Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway

Li, Lizhong; Zhao, Zhenze; Zhang, Li; He, Jun; Zhang, Tingfen; Guo, Jiabin; Yu, Lin; Zhao, Jun; Yuan, Xiaoyan; Peng, Shuangqing

doi:10.1002/jat.3825

Cited by 14 publications

(9 citation statements)

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“…Apoptosis plays an important role in the study of hepatotoxicity [31,32]. Li et al [33] found that ATO induced mitochondrial dysfunction and apoptosis in hepatoma cells by inhibiting the Nrf2 pathway. Previously, Zhang et al [34] revealed that AS IV, a potential neuroprotective agent, inhibited apoptosis in oxygen-glucose-deprived/re-oxygenated HT22 cells by balancing Bcl-2 and Bax expression.…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV Alleviates Atorvastatin-Induced Hepatotoxicity via AMPK/SIRT1 Pathway

et al. 2022

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Introduction: Atorvastatin (ATO) is often used to reduce blood lipids and prevent atherosclerosis, but excessive use of ATO will lead to hepatotoxicity. This paper investigated the effects of astragaloside IV (AS IV), which has multiple biological functions, on ATO-induced hepatotoxicity and the underlying mechanism. Methods: ATO treatment induced a rat model of hepatotoxicity, followed by AS IV treatment. Colorimetric kits were used to detect rat liver function indexes including aspartate aminotransferase (AST), alanine transaminase (ALT), malondialdehyde (MDA), and reduced glutathione (GSH). Reactive oxygen species (ROS) level was determined by 2′, 7′-Dichlorodihydrofluorescein diacetate kit. The liver fibrosis and F4/80 expression were detected by Sirius red staining and immunochemistry. Mitochondrial electron transport chain complex I and complex IV activities were examined. The level of mitochondrial membrane potential (MMP) was detected by JC-1 staining. The inflammatory factor levels were detected by quantitative real-time polymerase chain reaction. Western blot detected apoptosis-related proteins and AMPK/SIRT1-related proteins. Results: ATO increased ALT, AST, MDA, and ROS levels and decreased GSH content but was subsequently reversed by AS IV. AS IV alleviated liver tissue damage caused by ATO. AS IV elevated complex I and complex IV activity and promoted MMP levels in ATO rats. ATO promoted inflammatory factor release in SD rats but was then suppressed by AS IV. AS IV inhibited Bax, cleaved caspase-3 but up-regulated Bcl-2 in ATO-induced rats. ATO inhibited SIRT1 expression and AMPK phosphorylation, which was subsequently promoted by AS IV. Conclusion: AS IV inhibits ATO-induced hepatotoxicity by activating the AMPK/SIRT1 pathway.

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Section: Discussionmentioning

confidence: 99%

Astragaloside IV Alleviates Atorvastatin-Induced Hepatotoxicity via AMPK/SIRT1 Pathway

et al. 2022

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“…Consequently, mitochondrial dysfunction is largely associated with the occurrence and development of cancers, aging, as well as age-related neurodegenerative diseases and metabolic syndrome [25]. Meanwhile, it has been shown that the destructive mitochondria, reduced mitochondrial membrane potential (Δψ m ) can be lead by the increased levels of ROS, and ultimately cause apoptosis [26,27]. In this study, NCTD-treated cells showed a significantly decreased Δψ m and an increased ROS production, suggesting that NCTD can lead to mitochondrial dysfunction and subsequently induce apoptosis in MDA-MB-231 cells.…”

Section: Discussionmentioning

confidence: 99%

Norcantharidin induces apoptosis through autophagosome accumulation in breast cancer MDA-MB-231 cells

xia

Jiang²,

Yang³

et al. 2022

Preprint

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Triple-negative breast cancer (TNBC), one of the grievous types of breast cancer, is extremely harmful to women’s health. Norcantharidin (NCTD), a synthetic demethylated analogue of zebularin, has been reported to exhibit anticancer efficacy. During this study, we discovered that NCTD obviously induced breast cancer MDA-MB-231 cell apoptosis through upregulating the levels of Bax/Bcl-2 and cleaved-PARP/PARP and the expression of cleaved-caspase-9 and cleasved-caspase-3 and downregulating the levels of MCL-1 and pro-caspase-8, ultimately inhibiting MDA-MB-231 cell proliferation. Furthermore, flow cytometry analyses showed that NCTD observably reduced mitochondrial membrane potential and rose mitochondrial ROS. Confocal microscopy showed that autophagic flow was blocked in NCTD-treated cells expressing mCherry-EGFP-LC3. Moreover, NCTD upregulated the levels of LC3-II/LC3-I and mitochondrial translocation of Parkin. Finally, we found that the combination of NCTD with chloroquine (CQ), an inhibitor that breaks the fusion of autophagosomes with lysosomes, exacerbated NCTD-induced MDA-MB-231 cell apoptosis, while the combination of NCTD with 3-methyladenine (3-MA), an inhibitor that blocks the formation of autophagosome, decreased NCTD-induced MDA-MB-231 cell apoptosis. Together, our data suggest that NCTD can induce autophagosome accumulation and cause apoptosis, providing a theoretical basis for the treatment of MDA-MB-231 cells.

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“…An in vitro study by Wang et al [ 17 ] reported that a combination of atorvastatin and caffeine suppressed proliferation and induced apoptotic death in prostate cancer cells. Li et al [ 18 ] found that atorvastatin induced mitochondrial dysfunction and apoptosis in HepG2 cells. Finally, an in vitro study [ 19 ] showed that atorvastatin reduced aldosterone-induced vascular damage by inhibiting oxidative stress and inflammation in cultured chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin attenuates intermittent hypoxia-induced myocardial oxidative stress in a mouse obstructive sleep apnea model

Zhang

Cheng

Yuan

et al. 2021

Aging

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Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), is associated with various cardiovascular diseases. In the present study, we assessed the effect of the lipid reducing agent atorvastatin on CIH-induced myocardial oxidative stress and apoptosis in a mouse OSA model. Forty-eight C57BL/6J mice were evenly divided among normoxia + vehicle, normoxia + atorvastatin, CIH + vehicle, and CIH + atorvastatin groups. CIH consisted of a hypoxia-reoxygenation cycle in which oxygen concentrations fluctuated from 21% to 6% and back over two minutes for 8 hours each day (30 events/hour). CIH exposure continued for 12 weeks. Atorvastatin (5 mg/kg) was administered from week 6 through the end of the experiment. CIH increased malondialdehyde levels and decreased superoxide dismutase activity, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 levels in cardiac tissue, indicating a reduction in antioxidant activity. Atorvastatin significantly reversed those effects ( p < 0.05). CIH also increased B-cell lymphoma 2-associated protein X and cleaved caspased-3 levels as well as the myocardial apoptotic rate, as indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Atorvastatin had no effect on those changes ( p > 0.05). Thus, atorvastatin administration exerts antioxidant but not anti-apoptotic effects after CIH and may therefore have therapeutic potential in OSA patients with cardiovascular comorbidities.

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Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway

Cited by 14 publications

References 50 publications

Astragaloside IV Alleviates Atorvastatin-Induced Hepatotoxicity via AMPK/SIRT1 Pathway

Astragaloside IV Alleviates Atorvastatin-Induced Hepatotoxicity via AMPK/SIRT1 Pathway

Norcantharidin induces apoptosis through autophagosome accumulation in breast cancer MDA-MB-231 cells

Atorvastatin attenuates intermittent hypoxia-induced myocardial oxidative stress in a mouse obstructive sleep apnea model

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