Efficacy and mechanism of Schisandra chinensis active component Gomisin A on diabetic skin wound healing: network pharmacology and in vivo experimental validation

Article

Author: Gu, Yong ; Yang, Wenkui ; Chen, Jiajia ; Zhang, Zhongyu ; Chen, Xuewen

ETHNOPHARMACOLOGICAL RELEVANCESchisandra chinensis (Turcz.) Baill., a common traditional Chinese herbal medicine, has been used for the treatment of diabetes mellitus and its complications. However, the major active component for treating diabetic foot ulcers, a serious complication of diabetes mellitus, was unclear. This study aimed to predict the treatment effect of the active components in Schisandra chinensis against diabetic skin wound using network pharmacology and to confirm the underlying mechanism using a diabetic skin wound model in vivo.AIM OF THE STUDYTo study the effects and underlying mechanisms of Schisandra chinensis and its main component Gomisin A on diabetic skin wound healing by network pharmacology and high-fat diet (HFD)-induced obese mice model in vivo.MATERIALS AND METHODSTo determine the effectiveness of Schisandra chinensis on diabetic skin wound, network pharmacology was first used. Components of Schisandra chinensis were obtained from the Traditional Chinese Medicine Systems Pharmacology database. The active components were further verified through absorption, distribution, metabolism and excretion. The potential targets of the active components were identified from the Traditional Chinese Medicine Systems Pharmacology, SwissTargetPrediction, TargetNet, and the Comparative Toxicogenomics Database. Targets related to diabetic skin wound were collected from the GeneCards, OMIM, DisGeNET, and PharmGKB databases. The interaction network formed by the intersection of the two datasets was analyzed using Gephi. Network-based proximity was used to predict the network distance between the active components of Schisandra chinensis and diabetic skin wound. Gomisin A was found to have the lowest Z-score and was administered either orally or via topical injection to HFD-induced obese mice daily until the wounds healed, and its effects on skin wound healing were evaluated.RESULTSOnly five active ingredients of Schisandra chinensis were screened in our system: Gomisin A, Longikaurin A, Deoxyharringtonine, Wuweizisu C, and Interiotherin B, which can regulate biological processes related to diabetic skin wound, including positive regulation of phosphorous metabolic process, positive regulation of cell migration, and response to wounding. Network proximity analysis found that Gomisin A has the closest distance-based Z-score among the diabetic skin wound modules and drug targets in the human protein-protein interaction network. The HFD-induced obese mice model further revealed that Gomisin A accelerated skin wound healing by increasing insulin sensitivity and decreasing the advanced glycation end-products mediated toll-like receptor 4 (TLR4)-p38 MAPK-IL6 inflammation signaling pathway.CONCLUSIONSThe network pharmacology and in vivo studies indicated that Gomisin A from Schisandra chinensis played a crucial role in improving diabetic skin wound healing.

01 Dec 2024·International Immunopharmacology

Schisandra chinensis lignans improve insulin resistance by targeting TLR4 and activating IRS-1/PI3K/AKT and NF-κB signaling pathways

Article

Author: Wu, Lin-Lin ; Li, Gen ; Liu, Guan-Ke ; Ding, Li-Qin ; Yao, Tie ; Qiu, Feng ; Cao, Shi-Jie ; Liu, Da ; Zhao, Shao-Li ; Liu, Guan-ke ; Wu, Lin-lin ; Kang, Ning ; Ding, Li-qin

Schisandra chinensis, a traditional Chinese medicine, has been widely applied in China to treat diabetes and its complications. The aim of this study was to discover the active compounds and explain related molecular mechanism contributing to the anti-diabetic effect of Schisandra chinensis. Herein, the therapeutic effects of Schisandra chinensis extracts on type 2 diabetes mellitus (T2DM) were firstly confirmed in vivo. Subsequently, various lignans were isolated from Schisandra chinensis and tested for hypoglycemic activity in palmitic acid-induced insulin-resistant HepG2 (IR-HepG2) cells. Among these lignans, R-biar-(7S,8R)-6,7,8,9-tetrahydro-1,2,3,12,13,14-hexamethoxy-7,8-dimethyl-7-dibenzo [a, c] cyclooctenol (compound 2) and Gomisin A (compound 4) were identified significantly increased the glucose consumption in IR-HepG2 cells. Meanwhile, compounds 2 and 4 activated the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT) pathway, which regulates glucose transporter 2 (GLUT2) and glucose-6-phosphatase (G6Pase), essential for gluconeogenesis and glucose uptake. These compounds also inhibited the nuclear factor-κB (NF-κB) signaling pathway, reducing interleukin-6 (IL-6) levels. Importantly, the hypoglycemic effects of compounds 2 and 4 were diminished after Toll-like receptor 4 (TLR4) knockdown. Cellular thermal shift assays confirmed increased TLR4 protein stability upon treatment with these compounds, indicating direct binding to TLR4. Furthermore, TLR4 knockdown reversed the effects of compounds 2 and 4 on the NF-κB and IRS-1/PI3K/AKT pathways. Taken together, compounds 2 and 4 alleviate IR by targeting TLR4, thereby modulating the NF-κB and IRS-1/PI3K/AKT pathways. These findings suggest that compounds 2 and 4 could be developed as therapeutic agents for T2DM.

01 Dec 2024·Molecular Biology Reports

Protective effect of gomisin N on benzyl butyl phthalate-induced dysfunction of testosterone production in TM3 Leydig cells

Article

Author: Yoo, Eunsoo ; Kim, Hye Kyung ; Park, Min Ju ; Park, Min Hi ; Jeong, Dong Hyeok ; Arunachalam, Rohith ; Lee, Seung Ju

BACKGROUNDExposure to benzyl butyl phthalate (BBP) may induce disorders in the male reproductive system. However, the molecular mechanisms remain unknown. Here we investigated the effect of BBP on testosterone production and its molecular mechanisms. Furthermore, we also investigated the role of gomisin N (GN) from Schisandra chinensis (S. chinensis) in testosterone synthesis in TM3 Leydig cells.METHOD AND RESULTSFirst, we examined the effects of BBP on expression levels of testosterone biosynthesis-related genes (StAR, CYP11α1, CYP17α1, 3βHSD, and 17βHSD) and attenuation-related genes (CYP1β1, CYP19α1, and Srd5α1-3). Although testosterone biosynthesis-related genes did not change, attenuation-related genes such as CYP1β1 and CYP19α1 were upregulated with ROS generation and testosterone level attenuation in the presence of 50 µM of BBP. However, the compound with the highest ROS and ONOO^- scavenging activity from S. chinensis, GN, significantly reversed the expression of BBP-induced testosterone attenuation-related gene to normal levels. Subsequently, GN improved the testosterone production levels in TM3 Leydig cells. These events may be regulated by the antioxidant effect of GN.CONCLUSIONSOn conclusion, our study suggests, for the first time, that BBP impairs testosterone synthesis by the modulation of CYP1β1 and CYP19α1 expression in TM3 cells; GN could potentially minimize the BBP-induced dysfunction of TM3 cells to produce testosterone by suppressing CYP19α1 expression.

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