Mitochondrial dysfunction is a basic mechanism leading to drug nephrotoxicity. Replacement of defective mitochondria with freshly isolated mitochondria is potentially a comprehensive tool to inhibit cytotoxicity induced by ifosfamide on renal proximal tubular cells (RPTCs). We hypothesize that the direct exposure of freshly isolated mitochondria into RPTCs affected by ifosfamide might restore mitochondrial function and reduce cytotoxicity. So, the aim of this study was to assess the protective effect of freshly isolated mitochondrial transplantation against ifosfamide-induced cytotoxicity in RPTCs. Therefore, the suspension of rat RPTCs (106 cells/ml) in Earle’s solution with the pH of 7.4 at 37°C was incubated for 2 h after ifosfamide (4 mM) addition. Fresh mitochondria were isolated from the rat kidney and diluted to the needed concentrations at 4°C. The media containing suspended RPTCs was replaced with mitochondrial-supplemented media, which was exposed to cells for 4 hours in flasks-rotating in a water bath at 37°C. Statistical analysis demonstrated that mitochondrial administration reduced cytotoxicity, lipid peroxidation (LPO), reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, lysosomal membrane damage, extracellular oxidized glutathione (GSSG) level, and caspase-3 activity induced by ifosfamide in rat RPTCs. Moreover, mitochondrial transplantation increased the intracellular reduced glutathione (GSH) level in RPTCs affected by ifosfamide. According to the current study, mitochondrial transplantation is a promising therapeutic method in xenobiotic-caused nephrotoxicity pending successful complementary in vivo and clinical studies.

IntroductionAlthough cisplatin is mainly utilized for treatment of various cancers such as ovarian, breast, stomach and prostate, its side effects and its drug resistance have led to more research for synthesis of new and nontoxic derivatives of platinum-group metals.1 Among the close elements of platinum in the periodic table, palladium complexes have high solubility and low renal toxicity; so several palladium complexes with different ligands such as phenanthroline derivatives, N-heterocyclic carbenes, Schiff bases etc were synthesized.2-4 One of the donor and lipophilic chelating ligands is 8-Hydroxyquinoline (8HQ), a multifunctional ligand, that possess therapeutic and antioxidant properties. It can act as a potent chelator for restoring metal balance, when the diseases are related to metal imbalance.5 Moreover, it can form a planar complex with palladium and thus complex can intercalate between DNA strands. In another mechanism, 8HQ metal complexes can facilitate the membrane damage, DNA cleavage and apoptotic cell death in tumors.

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Aims: Alzheimer is a multifactorial disease that is caused by several different etiopathogenic mechanisms. The aim of this study is to evaluate the protective effects of Allium jesdianum extract on cognitive dysfunction, mitochondrial/cellular, and genetic parameters in Streptozotocin-induced Alzheimer's disease (AD) Rat Model. Main methods: A single dose of STZ (3 mg/kg, i.c.v.) was injected to male Wistar rats in order to establish a model of sporadic AD. A. jesdianum extract (100,200, 400 mg/kg/day) and donepezil (5 mg/kg/day) were administered through oral gavage as treatment for 14 days after model induction. Cognitive function (radial arm water maze test), mitochondrial toxicity parameters consisting succinate dehydrogenase (SDH) activity, mitochondrial ROS formation, MMP decline, mitochondrial swelling and efflux of cytochrome c in various parts of the rat brain (whole brain, frontal cortex, hippocampus and cerebellum), and miR-330, miR-132, Bax and Bcl-2 genes expression in isolated rat brain neurons through RT-qPCR analysis were evaluated. Key findings: A.jesdianum extract significantly attenuated i.c.v-STZ-induced cognitive dysfunction and mitochondrial upstream toxic events. As a result of STZ injection, Bax gene was highly expressed, whereas miR-330, miR-132 and Bcl-2 gene were poorly expressed and A. jesdianumreverses the expression of the above miRNAs and genes in favor of improving AD and reducing neuronal apoptosis. Significance: A. jesdianum showed the neuroprotective capability against oxidative stress and cognitive impairment induced by STZ in rats shows its helpful therapeutic worth in AD.