Abstract
Salvia miltiorrhiza Bunge has been reported to possess excellent antifibrotic activity. In this study, we have investigated the effect and mechanism of tanshinone IIA1 (Tan-IIA1), salvianolic acid A (Sal-A) and salvianolic acid B (Sal-B), the important active compounds of Salvia miltiorrhiza Bunge, on areca nut extract (ANE)-induced oral submucous fibrosis (OSF) in vitro. Through human procollagen gene promoter luciferase reporter plasmid assay, hydroxyproline assay, gelatin zymography assay, qRT-PCR, ELISA and Western blot assay, the influence of these three compounds on ANE-stimulated cell viability, collagen accumulation, procollagen gene transcription, MMP-2/-9 activity, MMP-1/-13 and TIMP-1/-2 expression, cytokine secretion and the activation of PI3K/AKT, ERK/JNK/p38 MAPK and TGF-β/Smads pathways were detected. The results showed that Tan-IIA1, Sal-A and Sal-B could significantly inhibit the ANE-stimulated abnormal viability and collagen accumulation of mice oral mucosal fibroblasts (MOMFs), inhibit the transcription of procollagen gene COL1A1 and COL3A1, increase MMP-2/-9 activity, decrease TIMP-1/-2 expression and inhibit the transcription and release of CTGF, TGF-β1, IL-6 and TNF-α; Tan-IIA1, Sal-A and Sal-B also inhibited the ANE-induced activation of AKT and ERK MAPK pathways in MOMFs and the activation of TGF-β/Smads pathway in HaCaT cells. In conclusion, Tan-IIA1, Sal-A and Sal-B possess excellent antifibrotic activity in vitro and can possibly be used to promote the rehabilitation of OSF patients.
Highlights
It has been reported that there are about 600 million betel quid chewers around the world [1], and epidemiologic studies have indicated that betel quid chewing is a major risk factor of oral submucous fibrosis (OSF), oral leukoplakia and oral squamous cell carcinoma [2]
OSF is closely associated with areca nut chewing [7]; areca nut extract (ANE) can induce the production of TGF-β, IL-6 and prostaglandin E2, upregulate the expression of COX-2 and heat shock protein 27 and activate PI3K/Akt, PKC-α, ERK/JNK/p38 MAPK, NF-κB and TGF-β/Smads signaling pathways, some of which contribute to the malignant transformation of OSF [8,9,10,11,12,13]
We investigate the antifibrotic effect of tanshinone IIA (Tan-IIA), salvianolic acid A (Sal-A) and salvianolic acid B (Sal-B), the important active compounds of Salvia miltiorrhiza
Summary
It has been reported that there are about 600 million betel quid chewers around the world [1], and epidemiologic studies have indicated that betel quid chewing is a major risk factor of oral submucous fibrosis (OSF), oral leukoplakia and oral squamous cell carcinoma [2]. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, has antifibrotic, antioxidative, anti-inflammatory and antiapoptotic properties; it can ameliorate hepatic, pulmonary and cardiac fibrosis by suppressing the expression of type I/III collagen, α-SMA, CTGF, TGF-β, TNF-α, IL-1α and caspase-3, upregulating the expression of MMP-2/-9, decreasing MDA production and increasing SOD activity [15,16]. An important ethanol-soluble compound is tanshinone IIA (Tan-IIA); it can inhibit hepatic, pulmonary and cardiac fibrosis via inhibiting the activation of PI3K/AKT, ERK/JNK/p38 and NF-κB pathways [17,18]. Sal-B attenuates cardiac and hepatic fibrosis by inhibiting fibroblast migration, collagen deposition and activation of MEK/ERK/p38 MAPK, NF-κB and TGF-β1/Smads pathways [20,23,24]. We investigate the antifibrotic effect and mechanism of Tan-IIA, Sal-A and Sal-B in mice oral mucosal fibroblasts (MOMFs) and human HaCaT cells in vitro
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