Atorvastatin induced hepatic oxidative stress and apoptotic damage via MAPKs, mitochondria, calpain and caspase12 dependent pathways

Pal, Sankhadeep; Ghosh, Manoranjan; Ghosh, Shatadal; Bhattacharyya, Somnath; Sil, Parames C.

doi:10.1016/j.fct.2015.05.016

Cited by 61 publications

(57 citation statements)

References 50 publications

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“…The literature suggests that ROS, produced by the administration of various hepatotoxic agents, can activate JNK (Das et al, 2010; Du et al, 2014; Pal et al, 2015a). So, we first checked the level of JNK.…”

Section: Resultsmentioning

confidence: 99%

Silymarin Protects Mouse Liver and Kidney from Thioacetamide Induced Toxicity by Scavenging Reactive Oxygen Species and Activating PI3K-Akt Pathway

et al. 2016

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Silymarin (SMN) has been shown to possess a wide range of biological and pharmacological effects. Besides, SMN has antioxidant and free radical scavenging activities. Thioacetamide (TAA) is a well-documented liver toxin that requires oxidative bioactivation to elicit its hepatotoxic effect which ultimately modifies amine-lipids and proteins. Our study has been designed in a TAA exposed mouse model to investigate whether SMN could protect TAA-induced oxidative stress mediated hepatic and renal damage. Results suggest that TAA generated reactive oxygen species (ROS), caused oxidative stress and induced apoptosis in the liver and kidney cells via JNK as well as PKC and MAPKs signaling. All these detrimental effects of TAA could, however, be suppressed by SMN which not only scavenged ROS but also induced PI3K-Akt cell survival pathway in the liver and prevented apoptotic pathways in both the organs. Histological studies, collagen staining and DNA fragmentation analysis also supported our results. Combining, we say that SMN possess beneficial role against TAA mediated hepatic and renal pathophysiology.

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Section: Resultsmentioning

confidence: 99%

Silymarin Protects Mouse Liver and Kidney from Thioacetamide Induced Toxicity by Scavenging Reactive Oxygen Species and Activating PI3K-Akt Pathway

et al. 2016

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“…For example, drug-induced oxidative stress increases the abundance of calpain 1 and 2 levels in the liver [82]. Further, exposure of C2C12 myotubes to H 2 O 2 increases calpain 1 mRNA levels [69].…”

Section: Oxidative Stress Promotes Proteolysis In Skeletal Musclesmentioning

confidence: 99%

Redox control of skeletal muscle atrophy

Powers

Morton

Ahn

et al. 2016

Free Radical Biology and Medicine

143

157

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Skeletal muscles comprise the largest organ system in the body and play an essential role in body movement, breathing, and glucose homeostasis. Skeletal muscle is also an important endocrine organ that contributes to the health of numerous body organs. Therefore, maintaining healthy skeletal muscles is important to support overall health of the body. Prolonged periods of muscle inactivity (e.g., bed rest or limb immobilization) or chronic inflammatory diseases (i.e., cancer, kidney failure, etc.) result in skeletal muscle atrophy. An excessive loss of muscle mass is associated with a poor prognosis in several diseases and significant muscle weakness impairs the quality of life. The skeletal muscle atrophy that occurs in response to inflammatory diseases or prolonged inactivity is often associated with both oxidative and nitrosative stress. In this report, we critically review the experimental evidence that provides support for a causative link between oxidants and muscle atrophy. More specifically, this review will debate the sources of oxidant production in skeletal muscle undergoing atrophy as well as provide a detailed discussion on how reactive oxygen species and reactive nitrogen species modulate the signaling pathways that regulate both protein synthesis and protein breakdown.

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“…Excess ROS production may be a major contributor to ATO‐induced hepatic cell injury (Pal, Ghosh, Ghosh, Bhattacharyya, & Sil, ). Consistent with this notion, ATO induced dose‐dependent intracellular ROS accumulation in HepG2 cells as evidenced by CM‐H2DCFDA fluorometry (Figure A).…”

Section: Resultsmentioning

confidence: 99%

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

Zhao

Zhang

et al. 2019

J of Applied Toxicology

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Atorvastatin (ATO) is a 3‐hydroxy‐3‐methylglutaryl‐CoA reductase inhibitor widely used to treat hypercholesterolemia. However, clinical application is limited by potential hepatotoxicity. Nuclear factor‐erythroid 2‐related factor 2 (Nrf2) is a master regulator of cellular antioxidants, and oxidative stress is implicated in statin‐induced liver injury. This study investigated mechanisms of ATO‐induced hepatotoxicity and potential mitigation by Nrf2 signaling. ATO reduced Nrf2 and antioxidant enzyme superoxide dismutase‐2 (SOD2) expression in human hepatocarcinoma HepG2 cells. ATO also induced concentration‐dependent HepG2 cell toxicity, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential (MMP) and cellular adenosine triphosphate (ATP). Further, ATO induced mitochondria‐dependent apoptosis as indicated by increased Bax/Bcl‐2 ratio, cleaved caspase‐3, mitochondrial cytochrome c release and Annexin V‐fluorescein isothiocyanate/propidium iodide staining. Tert‐butylhydroquinone enhanced Nrf2 and SOD2 expression, and partially reversed ATO‐induced cytotoxicity, ROS accumulation, MMP reduction, ATP depletion and mitochondria‐dependent apoptosis. In conclusion, the present study demonstrates that ATO induces mitochondrial dysfunction and cell apoptosis in HepG2 cells, at least in part, via inhibition of the Nrf2 pathway. Nrf2 pathway activation is a potential prevention for ATO‐induced liver injury.

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Atorvastatin induced hepatic oxidative stress and apoptotic damage via MAPKs, mitochondria, calpain and caspase12 dependent pathways

Cited by 61 publications

References 50 publications

Silymarin Protects Mouse Liver and Kidney from Thioacetamide Induced Toxicity by Scavenging Reactive Oxygen Species and Activating PI3K-Akt Pathway

Silymarin Protects Mouse Liver and Kidney from Thioacetamide Induced Toxicity by Scavenging Reactive Oxygen Species and Activating PI3K-Akt Pathway

Redox control of skeletal muscle atrophy

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

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