Carbon monoxide alleviates ethanol-induced oxidative damage and inflammatory stress through activating p38 MAPK pathway.

Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8mg/kg for mice or 20μmol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals.

Li Y ，Gao C ，Shi Y ，Tang Y ，Liu L ，Xiong T ，Du M ，Xing M ，Liu L ，Yao P ... -  《-》

The protective role of HO-1 and its generated products (CO, bilirubin, and Fe) in ethanol-induced human hepatocyte damage.

Yao P ，Hao L ，Nussler N ，Lehmann A ，Song F ，Zhao J ，Neuhaus P ，Liu L ，Nussler A ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY》

The activation of HO-1/Nrf-2 contributes to the protective effects of diallyl disulfide (DADS) against ethanol-induced oxidative stress.

Diallyl disulfide (DADS) is a garlic-derived organosulfur compound. The current study is designed to evaluate the protective effects of DADS against ethanol-induced oxidative stress, and to explore the underlying mechanisms by examining the HO-1/Nrf-2 pathway. We investigated whether or not DADS could activate the HO-1 in normal human liver cell LO2, and then evaluated the protective effects of DADS against ethanol-induced damage in LO2 cells and in acute ethanol-intoxicated mice. The biochemical parameters were measured using commercial kits. HO-1 mRNA level was determined by RT-PCR. Histopathology and immunofluorescence assay were performed with routine methods. Protein levels were measured by western blot. DADS significantly increased the mRNA and protein levels of HO-1, stimulated the nuclear translocation of Nrf-2 and increased the phosphorylation of MAPK in LO2 cells. The nuclear translocation of Nrf-2 was abrogated by MAPK inhibitors. DADS significantly suppressed ethanol-induced elevation of lactate dehydrogenase (LDH) and aspartate transaminase (AST) activities, decrease of glutathione (GSH) level, increase of malondialdehyde (MDA) levels, and apoptosis of LO2 cells, which were all blocked by ZnPPIX. In mice, DADS effectively suppressed acute ethanol-induced elevation of aminotransferase activities, and improved liver histopathological changes, which might be associated with HO-1 activation. These results demonstrate that DADS could induce the activation of HO-1/Nrf-2 pathway, which may contribute to the protective effects of DADS against ethanol-induced liver injury. DADS may be beneficial for the prevention and treatment of ALD due to significant activation of HO-1/Nrf-2 pathway.

Zeng T ，Zhang CL ，Song FY ，Zhao XL ，Yu LH ，Zhu ZP ，Xie KQ ... -  《-》

Heme oxygenase-1 mediates the protective role of quercetin against ethanol-induced rat hepatocytes oxidative damage.

Quercetin, one of the most widely distributed flavonoids in plants, possesses strong free radical scavenging ability and potent hepatoprotective effects. However, the protective effect and mechanism of quercetin on ethanol-induced oxidative damage in hepatocytes remain unclear. In this study, primary rat hepatocytes were incubated with ethanol and quercetin in the presence or absence of ZnPP 9, an antagonist of HO-1 induction. The ethanol-induced hepatotoxicity was found to be greatly diminished by pre-treatment of quercetin and this hepatoprotective effect could be partly blocked by ZnPP 9. This study also showed that quercetin significantly stimulated HO-1 expression at both mRNA and protein levels, then subsequently induced HO-1 activity. To further study the signaling pathways underlying quercetin-induced HO-1 up-regulation, HO-1 expression and activity in cytosolic microsomal fractions and Nrf2 expression in nuclear fractions were analyzed following quercetin or/and MAPK inhibitor(s) as well as PI3K inhibitor incubation for primary rat hepatocytes. These results indicated that ERK was required to induce HO-1 expression in rat hepatocytes. In summary, these data suggested that quercetin attenuates ethanol-induced oxidative stress through a pathway which involves ERK activation and HO-1 upregulation.

Liu S ，Hou W ，Yao P ，Li N ，Zhang B ，Hao L ，Nüssler AK ，Liu L ... -  《-》

[Study on the role and possible mechanism of hemeoxygenase-1/carbon monoxide system in protection of quercetin against ethanol-induced hepatocytes oxidative injury].

Hou W ，Qiu P ，Chen NJ ，Yao P ，Liu S ，Qin H ... -  《-》