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1.
Clin Exp Hepatol ; 7(1): 30-40, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34027113

RESUMO

Aim of the study: Cholestasis is a serious complication affecting other organs such as the liver and kidney. Oxidative stress and mitochondrial impairment are proposed as the primary mechanisms for cholestasis-induced organ injury. Taurine (TAU) is the most abundant free amino acid in the human body, which is not incorporated in the structure of proteins. Several pharmacological effects have been attributed to TAU. It has been reported that TAU effectively mitigated oxidative stress and modulated mitochondrial function. The current study aimed to evaluate the impact of TAU on oxidative stress biomarkers and mitochondrial parameters in the kidney of cholestatic animals. Material and methods: Bile duct ligated (BDL) rats were used as an antioxidant model of cholestasis. Animals were treated with TAU (500 and 1000 mg/kg, oral) for seven consecutive days. Animals were anesthetized (thiopental 80 mg/kg, i.p.), and kidney and blood specimens were collected. Results: Severe elevation in serum and urine biomarkers of renal injury was evident in the BDL group. Significant lipid peroxidation, reactive oxygen species (ROS) formation, and protein carbonylation were detected in the kidney of BDL animals. Furthermore, depleted glutathione reservoirs and a significant decrease in the antioxidant capacity of renal tissue were detected in cholestatic rats. Renal tubular atrophy and interstitial inflammation were evident in BDL animals. Cholestasis also caused significant mitochondrial dysfunction in the kidney. TAU significantly prevented cholestasis-induced renal injury by inhibiting oxidative stress and mitochondrial impairment. Conclusions: These data indicate TAU as a potential therapeutic agent in the management of cholestasis-induced renal injury.

2.
Nutr Neurosci ; 23(9): 731-743, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30856059

RESUMO

Objective(s): Manganese (Mn) is an essential trace element physiologically incorporated in the structure of several vital enzymes. Despite its essentiality, excessive Mn exposure is toxic with brain tissue as the primary target organ. There is no specific and clinically available therapeutic/preventive option against Mn neurotoxicity. Carnosine is a neuropeptide with several physiological roles. The neuroprotective properties of this peptide have been evaluated in different experimental models. The current study was designed to investigate the effect of carnosine supplementation and its potential mechanisms of action in an animal model of Mn-induced neurotoxicity. Materials and Methods: Male C57BL/6 mice received Mn (100 mg/kg, s.c) alone and/or in combination with carnosine (10, 50, and 100 mg/kg, i.p). Several locomotor activity indices were monitored. Moreover, biomarkers of oxidative stress and mitochondrial function were assessed in the brain tissue of Mn-exposed animals. Results: Significant locomotor dysfunction was revealed in Mn-exposed animals. Furthermore, brain tissue biomarkers of oxidative stress were significantly increased, and mitochondrial indices of functionality were impaired in Mn-treated animals. It was found that carnosine supplementation (10, 50, and 100 mg/kg, i.p) alleviated the Mn-induced locomotor deficit. Moreover, this peptide mitigated oxidative stress biomarkers and preserved brain tissue mitochondrial functionality in the animal model of manganism. Conclusion: These data indicate that carnosine is a potential neuroprotective agent against Mn neurotoxicity. Antioxidative and mitochondria protecting effects of carnosine might play a fundamental role in its neuroprotective properties against Mn toxicity.


Assuntos
Antioxidantes/administração & dosagem , Carnosina/administração & dosagem , Manganês/toxicidade , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos
3.
Heliyon ; 5(6): e01996, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31294126

RESUMO

Imatinib is a tyrosine kinase inhibitor widely administered against chronic myeloid leukemia. On the other hand, drug-induced kidney proximal tubular injury, electrolytes disturbances, and renal failure is a clinical complication associated with imatinib therapy. There is no precise cellular mechanism(s) for imatinib-induced renal injury. The current investigation aimed to evaluate the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of imatinib nephrotoxicity. Rats received imatinib (50 and 100 mg/kg, oral, 14 consecutive days). Serum and urine biomarkers of renal injury and markers of oxidative stress in the kidney tissue were assessed. Moreover, kidney mitochondria were isolated, and mitochondrial indices, including mitochondrial depolarization, dehydrogenases activity, mitochondrial permeabilization, lipid peroxidation (LPO), mitochondrial glutathione levels, and ATP content were determined. A significant increase in serum (Creatinine; Cr and blood urea nitrogen; BUN) and urine (Glucose, protein, gamma-glutamyl transferase; γ-GT, and alkaline phosphatase; ALP) biomarkers of renal injury, as well as serum electrolytes disturbances (hypokalemia and hypophosphatemia), were evident in imatinib-treated animals. On the other hand, imatinib (100 mg/kg) caused an increase in kidney ROS and LPO. Renal tubular interstitial nephritis, tissue necrosis, and atrophy were evident as tissue histopathological changes in imatinib-treated rats. Mitochondrial parameters were also adversely affected by imatinib administration. These data represent mitochondrial impairment, renal tissue energy crisis, and oxidative stress as possible mechanisms involved in the pathogenesis of imatinib-induced renal injury and serum electrolytes disturbances.

4.
Biol Trace Elem Res ; 190(2): 384-395, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30357569

RESUMO

Manganese (Mn) is a trace element involved in many physiological processes. However, excessive Mn exposure leads to neurological complications. Although no precise mechanism(s) has been found for Mn-induced neurotoxicity, oxidative stress and mitochondrial injury seem to play a relevant role in this complication. On the other hand, there is no protective strategy against Mn neurotoxicity so far. Taurine is an amino acid with significant neuroprotective properties. The current study was designed to evaluate the effect of taurine supplementation and its potential mechanism(s) of action in a mouse model of manganism. Animals were treated with Mn (100 mg/kg, s.c) alone and/or in combination with taurine (50, 100, and 500 mg/kg, i.p, for eight consecutive days). Severe locomotor dysfunction along with a significant elevation in brain tissue biomarkers of oxidative stress was evident in Mn-exposed mice. On the other hand, it was revealed that mitochondrial indices of functionality were hampered in Mn-treated animals. Taurine supplementation (50, 100, and 500 mg/kg, i.p) alleviated Mn-induced locomotor deficit. Moreover, this amino acid mitigated oxidative stress biomarkers and preserved brain tissue mitochondrial indices of functionality. These data introduce taurine as a potential neuroprotective agent against Mn neurotoxicity. Antioxidative and mitochondria protecting effects of taurine might play a fundamental role in its neuroprotective properties against Mn toxicity.


Assuntos
Modelos Animais de Doenças , Manganês/toxicidade , Fármacos Neuroprotetores/farmacologia , Taurina/farmacologia , Animais , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Locomoção/efeitos dos fármacos , Masculino , Manganês/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Taurina/administração & dosagem
5.
J Basic Clin Physiol Pharmacol ; 30(1): 91-101, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30205645

RESUMO

Background Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis. Methods BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery). Results Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery). Conclusions The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences.


Assuntos
Suplementos Nutricionais , Cirrose Hepática Biliar/tratamento farmacológico , Falência Hepática Aguda/prevenção & controle , Prolina/uso terapêutico , Animais , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Ligadura/efeitos adversos , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Prolina/farmacologia , Ratos , Ratos Sprague-Dawley
6.
Biomed Pharmacother ; 97: 1086-1095, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29136945

RESUMO

Cholestasis is the stoppage of bile flow which could lead to serious clinical complications if not managed. Cytotoxic bile acids are involved in the pathogenesis of liver injury during cholestasis. There are no promising pharmacological interventions against cholestasis and its associated complications. This study examined the impact of glycine supplementation on liver mitochondria as a major target of bile acids-induced toxicity during cholestasis. Mice underwent BDL operation and received glycine (0.25% and 1% w:v in drinking water). Blood and liver samples were collected at scheduled time intervals (3, 7, and 14 days after BDL surgery). Plasma biomarkers of liver injury, along with markers of oxidative stress in the liver tissue were evaluated. Furthermore, liver mitochondria were isolated, and several mitochondrial indices were assessed. BDL-induced cholestasis was evident in mice as a significant elevation in plasma biomarkers of liver injury. Markers of oxidative stress were significantly increased in the liver of BDL animals. Liver injury was histopathologically evident by tissue necrosis, bile duct proliferation, hydropic changes, inflammation, and fibrosis. Furthermore, high level of reactive oxygen species, lipid peroxidation, depleted glutathione reservoirs, and impaired tissue antioxidant capacity were also detected in the liver of cholestatic mice. An assessment of liver mitochondrial function in BDL animals revealed an inhibition of mitochondrial dehydrogenases activity, collapse of mitochondrial membrane potential, mitochondrial swelling, and increase of reactive oxygen species (ROS), and lipid peroxidation (LPO). Furthermore, a significant decrease in mitochondrial ATP was detected in the liver mitochondria isolated from cholestatic animals. Glycine supplementation (0.25% and 1%) decreased mitochondrial swelling, ROS, and LPO. Moreover, glycine treatment improved mitochondrial membrane potential and restored liver mitochondrial ATP. On the other hand, it was found that glycine supplementation attenuated oxidative stress markers in the liver of BDL animals. Moreover, liver histopathological changes and collagen deposition were markedly mitigated by glycine treatment. The mechanisms for the beneficial effects of glycine administration in cholestatic animals might be linked to its ability for preserving cellular redox environment, preventing oxidative stress, and maintaining mitochondrial functionality.


Assuntos
Colestase/tratamento farmacológico , Glicina/farmacologia , Fígado/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Ácidos e Sais Biliares/metabolismo , Biomarcadores/sangue , Colestase/complicações , Colestase/fisiopatologia , Colágeno/metabolismo , Modelos Animais de Doenças , Glicina/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias Hepáticas/patologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
7.
Ren Fail ; 39(1): 745-753, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29214868

RESUMO

Sulfasalazine is a commonly used drug for the treatment of rheumatoid arthritis and inflammatory bowel disease. There are several cases of renal injury encompass sulfasalazine administration in humans. The mechanism of sulfasalazine adverse effects toward kidneys is obscure. Oxidative stress and its consequences seem to play a role in the sulfasalazine-induced renal injury. The current investigation was designed to investigate the effect of sulfasalazine on kidney mitochondria. Rats received sulfasalazine (400 and 600 mg/kg/day, oral) for 14 consecutive days. Afterward, kidney mitochondria were isolated and assessed. Sulfasalazine-induced renal injury was biochemically evident by the increase in serum blood urea nitrogen (BUN), gamma-glutamyl transferase (γ-GT), and creatinine (Cr). Histopathological presentations of the kidney in sulfasalazine-treated animals revealed by interstitial inflammation, tubular atrophy, and tissue necrosis. Markers of oxidative stress including an increase in reactive oxygen species (ROS) and lipid peroxidation (LPO), a defect in tissue antioxidant capacity, and glutathione (GSH) depletion were also detected in the kidney of sulfasalazine-treated groups. Decreased mitochondrial succinate dehydrogenase activity (SDA), mitochondrial depolarization, mitochondrial GSH depletion, increase in mitochondrial ROS, LPO, and mitochondrial swelling were also evident in sulfasalazine-treated groups. Current data suggested that oxidative stress and mitochondrial injury might be involved in the mechanism of sulfasalazine-induced renal injury.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Rim/patologia , Mitocôndrias/efeitos dos fármacos , Sulfassalazina/efeitos adversos , Injúria Renal Aguda/sangue , Administração Oral , Animais , Antioxidantes/metabolismo , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Biomarcadores/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Glutationa/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Rim/citologia , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , gama-Glutamiltransferase/sangue
8.
Clin Res Hepatol Gastroenterol ; 41(4): 424-434, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28283328

RESUMO

AIM: Chronic liver injury and cirrhosis leads to liver failure. Hyperammonemia is a deleterious consequence of liver failure. On the other hand, oxidative stress seems to play a pivotal role in the pathogenesis of liver fibrosis as well as in the cytotoxic mechanism of ammonia. There is no promising therapeutic agent against ammonia-induced complications. The present study was conducted to evaluate the role of carnosine (CA) administration on liver pathological changes, elevated plasma ammonia, and its consequent events in cirrhotic rats. METHODS: Bile duct ligated (BDL) rats were used as a model of cirrhosis. CA (250, 500, and 1000mg/kg, daily, i.p) was administered for 28 consecutive days to BDL animals. At the end of treatments, markers of oxidative stress and liver fibrosis was determined in liver and serum biomarkers of liver injury and plasma ammonia was assessed. Moreover, changes in animals' locomotor activity were monitored. RESULTS: Severe bridging fibrosis, inflammation, and necrosis in liver, along with elevated serum biomarkers of liver injury were evident in BDL animals. Furthermore, plasma ammonia was drastically elevated in cirrhotic rats and animals' locomotor activity was suppressed. It was found that CA (250, 500, and 1000mg/kg, daily, i.p) significantly alleviated liver injury and its consequent events in cirrhotic rats. The data suggested that CA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia and brain damage as a deleterious consequence of cirrhosis and liver failure.


Assuntos
Carnosina/uso terapêutico , Hiperamonemia/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Animais , Hiperamonemia/complicações , Cirrose Hepática/complicações , Masculino , Ratos , Ratos Sprague-Dawley
9.
Biomed Pharmacother ; 86: 514-520, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28024286

RESUMO

Ammonia-induced mitochondrial dysfunction and energy crisis is known as a critical consequence of hepatic encephalopathy (HE). Hence, mitochondria are potential targets of therapy in HE. The current investigation was designed to evaluate the role of taurine treatment on the brain and liver mitochondrial function in a rat model of hepatic encephalopathy and hyperammonemia. The animals received thioacetamide (400mg/kg, i.p, for three consecutive days at 24-h intervals) as a model of acute liver failure and hyperammonemia. Several biochemical parameters were investigated in the serum, while the animals' cognitive function and locomotor activity were monitored. Mitochondria was isolated from the rats' brain and liver and several indices were assessed in isolated mitochondria. Liver failure led to cognitive dysfunction and impairment in locomotor activity in the rats. Plasma and brain ammonia was high and serum markers of liver injury were drastically elevated in the thioacetamide-treated group. An assessment of brain and liver mitochondrial function in the thioacetamide-treated animals revealed an inhibition of succinate dehydrogenase activity (SDA), collapsed mitochondrial membrane potential, mitochondrial swelling, and increased reactive oxygen species (ROS). Furthermore, a significant decrease in mitochondrial ATP was detected in the brain and liver mitochondria isolated from thioacetamide-treated animals. Taurine treatment (250, 500, and 1000mg/kg) decreased mitochondrial swelling, ROS, and LPO. Moreover, the administration of this amino acid restored brain and liver mitochondrial ATP. These data suggest taurine to be a potential protective agent with therapeutic capability against hepatic encephalopathy and hyperammonemia-induced mitochondrial dysfunction and energy crisis.


Assuntos
Encéfalo/efeitos dos fármacos , Hiperamonemia/tratamento farmacológico , Falência Hepática Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Taurina/farmacologia , Trifosfato de Adenosina/metabolismo , Amônia/farmacologia , Animais , Encéfalo/metabolismo , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/metabolismo , Hiperamonemia/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Tioacetamida/farmacologia
10.
Toxicol Lett ; 259: 108-115, 2016 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-27506418

RESUMO

Methimazole is the most frequently prescribed antithyroid agent. On the other hand, several cases of liver injury are attributed to this drug. The mechanism of methimazole-induced liver injury is obscure. Hepatocytes mitochondria seem to be a target for methimazole cytotoxicity. Current investigation aimed to evaluate the effects of methimazole on the hepatocytes mitochondria in different experimental models. In the in vivo model, methimazole (100, 200 and 400mg/kg, i.p) was administered to mice and liver mitochondria were isolated and assessed. In the in vitro experiments, intact isolated liver mitochondria were incubated with increasing methimazole concentrations (10µM-100mM). It was found that methimazole decreased liver mitochondrial ATP and glutathione, increased mitochondrial swelling, lipid peroxidation and reactive oxygen species (ROS), and collapsed mitochondrial membrane potential when administered to mice. Paradoxically, methimazole not only caused no significant injury toward isolated liver mitochondria in vitro but improved mitochondrial function and protected this organelle. The differences between two investigated models in the current study might be associated with drug bioactivation and reactive metabolites formation. These findings suggest mitochondrial dysfunction as a mechanism for methimazole-induced liver injury. Moreover, methimazole seems to be a novel mitochondrial protecting agent in vitro.


Assuntos
Antitireóideos/toxicidade , Metimazol/toxicidade , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Distribuição Aleatória
11.
Toxicol Rep ; 3: 870-879, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28959615

RESUMO

Hyperammonemia is associated with chronic and acute liver injury. There is no promising therapeutic agent against ammonia-induced complications. Hence, finding therapeutic molecules with safe profile of administration has clinical value. The present study was conducted to evaluate the role of taurine (TA) administration on plasma and brain ammonia and its consequent events in different models of chronic and acute liver injury and hyperammonemia. Bile duct ligated (BDL) rats were used as a model of chronic liver injury. Thioacetamide and acetaminophen-induced acute liver failure were used as acute liver injury models. A high level of ammonia was detected in blood and brain of experimental groups. An increase in brain ammonia level coincided with a decreased total locomotor activity of animals and significant changes in the biochemistry of blood and also liver tissue. TA administration (500 and 1000 mg/kg, i.p), effectively alleviated liver injury and its consequent events including rise in plasma and brain ammonia and brain edema. The data suggested that TA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia as a deleterious consequence of acute and chronic liver injury.

12.
Adv Pharm Bull ; 5(1): 1-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25789213

RESUMO

Drug-induced liver injury (DILI) is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU) are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s) of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

13.
J Biochem Mol Toxicol ; 29(2): 57-62, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25293820

RESUMO

Aminoglycoside antibiotics are widely used against Gram-negative infections. On the other hand, nephrotoxicity is a deleterious side effect associated with aminoglycoside therapy. Gentamicin is the most nephrotoxic aminoglycoside. Because of serious health complications ensue the nephrotoxicity induced by aminoglycosides, finding new therapeutic strategies against this problem has a great clinical value. This study has attempted to compare the nephrotoxic properties of gentamicin and a new nanosized formulation of this drug in a mice model. Animals were treated with gentamicin (100 mg/kg, i.p. for eight consecutive days) and nanogentamicin (100 mg/kg, i.p. for eight consecutive days). Blood urea nitrogen (BUN), plasma creatinine levels, and histopathological changes of kidney proximal tubule were monitored. It was found that gentamicin caused severe degeneration of kidney proximal tubule cells and an increase in serum creatinine and BUN. No severe injury was observed after nanogentamicin administration. This study proved that nanosized gentamicin is less nephrotoxic.


Assuntos
Antibacterianos/efeitos adversos , Gentamicinas/efeitos adversos , Nefropatias , Nanopartículas/efeitos adversos , Ureia/sangue , Animais , Antibacterianos/farmacologia , Creatinina/sangue , Gentamicinas/farmacologia , Nefropatias/sangue , Nefropatias/induzido quimicamente , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos
14.
Clin Mol Hepatol ; 20(3): 237-48, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25320726

RESUMO

Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.


Assuntos
Antitireóideos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Animais , Antitireóideos/química , Antitireóideos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Modelos Animais de Doenças , Doença de Graves/tratamento farmacológico , Humanos , Hipertireoidismo/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco
15.
Adv Pharm Bull ; 4(3): 249-54, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24754008

RESUMO

PURPOSE: Hepatotoxicity is one of the most important side effects of the statins therapy as lipid-lowering agents. However, the mechanism(s) of hepatotoxicity induced by these drugs is not clearly understood yet, and no hepatoprotective agent has been developed against this complication. METHODS: The protective effect of N-acetylcysteine (NAC) against statins-induced cytotoxicity was evaluated by using freshly isolated rat hepatocytes. Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. This technique is based on liver perfusion with collagenase after removal of calcium ion (Ca2+) with a chelator (ethylene glycol tetra acetic acid (EGTA) 0.5 mM). The level of parameters such as cell death, ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) in the statins-treated hepatocytes were determined. Additionally, the mentioned markers were assessed in the presence of NAC. RESULTS: Incubation of hepatocytes with the statins resulted in cytotoxicity characterized by an elevation in cell death, increasing ROS generation and consequently lipid peroxidation and impairment of mitochondrial function. Administration of NAC caused reduction in amount of ROS formation, lipid peroxidation and finally, cell viability and mitochondrial membrane potential (MMP) were improved. CONCLUSION: This study confirms that oxidative stress and consequently mitochondrial dysfunction is one of the mechanisms underlying the statins-induced liver injury and treating hepatocytes by NAC (200 µM) attenuates this cytotoxicity.

16.
Arh Hig Rada Toksikol ; 65(1): 101-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24535294

RESUMO

Statins are potent cholesterol-lowering drugs that can have serious adverse effects on the muscles and liver. The aim of our in vitro study was to establish the protective effect of coenzyme Q10 (CoQ10, in its optimal dose of 200 µmol L⁻¹) against cytotoxicity induced by atorvastatin, simvastatin, and lovastatin in isolated rat hepatocytes by observing parameters such as cell death, reactive oxygen species formation, lipid peroxidation, mitochondrial membrane potential, and cellular reduced and oxidised glutathione content. Our findings have shown that pretreatment with CoQ10 was effective in reducing the toxic effects of statins in rat hepatocytes. This work demonstrates that the addition of CoQ10 to statin treatment regimens may protect hepatocytes (and also other types of cells) from statin-induced injuries and alleviate their side effects.


Assuntos
Anticolesterolemiantes/toxicidade , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Substâncias Protetoras/farmacologia , Ubiquinona/análogos & derivados , Animais , Atorvastatina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Hepatócitos/patologia , Dose Letal Mediana , Peroxidação de Lipídeos/efeitos dos fármacos , Lovastatina/toxicidade , Masculino , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sinvastatina/toxicidade , Ubiquinona/farmacologia
17.
J Biochem Mol Toxicol ; 27(6): 287-94, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23761184

RESUMO

Statins are potent drugs, used as lipid-lowering agents in cardiovascular diseases. Hepatotoxicity is one of the serious adverse effects of statins, and the exact mechanism of hepatotoxicity is not yet clear. In this study, the cytotoxic effects of the most commonly used statins, that is, atorvastatin, lovastatin, and simvastatin toward isolated rat hepatocytes, were evaluated. Markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, and the amount of reduced and oxidized glutathione in the statin-treated hepatocytes, were investigated. It was found that the statins caused cytotoxicity toward rat hepatocytes dose dependently. An elevation in ROS formation, accompanied by a significant amount of lipid peroxidation and mitochondrial depolarization, was observed. Cellular glutathione reservoirs were decreased, and a significant amount of oxidized glutathione was formed. This study suggests that the adverse effect of statins toward hepatocytes is mediated through oxidative stress and the hepatocytes mitochondria play an important role in the statin-induced toxicity.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Animais , Atorvastatina , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Hepatócitos/patologia , Ácidos Heptanoicos/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Lovastatina/toxicidade , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pirróis/toxicidade , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sinvastatina/toxicidade
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