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1.
Chemosphere ; 287(Pt 3): 132245, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34543908

RESUMO

Aluminum phosphide is a well-known hazardous agent used as an agricultural pesticide to protect stored grains from insect damage. However, accidental consumption of a trivial amount of it caused irreversible damage to the human body or even death in acute cases. The present study used taurine and grape seed extract as a natural cardioprotective medicine against aluminum phosphide poisoning by decreasing oxidative stress. The activity of oxidative stress biomarkers (Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase) were evaluated in the cell line model on Human Cardiac Myocyte cells. In the beginning, to clarify the pure impact of aluminum phosphide poison, taurine, and grape seed extract on the human heart cells, their effects on the biomarkers quantity in cell line were measured. Subsequently, the effect of taurine and grape seed extract with various concentrations as a treatment on the oxidative stress biomarkers of the poisoned heart cells were studied. Data analysis reveals that taurine and grape seed extract treatment can successfully diminish the poisoning effect by their antioxidant properties. The oxidative markers values of the poisoned cells were recovered by taurine and grape seed extracts treatment. Taurine (2 g/l) can recover Malondialdehyde, Catalase, Protein carbonyl, and Superoxide dismutase by 56%, 78%, 88%, 78%, when the recovering power of grape seed extract (100 g/l) for the aforementioned enzymes are 56%, 0.71%,74%, 51%, respectively. Therefore, it is clear that the performance of taurine in the recovery of the biomarkers' value is better than grape seed extract.


Assuntos
Extrato de Sementes de Uva , Praguicidas , Vitis , Compostos de Alumínio , Antioxidantes , Biomarcadores , Extrato de Sementes de Uva/farmacologia , Humanos , Estresse Oxidativo , Fosfinas , Taurina/farmacologia
2.
J Pharm Pharmacol ; 73(11): 1539-1546, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33793778

RESUMO

OBJECTIVES: The effects of Crocin as a cardioprotective material against Aluminum phosphide poisoning by reducing the oxidative stress is investigated. METHODS: The level of biomarkers of oxidative stress (Catalase, Superoxide dismutase, Malondialdehyde and Protein carbonyl) were measured in the cell culture model on Human Cardiac Myocyte cells to detect the protective effect of crocin. Initially, to define the pure impact of aluminum phosphide poison and crocin on the heart cells, their effects on the biomarkers quantity in cell line were measured, separately, using the standard related kits. Later the effect of crocin with different concentration as a treatment on the oxidative stress biomarkers of the poisoned heart cells were monitored. Note that in pre-treatment case, the crocin was initially added to the cells before poisoning them. Data were analyzed using the analysis of variance method. KEY FINDINGS: Results showed that crocin treatment reduced the aluminum phosphide (AlP) poisoning effect significantly. The treatment resulted in substantial deviation in the biomarkers of oxidative stress at the pre- and post-treatment phases for all groups. The oxidative markers values of the poisoned cells were recovered by crocin treatment. CONCLUSIONS: Crocin is proposed as a potentially powerful antioxidant to treat the cardiotoxicity caused by aluminum phosphide poisoning.

3.
Life Sci ; 265: 118813, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33275984

RESUMO

AIMS: Although chemotherapeutic agents have highly beneficial effects against cancer, they disturb the body's normal homeostasis. One of the critical side effects of chemotherapeutic agents is their deleterious effect on the cardiac system, which causes limitations of their clinical usage. Taurine constitutes more than 50% of the amino acids in the heart. The use of taurine might prevent chemotherapy-induced cardiotoxicity. This systematic study aims to evaluate the protective role of taurine against cardiotoxicity induced by chemotherapy. METHODS: A systematic search was performed in databases up to November 2020, and the review is designed on PRISMA guidelines. The search keywords were selected based on our study target and were searched in the title and abstract. After the consecutive screening, out of a whole of 94 articles, 8 articles were included according to our inclusion and exclusion criteria. KEY FINDINGS: According to the study results, chemotherapy decreases body and heart weight and increases mortality. Also, it induces some biochemical and histological changes compared to the control group. By co-administration of taurine with chemotherapy, alterations returned near to the average level. These protective effects of taurine are mediated through anti-oxidant, anti-inflammatory, and anti-apoptotic properties. SIGNIFICANCE: Based on evaluated non-clinical studies, taurine ameliorates chemotherapy-induced cardiotoxicity, but its possible interaction with the efficacy of anti-cancer medicines that mostly act through induction of oxidants remains to be elucidated in the future. This needs conducting well-designed studies to assess the effectiveness and safety of this combination simultaneously.


Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/prevenção & controle , Taurina/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antineoplásicos/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Humanos , Neoplasias/tratamento farmacológico , Taurina/farmacologia
4.
Environ Sci Pollut Res Int ; 27(5): 4969-4975, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31845254

RESUMO

Paraquat (PQ) is a herbicide agent commonly used in agricultural applications. Hepatotoxicity is among clinical complications associated with PQ intoxication. Oxidative stress and its subsequent events are major mechanisms identified in PQ-induced liver toxicity. Berberine (BBR) is a natural antioxidant widely investigated for its hepatoprotective effects. The present study designed to evaluate the potential cytoprotective properties of BBR against PQ-induced cytotoxicity in primary cultured rat hepatocytes and in vivo test of liver function enzymes. Cellular and biochemical parameters including lactate dehydrogenase (LDH), cell viability, ROS formation, glutathione (GSH) content, and mitochondrial membrane potential in the PQ-treated hepatocytes were measured, and the mentioned markers were evaluated in the presence of BBR. BBR treatment caused significant decrease in PQ-induced cell death, ROS formation, and LDH release. On the other hand, it was found that BBR inhibits cellular glutathione depletion in PQ-treated hepatocytes. Also, BBR treatment significantly diminished PQ-induced the liver function enzyme elevation. These data mention the potential hepatoprotective effect of BBR with therapeutic capability against PQ-induced liver damage.


Assuntos
Berberina , Glutationa/química , Herbicidas , Fígado/efeitos dos fármacos , Paraquat/química , Animais , Berberina/química , Berberina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Ratos
5.
EXCLI J ; 18: 317-330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338005

RESUMO

The oral cavity and its appendices are exposed to considerable environmental and mechanical stress. Cell junctions play a pivotal role in this context. Among those, gap junctions permit the exchange of compounds between cells, thereby controlling processes such as cell growth and differentiation. Tight junctions restrict paracellular transportation and inhibit movement of integral membrane proteins between the different plasma membrane poles. Adherens junctions attach cells one to another and provide a solid backbone for resisting to mechanistical stress. The integrity of oral mucosa, normal tooth development and saliva secretion depend on the proper function of all these types of cell junctions. Furthermore, deregulation of junctional proteins and/or mutations in their genes can alter tissue functioning and may result in various human disorders, including dental and periodontal problems, salivary gland malfunction, hereditary and infectious diseases as well as tumorigenesis. The present manuscript reviews the role of cell junctions in the (patho)physiology of the oral cavity and its appendices, including salivary glands.

6.
Iran J Pharm Res ; 17(4): 1465-1475, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30568704

RESUMO

Thioridazine (TZ) is used mainly in the treatment of schizophrenia. However, hepatotoxicity as a life-threatening adverse effect is associated with its clinical use. In this context, we examined the cytotoxic mechanisms of TZ on freshly isolated rat hepatocytes to better understanding of the pathogenesis of TZ-induced hepatotoxicity. Hepatocytes were prepared by the method of collagenase enzyme perfusion via the portal vein. The level of parameters such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosomal membrane integrity and cellular glutathione (GSH) content in TZ-treated and non-treated hepatocytes were determined and the mentioned markers were assessed in the presence of Coenzyme Q10 and/or melatonin. Results showed that TZ caused an increase in ROS formation as well as induction of LPO and GSH depletion. Moreover, mitochondria and lysosomes seem to be targets of TZ-induced toxicity. The administration of Coenzyme Q10 and/or melatonin efficiently decreased the rate of ROS formation, LPO and improved cell viability, MMP, GSH level and lysosome membrane integrity. This study proposes the possible protective role of Coenzyme Q10 and/or melatonin against TZ-induced cellular injury probably through their radical scavenging properties and their effects on mitochondria and lysosomes.

7.
Biomed Pharmacother ; 99: 939-946, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29710494

RESUMO

Overexpression of renin angiotensin system (RAS) components and nuclear factor-kappa B (NF-kB) has a key role in various cancers. Blockade of RAS and NF-kB pathway has been suggested to reduce cancer cell proliferation. This study aimed to investigate the role of angiotensin II and NF-kB pathway in liver hepatocellular carcinoma cell line (HepG2) proliferation by using azilsartan (as a novel Ag II antagonist) and Bay 11-7082 (as NF-kB inhibitor). HepG2 cells were treated with different concentrations of azilsartan and Bay 11-7082. Cytotoxicity was determined after 24, 48, and 72?h by MTT assay. Reactive oxygen spices (ROS) generation and cytochrome c release were measured following azilsartan and Bay11- 7082 treatment. Apoptosis was analyzed qualitatively by DAPI staining and quantitatively through flow cytometry methodologies and Bax and Bcl-2 mRNA and protein levels were assessed by real time PCR and ELISA methods, respectively. The cytotoxic effects of different concentration of azilsartan and Bay11- 7082 on HepG2 cells were observed as a reduction in cell viability, increased ROS formation, cytochrome c release and apoptosis induction. These effects were found to correlate with a shift in Bax level and a downward trend in the expression of Bcl-2. These findings suggest that azilsartan and Bay11- 7082 in combination or alone have strong potential as an agent for prevention or treatment of liver cancer after further studies.


Assuntos
Benzimidazóis/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Oxidiazóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , NF-kappa B/metabolismo , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Oxidiazóis/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sulfonas/administração & dosagem , Sulfonas/farmacologia
8.
Pestic Biochem Physiol ; 144: 71-78, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29463411

RESUMO

Organophosphates (OP) are potent pesticide commonly utilized in agricultural and domestic use. However, plentitude of data represent their side effects in different body tissues. We attempted to study whether betanin (a natural pigment) is able to mitigate some OPs-induced hepatotoxicity in primary rat hepatocytes. Cell viability, lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), glutathione (GSH) depletion and mitochondrial depolarization were tested as toxicity markers. The outcomes revealed that betanin (25µM) significantly increased cell viability, plummeted ROS formation and LPO, restored cellular GSH reservoirs and protected mitochondria after chlorpyrifos (CPF) (300µM), diazinon (DZN) (600µM) and dichlrovos (DDVP) (400µM) treatment. Taken together, all data suggests the potential protective role of betanin in OPs-induced hepatotoxicity in which the mechanism appears to be inhibition of ROS formation and mitochondrial protection.


Assuntos
Antioxidantes/farmacologia , Betacianinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Organofosfatos/toxicidade , Praguicidas/toxicidade , Animais , Células Cultivadas , Clorpirifos/toxicidade , Diazinon/toxicidade , Diclorvós/toxicidade , Glutationa/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
9.
Environ Toxicol ; 33(2): 167-177, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29143438

RESUMO

Development of biocompatible antioxidant nanoparticles for xenobiotic-induced liver disease treatment by oral or parenteral administration is of great interest in medicine. In the current study, we demonstrate the protective effects of coenzyme Q10 nanoparticles (CoQ10-NPs) on hepatotoxicity induced by dichlorvos (DDVP) as an organophosphate. Although CoQ10 is an efficient antioxidant, its poor bioavailability has limited the applications of this useful agent. First, CoQ10-NPs were prepared then characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In DDVP-treated and non-treated hepatocytes in the presence of CoQ10-NPs, cell viability, the level of reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosome membrane integrity, and cellular glutathione (GSH) content were measured. The prepared CoQ10-NPs were mono-dispersed and had narrow size distribution with average diameter of 54 nm. In the in vivo study, we evaluated the enzymes, which are involved in the antioxidant system for maintenance of normal liver function. In comparison to nonparticulate CoQ10, the CoQ10-NPs efficiently decreased the ROS formation, lipid peroxidation and cell death. Also, particulate form of CoQ10 improved MMP, GSH level and lysosome membrane integrity. In the in vivo, study, we revealed that CoQ10-NPs were better hepatoprotective than its nonparticulate form (P < .05). Altogether, we propose that the CoQ10-NPs have potential capability to be used as a therapeutic and prophylactic agent for poisoning that is induced by organophosphate agents, especially in the case of DDVP. Furthermore, these positive remarks make this nanoparticle amenable for the treatment of xenobiotic-induced liver diseases.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Lisossomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Substâncias Protetoras/farmacologia , Ubiquinona/análogos & derivados , Animais , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Diclorvós/toxicidade , Glutationa/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Substâncias Protetoras/química , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Ubiquinona/química , Ubiquinona/farmacologia
10.
Drug Res (Stuttg) ; 67(4): 217-222, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28118671

RESUMO

Bupropion is a widely prescribed antidepressant/smoke cessation drug. However, hepatotoxicity is one of its side effects reported in some recipients. The mechanisms by which bupropion induces hepatotoxicity is not clear yet. This experiment was intended to assess the cytotoxic mechanisms of bupropion toward primary rat hepatocytes. Additionally, the effect of α-tocopherol succinate (ALPHA-TOS) and N-acetyl cysteine (NAC) and mitochondrial permeability transition (MPT) pore sealing agent cyclosporine A (Cs A) on this toxicity was investigated. Cell death, LDH leakage, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), and mitochondrial depolarization were examined as toxicity indicators. Results revealed that bupropion led to a surge in ROS formation, depletion of intracellular glutathione, elevation of LPO, and mitochondrial collapse. ALPHA-TOS, NAC and Cs A administration diminished the intensity of cellular damage caused by bupropion. This experiment suggests the protective role of ALPHA-TOS, NAC and Cs A against bupropion-mediated cytotoxicity possibly through their reactive radical scavenging properties and their impacts on mitochondria. Furthermore, mitochondria might be contributed to the oxidative stress response and subsequent toxicological results observed by bupropion.


Assuntos
Antidepressivos de Segunda Geração/efeitos adversos , Bupropiona/toxicidade , Hepatócitos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclosporina/farmacologia , Glutationa/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Estresse Oxidativo/efeitos dos fármacos , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , alfa-Tocoferol/farmacologia
11.
Arch Pharm Res ; 40(11): 1296-1313, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27271269

RESUMO

Even though citalopram is commonly used in psychiatry, there are several reports on its toxic effects. So, the current study was designed to elucidate the mechanisms of cytotoxic effects of in vitro and in vivo citalopram treatment on liver and the following cytolethal events. For in vitro experiments, freshly isolated rat hepatocytes were exposed to citalopram along with/without various agents. To do in vivo studies liver function enzyme assays and histological examination were performed. In the in vitro experiments, citalopram (500 µM) exposure demonstrated cell death, a marked elevation in ROS formation, mitochondrial potential collapse, lysosomal membrane leakiness, glutathione (GSH) depletion and lipid peroxidation. In vivo biochemistry panel assays for liver enzymes function (AST, ALT and GGTP) and histological examination confirmed citalopram (20 mg/kg)-induced damage. citalopram-induced oxidative stress cytotoxicity markers were significantly prevented by antioxidants, ROS scavengers, MPT pore sealing agents, endocytosis inhibitors, ATP generators and CYP inhibitors. Either enzyme induction or GSH depletion were concomitant with augmented citalopram-induced damage both in vivo and in vitro which were considerably ameliorated with antioxidants and CYP inhibitors. In conclusion, it is suggested that citalopram hepatotoxicity might be a result of oxidative hazard leading to mitochondrial/lysosomal toxic connection and disorders in biochemical markers which were supported by histomorphological studies.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Citalopram/toxicidade , Hepatócitos/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Animais , Antioxidantes/farmacologia , Morte Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Glutationa/metabolismo , Hepatócitos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Função Hepática , Mitocôndrias/metabolismo , Mitocôndrias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
12.
Toxicol Mech Methods ; 26(7): 520-528, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27387968

RESUMO

The hepatotoxic effects of the antipsychotic agent, risperidone (RIS) were investigated for better understanding the pathogenesis of RIS in liver toxicity in vivo and in in vitro. Isolated rat hepatocytes were obtained by collagenase perfusion technique and were then incubated with RIS, different antioxidants in particular coenzyme Q10 (CoQ10), N-acetyl cysteine (NAC). Our results showed that RIS could induce cytotoxicity via rising reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation. All of these effects were significantly (p < 0.05) inhibited by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Similar outcomes were obtained from the in vivo experiments. Liver function enzyme test and histopathological evaluation confirmed RIS-(6 mg/kg) induced damage. Based on these results, it is suggested that RIS-induced liver toxicity is associated with mitochondrial/lysosomal cross-talk following the initiation of oxidative stress. Thus, the use of CoQ10 and/or NAC seems to be a safe therapeutic option in this context.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Risperidona/toxicidade , Ubiquinona/análogos & derivados , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ubiquinona/farmacologia
13.
Expert Rev Gastroenterol Hepatol ; 10(11): 1279-1288, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27352778

RESUMO

INTRODUCTION: The current review aimed to outline the functions of the renin angiotensin system (RAS) in the context of the oxidative stress-associated liver disease. Areas covered: Angiotensin II (Ang II) as the major effector peptide of the RAS is a pro-oxidant and fibrogenic cytokine. Mechanistically, NADPH oxidase (NOX) is a multicomponent enzyme complex that is able to generate reactive oxygen species (ROS) as a downstream signaling pathway of Ang II which is expressed in liver. Ang II has a detrimental role in the pathogenesis of chronic liver disease through possessing pro-oxidant, fibrogenic, and pro-inflammatory impact in the liver. The alternative axis (ACE2/Ang(1-7)/mas) of the RAS serves as an anti-inflammatory, antioxidant and anti-fibrotic component of the RAS. Expert commentary: In summary, the use of alternative axis inhibitors accompanying with ACE2/ Ang(1-7)/mas axis activation is a promising new strategy serving as a novel therapeutic option to prevent and treat chronic liver diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Inflamatórios/efeitos adversos , Antioxidantes/efeitos adversos , Ativação Enzimática , Ativadores de Enzimas/uso terapêutico , Humanos , Fígado/metabolismo , Fígado/fisiopatologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Terapia de Alvo Molecular , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/agonistas , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
14.
Iran Biomed J ; 20(4): 217-22, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27090202

RESUMO

BACKGROUND: Stearic acid is known as a potent anti-inflammatory lipid. This fatty acid has profound and diverse effects on liver metabolism. The aim of this study was to investigate the effect of stearic acid on markers of hepatocyte transplantation in rats with acetaminophen (APAP)-induced liver damage. METHODS: Wistar rats were randomly assigned to 10-day treatment. Stearic acid was administered to the rats with APAP-induced liver damage. The isolated liver cells were infused intraperitoneally into rats. Blood samples were obtained to evaluate the changes in the serum liver enzymes, including activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and the level of serum albumin. To assess the engraftment of infused hepatocytes, rats were euthanized, and the liver DNA was used for PCR using sex-determining region Y (SRY) primers. RESULTS: The levels of AST, ALT and ALP in the serum of rats with APAP-induced liver injury were significantly increased and returned to the levels in control group by day six. The APAP-induced decrease in albumin was significantly improved in rats through cell therapy, when compared with that in the APAP-alone treated rats. SRY PCR analysis showed the presence of the transplanted cells in the liver of transplanted rats. CONCLUSION: Stearic acid-rich diet in combination with cell therapy accelerates the recovering of hepatic dysfunction in a rat model of liver injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos/métodos , Facilitação Imunológica de Enxerto/métodos , Sobrevivência de Enxerto/efeitos dos fármacos , Fígado/lesões , Ácidos Esteáricos/uso terapêutico , Acetaminofen/toxicidade , Alanina Transaminase/sangue , Alanina Transaminase/metabolismo , Fosfatase Alcalina/sangue , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/transplante , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Albumina Sérica/análise
15.
Adv Pharm Bull ; 6(4): 521-530, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28101459

RESUMO

Purpose: Depression is a public disorder worldwide. Despite the widespread use of venlafaxine in the treatment of depression, it has been associated with the incidence of toxicities. Hence, the goal of the current investigation was to evaluate the mechanisms of venlafaxine-induced cell death in the model of the freshly isolated rat hepatocytes. Methods: Collagenase-perfused rat hepatocytes were treated with venlafaxine and other agents. Cell damage, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential decline, lysosomal damage, glutathione (GSH) level were analyzed. Moreover, rat liver mitochondria were isolated through differential centrifugation to assess respiratory chain functionality. Results: Our results demonstrated that venlafaxine could induce ROS formation followed by lipid peroxidation, cellular GSH content depletion, elevated GSSG level, loss of lysosmal membrane integrity, MMP collapse and finally cell death in a concentration-dependent manner. N-acetyl cysteine, taurine and quercetine significantly decreased the aforementioned venlafaxine-induced cellular events. Also, radical scavenger (butylatedhydroxytoluene and α-tocopherol), CYP2E1 inhibitor (4-methylpyrazole), lysosomotropic agents (methylamine and chloroquine), ATP generators (L-gluthamine and fructose) and mitochondrial pore sealing agents (trifluoperazine and L-carnitine) considerably reduced cytotoxicity, ROS generation and lysosomal leakage following venlafaxine treatment. Mitochondrion dysfunction was concomitant with the blockade of the electron transfer complexes II and IV of the mitochondrial respiratory system. Conclusion: Therefore, our data indicate that venlafaxine induces oxidative stress towards hepatocytes and our findings provide evidence to propose that mitochondria and lysosomes are of the primary targets in venlafaxine-mediated cell damage.

16.
Adv Pharm Bull ; 6(4): 627-637, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28101470

RESUMO

Purpose: Triptans are the drug category mostly prescribed for abortive treatment of migraine. Most recent cases of liver toxicity induced by triptans have been described, but the mechanisms of liver toxicity of these medications have not been clear. Methods: In the present study, we obtained LC50 using dose-response curve and investigated cell viability, free radical generation, lipid peroxide production, mitochondrial injury, lysosomal membrane damage and the cellular glutathione level as toxicity markers as well as the beneficial effects of taurine and/or N-acetyl cysteine in the sumatriptan-treated rat parenchymal hepatocytes using accelerated method of cytotoxicity mechanism screening. Results: It was revealed that liver toxicity induced by sumatriptan in in freshly isolated parenchymal hepatocytes is dose-dependent. Sumatriptan caused significant free radical generation followed by lipid peroxide formation, mitochondrial injury as well as lysosomal damage. Moreover, sumatriptan reduced cellular glutathione content. Taurine and N-acetyl cysteine were able to protect hepatocytes against sumatriptan-induced harmful effects. Conclusion: It is concluded that sumatriptan causes oxidative stress in hepatocytes and the decreased hepatocytes glutathione has a key role in the sumatriptan-induced harmful effects. Also, N-acetyl cysteine and/or taurine could be used as treatments in sumatriptan-induced side effects.

17.
Xenobiotica ; 46(4): 369-78, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26364812

RESUMO

1. Olanzapine (OLZ) is a widely used atypical antipsychotic agent for the treatment of schizophrenia and other disorders. Serious hepatotoxicity and elevated liver enzymes have been reported in patients receiving OLZ. However, the cellular and molecular mechanisms of the OLZ hepatotoxicity are unknown. 2. In this study, the cytotoxic effect of OLZ on freshly isolated rat hepatocytes was assessed. Our results showed that the cytotoxicity of OLZ in hepatocytes is mediated by overproduction of reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation preceding cell lysis. All the aforementioned OLZ-induced cellular events were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate generators. Also, the present results demonstrated that CYP450 is involved in OLZ-induced oxidative stress and cytotoxicity mechanism. 3. It is concluded that OLZ hepatotoxicity is associated with both mitochondrial/lysosomal involvement following the initiation of oxidative stress in hepatocytes.


Assuntos
Benzodiazepinas/farmacologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/metabolismo , Morte Celular/efeitos dos fármacos , Separação Celular , Inibidores das Enzimas do Citocromo P-450/farmacologia , Dissulfeto de Glutationa/metabolismo , Hepatócitos/efeitos dos fármacos , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Olanzapina , Fenobarbital , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
18.
Adv Pharm Bull ; 5(3): 329-34, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26504754

RESUMO

PURPOSE: Amitriptyline, one of the commonly used tricyclic antidepressants, caused rare but severe hepatotoxicity in patients who received it continuously. Previous findings showed that the intermediate metabolites of amitriptyline produced by CYP450 are involved in hepatic injury. Melatonin is an antiaging and antioxidant hormone synthesized from pineal gland. The aim of present study was to evaluate the protective role of melatonin in an in vitro model of isolated rat hepatocytes. METHODS: Markers such as cell viability, reactive oxygen species formation, lipid peroxidation, mitochondrial membrane potential, and hepatocytes glutathione content were evaluated every 60 minutes for 180 minutes. RESULTS: Present results indicated that administration of 1mM of melatonin effectively reduced the cell death, ROS formation and lipid peroxidation, mitochondrial membrane potential collapse, and reduced cellular glutathione content caused by amitriptyline. CONCLUSION: Our results indicated that melatonin is an effective antioxidant in preventing amitriptyline-induced hepatotoxicity. We recommend further in vivo animal and clinical trial studies on the hepatoprotective effects of melatonin in patients receiving amitriptyline.

19.
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.

20.
Adv Pharm Bull ; 5(4): 447-54, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26819915

RESUMO

In recent decades, the use of nanomaterials has received much attention in industrial and medical fields. However, some reports have mentioned adverse effects of these materials on the biological systems and cellular components. There are several major mechanisms for cytotoxicity of nanoparticles (NPs) such as physicochemical properties, contamination with toxic element, fibrous structure, high surface charge and radical species generation. In this review, a brief key mechanisms involved in toxic effect of NPs are given, followed by the in vitro toxicity assays of NPs and prooxidant effects of several NPs such as carbon nanotubes, titanium dioxide NPs, quantum dots, gold NPs and silver NPs.

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