Comparison of the molecular mechanisms of Fuzi Lizhong Pill and Huangqin decoction in the treatment of the cold and heat syndromes of ulcerative colitis based on network pharmacology.

OBJECTIVE: The aim of this study was to illuminate the similarities and differences of two prescriptions as "cold" and "heat" drugs for treating ulcerative colitis (UC) with the simultaneous occurrence of heat and cold syndrome via network pharmacology. METHODS: (1) Active compounds of Fuzi-Lizhong Pill (FLP) and Huangqin Decoction (HQT) were retrieved from the TCMSP database, and their common active compounds were compared using the Venn diagram. (2) Potential proteins targeted to three sets of compounds either (i) shared by FLP and HQT, (ii) unique to FLP or (iii) unique to HQT were screened from the STP, STITCH and TCMSP databases, and three corresponding core compound sets were identified in Herb-Compound-Target (H-C-T) networks. (3) Targets related to UC were identified from the DisGeNET and GeneCards databases and compared with the FLP-HQT common targets to identify potential targets of FLP-HQT compounds related to UC. (4) Three potential target sets were imported into the STRING database for protein‒protein interaction (PPI) analysis, and three core target sets were defined. (5) The binding capabilities and interacting modes between core compounds and key targets were verified by molecular docking via Discovery Studio 2019 and molecular dynamics (MD) simulations via Amber 2018. (6) The target sets were enriched for KEGG pathways using the DAVID database. RESULTS: (1) FLP and HQT included 95 and 113 active compounds, respectively, with 46 common compounds, 49 FLP-specific compounds and 67 HQT-specific compounds. (2) 174 targets of FLP-HQT common compounds, 168 targets of FLP-specific compounds, and 369 targets of HQT-specific compounds were predicted from the STP, STITCH and TCMSP databases; six core compounds specific to FLP and HQT were screened in the FLP-specific and HQT-specific H-C-T networks, respectively. (3) 103 targets overlapped from the 174 predicted targets and the 4749 UC-related targets; two core compounds for FLP-HQT were identified from the FLP-HQT H-C-T network. (4) 103 FLP-HQT-UC common targets, 168 of FLP-specific targets and 369 of HQT-specific targets had shared core targets (AKT1, MAPK3, TNF, JUN and CASP3) based on the PPI network analysis. (5) Molecular docking demonstrated that naringenin, formononetin, luteolin, glycitein, quercetin, kaempferol and baicalein of FLP and HQT play a critical role in treating UC; meanwhile, MD simulations revealed the stability of protein‒ligand interactions. (6) The enriched pathways indicated that most targets were related to anti-inflammatory, immunomodulatory and other pathways. Compared with the pathways identified using traditional methods, FLP-specific pathways included the PPAR signaling pathway and the bile secretion pathway, and HQT-specific pathways included the vascular smooth muscle contraction pathway and the natural killer cell-mediated cytotoxicity pathway etc. CONCLUSION: In this study, we clarified the common mechanisms of FLP and HQT in treating UC and their specific mechanisms in treating cold and heat syndrome in UC through compound, target and pathway distinction and a literature comparison based on network pharmacology; these results provide a new perspective on the detailed mechanism of "multidrugs and single-disease" thought in traditional Chinese medicine.

MAPK signaling pathway-targeted marine compounds in cancer therapy.

PURPOSE: This paper reviews marine compounds that target the mitogen-activated protein kinase (MAPK) signaling pathway and their main sources, chemical structures, major targeted cancers and possible mechanisms to provide comprehensive and basic information for the development of marine compound-based antitumor drugs in clinical cancer therapy research. METHODS: This paper searched the PubMed database using the keywords "cancer", "marine*" and "MAPK signaling pathway"; this search was supplemented by the literature-tracing method. The marine compounds screened for review in this paper are pure compounds with a chemical structure and have antitumor effects on more than one tumor cell line by targeting the MAPK signaling pathway. The PubChem database was used to search for the PubMed CID and draw the chemical structures of the marine compounds. RESULTS: A total of 128 studies were searched, and 32 marine compounds with unique structures from extensive sources were collected for this review. These compounds are cytotoxic to cancer cell lines, although their targets are still unclear. This paper describes their anticancer effect mechanisms and the protein expression changes in the MAPK pathway induced by these marine compound treatments. This review is the first to highlight MAPK signaling pathway-targeted marine compounds and their use in cancer therapy. CONCLUSION: The MAPK signaling pathway is a promising potential target for cancer therapy. Searching for marine compounds that exert anticancer effects by targeting the MAPK signaling pathway and developing them into new marine anticancer drugs will be beneficial for cancer treatment.