Wen-Ling Mou,Shi-Ru Chen,Zhen-Ting Wu,Li-Hua Hu,Ji-Ye Zhang,Hong-Jie Chang,Hang Zhou,Ying Liu
Liver fibrosis results from liver inflammation and progresses to liver cirrhosis or liver cancer. It is known that nonalcoholic liver disease is mediated by the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2)–tumor necrosis factor-alpha (TNF-α) signaling pathway. This study aimed to investigate whether alcoholic liver disease is also mediated by this pathway. To this end, we first established rat models of liver fibrosis by administering alcohol. Next, the rats were injected with anti-TLR4 and anti-MD-2 antibodies. Real Time Quantitative PCR (RT-qPCR) and Western blotting were used to detect the activation of the TLR4/MD-2–TNF-α signaling pathway and hepatic stellate cells (HSCs). Moreover, the expression of molecules related to liver fibrosis was estimated. The morphology of rat liver tissue was observed through hematoxylin–eosin staining and Masson staining. For in vitro studies, Kupffer cells (KCs) isolated from the liver were transfected with si-TLR4 and si-MD-2 and co-cultured with HSCs to determine the activity of HSCs. It was found that alcohol treatment activated the TLR4/MD-2–TNF-α signaling pathway and upregulated the molecules associated with liver fibrosis. However, inhibition of TLR4 and MD-2 partially reversed this trend. Notably, in vitro studies indicated that knockdown of TLR4 and MD-2 in KCs partially inhibited LPS-induced activation of KCs and HSCs. Overall, this study showed that alcohol induces liver fibrosis via the LPS-TLR4/MD-2–TNF-α signaling pathway.
The objective of the current study was to explore the inhibitory effects of quercetin on cadmium-induced autophagy in mouse kidneys. Mice were intraperitoneally injected with cadmium and quercetin once daily for 3 days. The LC3-II/β-actin ratio was used as the autophagy marker, and autophagy was observed by transmission electron microscopy. Oxidative stress was investigated in terms of reactive oxygen species, total antioxidant capacity, and malondialdehyde. Cadmium significantly induced typical autophagosome formation, increased the LC3-II/β-actin ratio, reactive oxygen species level, and malondialdehyde content, and decreased total antioxidant capacity. Interestingly, quercetin markedly decreased the cadmium-induced LC3-II/β-actin ratio, reactive oxygen species levels, and malondialdehyde content, and simultaneously increased total antioxidant capacity. Cadmium can inhibit total antioxidant capacity, produce a large amount of reactive oxygen species, lead to oxidative stress, and promote lipid peroxidation, eventually inducing autophagy in mouse kidneys. Quercetin could inhibit cadmium-induced autophagy via inhibition of oxidative stress. This study may provide a theoretical basis for the treatment of cadmium injury.
Qian Tang,Mei Zhang,Zexuan Hong,Yao Chen,Pan Wang,Jian Wang,Zili Wang,Rendong Fang,Meilan Jin
To clarify the suppressive effects of astragalus injection (AI) on different stages of early hepatocarcinogenesis induced by weak promotion, SD rats initiated with a single intraperitoneal (i.p.) injection of N-diethylnitrosamine (DEN) at 200 mg/kg body weight and promoted with 0.5% piperonyl butoxide (PBO) in diet were repeatedly administered AI at 5 ml/kg body weight/day in the early postinitiation (EPI) or late postinitiation (LPI) period for 2 or 8 weeks, respectively. The number and area of glutathione S-transferase placental form (GST-P)-immunoreactive (+) foci tended to increase in the DEN+PBO group compared with the DEN-alone group. Among the PBO-promoted groups, number and area of GST-P+ foci did not visibly change in the DEN+PBO+AI-EPI group compared with the DEN+PBO group. In contrast, number and area of GST-P+ foci tended to decrease in the DEN+PBO+AI-LPI group compared with the DEN+PBO group. Number of Ki67+ cells was increased in the DEN+PBO group compared with the DEN-alone group and was decreased in both AI-administered groups compared with the DEN+PBO group. Gene expression analysis revealed that the DEN+PBO+AI-LPI group showed increased transcript levels of Ccne1, Cdkn1b, Rb1, Bax, Bcl2, Casp3, and Casp9 compared with the DEN+PBO group; however, the DEN+PBO+AI-EPI group did not show changes in the transcript levels of any genes examined compared with the DEN+PBO. These results suggest that AI administration during the LPI period caused weak suppression of hepatocarcinogenesis under weak promotion with a low PBO dose by the mechanism involving facilitation of cell cycle suppression causing G1/S arrest and apoptosis via the mitochondrial pathway. In addition, the results suggest that AI administration during the EPI period has no effect on weakly promoted hepatocarcinogenesis.
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