Toxicity of popular NSAIDs on hearth mitochondria

Introduction: Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account for their cardiotoxic and arrhythmic properties. Non-steroidal anti-inflammatory drugs (NSAIDs) are most prescribed drugs in human and veterinary medicine that provide anti-inflammatory, antipyretic, analgesic, antispasmodic and anticoagulant effects. Methods and Results: Rat heart mitochondria were obtained by differential ultracentrifugation and incubated with different concentrations of highly prescribed NSAIDs (diclofenac, naproxen, celecoxib). Our results showed that NSAIDs (diclofenac, naproxen, celecoxib) induced a rise in cardiac mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial membrane potential (MMP) collapse before mitochondrial swelling ensued on isolated rat heart mitochondria. Disturbance in oxidative phosphorylation was also confirmed by the decrease in ATP concentration in the NSAIDs (diclofenac, naproxen, celecoxib)-treated heart mitochondria. In addition, the collapse of MMP and mitochondrial swelling produced the release of cytochrome c via outer membrane rupture or mitochondrial permeability transition (MPT) pore opening. Conclusions: Our results suggested that NSAIDs (diclofenac, naproxen, celecoxib)-induced toxicity in heart tissue is the result of disruptive effect on mitochondrial respiratory chain that leads to ROS formation, lipid peroxidation, MMP decline, and cytochrome c expulsion which results in apoptosis signaling and cell loss in heart myocardial tissue

Toxicity of industrial waste water containing Ag/Tio2 on muscle mitochondria isolated from Solen dactylus scallop

Industrial waste water is of global concern due to its severe effects on the environment. Recent studies have suggested that these compounds can cause toxicity via mitochondria-involved mechanisms. According to the fact, that these compounds are freely dispersed in the environment, it is crucial to determine the exact mechanism of toxicity. Introduction: Compared with municipal waste water, industrial waste water generally contains high concentration of toxic or non-biodegradable pollutants. Recently, it was shown that scallop could filter waste water, but heavy metal such as Ag and TiO2 could induce Reactive Oxygen Species (ROS) in mitochondria isolated from scallop. Recent studies have suggested that mitochondria have a key role in toxicity via mitochondrial membrane potential collapse and generation of ROS. Therefore, it was decided to determine the mechanistic toxicity of waste water contained heavy metals towards isolated scallop muscle mitochondria using new and reliable methods. Methods and Results: Isolated scallop mitochondria were obtained by differential ultracentrifugation at before and after exposure to waste water. Our results showed that two heavy metals induced mitochondrial dysfunction via an increase in mitochondrial ROS production and membrane potential collapse, which correlated to cytochrome C release. Conclusions: Our results suggest that waste water contained heavy metals-induced toxicity in scallop is result of a disruptive effect on the mitochondrial respiratory chain and increasing the chance of cell death signaling in scallop muscle cells

Tropisetron attenuated the anxiogenic effects of social isolation by modulating nitrergic system and mitochondrial function.

Abstract BACKGROUND: Early social isolation stress (SIS) is associated with the occurrence of anxiety behaviors. It seems interaction between the nitrergic system and mitochondrial function plays a role in mediating the anxiety-like behaviors. In this study, we aimed to investigate the anxiolytic effects of tropisetron in animal model of SIS and we try to illustrate the possible role of nitrergic system and mitochondrial function. METHODS: We applied early social isolation paradigm to male NMRI mice. Animals treated with various doses of tropisetron, nitric oxide agents or their combination and anxiety-like behaviors of animals were assessed using valid behavioral tests including elevated plus maze (EPM), open-field test (OFT) and hole-board test (HBT) in their adulthood. Effects of housing conditions and drug treatments on the mitochondrial function were investigated in the hippocampus by assessing the ATP, GSH, ROS and nitrite levels. RESULTS: Anxiogenic effects of early SIS were assessed in the EPM, OFT, and HBT. Also, SIS disrupted mitochondrial function and caused oxidative stress in the hippocampus of stressed animals. Tropisetron showed an anxiolytic effect in the stressed mice. Also, these effects were mediated by nitrergic system by affecting mitochondrial function and modulating the oxidative stress. L-arginine, a nitric oxide precursor, abolished the anxiolytic effects of tropisetron in the behavioral tasks and blocked the protective effects of it against mitochondrial and oxidative challenge. CONCLUSIONS AND GENERAL SIGNIFICANCE: Our results demonstrated tropisetron attenuated the anxiogenic effects of SIS by mitigation of the negative effects of nitric oxide on mitochondrial functio

Attenuation of oxidative and nitrosative stress in cortical area associates with antidepressant-like effects of tropisetron in male mice following social isolation stress.

Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, tropisetron (5 mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20 mg/kg) augmented the protective effects of tropisetron (1 mg/kg) on SIS. Furthermore, l-arginine (nitric oxide precursor, 100 mg/kg) abolished the positive effects of tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral corte

Toxicity mechanisms of Cigarette Smoke on Eye and Kidney using Isolated Mitochondria: Toxicity of Cigarette Smoke on Eye and Kidney

Cigarette smoking is one of the main risk factors for premature human death associated to a variety of respiratory and vascular diseases, and cancer due to containing Hundreds of toxicants. Rat mitochondria were obtained by differential ultracentrifugation and incubated with different concentrations (1, 10 and 100%) of standardized cigarette smoke extract (CSE). Our results showed that cigarette smoke extract (CSE) induced a rise in mitochondrial ROS formation and mitochondrial membrane potential decrease before mitochondrial swelling ensued in isolated eye and kidney mitochondria. Disturbance in oxidative phosphorylation was also confirmed by decrease in ATP concentration in the CSE treated mitochondria. In addition, collapse of mitochondrial membrane potential (MMP) and mitochondrial swelling caused release of cytochrome c via outer membrane rupture or MPTpore opening. Our results suggested that cigarette smoke induced toxicity in both external directly exposed and visceral tissues is the result of disruptive effect on mitochondrial respiratory chain that leads to ROS formation, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion which starts apoptosis signaling and cell loss

A Search for Anti-Carcinogenic and Cytotoxic Effects of Persian Gulf Sea Snake (Enhydrina schistosa) Venom on Hepatocellular Carcinoma Using Mitochondria Isolated from Liver: Cytotoxic effects of Enhydrina schistosa venom

Common techniques for the treatment of Hepatocellular carcinoma (HCC) have not been successful, and thus the design and discovery of new compounds with better anti-cancer function are needed. Snake venom is among the most important compounds used by researchers to the treatment of various cancers. This study was designed to evaluate the toxicity effect of Persian Gulf snake venom (Enhydrina schistosa) on hepatocytes and mitochondria isolated from HCC rats model. HCC has been induced in rats with diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF). Then rat hepatocytes were isolated with collagen perfusion technique. The results showed that E. schistosa (5, 10, 20 and 40 μg/ml) increases the level of reactive oxygen species (ROS) generation, collapse in mitochondrial membrane potential (MMP), swelling in mitochondria, and cytochrome c release only in hepatocytes and mitochondria isolated from the HCC group. These results proposed that E.schistosa could be considered as a promising complementary therapeutic agent for the treatment of HCC

Toxicity of Atorvastatin on Isolated Brain Mitochondria: Neurotoxicity of Atorvastatin

Background: Although the bio kinetics, metabolism and chemical toxicity of Atorvastatin are well known, until recently little attention was paid to the potential neurotoxic effect of Atorvastatin (Atv). Regarding the concrete evidences indicating Atv may reduce Coenzyme Q10 (CoQ10) levels through blockage of metalonate cycle, the present work aims to determine if Atorvastatin may provide toxic effects on brain mitochondria and whether its supplementation with two lipidicantioxidants, CoQ10 and Vit E may improve such outcomes.Methods: to evaluate mitochondrial toxicity, male NMRI mice were first treated with Atorvastatin(bo; 20 and 60 mg/kg) every other day with or without supplementation with CoQ10 (200 mg/kg) or Vit E (40 u/kg). After a period of 4 weeks, the animals were euthanized and brain cortices were harvested ad subjected to mitochondria isolation procedure. ROS release, mitochondrial membrane potential (MMP) and cytochrome c release were performed to precisely address the probable mitochondrial injury.Findings: Our data showed increased ROS formation, MMP collapse, mitochondrial swelling and cytochrome c release in Atorvastatin treated mice, suggesting that mitochondrial ROS formation and apoptosis signaling are likely involved in Atorvastatin neurotoxicity. Importantly according to the data from animals receiving either CoQ10 or Vit E, supplementation with these lipophilic antioxidants, remarkable reverted the corresponding Atorvastatin mitochondrial toxicity markers.Concusion: Conclusively the present work addresses chronic Atorvastatin toxic effects on brain mitochondria and supports advantages of Vit E or CoQ10 supplementation. Whether such neurotoxic effect is correlated with CoQ10 depletion or if the improving effects of the due supplementation contribute toAtorvastatin receiving patients, needs more investigations

Embryotoxic Effects of Atorvastatin on Mouse Fetus: Embryo toxicity of atorvastatin

Although the biokinetics, metabolism, and chemical toxicity of atorvastatin calcium are well known, until recently little attention was paid to the potential toxic effects of atorvastatin calcium on re-production and development in mammals. In recent years, it has been shown that atorvastatin calcium is a developmental toxicant given orally or subcutaneously (SC) to mice. Decreased fertility, embryo/fetal toxicity including teratogenicity, and reduced growth of the offspring have been observed following atorvastatin calcium exposure at different gestation periods. On the other hand, an in vitro study using fetal isolated mitochondria nowadays has been recognized as a confident tool to evaluate the developmental toxicity of a number of chemicals. Although the developmental toxicity induced by atorvastatin has been investigated, the precise cellular mechanism of atorvastatin -induced embryo-toxicity has not been thoroughly recognized yet. For investigating the effects of atorvastatin calcium on pregnant animals, three groups (control, sham and test) of NMRI mice were chosen. In test group,50mg/kg,100mg/kg and 150mg/kgof atorvastatin calcium were intraperitonealy administered at 11 day of gestation, in sham group only normal saline injected to interior peritoneum as indicated in the test group and in Control group which was considered as the comparison base line of our research, no injection was made. Caesarean sections were performed at 15 day of the gestation; and their placentas were examined externally. Based on our results atorvastatin calcium caused significant external anomalies, and caused a significant decrease (p<0.001) in the weight and diameter of placentas, the number of the embryos, their body weight and crown-rump length of fetuses

Persian Gulf stonefish (Pseudosynanceia melanostigma) venom fractions selectively induce apoptosis on cancerous hepatocytes from hepatocellular carcinoma through ROS-mediated mitochondrial pathway

Background: Globally, hepatocellular carcinoma (HCC) is the 3rd leading reason for mortality associated with cancer and the 6th most widespread malignant tumor. Objectives: This study aims to investigate selective toxicity of venom fractions of Pseudosynanceia melanostigma, commonly known as stonefish, on hepatocytes and mitochondria obtained from diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC). Methods: Different dilutions of extracted fractions from crude stonefish venom were treated on hepatocytes and mitochondria isolated from a rat model of hepatocellular carcinoma induced by diethylnitrosamine (DEN). In response to stonefish venom fractions, mitochondrial related parameters including generation of reactive oxygen species (ROS), mitochondrialmembranepotential (MMP) collapse, mitochondrial swelling, cytochrome c release, activation of caspase 3, and induction of apoptosis were investigated. Results: Our results demonstrate that for the first time, fraction 3 of Pseudosynanceia melanostigma treatment on cancerous mitochondria had a significant accumulation of reactive oxygen species (ROS). In addition, mitochondrial membrane potential (MMP) disruption, mitochondrial swelling, and cytochrome c release increased. Moreover, fraction 3 induced selective toxicity only in cancerous hepatocytes from the HCC but not those from healthy cells. Additional research also determined a significant increase in activation of caspase 3 and induction of apoptosis. Conclusions: In conclusion, this study provides evidence that fraction 3 of Pseudosynanceia melanostigmavenomselectively induces apoptosis in cancerous hepatocytes from HCC through a ROS-mediated mitochondrial pathwa

Selective Toxicity of Ag/Tio2 Nanoparticles of Waste Water of Industrial Factories on Muscle Mitochondria Isolated from Solendactylus Scallop: Toxicity of Ag/TiO2 of on Solendactylus scallop

Industrial wastewater is of global concern due to its severe effects on the environment. Compared with municipal wastewater, industrial wastewater generally contains the high concentration of toxic or no biodegradable pollutants. In recently year, scientific showed that scallop could filtration wastewater. Therefore, it was decided to determine the mechanistic toxicity of wastewater contained NPs (Ag and TiO2) towards isolated mitochondria via reliable methods. Isolated muscle scallop mitochondria were obtained by differential ultracentrifugation on before and after exposure to wastewater. Our results showed that two NPs (Ag and TiO2) induced mitochondrial dysfunction via an increase in mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation (LPO) and mitochondrial membrane potential (MMP) collapse. Finally, Ag-NPs and TiO2-NPs have reduced the level of glutathione (GSH) and also induced apoptosis. Our results suggest that wastewater contained NPs -induced toxicity is the result of a disruptive effect on the mitochondrial respiratory chain, increasing the chance of cell death signaling