Therapeutic effect and potential mechanism of curcumin, an active ingredient in Tongnao Decoction, on COVID-19 combined with stroke: a network pharmacology study and GEO database mining
Authors: Yunze Li , Yangjing Yao , Rui Mao , Jiacheng Wu , Yan Liu , Qinghua Feng , Manyan Hu , Weiwei Chen , Minghua Wu , Jianjun Li 
Published: May 2024

Abstract

Background
The onset of severe acute respiratory syndrome coronavirus type 2 at the end of 2019 led to a global pandemic of acute respiratory diseases, commonly known as COVID-19, caused by this highly infectious and pathogenic coronavirus. As members of the Fifth-batch National TCM Medical Team sent by the Affiliated Hospital of Nanjing University of Chinese Medicine to assist Wuhan Jiangxia Mobile Cabin Hospital, it was observed that patients with COVID-19 had an elevated incidence of stroke and are prone to progression. The possible mechanisms included neuroinvasion by the virus, an imbalance between ACE1 and ACE2, hypercoagulability, and a pre-thrombotic state. However, effective treatment options are not yet available. Developed by the Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Tongnao Decoction (TND) is a prescribed medication. The chemical components within the TND extract were previously examined using Waters ACQUITY UPLC ultra-performance liquid chromatography. Notably, identified chemical constituents, including curcumin, exhibited protective effects on brain cells. In the current investigation, bioinformatics techniques were employed to mine the GEO database, aiming to assess the functional role and potential action mechanism of curcumin as a therapeutic agent for COVID-19 combined with stroke.Tongnao Decoction
Methods
The datasets of COVID-19 and stroke were retrieved from the GEO database to identify the differentially intersecting genes (DIGs) between the two diseases. These DIGs were then exposed to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses employing the clusterProfiler to extract TF genes in the Trrust database (TF in TRRUST). Core TF genes were found to be target genes in DEGs-related TF in Stroke and DEGs-related TF in COVID. The overlapping set of these target genes yielded intersected target genes, which were then imported into the DGIdb website for drug prediction. Subsequently, the selected core drugs were subjected to drug validation on the cMAP website. Target prediction was performed on four online platforms: SEA, SwissTargetPrediction, TargetNet, and TCMSP. Subsequently, the obtained results were imported into the String database to create an interaction network comprising core target genes and enriched pathways. Additionally, molecular docking was performed using AutoDock software. Finally, molecular docking scoring was applied to the core targets.
Results
The intersection of DEGs from stroke dataset GSE16561 with DEGs from COVID dataset GSE211979 yielded 205 intersected genes. These intersected genes, including E2F3, BCL6, ETS2, CEBPD, STAT1, MXD1, NFIL3, HDAC4, MMP9, CD163, FCGR1A, IFIT3, LY96, PLSCR1, TNFSF10:E2F3, BCL6, ETS2, CEBPD, STAT1, MXD1, NFIL3, HDAC4, MMP9, CD163, FCGR1A, IFIT3, LY96, PLSCR1, and TNFSF10, were subjected to GO and KEGG pathway enrichment analyses utilizing the clusterProfiler. Subsequently, the core drug curcumin was selected from the 17 intersected drugs. Curcumin inhibits NF-κb and MAPKs and possesses various pharmacological effects encompassing anti-proliferative, anti-oxidant, anti-inflammatory, and anti-angiogenic effects. The six core targets CCNA2, JAK2, MMP9, PPARG, PTGS2, and STAT3 had molecular docking scores of -2.86, -2.98, -5.01, -2.42, -3.83, and − 2.28, respectively.
Conclusion
Curcumin, the active ingredient in TND, can effectively intervene in COVID-19 combined with stroke through CCNA2, JAK2, MMP9, PPARG, PTGS2, and STAT3 target pathways, of which the most important target is MMP9.