Statins, such as lovastatin, have been known to inhibit 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase. Statins were reported to moderately suppress hepatitis C virus (HCV) replication in cultured cells harboring HCV RNA replicons. We report here using an HCV cell culture (HCVcc) system that high concentrations of lovastatin (5–20 μg/mL) markedly enhanced the release of HCV infectious particles (virion) in the culture supernatants by up to 40 times, without enhancing HCV RNA replication, HCV protein synthesis, or HCV virion assembly in the cells. We also found that lovastatin increased the phosphorylation (activation) level of extracellular‐signal‐regulated kinase 5 (ERK5) in both the infected and uninfected cells in a dose‐dependent manner. The lovastatin‐mediated increase of HCV virion release was partially reversed by selective ERK5 inhibitors, BIX02189 and XMD8‐92, or by ERK5 knockdown using small interfering RNA (siRNA). Moreover, we demonstrated that other cholesterol‐lowering statins, but not dehydrolovastatin that is incapable of inhibiting HMG‐CoA reductase and activating ERK5, enhanced HCV virion release to the same extent as observed with lovastatin. These results collectively suggest that statins markedly enhance HCV virion release from infected cells through HMG‐CoA reductase inhibition and ERK5 activation.

2024-08-26·Journal of Chemical Information and Modeling

Epithelial–Mesenchymal Transition Related Score Functions as a Predictive Tool for Immunotherapy and Candidate Drugs in Glioma

Article

作者: Fu, Xiaojun ; Ren, Ming ; Dai, Kaining ; Yan, Changxiang ; Ren, Changyuan

Gliomas are aggressive CNS tumors where the epithelial-mesenchymal transition (EMT) is crucial for prognosis. We developed an EMT-based score predicting overall survival (OS) and conducted pathway analyses, revealing functions such as cell proliferation and immune response in glioma progression. The EMT score, correlated with immune functions and cell infiltration, shows potential as an immune response indicator. We identified two promising compounds, BIX02189 and QL-XI-92, as potential glioma treatments based on candidate gene analysis.

2022-04-01·Journal of biochemical and molecular toxicology4区 · 医学

Hesperidin delays cell cycle progression into the G0/G1 phase via suspension of MAPK signaling pathway in intrahepatic cholangiocarcinoma

4区 · 医学

Article

作者: Liu, Li ; Yan, Fei ; Li, Li ; Sun, Jianhai ; Deng, Jie

Abstract:

Intrahepatic cholangiocarcinoma (iCCA) derived from epithelial cells of bile ducts is highly aggressive tumor. Hesperidin extracted from citrus fruits is a promising antitumor compound. The purpose of this study is to explore molecular mechanism by which hesperidin affects cholangiocarcinoma progression. Cellular functional experiments were performed and subcutaneous transplant xenograft model was established. Our findings indicated that hesperidin suppressed iCCA cell proliferation in time‐ and concentration‐dependent manners. Hesperidin treatment induced cell cycle arrest at G0/G1 phase, whereas it has no effect on cell apoptosis. Further, data revealed that hesperidin attenuated MEK5 and ERK5 phosphorylation and inhibited ERK5 nuclear localization by reducing MEKK2 activity in MAPK signaling pathway. It could cause alterations in expression of the downstream genes, including CDK4, CDK6 (cell cycle protein kinases), Cyclin D1 (a G1/S checkpoint), P21, and P27 (two G1‐checkpoint CDK inhibitors), thereby arresting cell cycle distribution of iCCA cells in the G0/G1 phase. BIX02189 treatment, a specific inhibitor of MEK5, in combination with hesperidin displayed synergistic inhibitory effects on cell cycle arrest and gene expressions. Furthermore, hesperidin administration alone or in combination with MEK5 inhibitor BIX02189 restrained iCCA tumor growth in vivo. Taken together, these results confirmed that hesperidin regulated the expression of cell cycle‐related genes by inhibiting the activation of MEKK2/MEK5/ERK5 signaling pathway, inducing iCCA cell cycle arrest at the G0/G1 phase. Our study provides a theoretical foundation and experimental basis for further development of hesperidin as a therapeutic agent for iCCA treatment.

100 项与 BIX02189 相关的药物交易

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