Mangiferin Mitigates Gastric Ulcer in Ischemia/ Reperfused Rats: Involvement of PPAR-γ, NF-κB and Nrf2/HO-1 Signaling Pathways

Abstract

Mangiferin (MF), a xanthonoid from Mangifera indica, has been proved to have antisecretory and antioxidant gastroprotective effects against different gastric ulcer models; however, its molecular mechanism has not been previously elucidated. Therefore, the aim of this study was to test its modulatory effect on several signaling pathways using the ischemia/reperfusion model for the first time. Animals were treated with MF, omeprazole (OMP), and the vehicle. The mechanistic studies revealed that MF mediated its gastroprotective effect partly via inducing the expression of Nrf2, HO-1 and PPAR-γ along with downregulating that of NF-κB. Surprisingly, the effect of MF, especially the high dose, exceeded that mediated by OMP except for Nrf2. The molecular results were reflected on the biomarkers measured, where the antioxidant effect of MF was manifested by increasing total antioxidant capacity and glutathione, besides normalizing malondialdehyde level. Additionally, MF decreased the I/R-induced nitric oxide elevation, an effect that was better than that of OMP. In the serum, MF, dose dependently, enhanced endothelial nitric oxide synthase, while reduced the inducible isoform. Regarding the anti-inflammatory effect of MF, it reduced serum level of IL-1β and sE-selectin, effects that were mirrored on the tissue level of myeloperoxidase, the neutrophil infiltration marker. In addition, MF possessed an antiapoptotic character evidenced by elevating Bcl-2 level and reducing that of caspase-3 in a dose related order. As a conclusion, the intimated gastroprotective mechanisms of MF are mediated, partially, by modulation of oxidative stress, inflammation and apoptosis possibly via the Nrf2/HO-1, PPAR-γ/NF-κB signaling pathways.

Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway

“…1) indicates that OM in concentrations up to 100 μM can be used to investigate its effects on HO-1 expression in HPMEC. Consistent with our study, OM has been reported to similarly increase gastric HO-1 expression in rats (Mahmoud-Awny et al , 2015) and humans (Becker et al , 2006). However, other studies suggest that OM fails to induce intestinal HO-1 expression (Higuchi et al , 2009; Yoda et al , 2010).…”

“…It is also possible that OM may regulate HO-1 expression partly via these transcription factors and signaling pathways. Although previous studies have shown that OM and its S-enantiomer, esomeprazole, increases gastric (Becker et al , 2006; Mahmoud-Awny et al , 2015) and pulmonary (Ghebremariam et al , 2015) HO-1 expression, respectively, the mechanisms of HO-1 induction were not investigated. To the best of our knowledge, this is the first study to demonstrate that Nrf2 is directly involved in OM-mediated induction of HO-1 in HPMEC in vitro .…”

Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor-independent mechanisms: Role of the transcription factor nuclear factor erythroid 2–related factor 2

“…Although Mahmoud-Awny et.al. [43] observed that OM increases Nrf2 mRNA levels in rats with an ischemic/reperfusion insult, OM had no effect on the Nrf2 mRNA levels (Fig. 3A) in our study.…”

The antiulcer and antioxidant mechanisms of the butanolic fraction extract obtained from Bauhinia forficata leaves: A medicinal plant frequently used in Brazilian folk medicine

“…Studies have shown that, in gastric ulcers induced by IR after reperfusion process, ROS are generated from xanthine oxidase and the activation of neutrophils, leading to gastric mucosa lipid peroxidation (LPO), in combination with acid-gastric secretion process, results in extremely harmful ulcerogenic injury and cell death (Mahmoud-Awny et al, 2007). Thus, it is fundamental to assess lipid peroxidation (LPO) in gastric ulcers induced by IR experimental protocol.…”