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Systematic Pharmacological Strategies to Explore the Regulatory Mechanism of Ma Xing Shi Gan Decoction on COVID-19?

ABSTRACT: Objective To use systematic pharmacological strategies to explore the regulatory mechanisms of Ma Xing Shi Gan Decoction (MXSGD) against the coronavirus disease 2019 (COVID-19). Methods Data on the compounds and targets of MXSGD were collected from the Traditional Chinese Medicene Systems Parmacology Database and Analysis Platform (TCMSP) and TCM Databases@Taiwan. Data on ACE2-related targets and the protein-protein interaction (PPI) were collected from the String database. The Cytoscape 3.7.2 was used to construct and analyze the networks. The DAVID platform was used for Gene Ontology (GO) and pathway enrichment analyses. Results Data on 272 MXSGD targets and 21 SARS-CoV-2 potential targets were collected. Four networks were constructed and analyzed based on the data: (1) compound-target network of MXSGD; (2) MXSGD-SARS-CoV-2-PPI network; (3) cluster of MXSGD-SARS-CoV-2-PPI network; (4) Herb-Pathway-Target network. The core targets included AKT1, MAPK3, IL-6, TP53, VEGFA, TNF, CASP3, EGFR, EGF and MAPK1. The antiviral biological processes were inflammatory responses (inflammatory cells, inflammatory cytokines and their signaling pathways), immune responses (T cells, monocytes, B cells and other immune cells), immune factors (IFN-?, TNF-? and so on), virus defense, humoral immunity and mucosal innate immune response. The antivirus-related signaling pathways included TNF, NOD-like receptor, FoxO, PI3K-AKT and Toll-like receptor signaling pathways. Conclusions MXSGD can control disease progression by regulating multiple compounds and targets; it can reduce inflammation and balance immunity by regulating several proteins that interact with ACE2 and signaling pathways closely related to disease development.

SUBMITTER: Shi-Ying Z

PROVIDER: S-EPMC7366106 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Project description:Ma Xing Shi Gan Decoction (MXD), a classical traditional Chinese medicine prescription, is widely used for the treatment of upper respiratory tract infection. However, the effect of MXD against particulate matters with diameter of less than 2.5 ?m (PM2.5) induced lung injury remains to be elucidated. In this study, rats were stimulated with PM2.5 to induce lung injury. MXD was given orally once daily for five days. Lung tissues were harvested to assess pathological changes and edema. Myeloperoxidase (MPO) activity and malonaldehyde (MDA) content in lung were determined to evaluate the degree of injury. To assess the barrier disruption, the bronchoalveolar lavage fluid (BALF) was collected to determine the total protein content and count the number of neutrophils and macrophages. For evaluating the activation of macrophage in lung tissue, CD68 was detected using immunohistochemistry (IHC). The levels of inflammatory factors including tumor necrosis factor-alpha (TNF-?), interleukin-1beta (IL-1?), and interleukin-6 (IL-6) in BALF and serum were measured. In vitro, a PM2.5-activated RAW 264.7 macrophages inflammatory model was introduced. To evaluate the protective effect of MXD-medicated serum, the cell viability and the release of inflammatory factors were measured. The effects of MXD on the High mobility group box-1/Toll-like receptor 4/Nuclear factor-kappa B (HMGB1/TLR4/NF?B) pathway in lung tissue and RAW 264.7 cells were assessed by Western blot. For further confirming the protective effect of MXD was mediated by inhibiting the HMGB1/TLR4/NF?B pathway, RAW 264.7 cells were incubated with MXD-medicated serum alone or MXD-medicated serum plus recombinant HMGB1 (rHMGB1). MXD significantly ameliorated the lung injury in rats, as evidenced by decreases in the pathological score, lung edema, MPO activity, MDA content, CD68 positive macrophages number, disruption of alveolar capillary barrier and the levels of inflammatory factors. In vitro, MXD-medicated serum increased cell viability and inhibited the release of inflammatory cytokines. Furthermore, MXD treatment was found to inhibit HMGB1/TLR4/NF?B signal pathway both in vivo and in vitro. Moreover, the protection of MXD could be reversed by rHMGB1 in RAW 264.7. Taken together, these results suggest MXD protects rats from PM2.5 induced acute lung injury, possibly through the modulation of HMGB1/TLR4/NF?B pathway and inflammatory responses.

Project description:BackgroundYeju Jiangya decoction (CIF) is an herbal formula from traditional Chinese medicine (TCM) for the treatment of hypertension.Materials and methodsBased on the analysis of network pharmacology, combined with in animal experiments, the network pharmacology was used to explore the potential proteins and mechanisms of CIF against hypertension. The bioactive compounds of CIF were screened by using the platform, and the targets of hypertension and CIF were collected. Then, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction network (PPI) core targets were carried out, and the useful proteins were found by molecular docking technology. Finally, we used N-nitro-L-arginine (L-NNA) induced hypertension model rats to confirm the effect and mechanism of CIF on hypertension.Results14 bioactive compounds of CIF passed the virtual screening criteria, and 178 overlapping targets were identified as core targets of CIF against hypertension. The CIF-related target network with 178 nodes and 344 edges is constructed. The topological results show that quercetin and luteolin are the key components in the network. The key targets NOS3 (nitric oxide synthase 3) and NOS2 (nitric oxide synthase 2) were screened by the protein-protein interaction network. The analysis of target protein pathway enrichment showed that the accumulation pathway is related to the vascular structure of CIF regulation of hypertension. Further verification based on molecular docking results showed that NOS3 had the good binding ability with quercetin and luteolin. On the other hand, NOS3 has an important relationship with the composition of blood vessels. Furthermore, the animal experiment indicated that after the L-NNA-induced hypertension rat model was established, CIF intervention was given by gavage for 3 weeks, and it can decrease serum concentrations of endothelin-1 (ET-1) and thromboxane B2 (TXB2), increase the expression of nitric oxide (NO) and prostacyclin 2 (PGI2), and improve renal, cardiac, and aortic lesions. At the same time, it can reduce blood pressure and shorten vertigo time. Western blot (WB) and immunohistochemistry (IHC) analyses indicated that CIF may downregulate the expression of NOS3, guanylyl cyclase-alpha 1 (GC-α1), guanylyl cyclase-alpha 2 (GC-α2), and protein kinase CGMP-dependent 1 (PRKG1). These results suggest that CIF may play an antihypertensive role by inhibiting the activation of the NOS3/PRKG1 pathway.ConclusionsThe results of this study indicate that CIF has the ability to improve target organs, protect endothelial function, and reduce blood pressure and that CIF might be a potential therapeutic drug for the prevention of hypertension. It provides new insight into hypertension and the potential biological basis and mechanism for CIF clinical research.

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Systematic Pharmacological Strategies to Explore the Regulatory Mechanism of Ma Xing Shi Gan Decoction on COVID-19?

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