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

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

Effect of mangiferin and omeprazole on ulcer index in ischemia/reperfused rats.

<p>Mangiferin (10 & 20 mg/kg; MF₁₀ & MF₂₀) and omeprazole (20 mg/kg; OMP₂₀) were administered intraperitoneally 30 min. before induction of ischemia/ reperfusion (I/R) and for 3 days after reperfusion. Values are means of 7–9 rats ± S.E.M; as compared with sham (*), I/R (^@), MF₁₀ (δ), and OMP (#) treated groups (one-way ANOVA followed by Student-Newman-Keuls multiple comparison tests), <i>P</i>< 0.05.</p

Effect of mangiferin and omeprazole on nitrosative stress parameters in ischemia/reperfused rats.

<p>Mangiferin (10 & 20 mg/kg; MF₁₀ & MF₂₀) and omeprazole (20 mg/kg; OMP₂₀) were administered intraperitoneally 30 min before induction of ischemia/ reperfusion (I/R) and for 3 days after reperfusion. Values are means of 7–9 rats ± S.E.M, as compared with sham (*), I/R (^@), MF₁₀ (δ) and OMP (#) treated groups (one-way ANOVA followed by student-Newman-Keuls multiple comparison tests), <i>P</i>< 0.05. NOx (total nitric oxide), eNOS (endothelial nitric oxide synthase), and iNOS (inducible nitric oxide synthase)</p

Effect of mangiferin and omeprazole on inflammatory cytokines, neutrophils infiltration and apoptotic biomarkers in ischemia/reperfused rats.

<p>Mangiferin (10 & 20 mg/kg; MF₁₀ & MF₂₀) and omeprazole (20 mg/kg; OMP₂₀) were administered intraperitoneally 30 min before induction of ischemia/ reperfusion (I/R) and for 3 days after reperfusion. Values are means of 7–9 rats ± S.E.M, as compared with sham (*), I/R (^@), MF₁₀ (δ), and OMP (^#) treated groups (one-way ANOVA followed by Student-Newman-Keuls multiple comparison tests) at <i>P</i>< 0.05. IL-1β (interleukin-1beta), MPO (myeloperoxidase), Bcl-2 (B cell leukemia/lymphoma2).</p

Effect of mangiferin and omeprazole on the mRNA expression of (A) Nrf2, (B) HO-1, (C) PPAR-γ, and (D) NF-κB genes in ischemia/reperfused rats.

<p>Mangiferin (10 & 20 mg/kg; MF₁₀ & MF₂₀) and omeprazole (20 mg/kg; OMP₂₀) were administered intraperitoneally 30 min before induction of ischemia/reperfusion (I/R) and for 3 days after reperfusion. Values are means of 7–9 rats ± S.E.M; as compared with sham (*), I/R (^@), MF₁₀ (δ), and OMP (#) treated groups (one-way ANOVA followed by Student-Newman-Keuls multiple comparison tests) at <i>P</i>< 0.05.</p

Representative photomicrographs of stomach mucosa.

<p>[A] Sham-operated rat section shows normal gastric mucosal (mu), submucosal (sm) and muscularis (mL) architecture. [B] Ischemia/reperfusion (I/R) sections show sloughed mucosa (m), juxtraposed with underlying haemorrhage (black arrow), [C] severe vascular congestion (V), focal inflammatory cells infiltration (m) and oedema (O) in submucosa. [D] MF₁₀ section reveals only congestion in the submucosal blood vessels (V) with mild inflammatory cell infiltration (yellow arrow) and/or edema. [E] MF₂₀ section, similar to sham-operated control, shows normal intact histological structure except for very mild vascular congestion (v) in the submucosa. [F] OMP₂₀ section mimics that of MF₂₀, but shows only congested blood vessels (V) in the submucosal layer.</p

Neuroprotective Effects of Some Nutraceuticals against Manganese-Induced Parkinson&rsquo;s Disease in Rats: Possible Modulatory Effects on TLR4/NLRP3/NF-&kappa;B, GSK-3&beta;, Nrf2/HO-1, and Apoptotic Pathways

Parkinson&rsquo;s disease (PD) is a progressive neurodegenerative disorder affecting the substantia nigra where functions controlling body movement take place. Manganese (Mn) overexposure is linked to a neurologic syndrome resembling PD. Sesamol, thymol, wheat grass (WG), and coenzyme Q10 (CoQ10) are potent antioxidants, anti-inflammatory, and anti-apoptotic nutraceuticals. We investigated the potential protective effects of these nutraceuticals alone or in combinations against MnCl2-induced PD in rats. Seven groups of adult male Sprague Dawley rats were categorized as follows: group (I) was the control, while groups 2&ndash;7 received MnCl2 either alone (Group II) or in conjunction with oral doses of sesamol (Group III), thymol (Group IV), CoQ10 (Group V), WG (Group VI), or their combination (Group VII). All rats were subjected to four behavioral tests (open-field, swimming, Y-maze, and catalepsy tests). Biochemical changes in brain levels of monoamines, ACHE, BDNF, GSK-3&beta;, GABA/glutamate, as well as oxidative stress, and apoptotic and neuroinflammatory biomarkers were evaluated, together with histopathological examinations of different brain regions. Mn increased catalepsy scores, while decreasing neuromuscular co-ordination, and locomotor and exploratory activity. It also impaired vigilance, spatial memory, and decision making. Most behavioral impairments induced by Mn were improved by sesamol, thymol, WG, or CoQ10, with prominent effect by sesamol and thymol. Notably, the combination group showed more pronounced improvements, which were confirmed by biochemical, molecular, as well as histopathological findings. Sesamol or thymol showed better protection against neuronal degeneration and some behavioral impairments induced by Mn than WG or CoQ10, partly via interplay between Nrf2/HO-1, TLR4/NLRP3/NF-&kappa;B, GSK-3&beta; and Bax/Bcl2 pathways