ABSTRACT
Pioglitazone (PG) is one of the thiazolidinedione (TZDs) drugs used in diabetic patients. TZDs are known as peroxisome proliferator-activated receptor gamma (PPARγ) agonists. Mitochondria are considered as one of the targets of these drugs. The mechanisms of the effect of PG on mitochondria are not well understood. In this study, we investigated the effect of PG on mitochondria isolated from brain and heart. Mitochondrial parameters such as succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) generation, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release were evaluated. The results showed that PG at concentrations of 12.5, 25 and 50 µg/ml increased the generation of ROS, the collapse of MMP, mitochondrial swelling and the release of cytochrome c in mitochondria isolated from both brain and heart tissues. The underlying mechanisms of PG induced neuro-toxicity and cardio-toxicity may be associated with changes in mitochondrial function, ROS generation (oxidative stress), and changes in the mitochondrial membrane.
Subject(s)
Cardiotoxicity/etiology , Mitochondria/drug effects , Neurotoxicity Syndromes/etiology , Pioglitazone/toxicity , Animals , Brain/drug effects , Brain/metabolism , Dose-Response Relationship, Drug , Heart/drug effects , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/toxicity , Male , Membrane Potential, Mitochondrial/drug effects , Mitochondrial Swelling/drug effects , Oxidative Stress/drug effects , PPAR gamma/agonists , Pioglitazone/administration & dosage , Rats , Rats, Wistar , Reactive Oxygen Species/metabolismABSTRACT
The effect of nanotitanium dioxide (TiO2-NP) in human monocytes is still unknown. Therefore, an understanding of probable cytotoxicity of TiO2-NP on human monocytes and underlining the mechanisms involved is of significant interest. The aim of this study was to assess the cytotoxicity of TiO2-NP on human monocytes. Using biochemical and flow cytometry assessments, we demonstrated that addition of TiO2-NP at 10 µg/ml concentration to monocytes induced cytotoxicity following 12 h. The TiO2-NP-induced cytotoxicity on monocytes was associated with intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation, and depletion of glutathione. According to our results, TiO2-NP triggers oxidative stress and organelles damages in monocytes which are important cells in defense against foreign agents. Finally, our findings suggest that use of antioxidants and mitochondrial/lysosomal protective agents could be of benefit for the people in the exposure with TiO2-NP.
Subject(s)
Metal Nanoparticles/toxicity , Mitochondria/drug effects , Monocytes/drug effects , Titanium/toxicity , Cell Death/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Reactive Oxygen Species/metabolismABSTRACT
To reduce costly late-phase compound scrubbing, there has been an increased focus on assessing compounds within in vitro assays that predict properties of human safety liabilities, before preclinical in vivo studies. The aim of our study was to answer the questions that whether the toxicity risk of a series of 3-oxobutanamide derivatives could be predicted by using of human lymphocytes and their isolated mitochondria. Using biochemical and flow cytometry assessments, we demonstrated that exposure of lymphocytes and isolated mitochondria to five 3-oxobutanamide derivatives (1-5) did not exhibit remarkable toxicity at low concentrations (50-500µM) but toxicity could be observed at high concentrations (1000 and 2000µM), particularly for N-(5-(4-bromophenyl)-3-isoxazolyl)-3-oxobutanamide (4) and N-(2-benzothiazolyl)-3-oxo butanamide (5). Compounds 4, 5 and partly N-(5-methyl-3-isoxazol yl)-3-oxo butanamide (1) also showed a marked cellular and mitochondrial toxicity while compound 5 displayed superior toxicity. Compound 5 induced cytotoxicity on human blood lymphocytes which was associated with the generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation and depletion of glutathione. Our results suggested that among assessed compounds, increased toxicity of compound 5 compared to other compounds could be likely attributed to the presence of bromine substituent in 5. Finally our findings proposed that using of antioxidants and mitochondrial/lysosomal protective agents could be beneficial in decreasing the toxicity of 5.
