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Environ Toxicol. 2018 Jun;33(6):686-694. doi: 10.1002/tox.22557. Epub 2018 Apr 17.

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

Su TR1,2, Liao YW3, Hsieh PL4, Tsai LL5,6, Fang CY5,6, Lin T3,7, Lee YH3,7, Harn HJ8, Yu CC3,4,7.

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Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Pingtung, Taiwan.
Department of beauty science, Meiho University, Pingtung, Taiwan.
School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.
Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.
School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.
Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
Bioinnovation Center, Buddhist Tzu Chi Foundation, Department of Pathology, Hualien Tzu Chi hospital, Tzu Chi University, Hualien, Taiwan.


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.


arecoline; butylidenephthalide; myofibroblast; oral submucous fibrosis

[Indexed for MEDLINE]

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