Polyphenol-based targeted therapy for oral submucous fibrosis

Abstract

Oral submucous fibrosis (OSF) is a chronic, progressive, and precancerous condition mainly caused by chewing areca nut. Currently, OSF therapy includes intralesional injection of corticosteroids with limited therapeutic success in disease management. Therefore, a combined approach of in silico, in vitro and in vivo drug development can be helpful. Polyphenols are relatively safer than other synthetic counterparts. We used selected polyphenols to shortlist the most suitable compound by in silico tools. Based on the in silico results, epigallocatechin-3-gallate (EGCG), quercetin (QUR), resveratrol, and curcumin had higher affinity and stability with the selected protein targets, transforming growth factor beta-1 (TGF-β1), and lysyl oxidase (LOX). The efficacy of selected polyphenols was studied in primary buccal mucosal fibroblasts followed by in vivo areca nut extract induced rat OSF model. In in vitro studies, the induced fibroblast cells were treated with EGCG and QUR. EGCG was safer at higher concentrations and more efficient in reducing TGF-β1, collagen type-1A2 and type-3A1 mRNA expression than QUR. In vivo studies confirmed that the EGCG hydrogel was efficient in improving the disease conditions compared to the standard treatment betamethasone injection with significant reduction in TGF-β1 and collagen concentrations with increase in mouth opening. EGCG can be considered as a potential, safer and efficient phytomolecule for OSF therapy and its mucoadhesive topical formulation help in the improvement of patient compliance without any side effects. Graphical abstract Highlights Potential polyphenols were shortlisted to treat oral submucous fibrosis (OSF) using in silico tools Epigallocatechin 3-gallate (EGCG) significantly reduced TGF-β1 and collagen both in vitro and in vivo EGCG hydrogel enhanced antioxidant defense, modulated inflammation by reducing TGF-β1 and improved mouth opening in OSF rat model.

Development of Epigallocatechin 3-gallate-Loaded Hydrogel Nanocomposites for Oral Submucous Fibrosis

“…Also, the absence of rete ridges was seen in the epithelium, and lymphocytic infiltrates, congested blood vessels, and many macrophages were seen in the dermis. Fibrosed areas are seen in the dermis [9]. The submucous histopathology of rats treated with HNC had an increase in epidermis thickness nearer to healthy rats (6-10 layers) with rete ridges on the epithelium membrane.…”

“…BTM Inj. EGCG-and EGCG hydrogel-treated rats indicated a presence of tightly collagen fibre arrangement, while the nanoformulation loaded hydrogel (HNC) treated group showed a significant reduction in the collagen concentration [9]. The histopathological images of the buccal mucosa by H&E staining and Masson trichome staining are shown in Fig.…”

“…2. Sub-buccal injection of (100 µL, 20 mg/mL) ANE was given at left buccal mucosal tissue of rats for induction of OSF for 2 months, followed by treatment of disease-induced rats with optimized formulations [9,24]. The standard treatment was betamethasone injection (BTM Inj.…”

“…In silico studies, it was proved that the EGCG acts on multiple targets. Compared to other polyphenols, EGCG was effective in in vitro safety studies and efficient in reducing the expression of collagen mRNA (type-1A2 and 3A1) and TGF-β1 [9]. EGCG hydrogel showed significant improvement in OSF condition by reducing collagen and TGF-β1 concentrations and improving mouth-opening in rat models of OSF [9].…”

“…Compared to other polyphenols, EGCG was effective in in vitro safety studies and efficient in reducing the expression of collagen mRNA (type-1A2 and 3A1) and TGF-β1 [9]. EGCG hydrogel showed significant improvement in OSF condition by reducing collagen and TGF-β1 concentrations and improving mouth-opening in rat models of OSF [9]. However, EGCG has a very short half-life of 3-4 h and is susceptible to oxidation in the presence of sunlight [10].…”