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Petrol vapors as important occupational and environmental pollutants can cause oxidative stress and may play a role in the development of neurodegenerative diseases along with the risk factors involved. This research is designed as a preliminary study to evaluate the protective effects of apigenin (APG) on oxidative stress caused by petrol vapors inhalation in rats. A total of 24 male Wistar rats were randomly divided into four groups inside the inhalation chamber. Body weight changes and oxidative stress markers were investigated. The average body weight of the group exposed to petrol vapors was significantly lower compared to the other groups. The level of reactive oxygen species (ROS), content of oxidized-glutathione (GSSG), and Malondialdehyde were found to be higher in the petrol-inhaled group, while the content of reduced-glutathione (GSH) was lower compared to the other groups. APG administration did result in any significant improvement in these toxicities induced by petrol vapor. APG administration may ameliorate the petrol-induced oxidative stress. In chronic exposures, in addition to personal protection and engineering control, the use of compounds of natural origin may help in reducing the side effects (such as CNS) caused by exposure to petrol vapors.
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Vasogenic brain edema, a potentially life-threatening consequence following an acute ischemic stroke, is a major clinical problem. This research aims to explore the therapeutic benefits of nimodipine, a calcium channel blocker, in mitigating vasogenic cerebral edema and preserving blood-brain barrier (BBB) function in an ischemic stroke rat model. In this research, animals underwent the induction of ischemic stroke via a 60-min blockage of the middle cerebral artery and treated with a nonhypotensive dose of nimodipine (1 mg/kg/day) for a duration of five days. The wet/dry method was employed to identify cerebral edema, and the Evans blue dye extravasation technique was used to assess the permeability of the BBB. Furthermore, immunofluorescence staining was utilized to assess the protein expression levels of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). The study also examined mitochondrial function by evaluating mitochondrial swelling, succinate dehydrogenase (SDH) activity, the collapse of mitochondrial membrane potential (MMP), and the generation of reactive oxygen species (ROS). Post-stroke administration of nimodipine led to a significant decrease in cerebral edema and maintained the integrity of the BBB. The protective effects observed were associated with a reduction in cell apoptosis as well as decreased expression of MMP-9 and ICAM-1. Furthermore, nimodipine was observed to reduce mitochondrial swelling and ROS levels while simultaneously restoring MMP and SDH activity. These results suggest that nimodipine may reduce cerebral edema and BBB breakdown caused by ischemia/reperfusion. This effect is potentially mediated through the reduction of MMP-9 and ICAM-1 levels and the enhancement of mitochondrial function.
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Barreira Hematoencefálica , Edema Encefálico , Bloqueadores dos Canais de Cálcio , AVC Isquêmico , Metaloproteinase 9 da Matriz , Nimodipina , Animais , Nimodipina/farmacologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Masculino , Ratos , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Modelos Animais de Doenças , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos Sprague-Dawley , Molécula 1 de Adesão Intercelular/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/complicações , Dilatação Mitocondrial/efeitos dos fármacos , Succinato Desidrogenase/metabolismoRESUMO
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.
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The hallmark of aluminum phosphide (AlP) poisoning is heart failure in victims which is associated with reactive oxygen species (ROS), mitochondrial dysfunction, oxidative stress, alteration in antioxidant defense system and depletion of ATP in cardiomyocytes. In the present study, we hypothesized that the injection of isolated mitochondria into blood or mitochondrial transplantation can likely create a primary target for phosphine released from AlP and inhibit AlP-induced mortality and cardiotoxicity in rat. Male, Wistar, healthy and adult rats were randomly divided into 5 groups as control, AlP (12.5 mg/kg, orally), AlP + mitochondria (125 µg/kg), AlP + mitochondria (250 µg/kg) and mitochondria (250 µg/kg) alone. Functional and intact mitochondria isolated from rat heart and transplantation was carried out via tail vein, 30 min after exposure to AlP. Survival rate, histopathological alterations, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters were monitored and analyzed during 30 days. We found that injection of healthy mitochondria into blood at concentrations of 125 and 250 125 µg/ml significantly increased the survival of rats up to 40% and 56.25% respectively, during 30 days. Moreover, we observed that mitochondria injection into blood decreased histopathological damages, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters. To our knowledge, the current study is the first report in the literature that demonstrated good therapeutic effects of mitochondrial transplantation in AlP-induced mortality and cardiotoxicity. The findings of the present study suggests that injection of exogenous mitochondria into blood could be an effective therapeutic strategy in treating AlP poisoning.
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Compostos de Alumínio , Cardiotoxicidade , Mitocôndrias Cardíacas , Estresse Oxidativo , Fosfinas , Ratos Wistar , Animais , Fosfinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/patologia , Compostos de Alumínio/toxicidade , Modelos Animais de Doenças , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Injeções Intravenosas , Espécies Reativas de Oxigênio/metabolismo , Ratos , Antioxidantes/farmacologia , Fatores de TempoRESUMO
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.
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Modelos Animais de Doenças , Etilnitrosoureia , Glioma , Hesperidina , Estresse Oxidativo , Animais , Hesperidina/farmacologia , Glioma/patologia , Glioma/tratamento farmacológico , Glioma/prevenção & controle , Feminino , Camundongos , Gravidez , Etilnitrosoureia/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/etiologia , Comportamento Animal/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Antioxidantes/farmacologiaRESUMO
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.
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Atorvastatina , Ácidos Cumáricos , Hesperidina , Potencial da Membrana Mitocondrial , Mitocôndrias , Dilatação Mitocondrial , Pâncreas , Espécies Reativas de Oxigênio , Ácido Vanílico , Animais , Atorvastatina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Ácidos Cumáricos/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Masculino , Dilatação Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Vanílico/farmacologia , Hesperidina/farmacologia , Glutationa/metabolismo , Ratos Wistar , Succinato Desidrogenase/metabolismo , Malondialdeído/metabolismoRESUMO
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 80â¯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 20â¯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.
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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.
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Antioxidantes , Cardiotoxicidade , Celecoxib , Modelos Animais de Doenças , Doxorrubicina , Insuficiência Cardíaca , Mitocôndrias Cardíacas , Estresse Oxidativo , Ratos Wistar , Vitamina D , Animais , Doxorrubicina/toxicidade , Celecoxib/farmacologia , Antioxidantes/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Vitamina D/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Ratos , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Peripheral blood lymphocytes as primary cells can be isolated from human, animal, fetus, and placenta. These cells are an excellent cellular model for the assessment of cytotoxicity, genotoxicity, oxidative stress, and mitochondrial and lysosomal dysfunction induced by drug and chemicals. Moreover, peripheral blood lymphocytes are an easily available source of primary cells appropriate for basic research and in cellular studies regarding teratogenic, genotoxic, and cytotoxic effect of drugs and chemicals. Most drugs and other chemicals that produce birth defects, known as teratogenic agents, produce reactive oxygen species (ROS) formation and mitochondrial and lysosomal dysfunction. It seems that there is an important mechanistic link between oxidative stress, mitochondrial damages, lysosomal integrity, and teratogenic drug-induced birth defects. One of the most sensitive periods in the embryo is transition from an important developmental event to another such as transition from proliferation to differentiation. Mitochondria, lysosomes, and cellular ROS have an important role in proliferative, differentiative, and apoptotic activities during the development. Therefore, disruption of the function of mitochondria, lysosomes, oxidative stress, and redox imbalance leads to cellular dysfunctions and subsequently poor developmental outcomes in the fetus. In this chapter, we will focus on evaluation of mitochondrial/lysosomal functions and estimation of ROS formation using flow cytometry methods in isolated lymphocytes and their isolated mitochondria.
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Teratogênese , Animais , Humanos , Feminino , Gravidez , Citometria de Fluxo , Espécies Reativas de Oxigênio , Feto , Teratogênicos/toxicidade , LinfócitosRESUMO
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.
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Ácidos Cumáricos , Doenças Mitocondriais , Tramadol , Ratos , Animais , Espécies Reativas de Oxigênio/metabolismo , Tramadol/toxicidade , Mitocôndrias , Estresse Oxidativo , Peroxidação de Lipídeos , Encéfalo , Potencial da Membrana MitocondrialRESUMO
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.
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Ifosfamida , Estresse Oxidativo , Ratos , Animais , Ifosfamida/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/metabolismo , Rim , Potencial da Membrana MitocondrialRESUMO
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.
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Transtornos do Espectro Alcoólico Fetal , Hesperidina , Estresse Oxidativo , Animais , Feminino , Masculino , Gravidez , Ratos , Animais Recém-Nascidos , Antioxidantes/farmacologia , Antioxidantes/administração & dosagem , Modelos Animais de Doenças , Etanol/administração & dosagem , Etanol/efeitos adversos , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Transtornos do Espectro Alcoólico Fetal/metabolismo , Hesperidina/administração & dosagem , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/metabolismoRESUMO
Most of the literature has focused on titanium dioxide (TiO2) nanoparticles (NPs) toxicity, showing the importance of oxidative stress, mitochondrial dysfunction, and cell death in TiO2-induced toxicity. For this purpose, in the current study, we investigated the protective role of antioxidant and mitochondrial/lysosomal protective agents to minimize TiO2 NPs-induced toxicity in human lymphocytes. Human lymphocytes were obtained from heathy individuals and treated with different concentrations (80, 160, and 320 µg/mL) of TiO2 NPs, and then human lymphocytes preincubated with butylated hydroxytoluene (BHT), cyclosporin A (CsA), and chloroquine separately were exposed to TiO2 NPs for 6 h. In all the above-mentioned treated groups, adverse parameters such as cytotoxicity, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), lysosomal membrane destabilization, the levels of malondialdehyde (MDA), and glutathione (GSH) were measured. The results showed that TiO2 nanoparticles induced cytotoxicity through ROS formation, MMP collapse, lysosomal damages, depletion of GSH, and lipid peroxidation. However, BHT as an antioxidant, CsA as a mitochondrial permeability transition (MPT) pore sealing agent, and chloroquine as a lysosomotropic agent, significantly inhibited all the TiO2 NPs-induced cellular and organelle toxicities. Thus, it seems that antioxidant and mitochondrial/lysosomal protective agents are promising preventive strategies against TiO2 NPs-induced toxicity.
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Antioxidantes , Nanopartículas , Humanos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio , Substâncias Protetoras , Lisossomos , Mitocôndrias , Glutationa , Cloroquina/toxicidade , Linfócitos , Nanopartículas/toxicidadeRESUMO
Lithium is commonly used in the treatment of bipolar disorders (BD) and consumer electronics. It has been reported that lithium exposure is associated with mitochondrial dysfunction and oxidative stress in isolated cardiac mitochondria. Mitochondrial protection has a key role in myocardial tissue homeostasis, cardiomyocyte survival and inhibition of cardiotoxicity. Hesperidin as a flavanone and cardioprotective agent has shown high potential in antioxidant activity and restoration of mitochondrial dysfunction in different models. Therefore, we aimed to evaluate the ameliorative effects of hesperidin against lithium-induced mitochondrial toxicity in rat cardiac mitochondria. Isolated mitochondria were classified into six groups; control, lithium carbonate (125 µM), three groups of lithium + hesperidin-treated received lithium (125 µM) and hesperidin with various concentrations (10, 50, and 100 µM) and hesperidin (100 µM). Succinate dehydrogenases (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitochondrial glutathione (GSH) and lipid peroxidation (LPO) were measured. The mitochondria received lithium showed a significant reduction of SDH activity, MMP collapse, mitochondrial swelling, induction of ROS formation and lipid peroxidation. However, we observed that the administration of hesperidin (50 and 100 µM) resulted in the increase of SDH activity, improved MMP collapse, mitochondrial swelling, and reduced ROS formation and lipid peroxidation. Also, there were no obvious changes in cardiac mitochondria received of hesperidin. These findings suggest that hesperidin could reduce lithium-induced mitochondrial dysfunction through antioxidant activities in cardiac mitochondria, may be beneficial for prevention and treatment of lithium toxicities, either as a drug to treat BD or as an environmental pollutant.
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Ifosfamide (IFO) kidney damage is an important organ toxicity in children and adults undergoing chemotherapy. Previous evidence has shown that IFO toxic metabolites such as acrolein and are associated with mitochondrial dysfunction, depletion of antioxidants, oxidative stress and may predispose the kidney to IFO toxicity. Bioactive food compounds such as ellagic acid (EA) found in fruits has been described as antioxidant and mitochondrial protective agents against toxicity-related mitochondrial damage and oxidative stress. In current study, the protective effects of EA on IFO-induced nephrotoxicity in male Wistar rats were investigated with histopathological, biochemical, and mitochondrial methods. The rats were randomly divided into four groups, control, IFO, IFO + EA, and EA groups. EA (25 mg/kg, i.p. daily) were administered to animals for 2 consecutive days and IFO (500 mg/kg, i.p.) was administered on third day. The results showed that pretreatment EA significantly increased mitochondrial succinate dehydrogenases (SDH) activity, and protected mitochondrial swelling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, lipid peroxidation (LPO) and depletion glutathione (GSH). Histopathological findings demonstrated that EA had protective effects and reduced histopathological abnormalities caused by IFO. These results showed that EA administration protects the kidneys against mitochondrial dysfunction, oxidative stress and histopathological abnormality induced by IFO. Taken together, our results demonstrated that EA played a protective role against IFO-induced nephrotoxicity through mitochondrial protection and antioxidant properties.
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BACKGROUND: Methamphetamine is widely abused in all parts of the world. It has been reported that short-term and long-term methamphetamine exposure could damage the dopaminergic system and induce cardiomyopathy and cardiotoxicity via mitochondrial dysfunction and oxidative stress. Vanillic acid (VA), a phenolic acid compound derived from plants, is known for its antioxidant and mitochondrial protection properties. METHODS: In the current study we used VA for attenuating of Methamphetamine-induced mitochondrial toxicity in cardiac mitochondria. Isolated mitochondria obtained from rat heart were grouped as: control, methamphetamine (250 µM), VA (10, 50 and 100 µM) was cotreated with methamphetamine (250 µM) and VA (100 µM) alone. After 60 min, mitochondrial fraction including: succinate dehydrogenases (SDH) activity, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial glutathione (GSH), reactive oxygen species (ROS) and lipid peroxidation (LPO) were evaluated. RESULTS: Methamphetamine exposure significantly disrupted mitochondrial function and induced ROS formation, lipid peroxidation, GSH depletion, MMP collapse and mitochondrial swelling, while VA significantly increased SDH activity as indicator of mitochondrial toxicity and dysfunction. VA also significantly decreased ROS formation, lipid peroxidation, mitochondrial swelling, MMP collapse and depletion of GSH in cardiac mitochondria in the presence of methamphetamine. CONCLUSION: These findings suggested that VA is able to reduce methamphetamine-induced mitochondrial dysfunction and oxidative stress. Our results demonstrate that VA could potentially serve as a promising and accessible cardioprotective agent against methamphetamine-induced cardiotoxicity, via antioxidant and mitochondrial protection properties.
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Antioxidantes , Metanfetamina , Ratos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Metanfetamina/toxicidade , Metanfetamina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido Vanílico/farmacologia , Ácido Vanílico/metabolismo , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Estresse Oxidativo , Mitocôndrias/metabolismo , Glutationa/metabolismo , Peroxidação de Lipídeos , Potencial da Membrana MitocondrialRESUMO
BACKGROUND: Ifosfamide (IFO) is a widely used antineoplastic drug with broad-spectrum efficacy against various types of cancer. However, different toxicities associated with IFO has limited its use. This study was to establish the prophylactic effects of betanin, chrysin and ellagic acid against IFO-induced neurotoxicity in rats. METHODS: Animals were randomly divided into eight groups, control, IFO, IFO + betanin, IFO + chrysin, IFO + ellagic acid, betanin, chrysin and ellagic acid groups. Betanin (50 mg/kg, i.p.), chrysin (25 mg/kg, i.p.) and ellagic acid (25 mg/kg, i.p.) were administered to rats once daily for two consecutive days. IFO (500 mg/kg, i.p.) was administered on third day. RESULTS: Results demonstrated that only ellagic acid markedly decreased the activity of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) compared with IFO alone, while chrysin was only effective on BChE activity. Also, ellagic acid ameliorated IFO-induced lipid peroxidation and glutathione (GSH) depletion, while chrysin only decreased GSH depletion. Histopathological alteration in the IFO-induced brain tissues were decreased especially after administration of ellagic acid. Intraperitoneal pretreatment with betanin, followed by IFO resulted in death of all treated animals. In addition, all mitochondrial toxicity parameters induced by IFO in the rat brain tissue were ameliorated by ellagic acid, chrysin and even betanin. CONCLUSION: Taken together, our results demonstrated that especially ellagic acid and to some extent chrysin show a typical neuroprotective effect on IFO-induced acute neurotoxicity through mitochondrial protection and antioxidant properties. Also, the results of our studies showed that pretreatment with betanin followed by IFO was lethal.
Assuntos
Ácido Elágico , Ifosfamida , Ratos , Masculino , Animais , Ifosfamida/toxicidade , Ratos Wistar , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Acetilcolinesterase , Betacianinas/farmacologia , Antioxidantes/farmacologia , Glutationa/metabolismo , Estresse OxidativoRESUMO
It has been suggested that cytarabine (Ara-C) induces toxicity via mitochondrial dysfunction and oxidative stress. Therefore, we hypothesized that mitochondrial protective agents and antioxidants can reduce cytarabine-induced neurotoxicity. For this purpose, 48 male Wistar rats were assigned into eight equal groups include control group, Ara-C (70 mg/kg, i.p.) group, Ara-C plus betanin (25 mg/kg, i.p.) group, Ara-C plus vitamin D (500 U/kg, i.p.) group, Ara-C plus thymoquinone (0.5 mg/kg, i.p.) group, betanin group, vitamin group, and thymoquinone group. The activity of acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), the concentrations of antioxidants (reduced glutathione and oxidized glutathione), oxidative stress (malondialdehyde) biomarkers, mitochondrial toxicity parameters as well as histopathological alteration in brain tissues were measured. Our results demonstrated that Ara-C exposure significantly declines the brain enzymes activity (AChE and BChE), levels of antioxidant biomarkers (GSH), and mitochondrial functions, but markedly elevate the levels of oxidative stress biomarkers (MDA) and mitochondrial toxicity. Almost all of the previously mentioned parameters (especially mitochondrial toxicity) were retrieved by betanin, vitamin D, and thymoquinone compared to Ara-C group. These findings conclusively indicate that betanin, vitamin D, and thymoquinone administration provide adequate protection against Ara-C-induced neurotoxicity through modulations of oxidative, antioxidant activities, and mitochondrial protective (mitoprotective) effects.
Assuntos
Antioxidantes , Fármacos Neuroprotetores , Ratos , Animais , Masculino , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Ratos Wistar , Citarabina/toxicidade , Citarabina/metabolismo , Vitamina D/farmacologia , Acetilcolinesterase/metabolismo , Betacianinas/farmacologia , Butirilcolinesterase/metabolismo , Estresse Oxidativo , Vitaminas/metabolismo , Vitaminas/farmacologia , Mitocôndrias/metabolismo , Encéfalo , Biomarcadores/metabolismo , Fármacos Neuroprotetores/farmacologiaRESUMO
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.
Assuntos
Quitosana , Curcumina , Nanopartículas , Ratos , Animais , Curcumina/farmacologia , Celecoxib/farmacologia , Antioxidantes/farmacologia , Quitosana/farmacologia , Miócitos Cardíacos , Mitocôndrias , Tamanho da Partícula , Portadores de FármacosRESUMO
From ancient times to the present-day animal venoms had been used as medicinal and therapeutic agents. Recently it has been reported that the scorpion venom is a potential source of active and therapeutic compounds to design potent drugs against variety of cancerous cells and other diseases. The current study aimed to evaluate the selective toxicity of Iranian Mesobuthus eupeus (IMe) crude venom as a potential source of anticancer compounds on cancerous CLL B-lymphocytes and normal lymphocytes. For this purpose, we isolated cancerous CLL B-lymphocytes and normal lymphocytes from chronic lymphocytic leukemia patients and healthy volunteers. Cancerous CLL B-lymphocytes and normal lymphocytes were treated with different concentration (0, 5, 10, 20, 40 and 80 µg/ml) of IMe crude venom for 12 hours and cytotoxicity, reactive oxygen species (ROS) production, collapse of mitochondrial membrane potential (MMP) and lysosomal membrane integrity were determined. The data demonstrated the significant cytotoxic effect of IMe crude venom on cancerous CLL B-lymphocytes, with a concentration value (IC50) that inhibits 50% of the cell viability of 60 µg/ ml after 12 h of incubation. MTT assay proved that the IMe crude venom is selectively toxic to cancerous CLL B-lymphocytes, and IMe crude venom induced selective cell death via activation of ROS formation and mitochondrial/lysosomal dysfunction. These finding showed that IMe crude venom has a selective mitochondrial/lysosomal-mediated cell death effect on cancerous CLL B-lymphocytes. Therefore, the IMe crude venom and its fractions may be promising in the future anticancer drug development for treatment of CLL and variety of cancers.