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1.
Andrologia ; 53(5): e14033, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33660882

RESUMO

The aim of this study was to investigate the protective and therapeutic effects of thymoquinone against the negative effects of varicocele on testicular tissue and sperm morphology. Five groups were formed by random selection from a total of 40 adult male Wistar rats (n = 8). Thymoquinone (5 mg/kg/day) was administered intraperitoneally to the varicocele-dimethyl sulfoxide-olive oil-thymoquinone (VT) group and the sham-thymoquinone group. At the end of the 60th day, all groups were anaesthetised and the left testis was removed from the body quickly. One half of the testis tissue, which was divided into two, was separated for biochemical and Western blot analysis, while the other half were fixed in Bouin's fixative. As a result of biochemical, molecular and histopathological analyses, a statistically significant increase was found in the varicocele group testicular tissues in the malondialdehyde level, apoptotic index, Bax expression, cytochrome c expression and Bax/Bcl-2 ratio compared with the sham group. In addition, histopathological changes characterised by partial or complete degeneration of the germinal epithelium were observed in the seminiferous tubules in the same group. Total oxidant status level and sperm count with abnormal morphology increased in varicocele group, whereas total antioxidant status level decreased. In the VT group, all of the biochemical, molecular and histopathological changes detected in the varicocele group were statistically significantly reduced. When the findings obtained in this study are evaluated, it can be said that thymoquinone has the potential to be used as a preventive and therapeutic pharmacological agent in the medical treatment of varicocele. Although the exact mechanism of action of thymoquinone has not been fully elucidated, the findings obtained in this study support the view that thymoquinone showed a cytoprotective effect by reducing apoptosis, oxidative stress and lipid peroxidation.


Assuntos
Varicocele , Animais , Benzoquinonas , Humanos , Masculino , Ratos , Ratos Wistar , Espermatozoides , Testículo
2.
Arch Environ Contam Toxicol ; 81(1): 46-57, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33864096

RESUMO

The present study investigates the toxicity of the herbicide tribenuron methyl (TBM) as an anthropogenic agent and ammonia as an abiotic factor on Daphnia magna at environmentally relevant concentrations. These stressors may coexist in surface waters in agricultural regions. To achieve this objective, D. magna were exposed to TBM at a nominal concentration of 0.81 µg/L in association with a low ammonia (LA) concentration of 0.65 mg/L and a high ammonia (HA) concentration of 1.61 mg/L in acute toxicity tests of 96-h duration and chronic toxicity tests of 21-day duration. The D. magna also were exposed to TBM, HA, and LA singly. The D. magna were analysed for various biomarkers of sublethal toxicity. Glutathione peroxidase (GPx), glutathione S-transferase (GST), cholinesterase (ChE) enzyme activities, and levels of thiobarbituric acid reactive substances (TBARS) and total protein were determined spectrophotometrically. Mitochondrial membrane potential (MMP) was analysed by microscopy with fluorescence staining. Cytochrome c and 5' AMP-activated protein kinase (AMPK) were analysed by Western blotting. Morphometric properties were examined microscopically. This is the first study in which AMPK, an indicator of intracellular energy, was measured in D. magna. GST and ChE enzyme activities and TBARS and total protein levels did not change during acute exposures (i.e., 96 h) in all treatments. GPx activity increased in D. magna from the HA + TBM treatment compared with single-exposure groups. The level of cytochrome c protein was elevated in D. magna from the LA and LA + TBM treatments. AMPK protein levels increased in all treatments with daphnids, except in the LA group. MMP was depolarised in D. magna from all treatments, whereas the most notable change was observed in HA + TBM mixture group in chronic exposures. The results show that GST and ChE may not be sensitive biomarkers for evaluating the sublethal toxic effects to D. magna exposed to environmentally relevant concentrations of ammonia and TBM. Acute and chronic exposure to ammonia and TBM probably caused an energetic crisis in D. magna. Therefore, AMPK and MMP are promising biomarkers for these toxicants.


Assuntos
Daphnia , Poluentes Químicos da Água , Amônia/toxicidade , Animais , Sulfonatos de Arila , Testes de Toxicidade Aguda , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
3.
Clin Exp Hypertens ; 39(7): 592-600, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28635325

RESUMO

BACKGROUND: High dietary salt, as well as renal mass reduction, is known to decrease baroreflex sensitivity in rats. However, the effect of high salt intake on baroreflex sensitivity is unknown in reduced renal mass (RRM) hypertension; therefore, the aim of this study was to investigate the effects of salt loading on arterial baroreflex sensitivity and mean arterial pressure (MAP) in RRM hypertension. METHODS: Both RRM and sham-operated control (SO) rats were loaded with 0.25 or 0.5% NaCl for five weeks. Plasma Na+, K+, and creatinine levels were measured, and baroreflex sensitivity was evaluated before and after ß1 blockade. In addition, cardiac vagal tone and intrinsic heart rate (IHR) were measured. RESULTS: RRM decreased full baroreflex sensitivity of the tachycardic response under 0.5% NaCl loading and the parasympathetic bradycardic response under 0% NaCl loading. The NaCl loading did not affect the severity of RRM hypertension. Cardiac vagal tone and IHR decreased in RRM rats versus SO controls under all NaCl loading conditions. RRM decreased plasma K+ under 0% NaCl loading and increased plasma Na+ under 0.5% NaCl loading. High (0.5%) NaCl loading decreased IHR and increased plasma creatinine and left ventricular weight in RRM rats. CONCLUSIONS: RRM in combination with 0.5% NaCl loading led to a decrease in the sensitivity of full baroreflex and of the parasympathetic component of baroreflex. Changes in plasma Na+ and K+ levels, due to NaCl loading, may have contributed to the decrease in baroreflex sensitivities and IHR but had no effect upon MAP in RRM rats.


Assuntos
Barorreflexo/fisiologia , Hipertensão/fisiopatologia , Cloreto de Sódio na Dieta/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Coração/fisiologia , Frequência Cardíaca/fisiologia , Hipertensão Renal/fisiopatologia , Rim/cirurgia , Masculino , Tamanho do Órgão , Ratos Wistar , Sódio/metabolismo
4.
Med Sci Monit ; 22: 438-46, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26861593

RESUMO

BACKGROUND Doxorubicin (brand name: Adriamycin®) is used to treat solid tissue cancer but it also affects noncancerous tissues. Its mechanism of cytotoxicity is probably related to increased oxidation, mitochondrial dysfunction, and apoptosis. Melatonin is reported to have antiapoptotic and antioxidative effects. The aim of this study was to determine whether melatonin would counteract in vitro cytotoxicity of doxorubicin in mouse fibroblasts and determine the pathway of its action against doxorubicin-induced apoptosis. MATERIAL AND METHODS We measured markers of apoptosis (cytochrome-c, mitochondrial membrane potential, and apoptotic cell number) and oxidative stress (total oxidant and antioxidant status) and calculated oxidant stress index in 4 groups of fibroblasts: controls, melatonin-treated, doxorubicin-treated, and fibroblasts concomittantly treated with a combination of melatonin and doxorubicin. RESULTS Melatonin given with doxorubicin succesfully countered apoptosis generated by doxorubicin alone, which points to its potential as a protective agent against cell death in doxorubicin chemotherapy. This also implies that patients should be receiving doxorubicin treatment when their physiological level of melatonin is at its highest, which is early in the morning. CONCLUSIONS This physiological level may not be high enough to overcome doxorubicin-induced oxidative stress, but adjuvant melatonin treatment may improve quality of life. Further research is needed to verify our findings.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Doxorrubicina/toxicidade , Fibroblastos/efeitos dos fármacos , Melatonina/farmacologia , Mitocôndrias/efeitos dos fármacos , PPAR gama/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Interações Medicamentosas , Fibroblastos/citologia , Fibroblastos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Células NIH 3T3 , Estresse Oxidativo/efeitos dos fármacos
5.
Med Sci Monit ; 22: 1013-21, 2016 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-27019222

RESUMO

BACKGROUND: Adriamycin (ADR) is a drug used clinically for anticancer treatment; however, it causes adverse effects in the liver. The mechanism by which these adverse effects occur remains unclear, impeding efforts to enhance the therapeutic effects of ADR. Its hepatotoxicity might be related to increasing reactive oxygen species (ROS) and mitochondrial dysfunction. The interaction between ADR and the local renin-angiotensin system (RAS) in the liver is unclear. ADR might activate the RAS. Angiotensin-II (Ang-II) leads to ROS production and mitochondrial dysfunction. In the present study we investigated whether ADR's hepatotoxicity interacts with local RAS in causing oxidative stress resulting from mitochondrial dysfunction in the rat liver. MATERIAL/METHODS: Rats were divided into 5 groups: control, ADR, co-treated ADR with captopril, co-treated ADR with Aliskiren, and co-treated ADR with both captopril and Aliskiren. Mitochondria and cytosol were separated from the liver, then biochemical measurements were made from them. Mitochondrial membrane potential (MMP) and ATP levels were evaluated. RESULTS: ADR remarkably decreased MMP and ATP in liver mitochondria (p<0.05). Co-administration with ADR and Aliskiren and captopril improved the dissipation of MMP (p<0.05). The decreased ATP level was restored by treatment with inhibitors of ACE and renin. CONCLUSIONS: Angiotensin-II may contribute to hepatotoxicity of in the ADR via mitochondrial oxidative production, resulting in the attenuation of MMP and ATP production.


Assuntos
Angiotensina II/farmacologia , Doxorrubicina/efeitos adversos , Fígado/metabolismo , Fígado/patologia , Mitocôndrias Hepáticas/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Citosol/efeitos dos fármacos , Citosol/metabolismo , Fígado/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley
6.
Med Sci Monit ; 22: 4587-4595, 2016 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-27889788

RESUMO

BACKGROUND Myocardial ischemia and reperfusion lead to impairment of electrolyte balance and, eventually, lethal arrhythmias. The aim of this study was to investigate the effects of pharmacological inhibition of angiotensin-II (Ang-II) production on heart tissue with ischemia-reperfusion damage, arrhythmia, and oxidative stress. MATERIAL AND METHODS Rats were divided into 4 groups: only ischemia/reperfusion (MI/R), captopril (CAP), aliskiren (AL), and CAP+AL. The drugs were given by gavage 30 min before anesthesia. Blood pressure and electrocardiography (ECG) were recorded during MI/R procedures. The heart tissue and plasma was kept so as to evaluate the total oxidant (TOS), antioxidant status (TAS), and creatine kinase-MB (CK-MB). RESULTS Creatine kinase-MB was not different among the groups. Although TAS was not affected by inhibition of Ang-II production, TOS was significantly lower in the CAP and/or AL groups than in the MI/R group. Furthermore, oxidative stress index was significantly attenuated in the CAP and/or AL groups. Captopril significantly increased the duration of VT during ischemia; however, it did not have any effect on the incidence of arrhythmias. During reperfusion periods, aliskiren and its combinations with captopril significantly reduced the incidence of other types of arrhythmias. Captopril alone had no effect on the incidence of arrhythmias, but significantly increased arrhythmias score and durations of arrhythmias during reperfusion. MAP and heart rate did not show changes in any groups during ischemic and reperfusion periods. CONCLUSIONS Angiotensin-II production appears to be associated with elevated levels of reactive oxygen species, but Ang-II inhibitions increases arrhythmia, mainly by initiating ventricular ectopic beats.


Assuntos
Angiotensina II/biossíntese , Arritmias Cardíacas/metabolismo , Coração/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , Amidas/farmacologia , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Creatina Quinase Forma MB/metabolismo , Fumaratos/farmacologia , Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos
7.
Med Sci Monit ; 20: 399-405, 2014 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-24614724

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is a major health problem worldwide. Oxidative stress is one of the mediators of this disease. Systemic complications of oxidative stress are involved in the pathogenesis of hypertension, endothelial dysfunction, shortened erythrocyte lifespan, deformability, and nitric oxide (NO) dysfunction. L-carnosine is known as an antioxidant. In this study, our aim was to investigate the effect of carnosine on hemorheologic and cardiovascular parameters in CKD-induced rats. MATERIAL AND METHODS: We used 4-month-old male Sprague-Dawley rats divided into 4 groups of 6 rats each. Three days after subtotal nephrectomy and sham operations, the surviving rats were divided into the 4 groups; 1) Sham (S), 2) Sham+Carnosine (S-C), 3) Subtotal nephrectomy (Nx), and 4) Subtotal nephrectomy + Carnosine (N-C). Carnosine was injected intraperitoneally (i.p.) (50 mg/kg) for 15 days. The control group received the same volume of physiological saline. RESULTS: In CKD rats, malondialdehyde (MDA) levels were increased, and NO and RBC deformability were decreased compared to Sham. Carnosine treatment decreased MDA levels, improved RBC (red blood cell) ability to deform, and increased NO levels. However, carnosine did not affect blood pressure levels in these rats. CONCLUSIONS: We found that carnosine has beneficial effects on CKD in terms of lipid peroxidation and RBC deformability. Carnosine may have a healing effect in microcirculation level, but may not have any effect on systemic blood pressure in CKD-induced rats.


Assuntos
Carnosina/farmacologia , Hemorreologia/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Nefrectomia , Animais , Pressão Sanguínea/efeitos dos fármacos , Deformação Eritrocítica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Ratos , Ratos Sprague-Dawley , Resistência ao Cisalhamento/efeitos dos fármacos
8.
Ren Fail ; 36(4): 606-12, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24502693

RESUMO

Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p<0.05). ADR significantly decreased MMP and ATP level in kidney mitochondria (p<0.05). Co-administration with ADR and Aliskren and CAP improved the dissipation of MMP (p<0.05). The decrease in ATP level was restored by treatment with inhibitors of ACE and renin. We concluded that inhibitors of angiotensin-II are effective against acute ADR induced nephrotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.


Assuntos
Angiotensina II/biossíntese , Doxorrubicina/toxicidade , Nefropatias/fisiopatologia , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Amidas/farmacologia , Animais , Captopril/farmacologia , Creatina Quinase/sangue , Fumaratos/farmacologia , Rim/metabolismo , Nefropatias/induzido quimicamente , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Renina/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos
9.
Biotech Histochem ; 99(3): 113-124, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38439686

RESUMO

Doxorubicin (DOX)-induced cardiotoxicity is a well known clinical problem, and many investigations have been made of its possible amelioration. We have investigated whether diazoxide (DIA), an agonist at mitochondrial ATP-sensitive potassium channels (mitoKATP), could reverse DOX-induced apoptotic myocardial cell loss, in cultured rat cardiomyocytes. The role of certain proteins in this pathway was also studied. The rat cardiomyocyte cell line (H9c2) was treated with DOX, and also co-treated with DOX and DIA, for 24 h. Distribution of actin filaments, mitochondrial membrane potential, superoxide dismutase (SOD) activity, total oxidant and antioxidant status (TOS and TAS, respectively), and some protein expressions, were assessed. DOX significantly decreased SOD activity, increased ERK1/2 protein levels, and depolarised the mitochondrial membrane, while DIA co-treatment inhibited such changes. DIA co-treatment ameliorated DOX-induced cytoskeletal changes via F-actin distribution and mitoKATP structure. Co-treatment also decreased ERK1/2 and cytochrome c protein levels. Cardiomyocyte loss due to oxidative stress-mediated apoptosis is a key event in DOX-induced cytotoxicity. DIA had protective effects on DOX-induced cardiotoxicity, via mitoKATP integrity, especially with elevated SUR2A levels; but also by a cascade including SOD/AMPK/ERK1/2. Therefore, DIA may be considered a candidate agent for protecting cardiomyocytes against DOX chemotherapy.


Assuntos
Cardiotoxicidade , Diazóxido , Doxorrubicina , Miócitos Cardíacos , Animais , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Ratos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Diazóxido/farmacologia , Cardiotoxicidade/prevenção & controle , Linhagem Celular , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Canais de Potássio/metabolismo , Canais de Potássio/efeitos dos fármacos
10.
J Biol Chem ; 287(49): 41258-67, 2012 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-23066018

RESUMO

Ventricular ATP-sensitive potassium (K(ATP)) channels link intracellular energy metabolism to membrane excitability and contractility. Our recent proteomics experiments identified plakoglobin and plakophilin-2 (PKP2) as putative K(ATP) channel-associated proteins. We investigated whether the association of K(ATP) channel subunits with junctional proteins translates to heterogeneous subcellular distribution within a cardiac myocyte. Co-immunoprecipitation experiments confirmed physical interaction between K(ATP) channels and PKP2 and plakoglobin in rat heart. Immunolocalization experiments demonstrated that K(ATP) channel subunits (Kir6.2 and SUR2A) are expressed at a higher density at the intercalated disk in mouse and rat hearts, where they co-localized with PKP2 and plakoglobin. Super-resolution microscopy demonstrate that K(ATP) channels are clustered within nanometer distances from junctional proteins. The local K(ATP) channel density, recorded in excised inside-out patches, was larger at the cell end when compared with local currents recorded from the cell center. The K(ATP) channel unitary conductance, block by MgATP and activation by MgADP, did not differ between these two locations. Whole cell K(ATP) channel current density (activated by metabolic inhibition) was ∼40% smaller in myocytes from mice haploinsufficient for PKP2. Experiments with excised patches demonstrated that the regional heterogeneity of K(ATP) channels was absent in the PKP2 deficient mice, but the K(ATP) channel unitary conductance and nucleotide sensitivities remained unaltered. Our data demonstrate heterogeneity of K(ATP) channel distribution within a cardiac myocyte. The higher K(ATP) channel density at the intercalated disk implies a possible role at the intercellular junctions during cardiac ischemia.


Assuntos
Canais KATP/química , Miócitos Cardíacos/citologia , Difosfato de Adenosina/química , Trifosfato de Adenosina/química , Animais , Membrana Celular/metabolismo , Desmossomos/metabolismo , Masculino , Camundongos , Microscopia/métodos , Isquemia Miocárdica/patologia , Placofilinas/metabolismo , Ratos , Ratos Sprague-Dawley , gama Catenina/metabolismo
11.
J Mol Cell Cardiol ; 52(3): 596-607, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22245446

RESUMO

Since ion channels move electrical charge during their activity, they have traditionally been studied using electrophysiological approaches. This was sometimes combined with mathematical models, for example with the description of the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon by Hodgkin and Huxley. The methods for studying ion channels also have strong roots in protein chemistry (limited proteolysis, the use of antibodies, etc.). The advent of the molecular cloning and the identification of genes coding for specific ion channel subunits in the late 1980s introduced a multitude of new techniques with which to study ion channels and the field has been rapidly expanding ever since (e.g. antibody development against specific peptide sequences, mutagenesis, the use of gene targeting in animal models, determination of their protein structures) and new methods are still in development. This review focuses on techniques commonly employed to examine ion channel function in an electrophysiological laboratory. The focus is on the K(ATP) channel, but many of the techniques described are also used to study other ion channels.


Assuntos
Canais KATP/metabolismo , Miocárdio/metabolismo , Animais , Técnicas Eletrofisiológicas Cardíacas/métodos , Expressão Gênica , Marcação de Genes/métodos , Humanos , Canais KATP/química , Canais KATP/genética , Camundongos , Camundongos Transgênicos , Complexos Multiproteicos/metabolismo , Processamento de Proteína Pós-Traducional , Subunidades Proteicas , Transporte Proteico
12.
J Mol Cell Cardiol ; 52(2): 410-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21888913

RESUMO

AMPK is an important sensor of cellular energy levels. The aim of these studies was to investigate whether cardiac K(ATP) channels, which couple cellular energy metabolism to membrane excitability, are regulated by AMPK activity. We investigated effects of AMPK on rat ventricular K(ATP) channels using electrophysiological and biochemical approaches. Whole-cell K(ATP) channel current was activated by metabolic inhibition; this occurred more rapidly in the presence of AICAR (an AMPK activator). AICAR had no effects on K(ATP) channel activity recorded in the inside-out patch clamp configuration, but ZMP (the intracellular intermediate of AICAR) strongly activated K(ATP) channels. An AMPK-mediated effect is demonstrated by the finding that ZMP had no effect on K(ATP) channels in the presence of Compound C (an AMPK inhibitor). Recombinant AMPK activated Kir6.2/SUR2A channels in a manner that was dependent on the AMP concentration, whereas heat-inactivated AMPK was without effect. Using mass-spectrometry and co-immunoprecipitation approaches, we demonstrate that the AMPK α-subunit physically associates with K(ATP) channel subunits. Our data demonstrate that the cardiac K(ATP) channel function is directly regulated by AMPK activation. During metabolic stress, a small change in cellular AMP that activates AMPK can be a potential trigger for K(ATP) channel opening. This article is part of a Special Issue entitled "Local Signaling in Myocytes".


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo Energético/fisiologia , Canais KATP/metabolismo , Monofosfato de Adenosina/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Células COS , Chlorocebus aethiops , Canais KATP/agonistas , Canais KATP/genética , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ribonucleotídeos/farmacologia , Transdução de Sinais , Estresse Fisiológico
13.
Neuroendocrinology ; 94(3): 218-27, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21778690

RESUMO

BACKGROUND: Manipulating thyroid hormones has been shown to influence learning and memory. Although a large body of literature is available on the effects of thyroid hormone deficiency on learning and memory functions during developmental or adult-onset hypothyroidism, electrophysiological findings are limited. This limitation is especially notable with respect to thyroxine administration in adult, normothyroid animals. METHODS: Experiments were carried out on 12 adult male Wistar rats, each 9-10 months of age. Rats were randomly divided into hyperthyroid (0.2 mg/kg/day intraperitoneal thyroxine injection, for 21 days) and control groups (n = 6 animals in each group). Following spatial learning performance tests on hyperthyroid and control groups, rats were anesthetized with urethane and placed in a stereotaxic frame. A bipolar, tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted within the granule cell layer of the ipsilateral dentate gyrus to record field excitatory postsynaptic potentials (fEPSP). Following a 15-min baseline recording of fEPSPs, long-term potentiation (LTP) was induced by four sets of tetanic pulse trains. RESULTS: Thyroxine-treated rats showed significantly worse performance in the spatial memory task and attenuated input-output relationships in the electrophysiological analyses. Treated rats also showed a lower efficacy of LTP induction when compared with controls. CONCLUSION: The present study provides clear in vivo evidence for the action of L-thyroxine in the impairment of synaptic plasticity and in inducing spatial memory task deficits in adult rats. These findings may explain the complaints of cognitive function reductions in hyperthyroid patients.


Assuntos
Hipocampo/efeitos dos fármacos , Hipertireoidismo/induzido quimicamente , Hipertireoidismo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Tiroxina/efeitos adversos , Fatores Etários , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Hipocampo/fisiologia , Hipertireoidismo/sangue , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/sangue , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Ratos , Ratos Wistar , Hormônios Tireóideos/sangue , Tiroxina/farmacologia
14.
Drug Chem Toxicol ; 34(2): 199-207, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21314470

RESUMO

Adriamycin (ADR) causes morphological and functional alterations in mitochondrial structure in the heart. The study's aim was to determine whether there is a protective effect of selenium (Se) on ADR-induced cardiac damage. Rats were divided into four groups: The first group was injected saline intraperitoneally (i.p.) for 21 days; the second group received 4 mg/kg i.p. ADR every alternate day for 8 days; the third group received 50 µg/kg i.p. Se for 21 days; and the fourth received the Se (for 21 days) and ADR (for 8 days) coadministration i.p. Left ventricular functions, electrocardiography parameters, and blood pressures were assessed. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) level, and thioredoxin reductase (TrxR) activity were determined. Total antioxidant (TAS) and oxidant status (TOS) in cytosol, mitochondria of myocytes, and plasma were measured. Left ventricular data demonstrated left ventricular systolic pressure (LVSP) decreased, left ventricular developed pressure (LVDP) decreased, and left ventricular end-diastolic pressure (LVEDP) increased in ADR-treated animals, compared to the control and Se groups. ADR decreased the membrane potential and ATP level in myocyte mitochondria. TrxR activity decreased in the ADR group, compared to the Se group. Cytosolic and mitochondrial TAS decreased and mitochondrial and plasma TOS increased in the ADR group, compared to the control. The coadministration of Se with ADR attenuated left ventricular dysfunction, improved MMP and ATP levels, and prevented oxidative stress by increasing antioxidants (especially TrxR) and decreasing oxidants. We concluded that Se is effective against ADR-induced cardiac damage via the restoration of TAS and TOS, which prevented mitochondrial damage.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Selenito de Sódio/farmacologia , Adenosina Trifosfatases/metabolismo , Animais , Antioxidantes/administração & dosagem , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Eletrocardiografia/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Ratos , Ratos Sprague-Dawley , Selenito de Sódio/administração & dosagem , Tiorredoxinas/metabolismo
15.
Brain Res ; 1759: 147367, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582122

RESUMO

Vulnerable areas like the hippocampus are sensitive to insults such as sleep deprivation (SD); they are also susceptible to environmental enrichment. Much evidence is accumulating that chronic sleep deprivation causes alterations in the hippocampus that responsible for spatial memory. However, there is conflicting about the differences between acute and chronic SD results. The purpose of this study was to determine the protective effects of mild treadmill exercise on acute SD rats. Four groups were created as control, exercise, sleep deprivation, exercise + sleep deprivation. Multiple platforms method was used to induce REM sleep deprivation (RD) for 48 h. The exercise was applied fivedaysperweekforfour weeks(5 × 4). For the first and second weeks, the length of the exercise was 15 min in two sessions (5 min interval) followed by 15 min in three, 15 min in four sessions. Morris water maze (MWM) was used as a spatial memory test. Gene level was determined by using the qPCR technique. Malondialdehyde (MDA) content in the hippocampus was measured as an extent of peroxidative damage to lipids by using the ELISA method. 48 h RD impaired long-term spatial memory significantly. Mild, regular treadmill exercise ameliorated the detrimental effects of acute sleep deprivation on memory. There was no significant difference in MDA between groups. Hippocampal gene expression did not show any changes in all groups. Lack of correlation between memory impairment and levels of genes in the hippocampus is likely to be related to the differences in behavioral and genetic mechanisms.


Assuntos
Teste de Esforço/métodos , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/fisiologia , Privação do Sono/terapia , Sono REM/fisiologia , Memória Espacial/fisiologia , Animais , Teste de Esforço/psicologia , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Condicionamento Físico Animal/psicologia , Ratos , Ratos Wistar , Privação do Sono/fisiopatologia , Privação do Sono/psicologia
16.
Int J Dev Neurosci ; 81(7): 643-654, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34228828

RESUMO

OBJECTIVE: Maternal mood disorders such as postpartum depression (PPD) can negatively affect the lives not only of mothers but also of partners. The purpose of this study investigates emotional behavior and hippocampal apoptosis alterations of the male live with a postpartum depressed female. METHODS: Pregnant rats in the stress group were exposed to restraint stress (RS). The male rats who shared the same cages were not exposed to RS. To explain the consequences of depressive-like behavior and anxiety, animals were exposed to the forced swim test (FST), open-field test (OFT), and elevated plus maze (EPM). The apoptotic cell number was detected by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP biotin nick-end labeling (TUNEL) staining. RESULTS: According to FST, PPD caused more immobility, reduced swimming, and climbing compared to control groups in the stressed female and male (p < 0.05). For the crossing number of squares in the center area, the main effect of the group was significant (p < 0.05). Stressed groups have a higher crossing number of squares in the center area compared to control groups. In the OFT, there was a significant increase in the time spent in the center area in the stress female and male group compared to the control female and male group (p < 0.05). For the EPM, time spent in the close arms was increased in the control male and stress male compared to the stress female group (p < 0.05). Female and male rats with PPD demonstrated apoptosis in neuron and glial cells in the hippocampus. CONCLUSIONS: The present study demonstrates that RS results in PPD in females. Furthermore, it implicates RS as a potential risk factor for the development of postpartum mood disorder in males. Most of the studies on paternal PPD have been done by using self-report questionnaires. Studies on physiological and hormonal changes during the postpartum period among fathers would provide information on biological factors of depression.


Assuntos
Apoptose/fisiologia , Comportamento Animal/fisiologia , Depressão/fisiopatologia , Hipocampo/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Ansiedade/fisiopatologia , Feminino , Abrigo para Animais , Masculino , Gravidez , Ratos , Ratos Wistar , Restrição Física
17.
Arh Hig Rada Toksikol ; 71(3): 211-222, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33074175

RESUMO

The aim of this study was to investigate the oxidative and apoptotic potential of fluoxetine, a widely used antidepressant in Turkey and the world, and of its metabolite norfluoxetine on a model non-target organism, Daphnia magna to see how exposure to this group of antidepressants (specific serotonin reuptake inhibitors) could affect the aquatic environment in which they end up. Juvenile D. magna specimens were chronically exposed to fluoxetine and norfluoxetine alone and in combination at concentrations found in the aquatic environment (0.091 and 0.011 µg/L, respectively) and to their 10-fold environmental concentrations for 21 days. Another group of 17-day-old animals were subacutely exposed to 100-fold environmental concentrations for four days. After exposure, we measured their glutathione peroxidase (GPx) and cholinesterase (ChE) activities, thiobarbituric acid-reactive substances (TBARS), and total protein content spectrophotometrically, while mitochondrial membrane potential (MMP) was analysed by fluorescence staining, and cytochrome c and ERK1/2 protein content by Western blotting. This is the first-time cytochrome c and ERK1/2 were determined at the protein level in D. magna. We also measured their carapace length, width, and caudal spine length microscopically. At environmental concentrations fluoxetine and norfluoxetine caused an increase in ChE activity and brood production. They also caused a decrease in juvenile carapace length, width, and caudal spine length and depolarised the mitochondrial membrane. At 10-fold environmental concentrations, GPx activity, lipid peroxidation levels, cytochrome c, and ERK1/2 protein levels rose. The most pronounced effect was observed in D. magna exposed to norfluoxetine. Norfluoxetine also decreased brood production. Similar effects were observed with subacute exposure to 100-fold environmental concentrations. However, total protein content decreased. All this confirms that fluoxetine and norfluoxetine have oxidative and apoptotic potential in D. magna. Daphnia spp. have a great potential to give us precious insight into the mechanisms of environmental toxicants, but there is still a long way to go before they are clarified in these organisms.


Assuntos
Daphnia , Fluoxetina , Animais , Fluoxetina/análogos & derivados , Fluoxetina/toxicidade , Oxirredução , Estresse Oxidativo
18.
J BUON ; 25(1): 554-565, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32277683

RESUMO

PURPOSE: Adriamycin (ADR) is a commonly used anti-cancer drug. ADR has toxic effects on cardiomyocytes and leads to heart failure. However, the underlying mechanism(s) by which ADR causes heart failure is still not clarified exactly. The aim of present study is to investigate whether ADR-induced heart failure is mediated via HMGB1/TLR4 to initiate the apoptosis through MAPK/AMPK pathways. METHODS: H9c2 cell line was used to create four groups as a control, HMGB1 inhibition, ADR, ADR+HMGB1 inhibition. Silencing HMGB1 was performed with specific small interfering RNA. ADR was used at 2 µM concentration for 36 and 48 hours. Protein and genes expressions, apoptosis was measured. RESULTS: Although ADR decreased AMPK, pAMPK, ERK1/2, pERK1/2, p38, JNK protein expression, ADR+HMGB1 inhibition led to change those protein expressions. The effect of silencing of HMGB1 prevented apoptosis induced by ADR in the cells. HMGB1 caused changes a kind of posttranscriptional modification on the TLR4 receptor. This posttranscriptional modification of TLR4 receptor led to decreased AMPK protein level, but phosphorylated-AMPK. This alternation of AMPK protein caused enhancing of JNK protein, resulting from the decline of p38 and ERK protein levels. Eventually, JNK triggered apoptosis by a caspase-dependent pathway. The number of TUNEL positive and active caspase 8 cells at ADR was high, although HMGB1 silencing could decrease the cell numbers. CONCLUSIONS: Inhibition of HMGB1 might prevent the lose of the cardiac cell by inhibition of apoptotic pathway, therefore HMGB1 plays an essential role as amplifying on ADR toxicity on the heart by TLR4.


Assuntos
Doxorrubicina/efeitos adversos , Proteína HMGB1/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Receptor 4 Toll-Like/metabolismo , Humanos , Transdução de Sinais , Transfecção
19.
Life Sci ; 233: 116704, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369761

RESUMO

AIMS: Doxorubicin, an anticancer drug, has a toxic effect on many tissues such as heart, pancreas, liver, kidney, and testis. The aim of current study is to investigate whether melatonin would be protective in doxorubicin-induced beta (ß) cell toxicity via HMGB1/TLR2/TLR4/MAPK/NF-қB signaling pathway. MAIN METHODS: Human pancreatic ß cell (1.1B4) was used in the present study. Four experimental groups were created as control, melatonin (10 µM), doxorubicin (2 µM) and the combination of melatonin with doxorubicin. Following 24-h treatment, Mitogen-activated protein kinase (MAPKs), Toll like receptors (TLRs) including TLR2 and TLR4, pro-and anti-apoptotic protein expression levels were determined by western blotting. Total antioxidant (TAS), oxidant status (TOS) and oxidative stress index (OSI) of the cells as well as superoxide dismutase (SOD) levels were determined. Active caspase-8 activity was measured and TUNEL staining was performed to study apoptotic pathways. Mitochondrial membrane potential (MMP), some protein expressions and F-actin distribution were analyzed. KEY FINDINGS: Doxorubicin caused to depolarize MMP, resulting in enhancing apoptosis by activation of caspase-8 via MAPKs/NF-кB pathway via elevation of TOS and decreasing TAS. Also, doxorubicin destroyed F-actin distribution and elevated TLR2 and some apoptotic proteins, including Bax. However, co-treatment of melatonin with doxorubicin could reverse depolarization of MMP and inhibition of apoptosis through MAPK/NF-кB signaling by decreasing TOS and increasing TAS. The co-treatment reversed the alternations of TLR2, TLR4, MAPKs and apoptotic protein expressions induced by doxorubicin. SIGNIFICANCE: Melatonin could be a good candidate against pancreatic ß cell toxicity-induced by doxorubicin through TLR2/TLR4/MAPK/NF-кB pathways.


Assuntos
Doxorrubicina/efeitos adversos , Células Secretoras de Insulina/efeitos dos fármacos , Melatonina/farmacologia , Substâncias Protetoras/farmacologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Antibióticos Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Proteína HMGB1/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Arch Physiol Biochem ; 125(2): 114-121, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-29457517

RESUMO

CONTEXT: Cardiovascular dysfunctions such as life-threatening arrhythmias are one of the main reasons of mortality and morbidity in diabetic patients Objective: We aimed to investigate the long-term effects of resveratrol, berberine and glibenclamide combinations on the ischemia/reperfusion (I/R) induced arrhythmias in streptozotocin (STZ)-induced diabetic rats and to investigate the role of myocardial KATP channel in the possible anti-arrhythmic actions of the treatments. METHODS: Two days after induction of diabetes, diabetic rats were treated with resveratrol [5 mg/kg, intraperitoneally (i.p.)], berberine (10 mg/kg, i.p) and glibenclamide (5 mg/kg, i.p) for 6 weeks. On the 43th day, experimental animals were subjected to 6-min ischemia and 6-min reperfusion in vivo. RESULTS: The protein expression of Kir6.2 subunits was downregulated in the diabetic hearts. However, all drug treatments restored the protein expression of Kir6.2 subunits. Resveratrol alone and its combination with glibenclamide decreased the arrhythmia score, the arrhythmic period and the incidence of other types of arrhythmias during the reperfusion period. CONCLUSIONS: The combination of resveratrol with glibenclamide may alleviate reperfusion-induced arrhythmias via an underlying mechanism not be only associated with the restoration of the protein expression of Kir6.2 subunits but also associated with the other subunits or ion channels underlying cardiac action potential.


Assuntos
Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Diabetes Mellitus Experimental/complicações , Glibureto/farmacologia , Traumatismo por Reperfusão Miocárdica/complicações , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Resveratrol/farmacologia , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Berberina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
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