Curcumin attenuates quinocetone induced apoptosis and inflammation via the opposite modulation of Nrf2/HO-1 and NF-kB pathway in human hepatocyte L02 cells.

The potential toxicity of quinocetone (QCT) has raised widely concern, but its mechanism is still unclear. This study aimed to investigate the protective effect of curcumin on QCT induced apoptosis and the underlying mechanism in human hepatocyte L02 cells. The results showed that QCT treatment significantly decreased the cell viability of L02 cell and increased the release of lactate dehydrogenase (LDH), which was attenuated by curcumin pre-treatment at 1.25, 2.5 and 5 μM. Compared to the QCT alone group, curcumin pre-treatment significantly attenuated QCT induced oxidative stress, mitochondrial dysfunction and apoptosis. In addition, curcumin pretreatment markedly attenuated QCT-induced increase of iNOS activity and NO production in a dose-dependent manner. Meanwhile, curcumin pretreatment markedly down-regulated the expression of nuclear factor -kB (NF-kB) and iNOS mRNAs, but up-regulated the expressions of Nrf2 and HO-1 mRNAs, compared to the QCT alone group. Zinc protoporphyrin IX, a HO-1 inhibitor, markedly partly abolished the cytoprotective effect of curcumin against QCT-induced caspase activation, NF-kB mRNA expression. These results indicate that curcumin could effectively inhibit QCT induced apoptosis and inflammatory response in L02 cells, which may involve the activation of Nrf2/HO-1 and inhibition of NF-kB pathway.

Dai C ，Li B ，Zhou Y ，Li D ，Zhang S ，Li H ，Xiao X ，Tang S ... -  《-》

Quercetin Attenuates Manganese-Induced Neuroinflammation by Alleviating Oxidative Stress through Regulation of Apoptosis, iNOS/NF-κB and HO-1/Nrf2 Pathways.

Bahar E ，Kim JY ，Yoon H 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Quinocetone-induced Nrf2/HO-1 pathway suppression aggravates hepatocyte damage of Sprague-Dawley rats.

Quinocetone (3-methyl-2-quinoxalin benzenevinylketo-1,4-dioxide, QCT) is a widely used veterinary drug in PR China that promotes feed efficiency and growth of various animals. However, its potential toxicity has been concerned recently. In the present study, we investigated QCT-induced hepatocyte changes and its related mechanism, especially the expression of Nrf2/HO-1 pathway. Oxidative stress induced by QCT in hepatocyte led to DNA damage, inflammation and apoptosis. Nevertheless, hepatocyte has a self-repair system to protect itself from oxidative stress. In the 50 mg/kg/day QCT group, the morphology and function of liver were approximately maintained on normal level, which indicated that the damaged cell might have a self-repair mechanism. Notably, nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway plays a critical role in protecting cells against reactive oxygen species (ROS) generation. However, higher doses of QCT (800 mg/kg/day and 2400 mg/kg/day) inhibited the expression of Nrf2/HO-1 pathway, which resulted in excessive ROS generation and irreversible oxidative DNA damage, inflammation and apoptosis. In conclusion, although QCT-induced oxidative stress activates the expression of Nrf2/HO-1 pathway initially, persistent QCT exposure will inhibit this expression and aggravate hepatocyte damage. Simultaneously, inflammation and apoptosis continues to progress, liver dysfunction and tissue damage will be occurred eventually.

Yu M ，Wang D ，Xu M ，Liu Y ，Wang X ，Liu J ，Yang X ，Yao P ，Yan H ，Liu L ... -  《-》

Molecular mechanism of olaquindox-induced hepatotoxicity and the hepatic protective role of curcumin.

Olaquindox (OLA) is a chemosynthetic growth promoter, which could promote the treatment of bacterial infections and improve feed energy efficiency. Hepatotoxicity is still a poor feature associated with the adverse effects of OLA. The present study aimed to investigate the molecular mechanism of OLA-induced hepatotoxicity and the protective role of curcumin in mice and HepG2 cells. The result showed that representative biomarkers involved in mitochondrial pathway, p53 pathway, mitogen-activated protein kinase (MAPK) pathway, autophagy and antioxidant pathway were activated. Furthermore, curcumin attenuated OLA-induced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and liver damage in mice. In addition, cell viability of HepG2 was enhanced by curcumin pretreatment at 5, 10 and 20 μM. Meanwhile, curcumin markedly ameliorated OLA-induced oxidative stress, apoptosis and mitochondrial dysfunction. Moreover, curcumin pretreatment significantly up-regulated the expressions of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) and down-regulated the expressions of nuclear factor-kappaB (NF-kB) and p53 through reduced the nuclear translocation of NF-kB induced by OLA. In summary, our findings indicated that OLA-induced hepatotoxicity involved in mitochondrial apoptosis, autophagy, p53 pathway, Nrf2/HO-1 pathways, and curcumin regulated OLA-induced liver damage, oxidative stress and apoptosis via activation of Nrf2/HO-1 pathway and suppression of p53 and NF-kB pathway.

Li D ，Zhang Y ，Pei X ，Liu X ，Dai C ，Li C ，Li L ，Zhang J ，Xiao X ，Tang S ... -  《-》

Hydrangenol inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-mediated HO-1 pathway.

We previously demonstrated the anti-inflammatory effect of water extract of Hydrangea macrophylla in lipopolysaccharide (LPS)-stimulated macrophage cells. Here, we investigated whether hydrangenol, a bioactive component of H. macrophylla, attenuates the expression of nitric oxide (NO) and its associated gene, inducible NO synthase (iNOS), in LPS-stimulated BV2 microglial cells. Our data showed that low dosages of hydrangenol inhibited LPS-stimulated NO release and iNOS expression without any accompanying cytotoxicity. Hydrangenol also suppressed LPS-induced nuclear translocation of nuclear factor-κB (NF-κB) subunits, consequently inhibiting DNA-binding activity of NF-κB. Additionally, the NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC) and PS-1145, significantly attenuated LPS-induced iNOS expression, indicating that hydrangenol-induced NF-κB inhibition might be a key regulator of iNOS expression. Furthermore, our data showed that hydrangenol suppresses NO production by inducing heme oxygenase-1 (HO-1). The presence of cobalt protoporphyrin, a specific HO-1 inducer, potently suppressed LPS-induced NO production. Hydrangenol also promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequently increased its binding activity at the specific antioxidant response element sites. Additionally, transient knockdown of Nrf2 significantly downregulated hydrangenol-induced HO-1 expression, indicating that hydrangenol-induced Nrf2 is an upstream regulator of HO-1. Taken together, these data suggest that hydrangenol attenuates NO production and iNOS expression in LPS-stimulated BV2 microglial cells by inhibiting NF-κB activation and by stimulating the Nrf2-mediated HO-1 signaling pathway. Therefore, hydrangenol is a promising therapeutic agent for treatment of LPS-mediated inflammatory diseases.

Kim HJ ，Kang CH ，Jayasooriya RGPT ，Dilshara MG ，Lee S ，Choi YH ，Seo YT ，Kim GY ... -  《-》