Cryptotanshinone from the Salvia miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK/SIRT1 and Nrf2 Signaling Pathways

Abstract

Cryptotanshinone (CT), a diterpene that is isolated from Salvia miltiorrhiza Bunge, exhibits anti-cancer, anti-oxidative, anti-fibrosis, and anti-inflammatory properties. Here, we examined whether CT administration possess a hepatoprotective effect on chronic ethanol-induced liver injury. We established a chronic alcohol feeding mouse model while using C57BL/6 mice, and examined the liver sections with hematoxylin-eosin (H&E) and Oil Red O (ORO) staining. Further, we analyzed the lipogenesis, fatty acid oxidation, oxidative stress, and inflammation genes by using quantitative polymerase chain reaction (qPCR) and immunoblotting in in vivo, and in vitro while using HepG2 and AML-12 cells. CT treatment significantly ameliorated ethanol-promoted hepatic steatosis, which was consistent with the decreased hepatic triglyceride levels. Interestingly, CT activated the phosphorylation of AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and nuclear factor E2-related factor 2 (Nrf2) proteins. Importantly, compound C (AMPK inhibitor) significantly blocked the CT-mediated reduction in TG accumulation, but not Ex52735 (SIRT1 inhibitor), which suggested that CT countering ethanol-promoted hepatic steatosis is mediated by AMPK activation. Furthermore, CT significantly inhibited cytochrome P450 2E1 (CYP2E1) and enhanced both the expression of antioxidant genes and hepatic glutathione levels. Finally, CT inhibited the ethanol-induced inflammation in ethanol-fed mice and HepG2 cells. Overall, CT exhibits a hepatoprotective effect against ethanol-induced liver injury by the inhibition of lipogenesis, oxidative stress, and inflammation through the activation of AMPK/SIRT1 and Nrf2 and the inhibition of CYP2E1. Therefore, CT could be an effective therapeutic agent for treating ethanol-induced liver injury.

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

“…SIRT1 is downregulated during HSCs activation as demonstrated in in vitro studies, including TGFβ-stimulated LX2 cells [ 90 , 91 ], and activated rat [ 92 ] and mouse [ 90 , 93 ] primary HSCs. It has also been found downregulated in fibrotic liver tissues from in vivo studies in models such as CCl 4 [ 90 , 93 , 94 ], thioacetamide (TAA) [ 93 ] and ethanol-induced liver injury in mice [ 95 ], and CCl 4 [ 92 ] and BDL rat models [ 96 , 97 ], as well as in non-alcoholic fatty liver disease (NAFLD) patients liver tissues [ 98 ]. SIRT1 downregulation in hepatic fibrogenesis seems to be modulated in part by epigenetic mechanisms, including HDAC4 and lncRNA MALAT1-mediated SIRT1 repression [ 90 , 93 ].…”

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

“…By Nrf2 induction, CT inhibits ROS production and subsequent oxidative stress to attenuate cell death. Also, CT induces AMPK/sirtuin 1 (SIRT1) axis to alleviate lipogenesis in liver (Nagappan, Kim, Jung, & Jung, 2020).…”

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

“…Cryptotanshinone, an active component from the herb Salvia miltiorrhiza , has been shown to possess pharmacological activities, such as anti‐inflammatory, anti‐oxidative, anti‐apoptosis and neuroprotection activities. [ 42‐44 ] Cryptotanshinone can increase ADAM10 level and promote non‐amyloidogenic α‐secretase processing of APP in SweAPP cortical neurons, which has been shown that improve learning and memory on AD rat model. [ 45 ] Cryptotanshinone could ameliorate the impaired learning and memory function of AD mice via shorten the latency of searching the hidden platform in directional swimming test, increase the time spent in swimming in the target quadrant in probe test, improve the activities of glutathione peroxidase (GSH‐Px) and SOD, and decrease the MDA content.…”