Protective Role of Ellagic Acid Against Ethanol-Induced Neurodevelopmental Disorders in Newborn Male Rats: Insights into Maintenance of Mitochondrial Function and Inhibition of Oxidative Stress.

OBJECTIVE: Ellagic acid (EA) exerts, neuroprotective, mitoprotective, anti-oxidative and anti-inflammatory effects. We evaluated protective effect of EA on ethanol-induced fetal alcohol spectrum disorders (FASD). METHODS: A total of 35 newborn male rats were used, divided into five groups, including; control (normal saline), ethanol (5.25 g/kg per day), ethanol (5.25 g/kg per day) + EA (10 mg/kg), ethanol (5.25 g/kg per day) + EA (20 mg/kg) and ethanol (5.25 g/kg per day) + EA (40 mg/kg). Thirty-six days after birth behavioral tests (Morris water maze and Elevated Plus Maze), tumor necrosis factor-α (TNF-α) levels, oxidative markers (malondialdehyde, glutathione and superoxide dismutase), mitochondrial examination such as succinate dehydrogenases (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) formation were analyzed. RESULTS: The results revealed that ethanol exposure adversely affected cognitive and mitochondrial functions and as well as induced oxidative stress and inflammation in brain tissue. However, EA (20 and 40 mg/kg) administration effectively prevented the toxic effects of ethanol in FASD model. CONCLUSIONS: These findings demonstrate that ethanol application significantly impairs the brain development via mitochondrial dysfunction and induction of oxidative stress. These data indicate that EA might be a useful compound for prevention of alcohol-induced FASD.

Pre-mating exposure with hesperidin protects N-ethyl-N-nitrosourea-induced neurotoxicity and congenital abnormalities in next generation of mice as a model of glioma.

Chemical carcinogen-induced oxidative stress has a key role in cell signaling linked to the development of cancer. Oxidative stress leads to oxidative damage to cellular membranes, proteins, chromosomes and genetic material. It is thought that compounds like hesperidin with high antioxidant and anticancer potential can reduce development of cancer induced by chemical carcinogens via neutralizing their oxidative damages. We investigated protective effect of hesperidin against N-Ethyl-N-Nitrosourea (ENU)-induced neurotoxicity, congenital abnormalities and possible brain cancer after exposure of mice during pregnancy as model of glioma. The mice were divided to four groups; control (normal saline), ENU (40 mg/kg daily for three consecutive days from the 17th to the 19th of pregnancy), hesperidin (pretreated with 25 mg/kg for 30 consecutive days, before mating) + ENU and hesperidin alone. Developmental toxicity parameters (the number of pregnant mice, stillbirths, abortion, live and dead offspring), behavioral tests (novel object recognition, open field and elevated plus maze) were performed. Moreover, the activity of butrylcholinesterase and acetylcholinesterase enzymes, oxidative markers and histopathological abnormalities were detected in brain tissue. Our data showed that conversely, the pretreatment of hesperidin reduces various degrees of developmental toxicity, neurobehavioral dysfunction, neurotoxicity, oxidative stress and histopathological abnormalities induced by ENU as a neurotoxic and carcinogenic agent in the next generation. In conclusion, pre-mating exposure with hesperidin may open new avenues for prevention of primary brain cancer in next generation and could be valuable for enhancing the antioxidant defense and minimizing the developmental and neurotoxicity of DNA alkylating agents.

Hesperidin, vanillic acid, and sinapic acid attenuate atorvastatin-induced mitochondrial dysfunction via inhibition of mitochondrial swelling and maintenance of mitochondrial function in pancreas isolated mitochondria.

It has been reported that lipophilic statins such as atorvastatin can more readily penetrate into ß-cells and reach the mitochondria, resulting in mitochondrial dysfunction, oxidative stress, decrease in insulin release. Many studies have shown that natural products can protect mitochondrial dysfunction induced by drug in different tissue. We aimed to explore mitochondrial protection potency of hesperidin, vanillic acid, and sinapic acid as natural compounds against mitochondrial dysfunction induced by atorvastatin in pancreas isolated mitochondria. Mitochondria were isolated form rat pancreas and directly treated with toxic concentration of atorvastatin (500 µM) in presence of various concentrations hesperidin, vanillic acid, and sinapic acid (1, 10, and 100 µM) separately. Mitochondrial toxicity parameters such as the reactive oxygen species (ROS) formation, succinate dehydrogenases (SDH) activity, mitochondrial swelling, depletion of glutathione (GSH), mitochondrial membrane potential (MMP) collapse, and malondialdehyde (MDA) production were measured. Our findings demonstrated that atorvastatin directly induced mitochondrial toxicity at concentration of 500 µM and higher in pancreatic mitochondria. Except MDA, atorvastatin caused significantly reduction in SDH activity, mitochondrial swelling, ROS formation, depletion of GSH, and collapse of MMP. While, our data showed that all three protective compounds at low concentrations ameliorated atorvastatin-induced mitochondrial dysfunction with the increase of SDH activity, improvement of mitochondrial swelling, MMP collapse and mitochondrial GSH, and reduction of ROS formation. We can conclude that hesperidin, vanillic acid, and sinapic acid can directly reverse the toxic of atorvastatin in rat pancreas isolated mitochondria, which may be beneficial for protection against diabetogenic-induced mitochondrial dysfunction in pancreatic ß-cells.

Vanillic acid protects mortality and toxicity induced by N-ethyl-N-nitrosourea in mice; in vivo model of chronic lymphocytic leukemia.

Alkylating agents such as N-Ethyl-N-Nitrosourea (ENU) are ubiquitous within living cells and in the environment. This study designed to evaluate the chemopreventive activity of vanillic acid on ENU-induced toxicity and carcinogenesis in mice as an animal model of chronic lymphocytic leukemia (CLL). The female, Swiss albino mice were divided into three groups each with 7 mice, group I received normal saline, group II, mice received ENU at a dose of 80 mg/kg body weight i.p. to induce CLL on the 31th day of the study, and group III, the mice pretreated with vanillic acid at a dose of 20 mg/kg body weight/day, i.p. up to 30 days and received ENU. The animals were monitored for weight changes and mortality during 120 days, and then were sacrificed for isolation of lymphocytes, as target cells in CLL. Cellular parameters like reactive oxygen species (ROS) formation, malondialdehyde (MDA) production, depletion of glutathione (GSH), mitochondrial membrane potential (MMP) and lysosomal membrane integrity were studied. We found that pretreatment with vanillic acid significantly increased the survival of mice up to 57%, delay in death time (30%) and prevented weight changes after exposure to ENU. In addition, it was found that vanillic acid protected ROS formation, lipid peroxidation mitochondrial dysfunction, and lysosomal membrane destabilization in isolated lymphocytes. These data suggest that vanillic acid exhibited significant protection against ENU-induced toxicity and carcinogenicity, which might be related to the protection of the mitochondria and lysosomes and the reduction of ROS formation and oxidative stress.

Vitamin D ameliorates celecoxib cardiotoxicity in a doxorubicin heart failure rat model via enhancement of the antioxidant defense and minimizing mitochondrial dysfunction.

Recent evidence suggests the mechanistic role of mitochondria and oxidative stress in the development of celecoxib-induced cardiotoxicity. On the other, it has reported the positive effects of vitamin D on oxidative stress and the maintenance of mitochondrial functions. This current study examined the cardiac effects of celecoxib, doxorubicin, vitamin D, and a combination of them in rats. The effect of 10 days of celecoxib (100 mg/kg/day), doxorubicin (2.5 mg/kg), vitamin D (60,000 U/kg), and their combination was studied on cardiac function according to serum lactate dehydrogenase (LDH), creatine kinase (CK), glutathione (GSH), and malondialdehyde (MDA) levels as well as mitochondrial succinate dehydrogenases (SDH) activity, reactive oxygen species (ROS) production, mitochondrial swelling, and mitochondrial membrane potential (MMP). Results showed that celecoxib and its combination with doxorubicin led to abnormality in paws and limbs, increased pressure in the eyes, blindness and animal death (in about 75% of the animals under study). Moreover, celecoxib and its combination with doxorubicin significantly increased cardiotoxicity biomarkers, oxidative stress markers (GSH and MDA), and mitochondrial toxicity parameters (SDH, ROS formation, MMP collapse, mitochondrial swelling). However, the combination of vitamin D with celecoxib and celecoxib + doxorubicin caused a significant reversal of deformity in paws and limbs, increased pressure in the eye, blindness, and animal death, as well as cardiotoxicity, oxidative stress, and mitochondrial parameters. This study proved for the first time the beneficial effect of vitamin D on celecoxib-induced cardiotoxicity, which is aggravated in the presence of doxorubicin through the maintenance of mitochondrial functions and its antioxidant potential.

Evaluation of in vitro effects of ifosfamide drug on mitochondrial functions using isolated mitochondria obtained from vital organs.

Mitochondrial toxicity has been shown to contribute to a variety of organ toxicities such as, brain, heart, kidney, and liver. Ifosfamide (IFO) as an anticancer drug, is associated with increased risk of neurotoxicity, cardiotoxicity nephrotoxicity, hepatotoxicity, and hemorrhagic cystitis. The aim of this study was to evaluate the direct effect of IFO on isolated mitochondria obtained from the rat brain, heart, kidney, and liver. Mitochondria were isolated with mechanical lysis and differential centrifugation from different organs and treated with various concentrations of IFO. Using biochemical and flowcytometry assays, we evaluated mitochondrial succinate dehydrogenase (SDH) activity, mitochondrial swelling, lipid peroxidation, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP). Our data showed that IFO did not cause deleterious alterations in mitochondrial functions, mitochondrial swelling, lipid peroxidation ROS formation, and MMP collapse in mitochondria isolated from brain, heart, kidney, and liver. Altogether, the data showed that IFO is not directly toxic in mitochondria isolated from brain, heart, kidney, and liver. This study proved that mitochondria alone does not play the main role in the toxicity of IFO, and suggests to reduce the toxicity of this drug, other pathways resulting in the production of toxic metabolites should be considered.

Maintenance of mitochondrial function by sinapic acid protects against tramadol-induced toxicity in isolated mitochondria obtained from rat brain.

It is reported that tramadol can induce neurotoxic effects with the production of DNA damage, mitochondrial dysfunction, and oxidative stress. The current study aimed to evaluate the potential role of mitochondrial impairment in the pathogenesis of tramadol-induced neurotoxicity, and protective effect of sinapic acid (SA) against it in isolated mitochondria from rat brain. Mitochondria were isolated and were incubated with toxic concentrations (100 µM) of tramadol and then cotreated with tramadol + SA (10, 50, and 100 µM). Biomarkers of mitochondrial toxicity including succinate dehydrogenases (SDH) activity, reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential (MMP), GSH depletion, and mitochondrial swelling were assessed. Our results showed a significant decrease in SDH activity, and a significant increase in ROS, LPO, GSH depletion, MMP collapse, and mitochondrial swelling was detected in tramadol group. We observed that 50 and 100 µM SA cotreatment for 1 h efficiently ameliorated tramadol-caused damage in mitochondrial dysfunction, accumulation of ROS, LPO, GSH depletion, depolarization of mitochondrial membrane potential, and mitochondrial swelling. These data suggest that mitochondrial impairment and oxidative stress are mechanisms involved in the pathogenesis of tramadol-induced neurotoxicity. Also, results indicate that SA antagonizes against tramadol-induced mitochondrial toxicity and suggest SA may be a preventive/therapeutic agent for tramadol-induced neurotoxicity complications.

Hesperidin Protects Alcohol-Induced Mitochondrial Abnormalities via the Inhibition of Oxidative Stress and MPT Pore Opening in Newborn Male Rats as a Fetal Alcohol Syndrome Model.

OBJECTIVE: Prenatal alcohol exposure causes fetal developmental abnormalities via mitochondrial dysfunction, reactive oxygen species (ROS) formation, and oxidative stress. Therefore, we aimed to investigate the potential of hesperidin as a mitochondrial protective and antioxidative agent in newborn male rats as a model for fetal alcohol syndrome (FAS). METHOD: Newborn male rats were divided randomly into five groups: a sham group (receiving 27.8 ml/ kg milk solution, orally), an ethanol group (5.25 g/kg in milk solution, orally, 2-10 days after birth), an ethanol + hesperidin group (25 mg/kg/ day orally), an ethanol + hesperidin group (50 mg/kg/day orally), and an ethanol + hesperidin group (100 mg/kg/day orally). Thirty-six days after birth, newborn male rats were sacrificed and brain mitochondria were isolated using differential centrifugation. Mitochondrial toxicity biomarkers of succinate dehydrogenase (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP), and ROS were measured. RESULTS: Offspring neonatally exposed to ethanol showed a significant reduction in SDH activity, mitochondrial swelling, MMP collapse, induction of ROS formation, and lipid peroxidation in isolated mitochondria. Oral administration of hesperidin restored SDH activity, improved MMP collapse and mitochondrial swelling, and reduced ROS formation. CONCLUSIONS: This study demonstrates that hesperidin exerts a potent protective effect against alcohol-induced mitochondrial toxicity in the FAS model. Moreover, these findings indicate that hesperidin might be a useful compound for prevention of alcohol-induced fetal developmental abnormalities during pregnancy.

Curcumin-Loaded Chitosan Nanoparticle Preparation and Its Protective Effect on Celecoxib-induced Toxicity in Rat isolated Cardiomyocytes and Mitochondria.

Curcumin has a wide range of pharmacological activities, including antioxidant, anti-inflammatory and tissue protective. In here we hypothesized that curcumin-loaded chitosan-coated solid lipid nanoparticles (CuCsSLN) are able to increase its overall bioavailability and hence its antioxidant and mitochondria;/lysosomal protective properties of curcumin. CuCsSLN were prepared using solvent diffusion technique for formation of solid lipid nanoparticles (SLNs) and electrostatic coating of positive-charged chitosan to negative surface of SLNs. CuCsSLN showed the encapsulation efficiency of 91.4±2.7%, the mean particle size of 208±9 nm, the polydispersity index of 0.34±0.07, and the zeta potential of+53.5±3.7 mV. The scanning electron microscope (SEM) images of nanoparticles verified their nanometric size and also spherical shape. Curcumin was released from CuCsSLN in a sustain release pattern up to 24 hours. Then isolated cardiomyocytes and mitochondria were simultaneously treated with (1) control (0.05% ethanol), (2) celecoxib (20 µg/ml) treatment, (3) celecoxib (20 µg/ml)+++CuCsSLN (1 µg/ml) treatment, (4) CuCsSLN (1 µg/ml) treatment, (5) celecoxib (20 µg/ml)+++curcumin (10 µM) treatment and (6) curcumin (10 µM) treatment for 4 h at 37°C. The results showed that celecoxib (20 µg/ml) induced a significant increase in cytotoxicity, reactive oxygen species (ROS) formation, mitochondria membrane potential (ΔΨm) collapse, lipid peroxidation, oxidative stress and mitochondrial swelling while CuCsSLN and curcumin reverted the above toxic effect of celecoxib. Our data indicated that the effect of CuCsSLN in a number of experiments, is significantly better than that of curcumin which shows the role of chitosan nanoparticles in increasing effect of curcumin.

Ellagic acid alleviates clozapine­induced oxidative stress and mitochondrial dysfunction in cardiomyocytes.

Clozapine (CLZ) as an antipsychotic agent is very effective in treating of psychosis disorders and resistant schizophrenia, but the risk of severe cardiac toxicity effects restricts its clinical use. There are several interrelated hypotheses to explain clozapine-induced cardiotoxicity which all of them may be related to oxidative stress. Therefore, the current study investigated the harmful effects of clozapine on cardiomyocytes and assessed the cytoprotective effect of ellagic acid (EA). Freshly isolated adult rat ventricular cardiomyocytes were incubated for 4 h at 37 °C with 00.05% ethanol as control, CLZ (50 µM), CLZ (50 µM) + a series of EA concentrations (10, 20 and 50 µM) and EA (50 µM). To evaluate the protective effect of EA, the markers of cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (ΔΨm) collapse, lysosomal membrane integrity, malondialdehyde (MDA) and oxidized/reduced glutathione (GSH/GSSG) content were checked by biochemical and flowcytometry techniques. Our results demonstrated that EA (10, 20 and 50 µM) effectively inhibited CLZ-induced cytotoxicity which is associated with ROS overproduction and amelioration of mitochondrial and lysosomal damages. In addition, EA (10, 20 and 50 µM) in the presence of CLZ reduced the production of MDA as a specific marker lipid peroxidation and GSSG. Collectively, these findings suggested that EA protects cardiomyocytes from oxidative injury through inhibiting ROS formation, mitochondria dysfunction, and lysosomal damages, which suggest a potential therapeutic strategy of EA for CLZ-induced oxidative stress and cardiotoxicity.

Celecoxib decreases mitochondrial complex IV activity and induces oxidative stress in isolated rat heart mitochondria: An analysis for its cardiotoxic adverse effect.

In spite of the cardiotoxic effect of selective cyclooxygenase-2 inhibitors, they are most widely used as anti-inflammatory and analgesic drugs. Today, valdecoxib and rofecoxib have been withdrawn in the market but celecoxib remains. In this study, we focused on an analysis of celecoxib toxic effects on isolated mitochondria. Isolated rat heart mitochondria were obtained using differential centrifugation. Using flow cytometry and biochemical assays, we searched succinate dehydrogenases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, mitochondrial swelling, ATP/ADP ratio, lipid peroxidation, and mitochondrial complexes activity in rat heart isolated mitochondria. Herein, our results indicated a significant decrease in the activity of complex IV after exposure with celecoxib (16 µg/ml). This decrease in the activity of complex IV is paralleled by the MMP collapse, ROS formation, mitochondrial swelling, depletion of ATP, and lipid peroxidation. For the first time, this introductory study has shown a significant decrease in the activity of complex IV and mitochondrial dysfunction after exposure with celecoxib in rat heart isolated mitochondria.

Calcitriol attenuates the cytotoxicity induced by aluminium phosphide via inhibiting mitochondrial dysfunction and oxidative stress in rat isolated cardiomyocytes.

These days, poisoning with aluminium phosphide (AlP), is one of the main health threats in human societies. Previous studies have been reported that cardiotoxicity induced by AlP, via mitochondrial dysfunction and oxidative stress is the main cause of death in victims. On the other, collectively, multiple lines of evidence strongly suggest that calcitriol has mitochondrial protective and antioxidant effects. Therefore, we assumed that calcitriol could presumably ameliorate AlP-induced oxidative stress and mitochondrial dysfunction in cardiomyocytes. Mitochondria and cardiomyocytes were isolated by differential centrifugation and collagenase perfusion respectively from rat heart. The isolated cardiomyocytes and mitochondria were cotreated with different concentrations of calcitriol (0.2, 0.4 and 1 µg/ml) and AlP (20 µg/ml) for 3 h. The parameters of cellular toxicity including; cytotoxicity, reactive oxygen species (ROS) formation, malondialdehyde (MDA) level, mitochondria membrane potential (ΔΨm) collapse, lysosomal membrane integrity, the level of oxidized and reduced glutathione (GSH and GSSG), and mitochondrial toxicity parameters including; succinate dehydrogenase (SDH) activity and mitochondrial swelling were analyzed using biochemical and flow cytometric evaluations. Administration of AlP significantly increased cytotoxicity, GSH depletion, cellular ROS formation, MDA level, mitochondrial and lysosomal dysfunction in isolated cardiomyocytes. In isolated mitochondria, AlP decreased SDH activity and mitochondrial swelling. The cotreatment of isolated cardiomyocytes and mitochondria with calcitriol (0.4 and 1 µg/ml) and AlP (20 µg/ml) showed the ability to reduce the toxic effects of AlP. These findings suggest a potential therapeutic role of calcitriol in protecting cardiomyocytes and cardiac mitochondria from oxidative damage induced by AlP. According to the results, calcitriol exerted ameliorative effects against AlP-induced cytotoxicity and mitochondrial toxicity, and the effect was attributed to the antioxidant properties.

Thymoquinone reduces mitochondrial damage and death of cardiomyocytes induced by clozapine.

The generation of a reactive nitrenium ion by microsomal/mitochondrial cytochrome P450 (CYPs) from clozapine (CLZ) has been suggested as the main cause of cardiotoxicity by this drug. Previous studies indicated that thymoquinone (TQ) as an active constituent of Nigella sativa has pharmacological effects such as antioxidant, reactive oxygen species (ROS) scavenger, and inhibitory effect on CYPs enzymes. Therefore, we hypothesized that TQ with these pharmacological effects can reduce CLZ-induced toxicity in isolated cardiomyocytes and mitochondria. Rat left ventricular cardiomyocytes and mitochondria were isolated by collagenase perfusion and differential centrifugation respectively. Then, isolated cardiomyocytes and mitochondria were pretreated with different concentrations of TQ (1, 5, and 10 µmol/l) for 30 min and then followed by exposure to CLZ (50 µmol/l) for 6 h. After 6 h of incubation, using biochemical evaluations and flow cytometric analysis, the parameters of cellular toxicity including cytotoxicity, the level of oxidized/reduced glutathione (GSH/GSSG), malondialdehyde (MDA), reactive oxygen species (ROS) formation, lysosomal membrane integrity, mitochondria membrane potential (ΔΨm) collapse, and mitochondrial toxicity including succinate dehydrogenase (SDH) activity and mitochondrial swelling were analyzed. We observed a significant toxicity in isolated cardiomyocytes and mitochondria after exposure with CLZ which was related to ROS formation, oxidative stress, GSH depletion, lysosomal and mitochondrial damages, and mitochondrial dysfunction and swelling, while TQ pretreatment reverted the above toxic effect of CLZ on isolated cardiomyocytes and mitochondria. Our results indicate that TQ prevents and reverses CLZ-induced cytotoxicity and mitochondrial damages in isolated cardiomyocytes and mitochondria, providing an experimental basis for clinical treatment on CLZ-induced cardiotoxicity.

Protection of clozapine-induced oxidative stress and mitochondrial dysfunction by kaempferol in rat cardiomyocytes.

Clozapine (CLZ) is unusually efficient in psychotic diseases. Nonetheless, its use is confined due to potentially life-threatening adverse events, including cardiotoxicity. Since the cardiotoxicity of CLZ is mediated through the generation of active metabolites, free radical, and inflammation. Here, we tested this hypothesis that kaempferol (KP) as antioxidant and anti-inflammatory agent could attenuate CLZ-induced mitochondrial/lysosomal and oxidative damages in rat ventricular cardiomyocytes. Rat ventricular cardiomyocytes were isolated by collagenase perfusion. Then isolated cardiomyocytes were simultaneously treated with different concentrations of KP (10, 20, and 50 µM) and CLZ (50 µM) for 4 h at 37°C. After 4 h of incubation, using by flow cytometry and biochemical evaluations, the parameters of cellular toxicity including: cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (ΔΨm) collapse, lysosomal membrane integrity, malondialdehyde, and oxidized/reduced glutathione were analyzed. The results showed that CLZ (50 µM) induced a significant increase in cytotoxicity, ROS formation, mitochondrial membrane potential collapse, lipid peroxidation, and oxidative stress while KP reverted the above toxic effect of CLZ on isolated cardiomyocytes. Our data suggest that KP prevents and reverses CLZ-induced oxidative and mitochondrial/lysosomal damages in isolated cardiomyocytes, providing an experimental basis for clinical treatment on CLZ-induced cardiotoxicity.

Apigenin attenuates Aluminum phosphide-induced cytotoxicity via reducing mitochondrial/Lysosomal damages and oxidative stress in rat Cardiomyocytes.

Apigenin, is a natural compound that found in high amounts in vegetables and fruits. This natural flavone has shown strong cardioprotective effects in animal and clinical studies. Due to cardioprotective effects of apigenin in previous studies, we hypothesized that apigenin protects isolated cardiomyocytes from aluminum phosphide(AlP)-induced toxicity as the most common disturbances after exposure with this agent. By using of biochemical and flowcytometry techniques; cell viability, reactive oxygen species (ROS) generation, mitochondria membrane potential (MMP), lysosomal membrane integrity, malondialdehyde (MDA) and oxidized/reduced glutathione (GSH/GSSG) content were measured in rat heart isolated cardiomyocytes. Our results showed that the administration of apigenin (5-100 µM) efficiently decreased (P < .05) cytotoxicity, oxidative, lysosomal and mitochondrial damages induced by AlP (20 µg/ml) in isolated cardiomyocytes. Taken together, apigenin protected the cardiomyocytes against AlP toxicity via the protection of mitochondria and lysosome mediated by its antioxidant properties.

Chrysin ameliorates aluminum phosphide-induced oxidative stress and mitochondrial damages in rat cardiomyocytes and isolated mitochondria.

Apart from the anticancer, antioxidant, anti-inflammatory effects, and inhibition of aromatase, chrysin is involved in the protection of cardiovascular disorders. Cardiovascular complications are the main cause of death induced by aluminum phosphide (AlP) which is related to oxidative stress and mitochondrial damages. For this purpose, we investigated the effect of chrysin as an antioxidant and mitochondrial protective agent against AlP-induced toxicity in isolated cardiomyocytes and mitochondria obtained from rat heart ventricular. Using by biochemical and flow cytometry, cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (MMP), lysosomal membrane integrity, malondialdehyde (MDA) content, and glutathione (GSH) and oxidized glutathione (GSSG) content were measured in isolated cardiomyocytes. Also, mitochondrial toxicity parameters such as mitochondrial NADH/succinate dehydrogenase activity, mitochondrial swelling, ROS formation, MMP collapse, and lipid peroxidation were analyzed in isolated mitochondria. Our results showed that the administration of chrysin (up to 10 µM) efficiently decreased (P < 0.05) cytotoxicity, oxidative, lysosomal, and mitochondrial damages induced by AlP, in isolated cardiomyocytes. Also, our finding in isolated mitochondria showed that chrysin (up to 10 µM) significantly (P < 0.05) decreased AlP-induced mitochondrial toxicity. These findings demonstrated that chrysin as an antioxidant and mitochondrial protective agent exert protective effect in wild-type cardiomyocyte treated with AlP. It was concluded that chrysin significantly reduced the toxicity of AlP in isolated cardiomyocytes and mitochondria. Due to the very low toxicity of chrysin for humans, it could be a promising agent in treatment of AlP poisoning.

Calcitriol Reduces Adverse Effects of Diclofenac on Mitochondrial Function in Isolated Rat Heart Mitochondria.

The safety of diclofenac (DIC) use in clinical practice has been questioned because of adverse cardiovascular effects. Previous studies have indicated that DIC cause mitochondrial dysfunction and oxidative stress in heart mitochondria. The aim of this study was to investigate the protective effect of calcitriol against the mitochondrial toxicity potency of diclofenac in heart rat mitochondria. For this purpose, rat heart mitochondria were isolated with mechanical lysis and differential centrifugation. Then isolated mitochondria were pretreated with 3 different concentrations of calcitriol (2.5, 5 and 10 µM) for 5 min at 37°C, after which DIC (10 µg/ml) was added to promote deleterious effects on mitochondria. During 1 hour of incubation, using by flow cytometry and biochemical evaluations, the parameters of mitochondrial toxicity were evaluated. Our results showed that DIC (10 µg/ml) caused a significant decrease in succinate dehydrogenase (SDH) activity, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling, and a significant increase in reactive oxygen species (ROS) formation, lipid peroxidation (LP) and oxidative stress. Also, our results revealed that co-administration of calcitriol (5 and 10 µM) with diclofenac markedly ameliorates the mitochondrial toxicity effects in rat hart mitochondria. In this study, we showed that DIC impairs mitochondrial function and induces mitochondrial toxicity in rat heart isolated mitochondria, which were ameliorated by calcitriol. These findings suggest that calcitriol may be a preventive/therapeutic strategy for cardiotoxicity complications caused by DIC.

Pathogenic Mechanisms and Therapeutic Implication in Nickel-Induced Cell Damage.

BACKGROUND: Nickel (Ni) is mostly applied in a number of industrial areas such as printing inks, welding, alloys, electronics and electrical professions. Occupational or environmental exposure to nickel may lead to cancer, allergy reaction, nephrotoxicity, hepatotoxicity, neurotoxicity, as well as cell damage, apoptosis and oxidative stress. METHODS: In here, we focused on published studies about cell death, carcinogenicity, allergy reactions and neurotoxicity, and promising agents for the prevention and treatment of the toxicity by Ni. RESULTS: Our review showed that in the last few years, more researches have focused on reactive oxygen species formation, oxidative stress, DNA damages, apoptosis, interaction with involving receptors in allergy and mitochondrial damages in neuron induced by Ni. CONCLUSION: The collected data in this paper provide useful information about the main toxicities induced by Ni, also, their fundamental mechanisms, and how to discover new ameliorative agents for prevention and treatment by reviewing agents with protective and therapeutic consequences on Ni induced toxicity.