探討余甘子萃取物對於防治口腔黏膜下纖維化症之效用與相關分子機轉

檳榔嚼食是罹患口腔黏膜下纖維化 (oral submucous fibrosis) 的主要致病因子。隨著疾病進展惡化，患者除了張口度受限外，還面會臨高度惡性轉化的風險。遺憾的是，儘管醫療技術持續進步，但卻尚未發展出有效的治療方法，因此口腔黏膜下纖維化仍是本國臨床乃至國民口腔衛生管理的重大議題。纖維母細胞在病理條件下持續活化是促成組織纖維化的主要推手。研究表明抑制細胞焦亡 (pyroptosis) 可以防止纖維母細胞活化，從而減少組織的慢性發炎和改善纖維化。然而目前對於細胞焦亡如何參與口腔黏膜下纖維化疾病進展的證據仍相當不足。余甘子 (Phyllanthus emblica) 在過去研究中被發現具有抗老化以及保肝等多種活性，然而目前仍沒有研究闡述余甘子改善口腔黏膜下纖維化的證據。因此本研究旨在探討余甘子萃取物阻止患者口腔肌纖維母細胞活化及抑制細胞焦亡的功效與機制。研究結果顯示 20 和 40 µg/mL 余甘子萃取物有效抑制促纖維化頰黏膜纖維母細胞 (primary fibrotic buccal mucosal fibroblasts，fBMFs) 的細胞活性與肌纖維母細胞活性，包括細胞遷移和收縮能力，同時對正常組織來源的 BMFs 沒有顯著毒性。實驗進一步發現檳榔鹼 (arecoline) 會誘導正常 BMFs 的肌纖維母細胞特性與細胞焦亡。余甘子萃取物不僅能夠減少 fBMFs 發炎小體表達，也能夠抑制檳榔鹼誘導 BMFs 的細胞焦亡。總結而言，本研究首次提出余甘子萃取物具有改善口腔黏膜下纖維化和細胞焦亡的生物活性，表明余甘子有潛力應用於口腔黏膜下纖維化的治療管理。

Chewing betel nut is the primary risk factor for oral submucous fibrosis (OSF). As the disease progresses, in addition to typical symptoms such as severe restrictions in mouth opening, patients also face a high risk of malignant transformation. Regrettably, the absence of effective diagnostic markers and treatments poses a significant challenge in clinical settings. Research indicates that inhibiting pyroptosis can prevent the activation of myofibroblasts, the primary contributors to fibrosis, thus mitigating ongoing chronic inflammation and fibrosis. However, the role of pyroptosis in activating oral myofibroblasts and fibrogenesis of OSF remains unclear. Phyllanthus emblica, is known for its multiple beneficial bioactivities. Previous studies have observed some encouraging results of anti-inflammatory and anti-fibrotic effects from its extracts in vitro and in vivo. This study aims to explore the effects of Phyllanthus emblica extract (PEE) on inhibiting the myofibroblastic activities and pyroptosis of oral fibroblasts. Our findings reveal that doses of 20 and 40 µg/mL of PEE effectively inhibit cell migration and contractility in fBMFs, while posing no harm to normal BMFs. We also established that arecoline-induced pyroptosis in normal BMFs, linking pyroptosis to myofibroblast activation. Notably, PEE not only diminished NLRP3 inflammasome expression in fBMFs but also curtailed pyroptosis triggered by arecoline. In summary, our preliminary results indicate that PEE effectively reduced myofibroblastic activation and pyroptosis in fBMFs and arecoline-induced BMFs. These findings suggest that PEE holds potential as a therapeutic or management option for OSF, particularly for conditions related to areca nut usage and uncontrolled inflammation.