Effect of artesunate and relation with TGF-β1 and SMAD3 signaling on experimental hypertrophic scar model in rabbit ear

Abstract

Artesunate (ART) is the derivative of artemisinin isolated from the traditional Chinese medicine qinghao. Although several studies reported the efficiency of artesunate in the treatment of malaria, inhibiting fibroblasts and collagen synthesis, the association between artesunate and scar formation is unclear. The research was designed to study the significance of artesunate (ART) on the expression of transforming growth factor (TGF-β1) and small mother against decapentaplegic (SMAD3) in rabbit's ear hypertrophic scar model. Twenty-four New Zealand white rabbits were randomly divided into six groups: control group, matrix group, low-concentration artesunate group (0.48%), medium-concentration artesunate group (0.96%), high-concentration artesunate group (1.92%) and silicone gel group. Punched defects were established on each rabbit’s ear which resulted in a hypertrophic scar. On the 28th day, topical artesunate creams were applied twice a day except on the control group. On the 56th day, scar samples were collected for histopathology and immunoassay. Hematoxylin and eosin staining, Van Gieson staining, immunohistochemistry and Western blot analysis were done. Amongst the six groups, findings showed that the medium-concentration artesunate group (0.92%) efficiently decreased hypertrophic scar formation and significantly reduced fibroblasts and collagen synthesis. The results had also shown a decrease in the expression of transforming growth factor (TGF-β1) and declined small signal mother against decapentaplegic (Smad3). The overall study shows efficacy and mechanism of artesunate. It concluded that the medium concentration of artesunate (0.92%) could be an effective therapeutic agent for hypertrophic scars.

Role of Artesunate on cardiovascular complications in rats with type 1 diabetes mellitus

“…Values of *P < 0.05, **P < 0.01 vs Healthy group. #P < 0.05, ##P < 0.01 vs DM group indicate a significant difference between each groups effects [30,33], anticancer [34], anti-inflammatory and anti-fibrosis [35] effects, as well as inhibiting angiogenesis, which has been strongly substantiated by recent studies. Su et al [36] and Yu et al [29] have suggested that ART can effectively inhibit the NF-κB signaling pathway and serve a corresponding regulatory role in its mediated signaling pathways.…”

Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics

“…In a rabbit ear model of hypertrophic scarring, application of cream containing either artemisinin or artesunate led to improved scar appearance, lessened hypertrophy, reduced volume of fibroblasts, and a greater degree of alignment of collagen fibers 96 . In another report using a rabbit ear hypertrophic scar model, topical application of artesunate in a cream formulation resulted in a significant decrease in scar hypertrophy and decreased expression of dermal TGF- β 1 and SMAD3 protein, suggesting that artesunate alleviates the formation of hypertrophic scar in the skin via downregulation of profibrotic TGF- β family signal transducers 97 . In a rabbit model of intraarticular scar adhesion induced by surgical removal of cortical bone, local injection of artesunate dose-dependently reduced the number of fibroblasts and the deposition of collagen in the scar tissue, suggesting that artesunate may be an effective therapeutic for suppression of intraarticular fibrotic adhesion 98 .…”

“…The in vivo anti-fibrotic literature described above regarding artemisinin compounds is summarized in Table 1 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 .…”

“…While a better understanding of the tissue distribution of ingested Artemisia in humans will be critical to assessment of the feasibility of this treatment modality to target fibrosis of internal organs, we also believe that published reports describing attenuation of fibrotic phenotypes in vitro and in vivo by artemisinin compounds in skin compared to those of some other organs 96 , 97 , 109 , as well as the demonstrated ability of artemisinin compounds to blunt inflammation in varied animal models, lend credence to a proposal for using artemisinin as a topical therapeutic for dermal fibrosis or even other inflammatory skin diseases 112 , 178 , 179 , 180 , 181 , 182 , without needing to consider as deeply the pharmacokinetic properties of these drugs. In summary, given all of these reports underlying their efficacy, it seems reasonable to suggest that artemisinin drugs and, perhaps especially DLA, may serve as a promising, cost-effective therapeutic modality for treatment of one or more types of tissue fibrosis.…”

Structure‐based discovery and redesign of TGF‐β1 Elbow epitope recognition by its type‐II receptor in hypertrophic scarring biotherapy

“…Previously, we have successfully bioengineered induced pluripotent stem cells (iPSCs) from mouse adult fibroblasts that exhibited suppressive effects on in vitro HS fibroblast activation 3 . The transforming growth factor‐β1 (TGF‐β1) is a member of the TGF superfamily that is generated by multiple types of cell, which plays an essential role in wound healing by regulating cell differentiation, collagen production, and extracellular matrix degradation 4 . The TGF‐β1 regulates the production of interleukin‐6 by human fibroblasts, and facilitates the growth of fibroblasts and osteoblasts 5 ; activation of TGF‐β1 signaling pathway has been found to be involved in the formation of HS and its inhibition may represent one of the attractive strategies for limiting excessive scarring 6 .…”