Dioscin Protects ANIT-Induced Intrahepatic Cholestasis Through Regulating Transporters, Apoptosis and Oxidative Stress

Abstract

Intrahepatic cholestasis, a clinical syndrome, is caused by excessive accumulation of bile acids in body and liver. Proper regulation of bile acids in liver cells is critical for liver injury. We previously reported the effects of dioscin against α-naphthylisothio- cyanate (ANIT)-induced cholestasis in rats. However, the pharmacological and mechanism data are limited. In our work, the animals of rats and mice, and Sandwich-cultured hepatocytes (SCHs) were caused by ANIT, and dioscin was used for the treatment. The results showed that dioscin markedly altered relative liver weights, restored ALT, AST, ALP, TBIL, GSH, GSH-Px, MDA, SOD levels, and rehabilitated ROS level and cell apoptosis. In mechanism study, dioscin not only significantly regulated the protein levels of Ntcp, OAT1, OCT1, Bsep and Mrp2 to accelerate bile acids excretion, but also regulated the expression levels of Bak, Bcl-xl, Bcl-2, Bax, Caspase 3 and Caspase 9 in vivo and in vitro to improve apoptosis. In addition, dioscin markedly inhibited PI3K/Akt pathway and up-regulated the levels of Nrf2, GCLc, GCLm, NQO1 and HO-1 against oxidative stress (OS) caused by bile acids. These results were further validated by inhibition of PI3K and Akt using the inhibitors of wortmannin and perifosine in SCHs. Our data showed that dioscin had good action against ANIT-caused intrahepatic cholestasis through regulating transporters, apoptosis and OS. This natural product can be considered as one active compound to treat intrahepatic cholestasis in the future.

Li-Dan-He-Ji Improves Infantile Cholestasis Hepatopathy Through Inhibiting Calcium-Sensing Receptor-Mediated Hepatocyte Apoptosis

“…The released Cyt-C elicits the sequential activation of cytosolic caspase-9 and caspase-3, followed by the activation of the caspaseindependent mitochondrial pathway. Yao et al reported a role for the mitochondrial pathway in ANIT-induced hepatocellular apoptosis (Yao et al, 2017). In the present study, LDHJ granules noticeably decreased the Bax/Bcl-2 ratio and the levels of Cyt-C and cleaved caspase-3 in the liver of ANIT-induced rats.…”

Emodin Rescues Intrahepatic Cholestasis via Stimulating FXR/BSEP Pathway in Promoting the Canalicular Export of Accumulated Bile

“…Therefore, in order to observe whether emodin could continue to promote the FXR signal pathway in the condition of low and high FXR levels, we chose guggulsterones/siRNA and GW4064/lentivirus to down- or up-regulate FXR. There is another natural product, Dioscin is also can rescue intrahepatic cholestasis in ANIT-Induced rat model through regulating transporters, apoptosis, and oxidative stress (Yao et al, 2017) and through regulating Oatps, Mrp2, and Bsep expression (Zhang et al, 2016).…”

Recent Advances in the Pharmacological Activities of Dioscin

“…Cholestasis, caused by excessive accumulation of bile salts in liver and featured by primary sclerosing cholangitis, biliary cirrhosis and atresia, could result in increased oxidative stress and apoptosis [26, 118]. In cholestasis models induced by α -naphthylisothiocyanate (ANIT), dioscin could clean toxic bile constituents from the liver through upregulation of multidrug resistance-associated protein 2 (Mrp2) and bile salt export pump (Bsep) [26, 118]. Aberrant changes in the expression of other transporters of bile salts (organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs) and Na + -taurocholate cotransporting polypeptide (Ntcp)) caused by ANIT could also be prevented by dioscin treatment.…”

“…Aberrant changes in the expression of other transporters of bile salts (organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs) and Na + -taurocholate cotransporting polypeptide (Ntcp)) caused by ANIT could also be prevented by dioscin treatment. Moreover, dioscin could increase the levels of antioxidative powers (such as GSH, GSH-Px, and SOD) and antiapoptotic proteins in animals, as well as in primary cultured cells, to mitigate oxidative stress and to reduce apoptosis in cholestasis [118].…”