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Background: Submucosal fibrosis (OSF) of the oral cavity is a chronic scarring disease. Arecoline (Are) is the driving factor for the occurrence and deterioration of OSF. Curcumin plays a vital anti-inflammatory role in Are-induced OSF development. However, its potential pharmacological mechanism needs to be elucidated., Methods: The relative molecular level was measured via qRT-PCR or Western blot. MTT assay, transwell assay and flow cytometry detected cell proliferation, migration, and apoptosis. The correlation between hypoxia-inducible factor-1α (HIF-1α) and LTBP2 promoter was confirmed through dual-luciferase reporter assay. ELISA was performed to detect inflammatory cytokines levels., Results: Curcumin alleviated Are-induced oral mucosal fibroblast cells fibrosis by reducing oral mucosa fibroblasts viability, promoting cell apoptosis, suppressing cell migration, and down-regulating the levels of fibrosis markers and inflammatory factors. Curcumin relieved Are-induced OSF via inhibiting HIF-1α. Mechanically, HIF-1α bound to the promoter of LTBP2 to transcriptionally activated LTBP2. LTBP2 knockdown relieved Are-induced OSF, and curcumin down-regulated LTBP2 via inhibiting HIF-1α to relieve Are-induced OSF. Moreover, curcumin decreased NF-κB signal associated proteins via inhibiting LTBP2 to relieve Are-induced OSF., Conclusion: Curcumin reduced the transcription level of LTBP2 by inhibiting HIF-1α, thereby inactivating NF-κB pathway to alleviate Are-induced OSF., (© 2023 Wiley Periodicals LLC.)

Purpose: Arecoline is one of the main toxic components of arecoline to cause oral mucosal lesions or canceration, which seriously affects the survival and life quality of patients. This study analyzed the mechanism of Jiawei Danxuan Koukang (JDK) in alleviating arecoline induced oral mucosal lesions, to provide new insights for the treatment of oral submucosal fibrosis (OSF) or cancerosis., Methods: Metabolomics was applied to analyze the composition of JDK and serum metabolites. The active ingredients of JDK were analyzed by the combined ultra-high performance liquid chromatography and mass spectrometry. The target network of JDK, metabolites and OSF was analyzed by network pharmacology, and molecular docking. Oral mucosal lesions and fibrosis were analyzed by HE and Masson staining. Cell differentiation, proliferation and apoptosis were detected. The expressions of α-SMA, Collagen I, Vimentin, Snail, E-cadherin, AR and NOTCH1 were detected by Western blot., Results: Arecoline induced the gradual atrophy and thinning of rat oral mucosal, collagen accumulation, the increase expressions of fibrosis-related proteins and Th17/Treg ratio. JDK inhibited arecoline-induced oral mucosal lesions and inflammatory infiltration. Arecoline induced changes of serum metabolites in Aminoacyl-tRNA biosynthesis, Alanine, aspartate and glutamate metabolism and Arginine biosynthesis pathways, which were reversed by M-JDK. Quercetin and AR were the active ingredients and key targets of JDK, metabolites and OSF interaction. Arecoline promoted the expression of AR protein, and the proliferation of oral fibroblasts. Quercetin inhibited the effect of arecoline on oral fibroblasts, but was reversed by AR overexpression. Arecoline induced NOTCH1 expression in CAL27 and SCC-25 cells, and promoted cell proliferation, but was reversed by M-JDK or quercetin., Conclusion: JDK improved the arecoline-induced OSF and serum metabolite functional pathway. Quercetin targeted AR protein to improve arecoline-induced OSF. JDK and quercetin inhibited arecoline-induced NOTCH1 protein expression in CAL27 and SCC-25 cells to play an anti-oral cancer role., Competing Interests: There is no conflict of interest to declare., (© 2023 Zhou et al.)