Reveals of quercetin's therapeutic effects on oral lichen planus based on network pharmacology approach and experimental validation.

Oral lichen planus (OLP) is a localized autoimmune disease of the oral mucosa, with an incidence of up to 2%. Although corticosteroids are the first-line treatment, they cause several adverse effects. Quercetin, a naturally occurring compound, has fewer side-effects and provides long-term benefits. Besides, it has powerful anti­inflammatory activities. Here, we combined network pharmacology with experimental verification to predict and verify the key targets of quercetin against OLP. First, 66 quercetin-OLP common targets were analyzed from various databases. The protein-protein interaction (PPI) network was constructed. Topology analysis and MCODE cluster analysis of common targets were conducted to identify 12 key targets including TP53, IL-6 and IFN-γ and their connections. Gene functions and key signaling pathways, including reactive oxygen species metabolism, IL-17 pathway and AGE-RAGE pathway, were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, in vitro experiments showed that quercetin interfered with Th1/Th2 balance by acting on IL-6 and IFN-γ to modulate the immune system in treating OLP. Quercetin considerably affected the apoptosis and migration of T lymphocytes in OLP patients. Our study reveals the potential therapeutic targets and signaling pathways of quercetin associated with OLP, and establishes the groundwork for future clinical applications.

Preliminary therapeutic and mechanistic evaluation of S-allylmercapto-N-acetylcysteine in the treatment of pulmonary emphysema.

The objective of this work was to study the effects and mechanisms of S-allylmercapto-N-acetylcysteine (ASSNAC) in the treatment of pulmonary emphysema based on network pharmacology analysis and other techniques. Firstly, the potential targets associated with ASSNAC and COPD were integrated using public databases. Then, a protein-protein interaction network was constructed using String database and Cytoscape software. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed on DAVID platform. The molecular docking of ASSNAC with some key disease targets was implemented on the SwissDock platform. To verify the results of the network pharmacology, a pulmonary emphysema mice model was established and treated with ASSNAC. Besides, the expressions of the predicted targets were detected by immunohistochemistry, Western blot analysis or enzyme-linked immunosorbent assay. Results showed that 33 overlapping targets are achieved, including CXCL8, ICAM1, MAP2K1, PTGS2, ACE and so on. The critical pathways of ASSNAC against COPD involved arachidonic acid metabolism, chemokine pathway, MAPK pathway, renin-angiotensin system, and others. Pharmacodynamic experiments demonstrated that ASSNAC decreased the pulmonary emphysema and inflammation in the pulmonary emphysema mice. Therefore, these results confirm the perspective of network pharmacology in the target verification, and indicate the treatment potential of ASSNAC against COPD.

Network pharmacology-based study of the protective mechanism of conciliatory anti-allergic decoction on asthma.

BACKGROUND: This study aimed to explore the underlying anti-asthma pharmacological mechanisms of conciliatory anti-allergic decoction (CAD) with a network pharmacology approach. METHODS: Traditional Chinese medicine related databases were utilized to screen the active ingredients of CAD. Targets of CAD for asthma treatment were also identified based on related databases. The protein-protein interaction network, biological function and KEGG pathway enrichment analysis, and molecular docking of the targets were performed. Furthermore, an asthma mouse model experiment involving HE staining, AB-PAS staining, and ELISA was also performed to assess the anti-asthma effect of CAD. RESULTS: There were 77 active ingredients in CAD, including quercetin, kaempferol, stigmasterol, luteolin, cryptotanshinone, beta-sitosterol, acacetin, naringenin, baicalin, and 48 related targets for asthma treatment, mainly including TNF, IL4, IL5, IL10, IL13 and IFN-γ, were identified with ideal molecular docking binding scores by network pharmacology analysis. KEGG pathway analysis revealed that these targets were directly involved in the asthma pathway, Th1 and Th2 cell differentiation, and signaling pathways correlated with asthma (NF-κB, IL17, T cell receptor, TNF, JAK-STAT signaling pathways, etc.). Animal experiments also confirmed that CAD could attenuate inflammatory cell invasion, goblet cell hyperplasia and mucus secretion. The levels of the major targets TNF-α, IL4, IL5, and IL13 can also be regulated by CAD in an asthma mouse model. CONCLUSION: The anti-asthma mechanism of CAD possibly stemmed from the active ingredients targeting asthma-related targets, which are involved in the asthma pathway and signaling pathways to exhibit therapeutic effects.

A network pharmacology approach to investigate the anti-inflammatory mechanism of effective ingredients from Salvia miltiorrhiza.

Salvia miltiorrhiza, known as Danshen in Chinese, has been widely used to treat cardiovascular diseases in China. Tanshinone I (Tan I) and cryptotanshinone (CST) are the lipid-soluble and effective components from Salvia miltiorrhiza. However, the molecular mechanism of Tan I and CST for treating inflammation is still not known. Therefore, this study was designed to use network pharmacology-based strategy to predict therapeutic targets of Tan I and CST against inflammation, and further to investigate the pharmacological molecular mechanism in vitro. Inflammation targets were identified and followed by acquisition of verified targets of Tan I and CST. After constructing target-functional protein interaction network of Tan I and CST against inflammation, the core therapeutic targets of Tan I and CST against inflammation were obtained. Further, pathway enrichment analyses were performed on core therapeutic targets to evaluate key signaling pathways of Tan I and CST against inflammation. As revealed in network pharmacology analysis, 8 key hub targets for Tan I and CST against inflammation were identified, respectively: JUN, VEGFA, IL-6, TNF, MAPK8, CXCL8, and PTGS2 for Tan I, while STAT3, AKT1, CCND1, MAPK14, VEGFA, ESR1, MAPK8 and AR for CST. Pathway enrichment analysis by DAVID database indicated that Tan I and CST principally regulated the inflammation-associated pathway, such as TLR, JAK-STAT signaling pathway, focal adhesion, apoptosis, mTOR signaling pathway. In vitro, we found that both Tan I and CST exerts significantly effect on LPS stimulated NO secretion and iNOS expression in macrophages. Taken together, our data elucidate that anti-inflammatory pharmacological activities of Tan I and CST may be predominantly related to inhibition of TLR signaling pathway and regulating iNOS synthesis. These findings highlight the predicted therapeutic targets may be potential targets of Tan I and CST for anti-inflammation treatment.

Pharmacology mechanism of Flos magnoliae and Centipeda minima for treating allergic rhinitis based on pharmacology network.

Chinese herbs such as Flos magnoliae (FM) and Centipeda minima (CM) can be effective in treating allergic rhinitis (AR). However, there is little research on the therapeutic mechanism of these two drugs acting on AR at the same time. In order to systematically understand the mechanism of action of two drugs acting on AR at the same time, we searched various databases to obtain 31 components and 289 target proteins of FM, 25 components and 465 target proteins of CM. The interaction networks of FM, CM, and AR proteins were constructed by Cytoscape-v3.2.1 software. The core protein of two network intersections was obtained by using Venny 2.1.0. The R platform was used for the core target protein gene ontology (GO) comment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis. Thirteen common targets and seven acting pathways were obtained. The results of animal experiments showed that FM and CM volatile oil could effectively improve the symptoms of AR by regulating the common targets. In summary, this study successfully explained the potential therapeutic mechanism of FM and CM in the treatment of AR. At the same time, it indicates that the two drugs can be compatible as a new application.

Network ethnopharmacological evaluation of the immunomodulatory activity of Withania somnifera.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal (Ashwagandha, WS) is one of the extensively explored Ayurvedic botanicals. Several properties including immunomodulation, anti-cancer and neuro-protection of the botanical have been reported. Even though, in indigenous medicine, WS is well known for its immunomodulatory activity, the molecular mechanism of immunomodulation has not been elucidated. AIM OF THE STUDY: This study aimed the evaluation of the immunomodulatory effect of WS using network ethnopharmacology technique to elucidate the in silico molecular mechanism. MATERIALS AND METHODS: Databases- DPED, UNPD, PubChem, Binding DB, ChEMBL, KEGG and STRING were used to gather information to develop the networks. The networks were constructed using Cytoscape 3.2.1. Data analysis was performed with the help of Excel pivot table and Cytoscape network analyzer tool. RESULTS: Investigation for WS immune modulation mechanism identified five bioactives that are capable of regulating 15 immune system pathways through 16 target proteins by bioactive-target and protein-protein interactions. The study also unveils the potential of withanolide-phytosterol combination to achieve effective immunomodulation and seven novel bioactive-immune target combinations. CONCLUSION: The study elucidated an in silico molecular mechanism of immunomodulation of WS. It unveils the potential of withanolide-phytosterol combination to achieve a better immunomodulation. Experimental validation of the network findings would aid in understanding the rationale behind WS immunomodulation as well as aid in bioactive formulation based drug discovery.