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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.
Highlights
The dried roots of Salvia miltiorrhiza Bunge, called Danshen, has been used in Chinese folk medicine for over a thousand years to treat various disorders, including heart disease, liver diseases, haematological abnormalities, cerebrovascular disease, haemorrhage, menstrual disorders, miscarriage, as well as oedema and insomnia [1,2,3,4]
We examined the effects of CT on the de novo lipogenesis, fatty acid oxidation, oxidative stress and inflammation, and measured AMPK/sirtuin 1 (SIRT1) signaling to elucidate the underlying mechanism of the protective effect of CT against ethanol-induced liver injury
ADH1 mRNA increased in mice treated with ethanol only and in mice treated with ethanol plus CT (Supplementary Figure S1D); ALDH2 expression significantly increased in the CT treatment groups (Supplementary Figure S1E)
Summary
The dried roots of Salvia miltiorrhiza Bunge, called Danshen, has been used in Chinese folk medicine for over a thousand years to treat various disorders, including heart disease, liver diseases, haematological abnormalities, cerebrovascular disease, haemorrhage, menstrual disorders, miscarriage, as well as oedema and insomnia [1,2,3,4]. Recent studies have demonstrated that S. miltiorrhiza ameliorates carbon tetrachloride (CCl4)-induced liver fibrosis in vivo and in vitro [5]. Tanshinone IIA, dihydrotanshinone I, tanshinone I, and cryptotanshinone are the major abietane diterpene isolates from the root of S. miltiorrhiza all of which are potent antioxidants that suppress lipid peroxidation and remedy for various metabolic disorders [6,7]. CT ameliorates ethanol-induced hepatotoxicity by blocking hepatic cell death and fatty acid synthesis in primary rat hepatocytes [10]. The protective effects of CT against alcohol-induced fatty liver, and the exact underlying molecular mechanisms have not yet been reported. Studying the protective effect of CT against alcoholic liver disease (ALD) might uncover the precise protective mechanism and provide a therapeutic potential for ALD treatment
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