Xiang-Feng Guo,Ji-Peng Liu,Si-Quan Ma,Peng Zhang,Wen-De Sun
5-Fluorouracil (5-Fu) and cisplatin (DDP) as important therapies in treatment of human gastric cancer have been widely determined. However, the therapeutic effects are usually hampered due to drug resistance or toxicity at high concentrations for application. Avicularin (AL, quercetin-3-α- l -arabinofuranoside), a bio-active flavonol isolated from a number of plants, has been reported to display diverse pharmacological properties. In this study, we explored the hypothesis by which AL reversed 5-Fu or DDP resistance in gastric cancer and the underlying molecular mechanism. Here, in vitro, the drug-resistant cancer cells were incubated to AL or DDP alone or the combination of AL and DDP. Then, MTT, colony formation, Hoechst 33258 , flow cytometry and western blot analysis were used to investigate the effects of AL in the regulation of drug-resistance gastric cancer cells. The results indicated that AL treatment markedly re-sensitizes the drug resistant cells (SGC-7901/5-Fu and SGC-7901/DDP) to cytotoxicity of 5-Fu or DDP. Molecular mechanism analysis indicated that AL and DDP combination treatment enhanced apoptosis in SGC-7901/DDP cells, accompanied with the up-regulation of cleaved Caspase-3 and PARP, as well as the activation of pro-apoptotic signals, including Bax and BOK. Significantly, down regulation of Bax or BOK expressions using Bax siRNA or BOK siRNA decreased the inhibitory role of DDP in apoptosis of SGC-7901/DDP cells pretreated with AL, demonstrating that AL-reversed DDP resistance was associated with Bax and BOK expression. In vivo, AL and DDP combination significantly reduced gastric tumor growth. Immunohistochemical analysis indicated that co-treatment of AL and DDP significantly induced apoptosis, and reduced tumor cell proliferation in tumor tissue samples. Furthermore, we also found that the Bax, BOK, cleaved Caspase-3 and PARP expression in tumor tissues were highly induced by AL and DDP co-treatment. Together, our findings may provide a novel combination therapeutic strategy in treatment of human gastric cancer.
Hong Ding,Wen-Xuan Wang,Qiong-Dan Liang,Chuan-Feng Tang,Tang-Di Xu,Zi-An Miao,Bang-Xing Han,Ling-Dong Kong
Mitochondria-mediated apoptosis is the key determinant of glomerular podocyte injury. NOD-like receptor family pyrin domain proteins (NLRPs) are aberrant in clinical kidney diseases, but the role in podocyte mitochondrial dysfunction is unclear. Here, we first observed only NLRP6 expression change in nephrotic syndrome patients with proteinuria. Next, we found that mouse glomerular podocyte NLRP6 expression was increased in high fructose-induced proteinuria with mitochondria-mediated apoptosis. Importantly, Nlrp6 deficiency ameliorated these disturbances in mice. NLRP6 downregulation inhibited podocyte mitochondrial outer membrane permeabilization (MOMP)-associated apoptosis via suppressing B-cell lymphoma 2-related ovarian killer (BOK) under high fructose stimulation. However, high NLRP6 expression blocked the binding of Tripartite motif-containing protein 7 (TRIM7) with Bok mRNA 3' untranslated region, decreased mRNA decay, and thereby downregulated antioxidant protein family with sequence similarity 213, member A (FAM213A), resulting in mitochondria-mediated apoptosis in high fructose-exposed podocytes. A nephroprotective agent gastrodin was found to decrease NLRP6 and relieve mitochondria-mediated apoptosis caused by high fructose, possibly through promoting TRIM7-driven Bok mRNA degradation and FAM213A antioxidant effect. This study uncovered that high NLRP6 expression-driven mitochondria-mediated apoptosis could participate in podocyte injury and the suppression of NLRP6 by gastrodin may be an attractive therapeutic approach for podocyte injury.
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