Fulminant viral hepatitis (FH) represents a significant clinical challenge, with its pathogenesis not yet fully elucidated. Heat shock protein (HSP)70, a molecular chaperone protein with a broad range of cytoprotective functions, is upregulated in response to stress. However, the role of HSP70 in FH remains to be investigated. Notably, HSP70 expression is upregulated in the livers of coronavirus-infected mice and patients. Therefore, we investigated the mechanistic role of HSP70 in coronavirus-associated FH pathogenesis. FH was induced in HSP70-deficient (HSP70 KO) mice or in WT mice treated with the HSP70 inhibitor VER155008 when infected with the mouse hepatitis virus strain A59 (MHV-A59). MHV-A59-infected HSP70 KO mice exhibited significantly reduced liver damage and mortality. This effect was attributed to decreased infiltration of monocyte-macrophages and neutrophils in the liver of HSP70 KO mice, resulting in lower levels of inflammatory cytokines such as IL-1β, TNFα, and IL-6, and a reduced viral load. Moreover, treatment with the HSP70 inhibitor VER155008 protected mice from MHV-A59-induced liver damage and FH mortality. In summary, HSP70 promotes coronavirus-induced FH pathogenesis by enhancing the infiltration of monocyte-macrophages and neutrophils and promoting the secretion of inflammatory cytokines. Therefore, HSP70 is a potential therapeutic target in viral FH intervention.

2024-09-01·Biomedicine & Pharmacotherapy

Oral matrine alleviates CCl4-induced liver fibrosis via preserved HSP72 from modulated gut microbiota

Article

作者: Yuan, Ruinan ; Ye, Ji-Ming ; Li, Bing ; Fang, Weiming ; Wu, Rihui ; Zhu, Junye ; Zhou, Xiu ; Su, Yibo ; Li, Wu ; Jin, Jingwei ; Li, Dongli

Hepatic fibrosis is intricately associated with dysregulation of gut microbiota and host metabolomes. Our previous studies have demonstrated that matrine can effectively reduce hepatosteatosis and associated disorders. However, it is poorly understood whether the gut microbiota involved in the attenuation of liver fibrosis by matrine. Herein we explored a novel mechanism of how oral administration of matrine alleviates liver fibrosis by modulating gut microbiota. Administration of matrine not only potently ameliorated liver fibrosis in carbon tetrachloride (CCl4)-induced mice, but also significantly preserved hepatic heat shock protein 72 (HSP72) in vivo and in vitro. Matrine was failed to reduce liver fibrosis when HSP72 upregulation was blocked by the HSP72 antagonist VER-155008. Also, consumption of matrine significantly alleviated gut dysbiosis and fecal metabonomic changes in CCl4-treated mice. Transplanted the faces of matrine-treated mice induced a remarkable upregulation of HSP72 and remission of fibrosis in liver in CCl4-exposed mice and inhibition of TGF-β1-induced inflammatory response and epithelial-mesenchymal transition (EMT) in AML-12 cells. Furthermore, deficiency of HSP72 partly reversed the intestinal microbial composition that prevented matrine from reducing CCl4-induced liver fibrosis in mice. This study reveals the "gut microbiota-hepatic HSP72" axis as a key mechanism of matrine in reducing liver fibrosis and suggest that this axis may be targeted for developing other new therapies for liver fibrosis.

2024-08-01·Molecular Biology of the Cell

HSPA8 inhibitors augment cancer chemotherapeutic effectiveness via potentiating necroptosis

Article

作者: Sun, Liming ; Jia, Kelong ; Wu, Chenlu ; Zhou, Shen'ao ; Wu, Erpeng

Our recent work has uncovered a novel function of HSPA8 as an amyloidase, capable of dismantling the RHIM-containing protein fibrils to suppress necroptosis. However, the impact of HSPA8 inhibitors on cancer regression via necroptosis remains unexplored. In this study, we conducted a comprehensive investigation to assess the potential of HSPA8 inhibitors in enhancing necroptosis both in vitro and in vivo. Our findings indicate that pharmacologic inhibition of HSPA8, achieved either through VER (VER-155008) targeting the nucleotide binding domain or pifithrin-μ targeting the substrate binding domain of HSPA8, significantly potentiates necroptosis induced by diverse treatments in cellular assays. These inhibitors effectively disrupt the binding of HSPA8 to the RHIM protein, impeding its regulatory function on RHIM amyloid formation. Importantly, HSPA8 inhibitors significantly enhanced cancer cell sensitivity to microtubule-targeting agents (MTAs) in vitro, while reversing chemoresistance and facilitating tumor regression by augmenting necroptosis in vivo. Our findings suggest a promising therapeutic approach to cancer through necroptosis modulation via HSPA8 targeting, particularly in combination with MTA drugs for enhanced treatment efficacy.

项与 VER-155008 相关的新闻（医药）

2024-08-21

·今日头条

激活糖酵解！南京医科大学合作发文：发现肝癌进展新机制

【导读】尽管近年来肝细胞癌（HCC）的治疗取得了显著进展，但许多患者在中晚期被诊断出患有该疾病，从而失去了手术切除的机会。因此，寻找有效的HCC治疗靶点非常重要。 8月20日，南京医科大学与上海交通大学以及天津中医药大学研究人员合作在期刊《Advanced Science》上发表了研究论文，题为“GJB2 Promotes HCC Progression by Activating Glycolysis Through Cytoplasmic Translocation and Generating a Suppressive Tumor Microenvironment Based on Single Cell RNA Sequencing”，在这项研究中，研究人员通过单细胞RNA测序发现，间隙连接蛋白β-2（GJB2）在恶性细胞中高度富集，并且GJB2表达水平越高，预后越差。与正常肝组织相比，HCC癌细胞中GJB2的定位发生了变化。在癌细胞中，GJB2倾向于位于细胞质和细胞核中，而在正常组织中，GJB2主要位于细胞膜上。GJB2与糖酵解有关，通过诱导IκBa的泛素化降解来促进NF-κB通路，激活HIF-1α/GLUT-1/PD-L1通路。此外，GJB2敲低可重塑肿瘤免疫微环境，丹酚酸 B可抑制GJB2的活性。总之，GJB2通过在细胞质中的转位激活糖酵解，促进HCC进展，并产生抑制性肿瘤微环境。丹酚酸 B抑制GJB2的表达，增强抗PD1疗法的敏感性，这可能为开发HCC的新型联合治疗策略提供启示。 https://onlinelibrary.wiley.com/doi/10.1002/advs.202402115 背景知识 01 肝癌虽然在癌症类型中排名靠后，但却是第三大死亡原因。值得注意的是，HCC占所有肝癌病例的80%。全球范围内，2019年约有747000例HCC病例，较1990年增加了70%，该疾病导致了480000人死亡。对于HCC，早期诊断时的治疗方案通常非常有效。然而，肿瘤复发仍然是一个重大挑战。可用的治疗模式包括经动脉化疗栓塞术（TACE）、肝移植、消融疗法和外科切除。不幸的是，由于该疾病的无症状性，大多数HCC患者在晚期才被发现。对于这些个体，系统性药物通常是可行的选择，因为手术替代方案可能不可行。近年来，肿瘤免疫治疗，尤其是免疫检查点抑制剂(ICIs)的使用显著改变了HCC的临床管理。贝伐珠单抗和阿替利珠单抗联合治疗被证明比一线治疗索拉非尼更有效。尽管取得了这些进展，肝癌仍然是最具挑战性的癌症之一，由于其频繁复发和耐药。不幸的是，相当一部分HCC患者要么经历了免疫相关的副作用，要么没有从这些免疫疗法中获益。尽管如此，免疫治疗的快速发展为HCC患者带来了新的希望，但仍需进一步研究以提高治疗的敏感性。 GJB2促进肝癌细胞的增殖、侵袭和迁移 02 为了研究GJB2 mRNA对肝癌细胞的影响，研究人员设计了3条针对GJB2的shRNA序列，从而抑制GJB2 mRNA合成的来源。这些序列被用来下调肝癌细胞中GJB2的表达。随后，采用qRT-PCR方法检测GJB2的表达水平。值得注意的是，研究结果显示sh1表现出最高的敲低效率。研究人员用sh1序列验证GJB2蛋白的表达，发现在HCCLM3和Hep-3B细胞中，敲低GJB2后的蛋白表达低于对照sh-NC组。在CCK8和EdU实验中，敲低GJB2抑制肝癌细胞增殖。在迁移实验和划痕实验中，与对照组相比，sh-GJB2抑制相对迁移和侵袭率。 GJB2促进人癌细胞的体外增殖、侵袭和迁移另外，研究人员对GJB2的膜蛋白区域进行突变，发现与WT组相比，细胞表型提示突变组更促进HCC的进展，包括增殖，侵袭和迁移。下调GJB2的表达，尤其是在细胞质和细胞核中的表达，可有效抑制肝癌的增殖、侵袭和迁移。这一发现为靶向GJB2治疗HCC的潜在治疗策略提供了希望。可减缓HCC进展的丹酚酸 B 03 本研究通过计算机虚拟筛选人GJB2蛋白结构的胞外活性位点Site1，以获得与靶蛋白结合能力强的小分子化合物。将MCE文库中的化合物与靶蛋白Human GJB2进行对接后，综合对接分数、脂溶性、水溶性评价，初步筛选出5个最优化合物，分别为Militarine、丹酚酸B、Parishin B、VER-155008、RGX-104。研究人员选择丹酚酸B (Sal B)作为进一步研究的药物。在蛋白质免疫印迹实验中，研究人员发现Sal B可以抑制肿瘤细胞的NF-κB通路。在CCK8和EdU实验中，Sal B抑制肝癌细胞增殖。在迁移实验和划痕实验中，与对照组相比，Sal B抑制了相对迁移和侵袭率。说明丹酚酸B能抑制肝癌细胞的增殖、侵袭和迁移。研究人员将H22细胞注射到C57BL/6小鼠体内，第7天进行Sal B注射和抗PD1抗体治疗，观察其抗肿瘤能力。结果显示，与抗PD1组相比，Sal B+抗PD1组的肿瘤体积和重量明显减小。上述药物验证结果表明，Sal B可通过抑制GJB2活性增强抗PD1免疫治疗的敏感性，证实了其在肿瘤免疫治疗中的促进作用，并具有在HCC中临床转化的潜力。研究小结 04 根据单细胞RNA测序结果，GJB2在HCC恶性细胞中高度富集，GJB2蛋白的更高表达表明预后更差。机制上，GJB2通过细胞质转位激活糖酵解途径，在肿瘤微环境中产生抑制性作用，促进HCC进展。丹酚酸 B有效地抑制了GJB2的活性，并增强了抗PD1疗法的敏感性，这可能为开发HCC的新型联合治疗策略提供启示。【参考资料】 https://onlinelibrary.wiley.com/doi/10.1002/advs.202402115 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 线上｜08月21日 19:00-20:30 ▶ “肿瘤免疫与实时活细胞成像技术”在线研讨会欢迎您的参与！ 🕓 线上｜08月22日 19:00-20:30 ▶ “RNA原位杂交在临床病理诊断及相关研究中的应用”网络研讨会欢迎您的参与！ 🕓 上海｜09月11日 ▶ 微驭万物-单细胞空间组学技术前沿与临床应用研讨会欢迎您的参与！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会欢迎您的参与！点击对应文字查看详情

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100 项与 VER-155008 相关的药物交易

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