Centella triterpenes cream as a potential drug for the treatment of hypertrophic scar through inhibiting the phosphorylation of STAT3: A network pharmacology analysis and in vitro experiments

Abstract

BackgroundHypertrophic scars (HS) often affect the normal function and appearance of the skin and bring adverse effects to the body and mind of patients, being a challenge in the fields of burns and plastic surgery as well as rehabilitation. Despite significant efficacy of centella triterpenes cream for treating HS clinically, its pharmacodynamics and molecular targets are still unclear. Therefore, the network pharmacology analysis combined with in vitro cell molecular biology experiments was used to explore the mechanism and targets of centella triterpenes cream treating HS in this study.MethodsFirst, target genes of asiaticoside (AC) were obtained from the databases including the Comparative Toxicogenomics Database, similarity ensemble approach, SwissTargetPrediction and TargetNet, and HS targets were acquired from the databases like Disgenet, GeneCards, and Online Mendelian Inheritance in Man. The common targets of AC‐HS were obtained through plotting a Venn diagram. Subsequently, STRING 11.0 was employed for analyzing the protein–protein interaction (PPI) network of the common targets, and cytoscape 3.9.0 for analyzing the connectivity of PPI and plotting the network diagram of “drug‐component‐target”. Additionally, a modified tissue culture method was applied to separate primary normal fibroblasts (NFs) in human skin and hypertrophic scar fibroblasts (HSFs). HSFs after 24‐h AC treatment were subjected to MTT assay to detect cell viability, scratch assay to assess cell migration ability, and western blot to test the protein expression levels of STAT3, p‐STAT3, transforming growth factor‐β1 (TGF‐β1), collagen I (COL 1), fibronectin 1 (FN1), and alpha‐smooth muscle actin (α‐SMA).ResultsIn network pharmacology analysis, 134 pharmacodynamic targets of AC and 2333 HS targets were obtained after retrieving the database, 50 AC‐HS common targets were obtained by a Venn diagram, and a total of 178 edges and 13 core genes such as JUN and STAT3 were acquired by PPI analysis. In vitro experiments showed that the phosphorylation level of STAT3 (p‐STAT3) was increased in HSFs. In addition to reducing p‐STAT3 in HSFs, AC significantly inhibited the cell viability and migration of HSFs and downregulated the protein levels of TGF‐β1, COL 1, FN 1, and α‐SMA.ConclusionSTAT3 can be activated in HS. AC may exert its pharmacological effects of inhibiting TGF‐β1 signal transduction and regulating extracellular matrix remodeling in HS by inhibiting STAT3 phosphorylation. However, the specific molecular mechanism of AC remains to be verified through further experiments.

Uncovering the Anti-Angiogenic Mechanisms of Centella asiatica via Network Pharmacology and Experimental Validation

“…Some studies used the method of network pharmacology to explore the potential therapeutic targets and biological mechanisms of CA in the treatment of fibrotic disorders, but only one or six compounds were involved [ 12 , 13 , 14 ]. In addition, through the combination of network pharmacological prediction and experimental verification, it was reported in the literature that CA can improve cardiac hypertrophy, hypertrophic scar, and liver injury [ 15 , 16 , 17 ]. The study of network pharmacology regarding CA involved very few components and has not yet been applied to an anti-angiogenesis activity.…”