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.

Background Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes. Methods Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling. Results Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC50 concentration for CQ is 20 µM and for HCQ is 50 µM. Based on two-way ANOVA analysis, the highest effect of CQ and HCQ on the generation of ROS, collapse in the MMP, and mitochondrial swelling were observed at 40 µM and 100 µM concentrations, respectively (p < 0.05). Also, the highest effect of these two drugs has been observed in 60 min (p < 0.05). The statistical results showed that compared to CQ, HCQ is able to cause the release of cytochrome c from mitochondria in all applied concentrations (p < 0.05). Conclusions The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.

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Ammonium ion (NH4+) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4+‐induced brain injury exists so far. Excitotoxicity is a well‐known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N‐Methyl‐ d‐aspartate (NMDA) receptors by agents such as glutamate, an NH4+ metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4+ neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4+ were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF‐α, IL‐6, and IL‐1β was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.

Background Kidney damage caused by colistin (polymyxin E) can bring about a decrease in creatinine clearance, potential proteinuria, cylindruria and oliguria in treated patients. It is therefore imperative to develop a new therapeutic strategy for reducing kidney damage after treatment with colistin. Mitochondrial damage is one of contributing factors in colistin-induced nephrotoxicity. Given the therapeutic benefits of mitochondrial transplantation by exogenous healthy mitochondria, we hypothesized that this strategy would be capable of ameliorating renal proximal tubular cells damage following exposure with colistin.Methods For this purpose, we isolated rat renal proximal tubular cells (RPTCs) form kidney and exposed them with toxic concertation of colistin with/without rat healthy isolated mitochondria for 4 hours. Cellular parameters such as lactate dehydrogenase (LDH), reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP), caspase 3 activation, lysosomal damage, glutathione and ATP content were measured.Results The results showed that administration of isolated mitochondria could improve colistin-induced nephrotoxicity and reduce mitochondrial dysfunction. Exogenous mitochondria reduced the activity of LDH, production of ROS, ATP and GSH depletion, loss of MMP, lysosomal damages and cell death.Conclusion To the best of our knowledge, these results provide the first direct experimental evidence that mitochondrial transplantation is capable of ameliorating cellular damage following treatment with colistin. These findings support that mitochondrial transplantation can be a promising therapeutic strategy for colistin-associated mitochondrial dysfunction and kidney damage.

Aim of the study: Cholestasis/cirrhosis could induce erythrocyte lysis. The incidence of various types of anemia in cirrhosis is approx. 75%. Several studies have mentioned the pivotal role of oxidative stress in this complication. Taurine (TAU) is the human body's most abundant free amino acid. TAU is known as a robust cell membrane stabilizer. Many studies have mentioned that TAU could counteract oxidative stress in various experimental models. The current study was intended to evaluate the effect of TAU on erythrocytes in cirrhotic rats. Material and methods: Bile duct ligation (BDL) surgery was carried out on rats. Then, complete blood count (CBC), hemoglobin (Hgb), hematocrit (HTC), and erythrocytes' G6PD, catalase (CAT), and superoxide dismutase (SOD) activity were measured. Moreover, biomarkers of oxidative stress were assessed, and the erythrocytes' morphological changes were monitored in the cirrhotic mice exposed to TAU (0.25%, 0.5%, and 1% w : v in drinking water). Results: Significant changes in the assessed erythrocyte parameters (G6PD activity, Hgb, HTC, and erythrocyte count) and red blood cells (RBC) morphological alterations were detected on day 42 after BDL surgery. Biomarkers of oxidative stress also did not change at the time points, except on post-BDL days 28 and 42. A significant decrease in blood parameters was evident at post-BDL day 42. All doses of TAU (0.25%, 0.5%, and 1% w : v in drinking water) significantly improved erythrocyte parameters and encountered oxidative stress in the erythrocytes of cirrhotic animals. Conclusions: These data indicate that TAU could be a safe agent to mitigate cirrhosis-induced erythrocyte damage and anemia. Further investigations are necessary to prove this in clinical settings.