Butylidenephthalide abrogates the myofibroblasts activation and mesenchymal transdifferentiation in oral submucous fibrosis

Abstract

Oral submucous fibrosis (OSF) is a premalignant disorder in the oral cavity, and areca nut chewing habit has been implicated in the persistent activation of myofibroblasts and the subsequent fibrosis. Therefore, it is critical to ameliorate the excessive activities of myofibroblasts prior to the malignant transformation of OSF. In the current study, we evaluated the cytotoxicity of butylidenephthalide (BP), a major phthalide ingredient of Angelica sinensis, in fibrotic buccal mucosal fibroblasts (fBMFs) as well as various myofibroblast hallmarks, including the phenotypical characteristics and fibrosis-related markers. Our results demonstrated that myofibroblast activities, including collagen gel contraction, migration, invasion and wound healing abilities were inhibited in response to BP. The expression levels of myofibroblast marker, α-smooth muscle actin (α-SMA), fibronectin and type 1 collagen A1 were decreased after exposure of BP. Moreover, we found that the EMT-related markers, Twist, Snail and ZEB1 were all downregulated after BP treatment. Most importantly, our findings demonstrated that BP impeded the binding of Snail to the E-box region in the α-SMA promoter, which may lead to inhibition of the arecoline-induced myofibroblast activities. Collectively, our data indicated that BP reduced numerous myofibroblast features in fBMFs and hindered the binding of Snail to α-SMA, thereby may function as an effective and natural antifibrosis compound.

LncRNA LINC00974 activates TGF‐β/Smad signaling to promote oral fibrogenesis

“…Cell movement toward the center of the wound area was photographed at 0 and 48 hours under a microscope. Cell movement into the wound area will be photographed at 0 and 24 hours under a microscope …”

Arctigenin Reduces Myofibroblast Activities in Oral Submucous Fibrosis by LINC00974 Inhibition

“…Over the past few years, growing attention has been paid to the use of natural products against a variety of diseases, including fibrosis and cancers [20,21]. Our group has also demonstrated the effect of various natural compounds on the suppression of oral cancer or OSF via the reduction of inflammation or mesenchymal transdifferentiation [22,23,24,25]. Current evidence has suggested that TGF-β signaling is the key pathway to trigger the manifestation of OSF [7,8].…”

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy

“…EMT-inducing transcription factors such as snail, slug, and twist are involved in the pathogenesis of betel nut related OSF. They initiate and facilitate the acquisition of a mesenchymal phenotype by repressing E-cadherin [27,73,75]. Zinc finger E-box binding homeobox 1 (ZEB1), another EMT-inducing transcription factor, is also implicated in betel nut associated OSF pathogenesis because it activates the α-SMA promoter [74].…”

“…It has demonstrated therapeutic efficacy against OSF. In vitro tests revealed that butylidenephthalide downregulates α-SMA, fibronectin, and type 1 collagen A1 and reduces myofibroblast bioactivity [75]. Glabridin is derived from the root of Glycyrrhiza glabra (licorice).…”

“…Decrease α-SMA and fibronectin and type 1 collagen A1 expression Inhibit myofibroblast activity (migration and contraction) [75] Glabridin Decrease α-SMA, type I collagen, and TGF-β Inhibit myofibroblast activity (migration and contraction) [131] Asiatic acid Inhibit TGF-β1, collagen 1 type 2, and collagen 3 type 1 [134] Tanshinone reactivate p53 [135] Salvianolic acid B with Triamcinolone acetonide…”