Proanthocyanidin protects against cisplatin-induced oxidative liver damage through inhibition of inflammation and NF-κβ/TLR-4 pathway.

Although cisplatin (CIS) is a highly effective anticancer drug, hepatotoxicity is one of the most common adverse effects associated with its use. Recently, reactive oxygen species (ROS) and inflammation are suggested to be key factors in the pathophysiology of CIS-induced acute liver damage. The aim of this study is to investigate the possible protective effect of proanthocyanidin (PRO) against CIS-induced acute hepatotoxicity. Rats were divided into four groups: 1, Control; 2, PRO; 3, CIS; and 4, PRO + CIS. Biochemical studies and histopathology were used to assess liver damage. ROS, inflammatory cytokines, nuclear factor kappa beta (NF-κβ), inducible cyclooxygenase enzyme (COX-2), inducible nitric oxide synthase (iNOS), toll-like receptor-4 (TLR-4) gene expression, and apoptotic markers were also assessed. PRO pretreatment protected the liver against CIS-induced toxicity as indicated by decreased plasma levels of liver function enzymes and the normal liver histopathology observed in the PRO + CIS group. PRO pretreatment also diminished indicators of oxidative stress in the liver, including nitric oxide (NO) and malondialdehyde (MDA). It also increased the antioxidants, reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) in the liver. Plasma interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) were all reduced. Liver gene expression of NF-κβ, COX-2, iNOS, and TLR-4 were all downregulated. Furthermore, PRO administration downregulated the liver expression of the apoptotic marker, Bax, while upregulated the antiapoptotic marker, Bcl2. In conclusion, our results revealed that PRO may protect against CIS-induced acute liver damage mainly through inhibition of ROS, inflammation, and apoptosis.

El-Shitany NA ，Eid B 《-》

Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats.

Famurewa AC ，Ekeleme-Egedigwe CA ，David EE ，Eleazu CO ，Folawiyo AM ，Obasi NA ... -  《-》

Quercetin protects mouse liver against CCl₄-induced inflammation by the TLR2/4 and MAPK/NF-κB pathway.

Quercetin (QE), a natural flavonoid, has many medical beneficial effects. However, its protective effects against carbon tetrachloride (CCl4) induced injury in liver have not been clarified. The aim of the present study is to illustrate the effects of QE on hepatic oxidative injury and inflammation in mice exposed to CCl4. ICR (Institute of Cancer Research) mice were exposed to CCl4 with or without QE co-administration for one week. Our results showed that QE administration significantly inhibited CCl4-induced liver injury. One of the potential mechanisms of QE action was decreasing the oxidative stress, which is consistent with decreasing of lipid peroxidation level and increasing the antioxidant enzyme activities in livers of mice. Furthermore, QE significantly decreased cytochrome P450 2E1 (CYP2E1) expression and production of pro-inflammatory markers such as inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) and nitric oxide (NO) in livers of CCl4-treated mouse. In the process of exploring the underlying mechanisms of QE action, we found that QE significantly inhibited the Toll-like receptor 2 (TLR2) and the Toll-like receptor 4 (TLR4) activation and mitogen-activated protein kinase (MAPK) phosphorylation, which in turn inactivated NF-κB and the inflammatory cytokines in livers of the CCl4-treated mice. In conclusion, these results suggested that the inhibition of CCl4-induced inflammation by QE is due to its anti-oxidant activity and its ability to modulate the TLR2/TLR4 and MAPK/NF-κB signaling pathway.

Ma JQ ，Li Z ，Xie WR ，Liu CM ，Liu SS ... -  《-》

The involvement of Nrf2 in the protective effects of diallyl disulfide on carbon tetrachloride-induced hepatic oxidative damage and inflammatory response in rats.

This study investigated the potential effect of diallyl disulfide (DADS) against carbon tetrachloride (CCl4)-induced oxidative hepatic damage and inflammatory response in rat liver. DADS at doses of 50 and 100 mg/kg/day was administered orally once daily for 5 days, prior to CCl4 administration. Pretreatment with DADS attenuated CCl4-induced elevated serum transaminase activities and histopathological alterations in liver. It prevented the hepatocellular apoptotic changes with induction of Bcl-2-associated X (Bax), cytochrome c, and caspase-3 caused by CCl4. An increase in the nuclear translocation of nuclear factor-kappaB (NF-κB) and phosphorylation of I kappaB alpha (IκBα) was observed in the livers of CCl4-treated rats that coincided with induction of inflammatory mediators or cytokines. In contrast, DADS inhibited NF-κB translocation and IκBα phosphorylation, and that subsequently decreased inflammatory mediators. Furthermore, DADS prevented CCl4-induced depletion of cytosolic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2, which, in turn, up-regulated phase II/antioxidant enzyme activities. Taken together, these results demonstrate that DADS increases the expression of phase II/antioxidant enzymes and simultaneously decreases the expression of inflammatory mediators in CCl4-induced liver injury. These findings indicate that DADS induces antioxidant defense mechanism by activating Nrf2 pathway and reduces inflammatory response by inhibiting NF-κB activation.

Lee IC ，Kim SH ，Baek HS ，Moon C ，Kang SS ，Kim SH ，Kim YB ，Shin IS ，Kim JC ... -  《-》

Zerumbone Protects against Carbon Tetrachloride (CCl(4))-Induced Acute Liver Injury in Mice via Inhibiting Oxidative Stress and the Inflammatory Response: Involving the TLR4/NF-κB/COX-2 Pathway.

Wang M ，Niu J ，Ou L ，Deng B ，Wang Y ，Li S ... -  《MOLECULES》