in global energy metabolism in a Seahorse Metabolic Analyzer to provide insights into the detrimental role of oligA? in SH-SY5Y and primary neurons testing their pharmacologic protection by small molecules.ResultsOur findings indicate that oligomeric A? induces a dramatic increase in ROS production and severely affects neuronal metabolism and bioenergetics. Assessment of global energy metabolism in real time demonstrated A?-mediated reduction in oxygen consumption affecting basal and maximal respiration and causing decreased ATP production. Pharmacologic targeting of A?-challenged neurons with a set of small molecules of known antioxidant and cytoprotective activity prevented the metabolic/bioenergetic changes induced by the peptide, fully restoring mitochondrial function while inducing an antioxidant response that counterbalanced the ROS production. Search for a mechanistic link among the protective small molecules tested identified the transcription factor Nrf2-compromised by age and downregulated in AD and transgenic models-as their main target and the PI3K/GSK-3 axis as the central pathway through which the compounds elicit their A? protective action.ConclusionsOur study provides insights into the complex molecular mechanisms triggered by oligA? which profoundly affect mitochondrial performance and argues for the inclusion of small molecules targeting the PI3K/GSK-3 axis and Nrf2-mediated pathways as part of the current or future combinatorial therapies.
| S-EPMC6958642 | biostudies-literature
Project description:Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser792 and leads to increase the promoter activity of OGG1 through upregulation of Nrf2. Downregulation of AMPK by DN-AMPK and raptor and Nrf2 by siRNA resulted in significant decease in promoter activity and protein expression of OGG1. On the other hand, downregulation of Akt by DN-Akt and rictor by siRNA resulted in significant increase in promoter activity and protein expression of Nrf2 and OGG1. Moreover, gel shift analysis shows reduction of Nrf2 binding to OGG1 promoter in cells treated with HG while cells treated with AICAR reversed the effect of HG. Furthermore, db/db mice treated with AICAR show significant increased in AMPK and raptor phosphroylation as well as OGG1 and Nrf2 protein expression that associated with significant decrease in oxidative DNA damage (8-oxodG) compared to non-treated mice. In summary, our data provide a novel protective mechanism by which AICAR prevents renal cell damage in diabetes and the consequence complications of hyperglycemia with a specific focus on nephropathy.
| S-EPMC5134712 | biostudies-literature