Yu Mei-Xiang, Song Xin, Ma Xiao-Qin, Hao Chen-Xia, Huang Jing-Jing, Yang Wan-Hua
Department of Pharmacy, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Ann Palliat Med. 2021 Apr;10(4):3960-3975. doi: 10.21037/apm-20-1384. Epub 2021 Apr 1.
The complication, pulmonary fibrosis (PF) secondary to COVID-19, may have a second wave of late mortality, given the huge number of individuals infected by COVID-19. However, the molecular mechanisms of PF secondary to COVID-19 haven't been fully elucidated, making the identification of novel strategies for targeted therapy challenging. This study aimed to systematically identify the molecular mechanisms and high-frequency core traditional Chinese medicine (TCM) targeting PF secondary to COVID-19 through network pharmacology and data mining.
The molecular mechanisms of PF secondary to COVID-19 were identified by mapping the COVID-19 differentially expressed gene and known targets associated with PF, protein-protein interactions network analysis, and enrichment pathway analysis; then the high-frequency core TCM targeting PF secondary to COVID-19 were identified by data mining and "Key targets related to PF secondary to COVID-19 - Ingredients" and "Key ingredients-key herbs" network analysis; and last we validated the interaction between the key ingredients and key targets by molecular docking.
The molecular mechanisms of PF secondary to COVID-19 were mainly related to tumor necrosis factor (TNF) signaling pathway, cytokine-cytokine receptor interaction pathway, and NF-κB signaling pathway. Among these, cytokines interleukin 6 (IL-6), TNF, and IL-1β were identified as the key targets associated with PF secondary to COVID-19. The high-frequency core TCM targeting these key targets were identified, including ingredients of quercetin, epigallocatechin-3-gallate, emodin, triptolide, resveratrol, and herb of Polygonum cuspidatum. Finally, our results were validated by quercetin and resveratrol both well docked to IL-6, TNF, and IL-1β protein, with the estimated docking energy <0 kcal/mol.
This study identified the cytokines-related molecular mechanisms of PF secondary to COVID-19, and the high-frequency core TCM against PF by targeting IL-6, TNF, and IL-1β. Which provides new ideas for the discovery of small molecular compounds with potential therapeutic effects on PF secondary to COVID-19.
鉴于感染新型冠状病毒肺炎（COVID-19）的人数众多，COVID-19继发的并发症肺纤维化（PF）可能会出现第二波晚期死亡。然而，COVID-19继发PF的分子机制尚未完全阐明，这使得确定靶向治疗的新策略具有挑战性。本研究旨在通过网络药理学和数据挖掘系统地确定COVID-19继发PF的分子机制和高频核心中药。
通过绘制COVID-19差异表达基因和与PF相关的已知靶点、蛋白质-蛋白质相互作用网络分析和富集通路分析，确定COVID-19继发PF的分子机制；然后通过数据挖掘以及“COVID-19继发PF相关关键靶点-成分”和“关键成分-关键草药”网络分析，确定靶向COVID-19继发PF的高频核心中药；最后通过分子对接验证关键成分与关键靶点之间的相互作用。
COVID-19继发PF的分子机制主要与肿瘤坏死因子（TNF）信号通路、细胞因子-细胞因子受体相互作用通路和NF-κB信号通路有关。其中，细胞因子白细胞介素6（IL-6）、TNF和IL-1β被确定为与COVID-19继发PF相关的关键靶点。确定了靶向这些关键靶点的高频核心中药，包括槲皮素、表没食子儿茶素-3-没食子酸酯、大黄素、雷公藤内酯醇、白藜芦醇以及虎杖药材的成分。最后，槲皮素和白藜芦醇与IL-6、TNF和IL-1β蛋白均能良好对接，估计对接能量<0千卡/摩尔，验证了我们的结果。
本研究确定了COVID-19继发PF的细胞因子相关分子机制，以及通过靶向IL-6、TNF和IL-1β抗PF的高频核心中药。这为发现对COVID-19继发PF具有潜在治疗作用的小分子化合物提供了新的思路。
