Phytol nanoemulsions encapsulated alginate hydrogel beads for the protection and management of alcohol-induced gastric ulcer via nitric oxide synthase and NF-κB/IL-6/TGF-β modulation.

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Background: Innovative treatment strategies are required for stomach ulcers because of their multifactorial nature. Nanotechnology has emerged as a promising and transformative platform for the formulation and targeted delivery of therapeutic agents.Methods and findings: The gastroprotective potential of both in its free form and encapsulated in calcium alginate beads was evaluated against ethanol-induced gastric ulceration in rats. Phytol-loaded nanoemulsions were incorporated into alginate beads to achieve controlled release. Alginate beads showed a pH-dependent release pattern. The release behavior showed a higher release rate at pH 6.8 than at pH 1.2. Phytol release kinetics followed the Korsmeyer-Peppas model, indicating a release mechanism governed by diffusion and polymer relaxation. Rats were pretreated with Phytol and/or nano-Phytol at 10 or 20 mg/kg doses administered one hour before ethanol exposure. Gastric ulcer was induced by administration of EtOH (1 mL/kg, p.o.) 0.5 h after NG-nitro-L-Arginine Methyl Ester (L-NAME) or Aminoguanidine (AMG) injection. Phytol treatment led to a reduction in ulcer index and severity and improved stomach gross morphology. Also, interleukin-6 (IL-6) gastric contents were reduced, whereas transforming growth factor β (TGF-β1) was elevated, and histopathological features were ameliorated. Western blot analysis revealed that nano-Phytol exerted greater inhibitory effects on caspase-3 and Nuclear Factor kappa B (NF-κB) than unformulated Phytol. Interestingly, Phytol's pharmacological effects on ulcers were enhanced by its nanoformulation in a dose-dependent way without exhibiting any toxicity symptoms. Confocal laser scanning microscopy (CLSM) confirmed significantly improved tissue penetration of nano-Phytol within the stomach layers compared to the Phytol. The Phytol or nano-Phytol gastroprotective effects were modified via the co-administration of L-NAME and AMG.Conclusions: The nano-Phytol formulation significantly enhanced the gastroprotective effect of Phytol against ethanol-induced gastric ulcers, primarily through modulation of the nitric oxide (NO) synthase pathway, suppression of inflammation, and upregulation of the growth factor TGF-β1.