Possible Implication of Nrf2, PPAR-γ and MAPKs Signaling in the Protective Role of Mangiferin against Renal Ischemia/Reperfusion in Rats

Abstract

Mangiferin (Mang) is a known glucosylxanthone that has proven its shielding effect against ischemia/reperfusion (Is/R). However, its full underlying mechanistic perspective against renal Is/R induced lesions is not fully revealed. Consequently, the purpose of this study is to track further non-investigated modulatory signals of Mang against the renal Is/R model involving nuclear factor erythroid 2-related factor (Nrf)2/heme oxygenase (HO)-1, peroxisome proliferator-activated receptor (PPAR)-γ/nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling. To ratify our aim, Mang was administrated (20 mg/kg, i.p for seven days) before the induction of bilateral Is/R. Mechanistic maneuver revealed that Mang balanced oxidative state via increasing the expression of the antioxidant Nrf2/HO-1 cue with subsequent enhancement of GSH besides MDA lessening. Additionally, Mang enhanced PPAR-γ mRNA expression and declined p-p38 MAPK and p-JNK expression with concomitant NF-κB downsizing leading to iNOS/NOx and TNF-α rebating. Furthermore, the Mang anti-apoptotic trait was affirmed by enriching Bcl-2 expression as well as decreasing Bax and caspase-3 expression. All these potentials were in the line with the molecular docking results and the improved histopathological findings and renal function biomarkers. Consequently, Mang provided plausible protective mechanisms against renal Is/R-related events, possibly by amending oxidative status, inflammatory mediators, and apoptotic cell death through the involvement of Nrf2, PPAR-γ, MAPK, JNK, and NF-κB signaling.

Ceibinin, a new positional isomer of mangiferin from the inflorescence of Ceiba pentandra (Bombacaceae), elicits similar antioxidant effect but no anti-inflammatory potential compared to mangiferin

“…Mechanistically, mangiferin is known to elicit its antioxidant and anti-inflammatory effects by acting on a wide range of targets, including the nuclear factor erythroid 2-related factor (Nrf)2/heme oxygenase (HO)-1, peroxisome proliferator-activated receptor (PPAR)-γ/nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), c -Jun N -terminal kinase (JNK), AMP-activated protein kinase (AMPK), and NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathways [ 48 , 49 ]. We postulate that these targets were engaged by mangiferin in this study and the isomer ceibinin could also have engaged some or all of these targets, although this remains to be determined.…”

Activation of Heme Oxygenase-1 by Mangiferin in Human Retinal Pigment Epithelial Cells Contributes to Blocking Oxidative Damage

“…Subsequently, biliverdin is converted into bilirubin, thereby exerting strong antioxidant action ( Yu et al ., 2018 ; Jenkins and Gouge, 2021 ). Recently, it has been reported that Nrf2-dependent activation of HO-1 in RPE cells contributes to protection against mitochondrial damage-mediated apoptosis caused by oxidative stress ( Clementi et al ., 2022 ; Park et al ., 2022 ), and the importance of the Nrf2/HO-1 axis as a mechanism for the antioxidant activity of mangiferin in numerous cell lines has been emphasized ( Saha et al ., 2016 ; Al-Saeedi, 2021 ; Gendy et al ., 2022 ; Zhou et al ., 2023 ). In this study, mangiferin not only increased the expression of Nrf2 protein but also its phosphorylation in ARPE-19 cells treated with H 2 O 2 , and they were expressed predominantly in the nucleus.…”

“…(2023) , mangiferin reduced ROS levels and increased the levels of SOD and glutathione (GSH) in a Parkinson’s disease model, and was able to reduce oxidative stress by targeting the Nrf2 pathway. Mangiferin also protected ischemia/reperfusion-related events and helped restore hyperglycemia-induced impaired angiogenesis through Nrf2 signaling, which was associated with increased expression of heme oxygenase (HO)-1 ( Gendy et al ., 2022 ; Zhou et al ., 2023 ). HO-1 is one of the representative downstream regulators of Nrf2 and contributes to the maintenance of redox homeostasis through its metabolites ( Yu et al ., 2018 ; Jenkins and Gouge, 2021 ).…”

Enhanced Wound Healing Potential of Spirulina platensis Nanophytosomes: Metabolomic Profiling, Molecular Networking, and Modulation of HMGB-1 in an Excisional Wound Rat Model

“…As formerly described by Gendy et al, (2022) [ 85 ], 5 µm slices were sliced into positive charged slides, rehydrated, and heat-retrieved before being incubated with primary anti-TNF- and VEGF for the duration of the night (at a dilution of 1:100). Following washing, tissue sections were incubated for 30 min at room temperature with a 1:1000 dilution of an HRP-labeled secondary antibody before being blocked for endogenous peroxidases.…”