The aim of this investigation was to evaluate the differential expression of the sterol O‐acyltransferase 1 (SOAT1) protein in gallbladder cancer tissues and cells, investigate the impact of Avastin on the proliferation, migration, invasion capabilities of gallbladder cancer cells, and its potential to induce cell apoptosis. Immunohistochemical analysis of samples from 145 gallbladder cancer patients was conducted, along with analysis of SOAT1 protein, mRNA expression levels, and cholesterol content in gallbladder cancer cell lines SGC‐996, NOZ, and gallbladder cancer (GBC)‐SD using Western blot and q‐PCR techniques. Furthermore, the effects of Avastin on the proliferation, migration, and invasion capabilities of these gallbladder cancer cell lines were studied, and its ability to induce cell apoptosis was evaluated using flow cytometry, Western blot, and immunohistochemical methods. Additionally, gene expression and pathway analysis were performed, and the synergistic therapeutic effects of Avastin combined with gemcitabine were tested in a gallbladder cancer xenograft model. The study found that SOAT1 expression was significantly upregulated in GBC tissues and positively correlated with lymph node metastasis and TNM staging. In vitro experiments demonstrated that Avastin significantly inhibited the proliferation, migration, and invasion capabilities of SGC‐996 and GBC‐SD cell lines and induced apoptosis. RNA sequencing analysis revealed multiple differentially expressed genes in cells treated with Avastin, primarily enriched in biological pathways such as signaling transduction, malignant tumors, and the immune system. In vivo, experiments confirmed that Avastin could effectively suppress tumor growth in a gallbladder cancer xenograft model and enhanced the treatment efficacy when used in combination with gemcitabine. Overall, these findings provide new insights and strategies for targeted therapy in gallbladder cancer.

2024-05-01·Antiviral research

Corrigendum to “Avasimibe can cooperate with a DC-targeting and integration-deficient lentivector to induce stronger HBV specific T cytotoxic response by regulating cholesterol metabolism” Antiviral Res. 2023 Aug:216:105662]

作者: Ma, Siyuan ; Zang, Guoqing ; Hu, Weiwei ; Chen, Xiaohua ; Zhang, Yi ; Tang, Zhenghao ; Lv, Mengjiao

2024-03-01·Journal of pharmaceutical and biomedical analysis

A study on cholesterol-cholesteryl ester metabolic homeostasis and drug intervention in hyperlipidemic hamsters using UHPLC-MS/MS

Article

作者: Wang, Zhiquan ; Zheng, Bowen ; Wang, Zhe ; Zhang, Jinlan ; Lin, Miao

Hyperlipidemia is a global metabolic disorder characterized by dysregulation of lipid metabolism. This dysregulation is closely associated with the altered homeostasis of cholesterol-cholesteryl ester (CE) metabolism in systemic circulation, and some organs. Additionally, the relationship between oxidized cholesteryl ester (oxCE) and the disease has also gained attention. Currently, there is a lack of comprehensive research on the alterations in cholesterol-CE metabolism in the context of hyperlipidemia, as well as the characteristics of lipid-lowering agents in regulating this metabolic state. Therefore, 40 oxCEs were identified in the hamster liver sample, and novel ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) methods were established for simultaneous analysis of cholesterol, 57 CEs, and 40 oxCEs in the serum, liver, adipose tissue, and intestine of hyperlipidemic hamsters. This study investigated the metabolic alterations between cholesterol-CE/oxCE in hyperlipidemic hamsters and those treated with lipid-lowering agents, including the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe and the acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitor avasimibe. The study findings demonstrate metabolic disorders in cholesterol-CE/oxCE homeostasis in hyperlipidemic hamsters. Lipid-lowering agent therapy can improve the metabolic dysregulation caused by hyperlipidemia, with distinct characteristics: ezetimibe is more effective in reducing cholesterol, while avasimibe is more effective in reducing CEs/oxCEs. Eight potential biomarkers indicating the dysregulation of cholesterol-CE metabolism caused by hyperlipidemia and its improvement by lipid-lowering agents have been identified in the serum. This study offers new insights into the hyperlipidemia pathophysiology and the mechanisms of lipid-lowering agents from a novel perspective on cholesterol-CE/oxCE metabolic homeostasis.

项与 Avasimibe 相关的新闻（医药）

2022-11-11

·中国生物技术网

上海药物所团队通过胆固醇代谢调控纳米粒，改善肿瘤光动力-免疫治疗效果

光动力疗法（PDT）介导的免疫激活作用使其兼具肿瘤免疫治疗的效果。然而，PDT免疫疗效的发挥受到肿瘤浸润的细胞毒性T细胞（CTLs）功能和状态的影响。改善肿瘤免疫抑制性微环境，有效激活并增强CTLs的功能，有望提高PDT的抗肿瘤免疫治疗效果。胆固醇代谢途径干预CTLs和肿瘤细胞的功能，通过调控胆固醇代谢，有望增强CTLs功能，提高抗肿瘤疗效。近日，上海药物所李亚平团队在 Small Methods 期刊发表了题为：Blocking cholesterol metabolism with tumor-penetrable nanovesicles to improve photodynamic cancer immunotherapy 的研究论文。该研究开发了一种基质金属蛋白酶（MMP-2）响应的促渗透纳米粒，通过促进药物瘤内渗透，同步调控CTLs和肿瘤细胞的胆固醇代谢行为，改善CTLs功能，协同增强光动力-免疫治疗抗肿瘤效果。该研究制备了脂质纳米囊泡共包载MMP-2酶敏促渗肽修饰的光敏剂PPa和胆固醇酯化酶抑制剂阿伐麦布，在进行PDT的同时干预胆固醇代谢以提高疗效。该递药系统具有以下特点：1）纳米粒在血液循环中保持稳定，通过EPR效应被动蓄积至肿瘤部位，在肿瘤高表达的MMP-2作用下，促渗肽iRGD从纳米粒中响应释放，促进阿伐麦布在瘤内的深部渗透；2）被肿瘤细胞摄取后，PPa介导的PDT诱导肿瘤细胞发生免疫原性细胞死亡（ICD），进而激活抗肿瘤免疫应答；3）阿伐麦布被释放后可以同时抑制肿瘤浸润性 CD8+ T细胞和肿瘤细胞的胆固醇代谢，恢复T细胞的功能，抑制肿瘤细胞迁移，使肿瘤细胞处于有效的免疫监视，协同PDT激活的免疫应答杀伤肿瘤。与单独PDT相比，基于该递药系统的联合治疗策略在黑色素瘤模型中展现出更强的抗肿瘤效果。该研究提出了通过调控胆固醇代谢通路提高光动力免疫治疗效果的新思路。胆固醇调控纳米粒的构建及其作用分子模式全文链接：https://onlinelibrary.wiley.com/doi/epdf/10.1002/smtd.202200898

免疫疗法

2022-11-07

·生物谷

上海药物所李亚平团队通过胆固醇代谢调控纳米粒，改善肿瘤光动力-免疫治疗效果

该研究制备了脂质纳米囊泡共包载MMP-2酶敏促渗肽修饰的光敏剂PPa和胆固醇酯化酶抑制剂阿伐麦布，在进行PDT的同时干预胆固醇代谢以提高疗效。光动力疗法（PDT）介导的免疫激活作用使其兼具肿瘤免疫治疗的效果。然而，PDT免疫疗效的发挥受到肿瘤浸润的细胞毒性T细胞（CTLs）功能和状态的影响。改善肿瘤免疫抑制性微环境，有效激活并增强CTLs的功能，有望提高PDT的抗肿瘤免疫治疗效果。胆固醇代谢途径干预CTLs和肿瘤细胞的功能，通过调控胆固醇代谢，有望增强CTLs功能，提高抗肿瘤疗效。近日，上海药物所李亚平团队在 Small Methods 期刊发表了题为：Blocking cholesterol metabolism with tumor-penetrable nanovesicles to improve photodynamic cancer immunotherapy 的研究论文。该研究开发了一种基质金属蛋白酶（MMP-2）响应的促渗透纳米粒，通过促进药物瘤内渗透，同步调控CTLs和肿瘤细胞的胆固醇代谢行为，改善CTLs功能，协同增强光动力-免疫治疗抗肿瘤效果。该研究制备了脂质纳米囊泡共包载MMP-2酶敏促渗肽修饰的光敏剂PPa和胆固醇酯化酶抑制剂阿伐麦布，在进行PDT的同时干预胆固醇代谢以提高疗效。该递药系统具有以下特点：1）纳米粒在血液循环中保持稳定，通过EPR效应被动蓄积至肿瘤部位，在肿瘤高表达的MMP-2作用下，促渗肽iRGD从纳米粒中响应释放，促进阿伐麦布在瘤内的深部渗透；2）被肿瘤细胞摄取后，PPa介导的PDT诱导肿瘤细胞发生免疫原性细胞死亡（ICD），进而激活抗肿瘤免疫应答；3）阿伐麦布被释放后可以同时抑制肿瘤浸润性 CD8+ T细胞和肿瘤细胞的胆固醇代谢，恢复T细胞的功能，抑制肿瘤细胞迁移，使肿瘤细胞处于有效的免疫监视，协同PDT激活的免疫应答杀伤肿瘤。与单独PDT相比，基于该递药系统的联合治疗策略在黑色素瘤模型中展现出更强的抗肿瘤效果。该研究提出了通过调控胆固醇代谢通路提高光动力免疫治疗效果的新思路。胆固醇调控纳米粒的构建及其作用分子模式上海药物所李亚平研究员、王当歌副研究员为本文的共同通讯作者，博士生刘晓琛为本文第一作者。该研究得到了国家自然科学基金、中科院青促会和上海市科学技术委员会等项目的资助。