Evaluation of the antiulcer activity of methanolic extract of Bidens biternata on experimental rats via involvement of the PGE2/Nrf2/HO-1/NF-κB/Caspase-3 pathways

Background: Bidens biternata (Lour.) Merr. & Sherff, a plant with notable ethnopharmacological relevance, has been traditionally employed for treating gastrointestinal disorders, microbial infections, and liver ailments. However, its protective role against ethanol-induced gastric injury and the underlying molecular mechanisms have not been systematically investigated. The present study is the first to evaluate the gastroprotective potential of the methanolic extract of Bidens biternata stem (MEBBS) in relation to the coordinated modulation of the prostaglandin E₂ (PGE₂)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/nuclear factor kappa-B (NF-κB)/caspase-3 signaling pathways. This investigation was designed to assess its protective effects against ethanol-induced gastric ulceration in rats and to elucidate the associated mechanisms involving oxidative stress regulation, inflammatory cytokine modulation, and activation of the Nrf2/HO-1 signaling cascade. Methods: Gastric ulcers were induced by administering absolute ethanol (5 mL/kg body weight) in rats. Prior to ulcer induction, animals received oral pretreatment with MEBBS at doses of 100, 200, or 400 mg/kg for 21 days. Ulcer index and total gastric acidity were measured to determine the extent of mucosal injury. Antioxidant profiles were evaluated by estimating superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and the lipid peroxidation marker malondialdehyde (MDA). Levels of inflammatory mediators—tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-6 (IL-6), and NF-κB, and the apoptotic marker caspase-3 were quantified. In addition, nitric oxide (NO) and PGE₂ contents were determined, alongside the expression of Nrf2 and HO-1. Histopathological analysis was performed to corroborate biochemical findings. Results: Pretreatment with MEBBS significantly (P < 0.05) reduced the ulcer index and gastric acidity dose-dependently. The extract enhanced endogenous antioxidant defenses by elevating SOD, CAT, and GSH activities while reducing MDA concentration (P < 0.05). Additionally, MEBBS suppressed (P < 0.05) pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, NF-κB) and caspase-3 expression, while upregulating Nrf2 and HO-1. The increased synthesis of NO and PGE₂ further supported mucosal protection (P < 0.05). Histological examination confirmed the restoration of gastric architecture, most prominently at the 400 mg/kg dose. Conclusions: The MEBBS exhibits significant gastroprotective effects through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. These effects appear to be mediated through the modulation of the Nrf2/HO-1/NF-κB/caspase-3 signaling network, highlighting its potential as a promising therapeutic candidate for ethanol-induced gastric ulceration.