The implication of the crosstalk of Nrf2 with NOXs, and HMGB1 in ethanol-induced gastric ulcer: Potential protective effect is afforded by Raspberry Ketone

Abstract

Ethanol consumption is one of the common causative agents implicated in gastric ulcer development. Oxidative stress plays a major role in the induction and development of gastric ulceration. NADPH oxidases (NOXs) and Nuclear factor erythroid 2-related factor 2 (Nrf2) are key players in ethanol-induced ulcers. High-mobility group box 1 (HMGB1), a ubiquitous nuclear protein, mediates various inflammation functions. However, the role of HMGB1 in ethanol-induced gastric ulcer is not yet elucidated. Raspberry Ketone (RK) is a natural phenolic compound with antioxidant and anti-inflammatory properties. In the present study, absolute ethanol (7.5 ml/kg) was used to induce gastric ulceration in rats. Raspberry Ketone (RK) (50 mg/kg) was given orally one hour before the administration of absolute ethanol. Interestingly, ethanol-induced gastric ulcer was associated with Nrf2 downregulation, which was correlated with NOX-1, 2 NOX-4, and HMGB1 upregulation, and was significantly reversed by RK pre-treatment. RK pre-treatment provided 80% gastroprotection. Gastroprotective properties of RK were mediated via antioxidant, anti-inflammatory (suppression of NF-kB and tumor necrosis factor-α), and antiapoptotic activities (reduction of Bax/Bcl2 ratio). Gastroprotective properties of RK were confirmed by histopathological examination. In conclusion, this study is the first to provide evidence to the role of HMGB1 in ethanol-induced gastric ulcer, and the crosstalk of Nrf2, NOXs and HMGB1. It also demonstrates that RK represents a promising gastroprotective activity comparable to omeprazole.

Gastroprotective Effect of Sinapic Acid on Ethanol-Induced Gastric Ulcers in Rats: Involvement of Nrf2/HO-1 and NF-κB Signaling and Antiapoptotic Role

“…The inflammatory response is a key process in the gastric mucosa defense mechanism ( Martin and Wallace, 2006 ). Ethanol encourages inflammation, which triggers the recruitment of macrophages and the accumulation of inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, thus promoting the accumulation of neutrophils at sites of inflammation, the destruction of mucosal barriers, and ROS production ( Abdelwahab, 2013 ; Philpott et al, 2014 ; Almasaudi et al, 2016 ; Badr et al, 2019 ). Ethanol intubation led to an enhancement of TNF-α and IL-6 levels and increased the level of the neutrophil infiltration index marker MPO compared with normal control rats.…”

“…The Nrf2/HO-1 signaling pathway plays a crucial role in protecting cells from oxidative-stress-induced injuries by restoring endogenous antioxidant enzymes (GSH, CAT, and HO-1) ( Yanaka, 2018 ; Badr et al, 2019 ). Nrf2 binds to the negative regulator Keap1 and remains inactive in the cytoplasm.…”

C‐phycocyanin protects against ethanol‐induced gastric ulcers in rats: Role of HMGB1/NLRP3/NF‐κB pathway

“…7 HMGB1 was found to play a role in gastric ulceration and inflammatory cytokine production. 8 However, its role in ethanol-induced gastric ulcer was not previously elucidated. Accordingly, HMGB1 is a new intervention factor for inflammation suppression.…”

Raspberry Ketones Attenuate Cyclophosphamide-Induced Pulmonary Toxicity in Mice through Inhibition of Oxidative Stress and NF-ΚB Pathway

“…Thus, the rise in their activities due to RKs contributes to the protection against CP-induced pulmonary injury. The antioxidant property of RKs was reported in several tissues including gastric [ 25 ], hepatic [ 14 ], and brain tissues [ 26 ].…”