Jiang Yong, Xie Yi-Zi, Peng Chen-Wen, Yao Kai-Nan, Lin Xue-Ying, Zhan Shao-Feng, Zhuang Hong-Fa, Huang Hui-Ting, Liu Xiao-Hong, Huang Xiu-Fang, Li Hang
Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China.
The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Pharmacol. 2022 Jun 8;13:865097. doi: 10.3389/fphar.2022.865097. eCollection 2022.
People suffering from coronavirus disease 2019 (COVID-19) are prone to develop pulmonary fibrosis (PF), but there is currently no definitive treatment for COVID-19/PF co-occurrence. Kaempferol with promising antiviral and anti-fibrotic effects is expected to become a potential treatment for COVID-19 and PF comorbidities. Therefore, this study explored the targets and molecular mechanisms of kaempferol against COVID-19/PF co-occurrence by bioinformatics and network pharmacology. Various open-source databases and Venn Diagram tool were applied to confirm the targets of kaempferol against COVID-19/PF co-occurrence. Protein-protein interaction (PPI), MCODE, key transcription factors, tissue-specific enrichment, molecular docking, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to clarify the influential molecular mechanisms of kaempferol against COVID-19 and PF comorbidities. 290 targets and 203 transcription factors of kaempferol against COVID-19/PF co-occurrence were captured. Epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase SRC (SRC), mitogen-activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 8 (MAPK8), RAC-alpha serine/threonine-protein kinase (AKT1), transcription factor p65 (RELA) and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) were identified as the most critical targets, and kaempferol showed effective binding activities with the above critical eight targets. Further, anti-COVID-19/PF co-occurrence effects of kaempferol were associated with the regulation of inflammation, oxidative stress, immunity, virus infection, cell growth process and metabolism. EGFR, interleukin 17 (IL-17), tumor necrosis factor (TNF), hypoxia inducible factor 1 (HIF-1), phosphoinositide 3-kinase/AKT serine/threonine kinase (PI3K/AKT) and Toll-like receptor signaling pathways were identified as the key anti-COVID-19/PF co-occurrence pathways. Kaempferol is a candidate treatment for COVID-19/PF co-occurrence. The underlying mechanisms may be related to the regulation of critical targets (EGFR, SRC, MAPK3, MAPK1, MAPK8, AKT1, RELA, PIK3CA and so on) and EGFR, IL-17, TNF, HIF-1, PI3K/AKT and Toll-like receptor signaling pathways. This study contributes to guiding development of new drugs for COVID-19 and PF comorbidities.
患有2019冠状病毒病（COVID-19）的人容易发生肺纤维化（PF），但目前对于COVID-19与PF共病尚无确切的治疗方法。具有抗病毒和抗纤维化作用的山奈酚有望成为治疗COVID-19和PF共病的潜在药物。因此，本研究通过生物信息学和网络药理学探索了山奈酚抗COVID-19与PF共病的靶点及分子机制。应用各种开源数据库和维恩图工具来确定山奈酚抗COVID-19与PF共病的靶点。采用蛋白质-蛋白质相互作用（PPI）、MCODE、关键转录因子、组织特异性富集、分子对接、基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析来阐明山奈酚抗COVID-19和PF共病的影响分子机制。捕获了山奈酚抗COVID-19与PF共病的290个靶点和203个转录因子。表皮生长因子受体（EGFR）、原癌基因酪氨酸蛋白激酶SRC（SRC）、丝裂原活化蛋白激酶3（MAPK3）、丝裂原活化蛋白激酶1（MAPK1）、丝裂原活化蛋白激酶8（MAPK8）、RAC-α丝氨酸/苏氨酸蛋白激酶（AKT1）、转录因子p65（RELA）和磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α异构体（PIK3CA）被确定为最关键的靶点，且山奈酚与上述8个关键靶点显示出有效的结合活性。此外，山奈酚抗COVID-19与PF共病的作用与炎症、氧化应激、免疫、病毒感染、细胞生长过程和代谢的调节有关。EGFR、白细胞介素17（IL-17）、肿瘤坏死因子（TNF）、缺氧诱导因子1（HIF-1）、磷脂酰肌醇3激酶/AKT丝氨酸/苏氨酸激酶（PI3K/AKT）和Toll样受体信号通路被确定为抗COVID-19与PF共病的关键途径。山奈酚是治疗COVID-19与PF共病的候选药物。其潜在机制可能与关键靶点（如EGFR、SRC、MAPK3、MAPK1、MAPK8、AKT1、RELA、PIK3CA等）以及EGFR、IL-17、TNF、HIF-1、PI3K/AKT和Toll样受体信号通路的调节有关。本研究有助于指导针对COVID-19和PF共病的新药开发。
