Metformin alleviates nickel-refining fumes-induced aerobic glycolysis via AMPK/GOLPH3 pathway in vitro and in vivo

Zhang, Tong; Wang, Yue; Chen, Yangyang; Gao, Ying; Zhang, Dan; Jin, Shuo; Yao, Wenxue; Li, Lina; Yang, Shikuan; Wu, Yang‐Chang

doi:10.1016/j.ecoenv.2022.113461

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…Therefore, the traceable effect of metformin in inhibiting nickel‐induced ROS is supported. In addition to our previous evidence, metformin also counters nickel‐refined smoke‐induced aerobic glycolysis and cell apoptosis through the ROS/AMPK/GOLPH3 pathway 40,41 …”

Section: Discussionsupporting

confidence: 56%

“…In addition to our previous evidence, metformin also counters nickel-refined smoke-induced aerobic glycolysis and cell apoptosis through the ROS/AMPK/GOLPH3 pathway. 40,41 In addition, evidence has demonstrated that metformin can substantially modulate the processes involved in histone modifications, DNA methylation and miRNAs via the regulation of epigenetic-related gene expression. In our past studies, metformin, in addition to preventing autophagy, can also reduce the expression of oncogenes and reduce the ability to metastasis.…”

Section: Discussionmentioning

confidence: 99%

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Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Kang,

Yang,

Huang

et al. 2023

Environmental Toxicology

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Nickel (Ni) is a human carcinogen with genotoxic and epigenotoxic effects. Environmental and occupational exposure to Ni increases the risk of cancer and chronic inflammatory diseases. Our previous findings indicate that Ni alters gene expression through epigenetic regulation, specifically impacting E‐cadherin and angiopoietin‐like 4 (ANGPTL4), involved in epithelial‐mesenchymal transition and migration. GST‐M2, a member of the glutathione S‐transferase (GST) enzyme family, plays a crucial role in cellular defense against oxidative damage and has been increasingly associated with cancer. GST‐M2 overexpression inhibits lung cancer invasion and metastasis in vitro and in vivo. Hypermethylation of its promoter in cancer cells reduces gene expression, correlating with poor prognosis in non‐small‐cell lung cancer patients. The impact of Ni on GST‐M2 remains unclear. We will investigate whether nickel exerts regulatory effects on GST‐M2 through epigenetic modifications. Additionally, metformin, an antidiabetic drug, is being studied as a chemopreventive agent against nickel‐induced damage. Our findings indicate that nickel chloride (NiCl2) exposure, both short‐term and long‐term, represses GST‐M2 expression. However, the expression can be restored by demethylation agent 5‐aza‐2′‐deoxycytidine and metformin. NiCl2 promotes hypermethylation of the GST‐M2 promoter, as confirmed by methylation‐specific PCR and bisulfite sequencing. Additionally, NiCl2 also influences histone acetylation, and metformin counteracts the suppressive effect of NiCl2 on histone H3 expression. Metformin reestablishes the binding of specificity protein 1 to the GST‐M2 promoter, which is otherwise disrupted by NiCl2. These findings elucidate the mechanism by which Ni reduces GST‐M2 expression and transcriptional activity, potentially contributing to Ni‐induced lung carcinogenesis.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Kang,

Yang,

Huang

et al. 2023

Environmental Toxicology

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“…Under conditions of metabolic stress, such as hypoxia and ischemia, AMPK is activated to increase ATP production and reduce ATP consumption to maintain cellular energy homeostasis (Burkewitz et al, 2014;Hardie, 2015). Zhang et al (2022) showed that AMPK antagonizes nickel-refining fume-induced aerobic glycolysis. Similarly, Tang et al (2021) found that enhanced glycolysis in lung fibroblasts induced by LPS can be prevented by regulating the AMPK pathway.…”

Section: Frontiers In Physiologymentioning

confidence: 99%

Vitamin D-VDR (vitamin D receptor) alleviates glucose metabolism reprogramming in lipopolysaccharide-induced acute kidney injury

Dai

Zhang²,

Tang³

et al. 2023

Front. Physiol.

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Background: Our previous study showed that vitamin D (VD)-vitamin D receptor (VDR) plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Recently, glucose metabolism reprogramming was reported to be involved in the pathogenesis of AKI.Objective: To investigate the role of VD-VDR in glucose metabolism reprogramming in LPS-induced AKI.Methods: We established a model of LPS-induced AKI in VDR knockout (VDR-KO) mice, renal proximal tubular-specific VDR-overexpressing (VDR-OE) mice and wild-type C57BL/6 mice. In vitro, human proximal tubular epithelial cells (HK-2 cells), VDR knockout and VDR overexpression HK-2 cell lines were used.Results: Paricalcitol (an active vitamin D analog) or VDR-OE reduced lactate concentration, hexokinase activity and PDHA1 phosphorylation (a key step in inhibiting aerobic oxidation) and simultaneously ameliorated renal inflammation, apoptosis and kidney injury in LPS-induced AKI mice, which were more severe in VDR-KO mice. In in vitro experiments, glucose metabolism reprogramming, inflammation and apoptosis induced by LPS were alleviated by treatment with paricalcitol or dichloroacetate (DCA, an inhibitor of p-PDHA1). Moreover, paricalcitol activated the phosphorylation of AMP-activated protein kinase (AMPK), and an AMPK inhibitor partially abolished the protective effect of paricalcitol in LPS-treated HK-2 cells.Conclusion: VD-VDR alleviated LPS-induced metabolic reprogramming in the kidneys of AKI mice, which may be attributed to the inactivation of PDHA1 phosphorylation via the AMPK pathway.

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Metformin beyond an anti-diabetic agent: A comprehensive and mechanistic review on its effects against natural and chemical toxins

Malaekeh-Nikouei,

Shokri-Naei,

Karbasforoushan

et al. 2023

Biomedicine & Pharmacotherapy

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Metformin alleviates nickel-refining fumes-induced aerobic glycolysis via AMPK/GOLPH3 pathway in vitro and in vivo

Cited by 4 publications

References 39 publications

Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S‐transferase M2

Vitamin D-VDR (vitamin D receptor) alleviates glucose metabolism reprogramming in lipopolysaccharide-induced acute kidney injury

Metformin beyond an anti-diabetic agent: A comprehensive and mechanistic review on its effects against natural and chemical toxins

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