Inspiration for COVID-19 Treatment: Network Analysis and Experimental Validation of Baicalin for Cytokine Storm

Abstract

Background: Cytokine storm (CS) is a systemic inflammatory syndrome and a major cause of multi-organ failure and even death in COVID-19 patients. With the increasing number of COVID-19 patients, there is an urgent need to develop effective therapeutic strategies for CS. Baicalin is an anti-inflammatory and antiviral traditional Chinese medicine. In the present study, we aimed to evaluate the therapeutic mechanism of baicalin against CS through network analysis and experimental validation, and to detect key targets of CS that may bind closely to baicalin through molecular docking.Method: Access to potential targets of baicalin and CS in public databases. We constructed the protein-protein interaction (PPI) network of baicalin and CS by Cytoscape 9.0 software and performed network topology analysis of the potential targets. Then, the hub target was identified by molecular docking technique and validated in the CS model. Finally, GO and KEGG pathway functional enrichment analysis of common targets were confirmed using R language, and the location of overlapping targets in key pathways was queried via KEGG Mapper.Result: A total of 86 overlapping targets of baicalin and CS were identified, among which MAPK14, IL2, FGF2, CASP3, PTGS2, PIK3CA, EGFR, and TNF were the core targets. Moreover, it was found that baicalin bound most closely to TNF through molecular docking, and demonstrated that baicalin can effectively inhibit the elevation of TNF-α in vitro and in vivo. Furthermore, bioenrichment analysis revealed that the TNF signaling pathway and IL-17 signaling pathway may be potential key pathways for baicalin to treat CS.Conclusion: Based on this study, baicalin was identified as a potential drug for the alleviation of CS, and the possible key targets and pathways of baicalin for the treatment of CS were elucidated to reveal the main pharmacological mechanisms.

Gene Networks of Hyperglycemia, Diabetic Complications, and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity?

“…The clinical evidence supports the role of some molecules revealed in this work in COVID-19 pathogenesis: ANGPT2 [48,49], CCL2 [50], ICAM1 [52,53], VCAM-1 [52], MIR21 [54], MMP9 [55,56], STAT3 [57], HMGB1 [58,59], SIRT1 [62,63], AGTR1 [66], APOE4 [69,70], ACE [73], CCL11 [86,87], FGF2 [89], TNF [92], PPAR-γ [95], CASP8 [115], IL8 [117], IL6 [118], PRL [119], SP1 [122], TLR4 [123], BDNF [124], CASP1 [125], CASP3 [126,127], IL18 [128], IL10 [129], TGFB1 [130], ANXA2 [131,132], HPSE [162], MAPK1 [163], CDH1 [166], FBN1 [180], GDF15 [182,183], PLAT [195][196][197], RHOA…”

“…Intradermal administration of eotaxin-1 upregulated DPP4 in rats [88], constituting a regulatory loop. The elevation of the serum level of fibroblast growth factor 2 (FGF2) in COVID-19 patients was closely associated with disease severity and admission to an intensive care unit [89]. The clinical significance of MMP-9 and HMGB1 in COVID-19 was mentioned above [55,56,59].…”

“…For some of these molecules, there is clinical evidence of an association with COVID-19 (Figure 8). Specifically, the levels of fibroblast growth factor 2 (FGF2), interleukin-6 (IL6), and heparanase (HPSE) were associated with COVID-19 disease severity [89,118,162]. The activation of the MAPK1 signaling pathway was involved in cytokine production in SARS-CoV-2 [163].…”

Clinical features and effectiveness of Chinese medicine in patients with COVID-19 from overseas: A retrospective study in Xiamen, China

“…We found that studies of the core components and targets showed anti-inflammatory activity in inflammation and immune regulation. Baicalin can be widely used in inflammatory responses caused by viral infections, such as inhibition of pro-inflammatory cytokines (TNF-α, IL-6) in influenza A ( 30 ), inhibition of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), and angiotensin-converting enzyme 2 (ACE2) activity to prevent SARS-CoV-2 from entering the host cells ( 31 , 32 ). Stigmasterol exerts potential anti-inflammatory effects by inhibiting the IL-1beta-induced NF-kappaB pathway, suppressing pro-inflammatory cytokine expression, and prostaglandin E2 [PGE(2)] production ( 33 ).…”

Uncovering the information immunology journals transmitted for COVID-19: A bibliometric and visualization analysis

“…Currently, monoclonal antibodies against a variety of cytokines and a variety of related signaling pathway modulatory agents have shown potential to control the SARS-CoV-2 cytokine storm, such as tocilizumab for IL-6 ( 140 , 141 ), emapalumab for IFN-γ ( 142 ), canakinumab for IL-1β and anakinra for IL-1R ( 143 ), JAK2/STAT3 inhibitors ( 131 , 144 ), NF-κB pathway regulators ( 145 ), MAPK/NF-κB pathway regulators ( 146 ), the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome signaling inhibitors ( 147 , 148 ). In addition, immunoglobulin ( 149 ), nanotechnology-based corticosteroid drugs ( 150 ), and traditional Chinese medicine ( 151 – 153 ) are also potential drugs to alleviate cytokine storms.…”