Mangiferin Ameliorates Cisplatin Induced Acute Kidney Injury by Upregulating Nrf-2 via the Activation of PI3K and Exhibits Synergistic Anticancer Activity With Cisplatin

Abstract

Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-κB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro-survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin.

Aqueous Extract of Davallia mariesii Attenuates 6-Hydroxydopamine-Induced Oxidative Damage and Apoptosis in B35 Cells Through Inhibition of Caspase Cascade and Activation of PI3K/AKT/GSK-3β Pathway

“…Therefore, we suggest that the DM extract inhibited GSK-3β phosphorylation and restored the protein expression of HO-1 and NQO-1 via activating the PI3K/AKT pathway and inhibiting mitochondria-dependent caspase cascade to counteract oxidative damage, mitochondrial dysfunction and apoptosis caused by 6-OHDA in B35 cells. There are reports about oxidative damage caused by toxins or ischemia-reperfusion, mangiferin and epicatechin protected against cardiac, intestinal, renal, or cerebral damage via activation of the PTEN/PI3K/AKT pathway or Nrf2/HO-1 pathway [ 39 , 40 , 41 , 42 , 43 ]. In fact, mangiferin and epicatechin have a preventative role in aging-associated symptoms and neurodegenerative diseases, as reported by many researchers [ 26 , 44 , 45 ].…”

pH-responsive and targeted delivery of curcumin via phenylboronic acid-functionalized ZnO nanoparticles for breast cancer therapy

“…The in vitro mode of cell death was checked by FACS analysis [29]. Briefly, after exposure to ZnO-PBA NPs, curcumin, or ZnO-PBA-Curcumin, cells were suspended in annexin V binding buffer and stained with annexin V dye for approximately 30 min.…”

“…All animals were distributed into 5 sets (n = 6/set). To develop a solid tumor model (in sets II, III, IV and V), Ehrlich ascites carcinoma (EAC) cells were injected (10 7 cells per 50 µL/mouse) into the left flank of the mice on day 0 [29]. EAC cells were not injected in set I.…”

Embelin attenuates cisplatin‐induced nephrotoxicity: Involving inhibition of oxidative stress and inflammation in addition with activation of Nrf‐2/Ho‐1 pathway

“…Results were standardized to the β‐actin expression in each group (mean ± SEM) as a percentage of control. No variations were detected in β‐actin expression among exploratory groups .…”