University Creative Research Initiatives Center, Shandong First Medical University, Jinan, Shandong, China.
Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China.
J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
Viruses such as human cytomegalovirus (HCMV), human papillomavirus (HPV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) represent a great burden to human health worldwide. FDA-approved anti-parasite drug ivermectin is also an antibacterial, antiviral, and anticancer agent, which offers more potentiality to improve global public health, and it can effectively inhibit the replication of SARS-CoV-2 in vitro. This study sought to identify ivermectin-related virus infection pathway alterations in human ovarian cancer cells. Stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomics was used to analyze human ovarian cancer cells TOV-21G treated with and without ivermectin (20 μmol/L) for 24 h, which identified 4447 ivermectin-related proteins in ovarian cancer cells. Pathway network analysis revealed four statistically significant antiviral pathways, including HCMV, HPV, EBV, and HIV1 infection pathways. Interestingly, compared with the reported 284 SARS-CoV-2/COVID-19-related genes from GencLip3, we identified 52 SARS-CoV-2/COVID-19-related protein alterations when treated with and without ivermectin. Protein-protein network (PPI) was constructed based on the interactions between 284 SARS-CoV-2/COVID-19-related genes and between 52 SARS-CoV-2/COVID-19-related proteins regulated by ivermectin. Molecular complex detection analysis of PPI network identified three hub modules, including cytokines and growth factor family, MAP kinase and G-protein family, and HLA class proteins. Gene Ontology analysis revealed 10 statistically significant cellular components, 13 molecular functions, and 11 biological processes. These findings demonstrate the broad-spectrum antiviral property of ivermectin benefiting for COVID-19 treatment in the context of predictive, preventive, and personalized medicine in virus-related diseases.
病毒，如人类巨细胞病毒（HCMV）、人类乳头瘤病毒（HPV）、爱泼斯坦-巴尔病毒（EBV）、人类免疫缺陷病毒（HIV）和冠状病毒（严重急性呼吸系统综合征冠状病毒 2 [SARS-CoV-2]），给全球人类健康带来了巨大的负担。经美国食品药品监督管理局（FDA）批准的驱虫药伊维菌素也是一种抗菌、抗病毒和抗癌药物，这为改善全球公共卫生提供了更多的潜力，并且它可以有效地抑制 SARS-CoV-2 在体外的复制。本研究旨在确定伊维菌素相关的病毒感染途径改变在人卵巢癌细胞中的作用。使用稳定同位素标记的氨基酸在细胞培养中的定量蛋白质组学（SILAC）分析，用和不用伊维菌素（20μmol/L）处理人卵巢癌细胞 TOV-21G 24 小时，鉴定了卵巢癌细胞中的 4447 种伊维菌素相关蛋白。通路网络分析显示了四个有统计学意义的抗病毒通路，包括 HCMV、HPV、EBV 和 HIV1 感染通路。有趣的是，与从 GencLip3 报告的 284 个与 SARS-CoV-2/COVID-19 相关的基因相比，我们在用和不用伊维菌素处理时，鉴定了 52 个与 SARS-CoV-2/COVID-19 相关的蛋白改变。基于 284 个与 SARS-CoV-2/COVID-19 相关的基因和 52 个受伊维菌素调节的与 SARS-CoV-2/COVID-19 相关的蛋白之间的相互作用，构建了蛋白质-蛋白质网络（PPI）。基于 PPI 网络的分子复合物检测分析，鉴定了三个枢纽模块，包括细胞因子和生长因子家族、MAP 激酶和 G 蛋白家族以及 HLA 类蛋白。基因本体论分析显示了 10 个有统计学意义的细胞成分、13 个分子功能和 11 个生物学过程。这些发现表明伊维菌素具有广谱抗病毒特性，有益于在预测、预防和个体化医学的背景下治疗 COVID-19 相关疾病。
