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.

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 Today, valdecoxib and rofecoxib have been withdrawn in the market but celecoxib remains.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.

Bevacizumab as a monoclonal antibody inhibits mitochondrial complex II in isolated rat heart mitochondria: ameliorative effect of ellagic acid.

Drug-induced cardiotoxicity usually manifests as heart failure or left ventricular systolic dysfunction. Left ventricular dysfunction is a rarely reported side effect of bevacizumab (BEV) with an incidence of 1.2%, and this occurs irrespective of the route of administration. In this study, we focused on an analysis of BEV effects on mitochondrial complexes activities and protective effect of ellagic acid (EA) against BEV-induced mitochondria toxicity. Rat heart mitochondria were isolated using differential centrifugation form wistar rats. Using biochemical and flowcytometry assays we evaluated mitochondrial complexes activity, succinate dehydrogenases (SDH), mitochondrial swelling, reactive oxygen species (ROS) formation and mitochondrial membrane potential (MMP) in isolated mitochondria. We observed only decreased activity of complexes II after exposure with BEV (50 and 100 µg/ml). The inhibition of complex II is paralleled by the decreased MMP, mitochondrial swelling, and ROS formation. Also, we showed that EA (10-100 µM) as an antioxidant and natural agent significantly decreases mitochondrial toxicity induced by BEV. Together, for the first time, this preliminary study has demonstrated a significant decrease in activity of complexes II after exposure with BEV and proved the protective effects of EA in alleviating BEV-mediated mitochondria toxicity.

Stabilization of Mitochondrial Function by Ellagic Acid Prevents Celecoxib-induced Toxicity in Rat Cardiomyocytes and Isolated Mitochondria.

The possible action of polyphenolic compounds in the reduction of reactive oxygen species (ROS) and mitochondrial toxicity may suggest them as putative agents for the treatment of drug-induced mitochondrial dysfunction and cardiotoxicity. This study was designed to explore protective effect of ellagic acid (EA) against celecoxib-induced cellular and mitochondrial toxicity in cardiomyocytes and their isolated mitochondria. In order to do this, isolated cardiomyocytes and mitochondria were pretreated with 3 different concentrations of EA (10, 50 and 100 µM), after which celecoxib (16 µg/ml) was added to promote deleterious effects on cells and mitochondria. Using flow cytometry and biochemical methods, the parameters of cellular and mitochondrial toxicity were investigated. Our results showed that celecoxib (16 µg/ml) caused a significant decrease in cell viability, mitochondrial membrane potential (MMP), glutathione (GSH) in intact cardiomyocytes and succinate dehydrogenase (SDH) activity, MMP collapse, and mitochondrial swelling, and a significant increase in reactive oxygen species (ROS) formation, lipid peroxidation (LP) and oxidative stress in isolated mitochondria. Also, our results revealed that co-administration of EA (50 and 100 µM) with celecoxib significantly attenuated the cellular and mitochondrial toxicity effects. In this study, we showed that simultaneous treatment with of EA ameliorated the cellular and mitochondrial toxicity induced by celecoxib, with cardiomyocytes presenting normal activity compared to the control group, and mitochondria retaining their normal activity.

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.

1,25-dihydroxyvitamin D3 prevents deleterious effects of erythromycin on mitochondrial function in rat heart isolated mitochondria.

Erythromycin (ERY) is a risk factor for cardiotoxicity through the mitochondria pathway. In the current study, we tested the hypothesis that erythromycin could impair mitochondrial function and oxidative stress and 1,25-dihydroxivitamin D3 (calcitriol) treatment could prevent these effects in rat heart isolated mitochondria. Rat heart mitochondria were isolated with mechanical lysis and differential centrifugation. Then isolated mitochondria were first pretreated with three different concentrations of 1,25-dihydroxivitamin D3 (2.5, 5 and 10 µmol/L) for 5 minutes at 37°C, after which erythromycin (10 µmol/L) 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, including: succinate dehydrogenase (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse, reactive oxygen species (ROS) formation and lipid peroxidation (LP). The results showed that erythromycin (10 µmol/L) caused a significant change in mitochondrial function, ROS formation, mitochondrial swelling, MMP collapse, increasing lipid peroxidation and oxidative stress. 1,25-dihydroxivitamin D3 (10 µmol/L) reverted the effect of erythromycin on the tested parameters . In this study, we showed that erythromycin impairs mitochondrial function and induces mitochondrial toxicity in rat heart isolated mitochondria, which were reverted by calcitriol. These findings suggest that 1,25-dihydroxivitamin D3 may be a preventive/therapeutic strategy for cardiotoxicity complications caused by erythromycin.

Curcumin attenuates bevacizumab-induced toxicity via suppressing oxidative stress and preventing mitochondrial dysfunction in heart mitochondria.

Heart failure was subsequently noted in 2-4% of patients on bevacizumab (BEV). Whereas mitochondria play an important role in myocardial tissue homeostasis, deterioration in mitochondrial function will eventually lead to cardiomyocyte cell death and consequently cardiovascular dysfunction. Therefore, the aim of our study is to search the effects of BEV on isolated rat heart mitochondria and cardiomyocytes, and survey the effect of curcumin as a mitochondrial protective and cardioprotective agent. Rat heart mitochondria and cardiomyocytes were isolated from adult rat heart ventricular. By using biochemical and flow cytometry evaluations, the parameters of mitochondrial toxicity including succinate dehydrogenase (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse, reactive oxygen species (ROS) formation and lipid peroxidation (LP), and cellular assays such as cytotoxicity and MMP collapse were evaluated. Results revealed that BEV (up to 50 µg/ml) induced a concentration- and time-dependent rise in mitochondrial ROS formation, MMP collapse, mitochondrial swelling, LP, and inhibition of SDH in rat heart mitochondria. Our results showed that curcumin (10-100 µM) significantly ameliorated BEV-induced mitochondrial toxicities. Also, our results in cellular assays confirmed amelioration effect of curcumin against BEV toxicity. These results indicate that the cardiotoxic effects of BEV are associated with mitochondrial dysfunction and ROS formation, which finally ends in MMP collapse and mitochondrial swelling as the "point of no return" in the cascade of events leading to apoptosis. Also, results of this study suggest that probably the combination therapy of BEV and curcumin could decrease mitochondrial effects of this drug.

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.