Protective Effects of Taraxasterol against Ethanol‐Induced Liver Injury by Regulating CYP2E1/Nrf2/HO‐1 and NF‐κB Signaling Pathways in Mice

Abstract

Taraxasterol, a pentacyclic-triterpene compound, is one of the main active components isolated from the traditional Chinese medicinal herb Taraxacum. The objective of this study is to evaluate the protective effects of taraxasterol and its possible underlying mechanisms against ethanol-induced liver injury in mice. ICR mice were fed with Lieber-DeCarli diet containing 5% ethanol for 10 d and then challenged with a single dose of 20% ethanol (5 g/kg BW) by intragastric administration. The mice were intragastrically treated daily with taraxasterol (2.5, 5, and 10 mg/kg). Tiopronin was used as a positive control. The liver index was calculated, and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in sera were detected. The contents of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) and the activity of superoxide dismutase (SOD) in the livers were measured. The histopathological changes of liver tissues were observed by hematoxylin and eosin (H&E) staining. The protein expression levels of hepatic cytochrome P450 2E1 (CYP2E1), nuclear factor erythroid 2-related factor 2 (Nrf2), antioxidant protein heme oxygenase-1 (HO-1), and nuclear factor-kappa B (NF-κB) signaling pathway in liver tissues were detected by immunohistochemistry and Western blot methods. Taraxasterol significantly reduced the ethanol-induced increases of liver index, ALT, AST, and TG levels in sera and TG and MDA contents in the livers and hepatic ROS production and suppressed the ethanol-induced decreases of hepatic GSH level and SOD activity. Taraxasterol also significantly inhibited the secretion of proinflammatory cytokines TNF-α and IL-6 induced by ethanol. In addition, taraxasterol improved the liver histopathological changes in mice with ethanol-induced liver injury. Further studies revealed that taraxasterol significantly inhibited the ethanol-induced upregulation of CYP2E1, increased the ethanol-induced downregulation of Nrf2 and HO-1, and inhibited the degradation of inhibitory kappa Bα (IκBα) and the expression level of NF-κB p65 in liver tissues of ethanol-induced mice. These findings suggest that taraxasterol possesses the potential protective effects against ethanol-induced liver injury in mice by exerting antioxidative stress and anti-inflammatory response via CYP2E1/Nrf2/HO-1 and NF-κB signaling pathways.

Taraxasterol from Taraxacum prevents concanavalin A-induced acute hepatic injury in mice via modulating TLRs/NF-κB and Bax/Bc1-2 signalling pathways

“…This result is line with the reduction of liver index and hepatomegaly ( Figure 2), and the restoration of pathological changes such as inflammatory cell infiltration and necrosis in hepatic tissues ( Figure 6). It is also consistent with our recent report that taraxasterol could inhibit inflammatory cytokines TNF-a and IL-6 production in mice with alcoholic liver injury [17]. It indicated that taraxasterol could prevent Con A-induced acute hepatic injury by suppressing the secretion of pro-inflammatory cytokines.…”

“…Namely, taraxasterol exerts the in vitro anti-inflammatory and immunomodulatory activity by inhibiting inflammatory cytokine and mediator production via regulating NF-jB and MAPKs signalling pathways [12,13], and exhibits the in vivo protective effects in various animal models of inflammation including LPS-induced mouse endotoxic shock [14], ovalbumin-induced mouse allergic asthma [15] and adjuvantinduced rat arthritis [16]. Our recent study has also shown that taraxasterol possesses the protective effects on alcoholic liver injury in mice by exerting anti-oxidative stress and antiinflammatory response via CYP2E1/Nrf2/HO-1 and NF-jB signalling pathways [17]. However, it is unknown whether taraxasterol possesses protective effects against immune-mediated hepatic injury and its underlying mechanisms.…”

“…The mice were randomly divided into six groups as follows (n ¼ 10 each group): normal group, Con A group, taraxasterol 10 mg/ kg þ Con A group, taraxasterol 5 mg/kg þ Con A group, taraxasterol 2.5 mg/kg þ Con A group and Bif 200 mg/kg þ Con A group. The mice in taraxasterol groups were orally administered with taraxasterol at doses of 10, 5 and 2.5 mg/kg in 0.5% carboxymethyl cellulose sodium (CMC-Na) once a day for 7 d. The doses of taraxasterol used in this study were based on our series of in vivo studies [14][15][16][17]. The mice in Bif group were orally administered with 200 mg/kg of Bif as a positive control.…”

5‐ALA/SFC Attenuated Binge Alcohol–Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats

“…Furthermore, up‐regulated HO activities by IL‐1β suppressed CYP2E1 expression in rat liver (Kudo and Kawano, ). Moreover, taraxasterol, natural terpene compounds in Chinese herbal medicine, can delay and reduce alcoholic liver damage (Bai et al, ) and also inhibited the EtOH‐induced up‐regulation of CYP2E1, with increased Nrf2 and HO‐1 expression (Xu et al, ). These data suggested the possibility of that up‐regulated HO‐1/2 by 5‐ALA/SFC suppressed CYP2E1 expression and directly protect against gut leakage, liver inflammation, and injury.…”

Ethnopharmacological Applications Targeting Alcohol Abuse: Overview and Outlook

“…Apart from the above studies, numerous plants are utilized in folklore medicine and as such are thoroughly investigated for their use in prevention or treatment of ethanol-induced liver injury. Some of these natural products like taraxasterol exhibit their protective potential against ethanol-induced liver damage because they regulate different signaling pathways like NF-kB and CYP2E1/Nrf2/HO-1 in mice models (Xu et al, 2018). Studies also showed that Monolluma quadrangula (Forssk.)…”