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Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment. [Pemetrexed + sildenafil] reduced the expression of multiple histone deacetylases that was blocked by knock down of autophagy regulatory proteins. [Pemetrexed + sildenafil] lethality was enhanced by the histone deacetylase inhibitors AR42 and sodium valproate; AR42 and valproate as single agents also rapidly reduced the expression of PD-L1, PD-L2 and ODC, and increased expression of MHCA and CerS6. Nitric oxide and CerS6 signaling was required for drug-induced death receptor activation and tumor cell killing. In vivo, [pemetrexed + sildenafil] lethality against lung cancer cells was enhanced by sodium valproate. Using syngeneic mouse lung cancer cells [pemetrexed + sildenafil] enhanced the anti-tumor effects of antibodies directed to inhibit PD-1 or CTLA4. [Pemetrexed + sildenafil] interacted with the anti-PD-1 antibody to strongly enhance tumor infiltration by M1 macrophages; activated NK cells and activated T cells. Our data demonstrate that treatment of tumor cells with [pemetrexed + sildenafil] results in tumor cell killing and via autophagy-dependent downregulation of HDACs, it opsonizes the remaining tumor cells to anti-tumor immunotherapy antibodies. 相似文献
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脾位于中焦,主运化,为气血生化之源。膏脂由脾运化水谷所生,中土得运,纳运有常,则膏脂可随血循环以濡养五脏六腑及四肢百骸;肝脏是脂质代谢重要的器官,其参与脂质消化、吸收、转运等功能,脾气健运,肝失疏泄,肝脏脂质代谢功能与"脾"运化功能相关。肝细胞自噬是维持肝脏脂质代谢稳态的关键因素之一,自噬功能正常则肝脏脂质代谢趋于平衡。本文基于脾与脂质相关性,从"脾主运化"探讨肝细胞自噬对脂质代谢的影响及机制。 相似文献
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Jin Jia Shi-qi Chen Wei-zhe Pan Sheng-nan Yu Xiao-tian Zhao Yan Hao Yong-mei Shen Ying Cheng Cai-ling Wei Feng-jie Tian Xiao-yan Yan Yu-lan Qiu 《Journal of applied toxicology : JAT》2022,42(3):490-505
Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m3) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 μM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 μM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS. 相似文献
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Rosa A González-Polo José M Bravo-San Pedro Rubén Gómez-Sánchez Elisa Pizarro-Estrella Mireia Niso-Santano José M Fuentes 《British journal of pharmacology》2013,168(1):60-62
Huntington''s disease (HD) is a neurodegenerative disorder caused by a mutation in the gene encoding the huntingtin protein. Although the precise mechanism by which neuronal degeneration occurs is still unclear, several elements are important to its development: (1) altered gene expression and protein synthesis, (2) mitochondrial damage and (3) improper regulation of the autophagy programme. In this issue of British Journal of Pharmacology, Galindo and co-workers provide the first evidence for a role of the mitochondrial permeability transition pore (mPTP) in mitochondrial fragmentation and autophagy activation. In a model of cell death induced by 3-nitropropionic acid (3-NP) in human neural cells, the authors describe clear functions for mPTP and Bax, but not the mitochondrial fusion/fission machinery, mitochondrial fragmentation and autophagy (mitophagy). This commentary summarises the significance of this relationship and suggests several points for future development. 相似文献
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《Toxicology in vitro》2014,28(5):769-777
Chalcones, naturally occurring open-chain flavonoids abundant in plants, have demonstrated anticancer activity in multiple tumor cells. In a previous work, the potential anticancer activity of three naphthylchalcones named R7, R13 and R15 was shown. In this study, the mechanism of actions of these chalcones was originally shown. The chalcones presented concentration and time-dependent cytotoxicity. To determine the type of cell death induced by chalcones, we assessed a series of assays including measurements of the caspase-8, -9 and -12 activities, expression of important apoptosis-related genes and proteins, changes in the cell calcium concentration and cytochrome c release. The activities of caspase-8, -9 and -12 increased after the treatment of L1210 cells with the three compounds. Chalcones R7 and R13 induced an increase of pro-apoptotic proteins Bax, Bid and Bak (only chalcone R13), as well as a decrease in anti-apoptotic Bcl-2 expression. These chalcones also induced an increase in Fas and a decrease in p21 and p53 expression. Chalcone R15 seems to act by a different mechanism to promote cell death, as it did not change the mitochondrion-related proteins, nor did it induce the cytochrome c release. All compounds induced an increase in cell calcium concentration and an increase in CHOP expression, which together with an increase in caspase-12 activity, suggest that chalcones could induce an endoplasmic reticulum (ER) stress. Taken together, these results suggest that chalcones induce apoptosis by different pathways, being an interesting strategy to suggest for cancer therapy. 相似文献
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肾间质纤维化(RIF)是慢性肾脏疾病进展至肾功能衰竭的共同通路,其发病机制主要与肾脏炎症损伤、氧化应激、细胞凋亡、细胞外基质(ECM)的过度沉积等相关,转化生长因子-β1(TGF-β1)信号通路、哺乳动物雷帕霉素靶蛋白(mTOR)信号通路等多种信号通路介导了RIF的发生发展。因其发生机制复杂,临床上尚无特异性防治措施。自噬是真核细胞产生的非损伤性应答,通过降解和重吸收作用,参与维持组织内稳态的平衡。目前,中医药在治疗慢性肾脏疾病延缓RIF的进程中以其多成分、多效应、多靶点的的独特优势取得了较好的临床疗效。学者研究发现自噬与中医阴阳学说、癥瘕积聚理论等在一定程度上相符合,并且自噬参与了RIF的诸多环节,RIF病程进展与自噬关系密切,通过干预自噬靶向治疗RIF已成为研究的前沿方向。然而,有关自噬在RIF中的作用及中医药调控自噬治疗RIF的研究相对比较少,因此,有必要进一步阐述自噬与RIF的关系,以明确自噬在RIF中发挥的作用机制及中医药调控自噬靶向治疗RIF的机制,该文就中医理论与自噬和RIF的相关性,结合自噬在RIF中炎症损伤、氧化应激、细胞凋亡、ECM过度沉积等的作用,自噬与TGF-β1信号通路、mTOR信号通路在RIF的调控机制,对自噬在RIF中的作用及中药干预的研究进行疏理和总结,以期为RIF的治疗及新药研发提供参考依据。 相似文献
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