Vladimiria souliei Ameliorated Aspirin-Induced Gastric Mucosal Injury by Activation Nrf2 and Inhibition RIP1 Signaling Pathways

Abstract

Prolonged or high-dose administration of nonsteroidal anti-inflammatory drugs (NSAIDs) can induce gastric mucosal injury (GMI), potentially progressing to gastric ulcer (GU). Studies have shown that oxidative stress and necroptosis were closely associated with GU. Vladimiria souliei, a traditional Chinese herb, has been used to treat digestive disorders, particularly GU, but its pharmacological mechanisms remain unidentified. This study aimed to investigate the pharmacological mechanisms of GMI treatment in this herb. Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to analyze blood-enterable components. Aspirin (ASP) was orally administered to induce GMI in mice. After intervention with Vladimiria souliei extract (VSE), the morphology of gastric tissues was observed, and the levels of pepsin and prostaglandin E2 (PGE2) were detected. Further therapeutic evaluation of VSE in GMI was performed using hematoxylin and eosin (H&E) and periodic acid-schif (PAS) staining. Serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) were measured, while immunohistochemistry and Western blot were used to assess nuclear factor erythroid 2-related factor 2 (Nrf2) and receptor interacting protein kinase 1 (RIP1)-related signaling. Six prototype components were identified in the drug-containing serum of the VSE. Moreover, VSE mitigated ASP-induced GMI with shrunken areas of ulcers and promoted gastric mucin secretion, increased the levels of SOD and PGE2, and decreased the levels of pepsin, MDA, IL-1β, IL-6, and TNF-α. Pharmacological studies revealed that VSE upregulated the expression of Nrf2, NAD (P) H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1) and down-regulated the expression of kelch-like ECH-associated protein-1 (Keap1), RIP1, RIP3, mixed lineage kinase domain-like protein (MLKL), phosphoglycerate mutase 5 (PGAM5), and dynamin-related protein 1 (Drp1) in the gastric mucosa. Therefore, VSE alleviated oxidative stress and necroptosis by regulating Nrf2 and RIP1 signaling in ASP-induced GMI mice, providing a theoretical basis for GU treatment and for the development of medicinal resources with this herb.