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1.
Gastroenterology ; 157(5): 1368-1382, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336123

RESUMO

BACKGROUND & AIMS: Hepatic ischemia/reperfusion injury is a complication of liver surgery that involves mitochondrial dysfunction resulting from mitochondrial permeability transition pore (mPTP) opening. Cyclophilin D (PPIF or CypD) is a peptidyl-prolyl cis-trans isomerase that regulates mPTP opening in the inner mitochondrial membrane. We investigated whether and how recently created small-molecule inhibitors of CypD prevent opening of the mPTP in hepatocytes and the resulting effects in cell models and livers of mice undergoing ischemia/reperfusion injury. METHODS: We measured the activity of 9 small-molecule inhibitors of cyclophilins in an assay of CypD activity. The effects of the small-molecule CypD inhibitors or vehicle on mPTP opening were assessed by measuring mitochondrial swelling and calcium retention in isolated liver mitochondria from C57BL/6J (wild-type) and Ppif-/- (CypD knockout) mice and in primary mouse and human hepatocytes by fluorescence microscopy. We induced ischemia/reperfusion injury in livers of mice given a small-molecule CypD inhibitor or vehicle before and during reperfusion and collected samples of blood and liver for histologic analysis. RESULTS: The compounds inhibited peptidyl-prolyl isomerase activity (half maximal inhibitory concentration values, 0.2-16.2 µmol/L) and, as a result, calcium-induced mitochondrial swelling, by preventing mPTP opening (half maximal inhibitory concentration values, 1.4-132 µmol/L) in a concentration-dependent manner. The most potent inhibitor (C31) bound CypD with high affinity and inhibited swelling in mitochondria from livers of wild-type and Ppif-/- mice (indicating an additional, CypD-independent effect on mPTP opening) and in primary human and mouse hepatocytes. Administration of C31 in mice with ischemia/reperfusion injury before and during reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage compared with vehicle. CONCLUSIONS: Recently created small-molecule inhibitors of CypD reduced calcium-induced swelling in mitochondria from mouse and human liver tissues. Administration of these compounds to mice during ischemia/reperfusion restored hepatic calcium retention capacity and oxidative phosphorylation parameters and reduced liver damage. These compounds might be developed to protect patients from ischemia/reperfusion injury after liver surgery or for other hepatic or nonhepatic disorders related to abnormal mPTP opening.


Assuntos
/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Animais , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , /metabolismo , Citoproteção , Modelos Animais de Doenças , Humanos , Fígado/enzimologia , Fígado/patologia , Hepatopatias/enzimologia , Hepatopatias/genética , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais
2.
J Ethnopharmacol ; 242: 112026, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31260758

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Disturbed mitochondrial function and energy crisis serve as key mechanisms for the development of liver injury. Hence, targeting cellular mitochondria in liver diseases might serve as a therapeutic option. Tapinanthus globifer (A.Rich.) Tiegh. has been used in traditional medicine in the management of liver disease. However, there is no scientific evidence supporting such use. AIM OF THE STUDY: The current investigation was designed to evaluate the protective role of Tapinanthus globifer treatment on the liver mitochondrial function after the induction of hepatotoxicity by the hepatotoxic agent Fe2+in vitro. MATERIALS AND METHODS: In this study, isolated mitochondria from rats' liver was incubated with Fe2+ (10 µM) for 1 h in the absence or presence of T. globifer (50, 100 and 200 µg/mL) metanolic extract (MVA). Mitochondrial viability, mitochondrial membrane potential (ΔΨm), mitochondrial swelling (MPTP)., total thiol content, lipid peroxidation (TBARS) and reactive oxygen species (ROS) production were measured. HPLC-DAD was used to identify potential phytochemicals in MVA. RESULTS: (MVA) was able to improve mitochondrial dysfunction induced by Fe2+, by attenuating MTT reduction, increased ΔΨm and mitochondrial swelling. Reduced total thiol and non-protein thiol contents which were associated with increased lipid peroxidation and ROS generation in Fe2+-treated mitochondria were significantly improved by MVA co-treatment. HPLC-DAD analysis revealed the presence of gallic acid, catechin, epigallocatechin, caffeic acid, rutin, glycoside flavonoid and quercetin in MVA that can be responsible for its beneficial effect. CONCLUSION: MVA phyto-compounds enhance mitochondrial redox signaling and possess mitochondrial function improving potential, thereby, providing scientific basis for its use in traditional medicine.


Assuntos
Loranthaceae , Mitocôndrias Hepáticas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Ferro/toxicidade , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/fisiologia , Dilatação Mitocondrial/efeitos dos fármacos , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Folhas de Planta , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
3.
Arch Biochem Biophys ; 663: 288-296, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30659803

RESUMO

Mitochondrial functions are closely related to the membrane structure. Mitochondrial swelling, which is accompanied with dissipation of the crista structure and rupture of the outer membrane, have been observed as mitochondrial damage when mitochondria are under Ca2+-overload or oxidative stress. Although these phenomena have been well studied, the detailed behaviors of individual mitochondria upon swelling remain unknown. The aim of this study was to investigate the detailed behavior of mitochondrial volume upon addition of Ca2+. Here, we report for the first time, time-lapse measurements of single mitochondrion swelling and permeability transition induced by Ca2+ by optical microscopy. We added 220 µM Ca2+ to mitochondria, and found that 1) the swelling rate depended on the mitochondrion, 2) a small number of mitochondria showed step-like swelling, 3) cyclosporin A decreased the percentage of mitochondria that underwent swelling induced by Ca2+, but did not affect the amplitude of swelling, 4) permeability transition is necessary but not sufficient for Ca2+-induced swelling, 5) permeability transition is more sensitive to Ca2+ than swelling, 6) Ca2+ stimulated mitochondrial swelling after permeability transition. These results suggest that single mitochondrion measurement of swelling is a powerful tool for examining the regulation of mitochondrial structure.


Assuntos
Cálcio/metabolismo , Dilatação Mitocondrial , Imagem com Lapso de Tempo , Animais , Calcimicina/farmacologia , Ciclosporina/farmacologia , Mitocôndrias Cardíacas/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Permeabilidade , Suínos
4.
Mol Neurobiol ; 56(5): 3244-3259, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30117103

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is an irreversible off-target adverse effect of many chemotherapeutic agents such as paclitaxel, yet its mechanism is poorly understood and no preventative measure is available. CIPN is characterized by peripheral nerve damages resulting in permanent sensory function deficits. Our recent unbiased genome-wide analysis revealed that heat shock protein (Hsp) 27 is part of a transcriptional network induced by axonal injury and highly enriched for genes involved in adaptive neuronal responses, particularly axonal regeneration. To examine if Hsp27 could prevent the occurrence of CIPN, we first demonstrated that paclitaxel-induced allodynia was associated directly with axonal degeneration in sensory neurons in a mouse model of CIPN. We therefore hypothesize that by preventing axonal degeneration could prevent the development of CIPN. We drove expression of human Hsp27 (hHsp27) specifically in neurons. Development of mechanical and thermal allodynia was prevented completely in paclitaxel-treated hHsp27 transgenic mice. Strikingly, hHsp27 protected against paclitaxel-induced neurotoxicity in vivo including degeneration of afferent nerve fibers, demyelination, mitochondrial swelling, apoptosis, and restored sensory nerve action potential. Finally, we delineated signaling cascades that link CIPN development to caspase 3 and RhoA/cofilin activation in sensory neurons and peripheral nerves. hHsp27 exerted anti-apoptotic effect and maintained axon integrity by restoring caspase 3 and RhoA expression to basal levels. Taken together, our data suggest that by preventing axonal degeneration might prove beneficial as anti-CIPN drugs, which represents an emerging research area for therapeutic development.


Assuntos
Antineoplásicos/efeitos adversos , Axônios/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Fatores de Despolimerização de Actina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Axônios/efeitos dos fármacos , Caspase 3/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Masculino , Camundongos Transgênicos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Dilatação Mitocondrial/efeitos dos fármacos , Bainha de Mielina/metabolismo , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Fibras Nervosas/patologia , Fármacos Neuroprotetores/metabolismo , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/metabolismo
5.
Free Radic Biol Med ; 130: 408-418, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445126

RESUMO

Chagas disease is caused by the hemoflagellate protozoa Trypanosoma cruzi and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from ß-lapachone were found to be most effective in vitro. Analysis of their mechanism of action via cellular, molecular and proteomic approaches indicates that the parasite mitochondrion contains one of the primary targets of these compounds, trypanothione synthetase (involved in trypanothione production), which is overexpressed after treatment with these compounds. Here, we further evaluated the participation of the mitochondria and reactive oxygen species (ROS) in the anti-T. cruzi action of naphthoimidazoles. Preincubation of epimastigotes and trypomastigotes with antioxidants (α-tocopherol and urate) strongly protected the parasites from the trypanocidal effect of naphthoimidazoles, decreasing the ROS levels produced and reverting the mitochondrial swelling phenotype. The addition of pro-oxidants (menadione and H2O2) before the treatment induced an increase in parasite lysis. Despite the O2 uptake and mitochondrial complex activity being strongly reduced by N1, N2 and N3, urate partially restored the mitochondrial metabolism only in N1-treated parasites. In parallel, MitoTEMPO, a mitochondrial-targeted antioxidant, protected the functionality of the mitochondria in N2- and N3-treated parasites. In addition, the trypanothione reductase activity was remarkably increased after treatment with N1 and N3, and molecular docking demonstrated that these two compounds were positioned in pockets of this enzyme. Based on our findings, the direct impairment of the mitochondrial electron transport chain by N2 and N3 led to an oxidative misbalance, which exacerbated ROS generation and led to parasite death. Although other mechanisms cannot be discounted, mainly in N1-treated parasites, further investigations are required.


Assuntos
Doença de Chagas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/genética , Doença de Chagas/parasitologia , Humanos , Peróxido de Hidrogênio , Imidazóis/química , Imidazóis/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Naftoquinonas/química , Compostos Organofosforados/farmacologia , Piperidinas/farmacologia , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/patogenicidade
6.
Biochim Biophys Acta Biomembr ; 1861(1): 288-297, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29920239

RESUMO

The paper considers the effects of bedaquiline (BDQ), an antituberculous preparation of the new generation, on rat liver mitochondria. It was shown that 50 µM BDQ inhibited mitochondrial respiration measured with substrates of complexes I and II (glutamate/malate and succinate/rotenone systems respectively) in the states V3 and VDNP. At the same time, at concentrations below 50 µM, BDQ slightly stimulated respiration with substrates of complex I in the state V2. BDQ was also found to suppress, in a dose-dependent manner, the activity of complex II and the total activity of complexes II + III of the mitochondrial transport chain. It was discovered that at concentrations up to 10 µM, BDQ inhibited H2O2 production in mitochondria. BDQ (10-50 µM) suppressed the opening of Ca2+-dependent CsA-sensitive mitochondrial permeability transition pore. The latter was revealed experimentally as the inhibition of Ca2+/Pi-dependent swelling of mitochondria, suppression of cytochrome c release, and an increase in the Ca2+ capacity of the organelles. BDQ also decreased the rate of mitochondrial energy-dependent K+ transport, which was evaluated by the energy-dependent swelling of mitochondria in a K+ buffer and DNP-induced K+ efflux from the organelles. The possible mechanisms of BDQ effect of rat liver mitochondria are discussed.


Assuntos
Diarilquinolinas/farmacologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Antituberculosos/farmacologia , Ciclosporina/metabolismo , Citocromos c/metabolismo , Transporte de Elétrons , Ácido Glutâmico/metabolismo , Peróxido de Hidrogênio/química , Malatos/metabolismo , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Mitocôndrias Hepáticas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Permeabilidade , Potássio/metabolismo , Ratos , Ratos Wistar , Rotenona/metabolismo , Ácido Succínico/metabolismo
7.
Acta cir. bras ; 33(12): 1043-1051, Dec. 2018. graf
Artigo em Inglês | LILACS | ID: biblio-973484

RESUMO

Abstract Purpose: To analyze the effect of methylene blue (MB) therapy during the liver ischemia-reperfusion injury (I/R) process. Methods: Thirty-five male Wistar rats were used, (70%) submitted to partial ischemia (IR) or not (NIR) (30%) were obtained from the same animal. These animals were divided into six groups: 1) Sham (SH), 2) Sham with MB (SH-MB); 3) I/R, submitted to 60 minutes of partial ischemia and 15 minutes of reperfusion; 4) NI/R, without I/R obtained from the same animal of group I/R; 5) I/R-MB submitted to I/R and MB and 6) NI/R-MB, without I/R. Mitochondrial function was evaluated. Osmotic swelling of mitochondria as well as the determination of malondialdehyde (MDA) was evaluated. Serum (ALT/AST) dosages were also performed. MB was used at the concentration of 15mg/kg, 15 minutes before hepatic reperfusion. Statistical analysis was done by the Mann Whitney test at 5%. Results: State 3 shows inhibition in all ischemic groups. State 4 was increased in all groups, except the I/R-MB and NI/R-MB groups. RCR showed a decrease in all I/R and NI/R groups. Mitochondrial osmotic swelling showed an increase in all I/R NI/R groups in the presence or absence of MB. About MDA, there was a decrease in SH values in the presence of MB and this decrease was maintained in the I/R group. AST levels were increased in all ischemic with or without MB. Conclusions: The methylene blue was not able to restore the mitochondrial parameters studied. Also, it was able to decrease lipid peroxidation, preventing the formation of reactive oxygen species.


Assuntos
Humanos , Animais , Masculino , Traumatismo por Reperfusão/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , Fígado/irrigação sanguínea , Azul de Metileno/uso terapêutico , Consumo de Oxigênio , Aspartato Aminotransferases/sangue , Valores de Referência , Fatores de Tempo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Traumatismo por Reperfusão/metabolismo , Reprodutibilidade dos Testes , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Ratos Wistar , Respiração Celular , Alanina Transaminase/sangue , Inibidores Enzimáticos/farmacologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Fígado/metabolismo , Malondialdeído/análise , Azul de Metileno/farmacologia , Dilatação Mitocondrial/efeitos dos fármacos
8.
Int J Mol Sci ; 19(11)2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405014

RESUMO

Calcium as a secondary messenger regulates the phosphorylation of several membrane-bound proteins in brain and liver mitochondria. Regulation of the activity of different protein kinases and phosphatases by Ca2+ occurs through its binding with calmodulin. The protein phosphorylation is strongly dependent on the Ca2+-induced mitochondrial permeability transition pore (mPTP) opening. 2',3'-Cyclic nucleotide-3'-phosphodiesterase (CNPase) was phosphorylated by protein kinases A and C. CNPase and melatonin (MEL) might interact with calmodulin. The effects of the calmodulin antagonist calmidazolium and the inhibitor of protein kinase A H89 on mPTP opening in rat brain mitochondria of male Wistar rats were investigated. In addition, the role of CNPase, serine/threonine kinases, and MEL in the mPTP opening was examined. The anti-CNPase antibody added to rat brain mitochondria (RBM) reduced the content of CNPase in mitochondria. The threshold [Ca2+] decreased, and mitochondrial swelling was accelerated in the presence of the anti-CNPase antibody. H89 enhanced the effect of anti-CNPase antibody and accelerated the swelling of mitochondria, while CmZ abolished the effect of anti-CNPase antibody under mPTP opening. The levels of phospho-Akt and phospho-GSK3ß increased, while the MEL content did not change. It can be assumed that CNPase may be involved in the regulation of these kinases, which in turn plays an important role in mPTP functioning.


Assuntos
2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Animais , Anticorpos/farmacologia , Respiração Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Imidazóis/farmacologia , Isoquinolinas/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Melatonina/metabolismo , Sulfonamidas/farmacologia
9.
Cell Death Dis ; 9(11): 1052, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30323190

RESUMO

Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me2NNMe2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me2NNMe2- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me2NNMe2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me2NNMe2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.


Assuntos
Antineoplásicos/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Expressão Gênica , Células HCT116 , Humanos , Sistema de Sinalização das MAP Quinases/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Piridinas/farmacologia , Compostos de Sulfidrila/antagonistas & inibidores , Compostos de Sulfidrila/metabolismo , Tiossemicarbazonas/síntese química
10.
Biochem Biophys Res Commun ; 504(2): 460-469, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30195498

RESUMO

Diabetes mellitus is a chronic metabolic disorder characterized by rise in blood glucose levels and generation of free radicals which could induce mitochondrial membrane permeability transition (MMPT) pore opening. This study examined the in vivo action of quercetin and vitamin E on MMPT in the liver of streptozotocin-induced diabetic rats orally pre-treated with 30 mg quercetin/kg body weight (STZQ), 10 mg vitamin E/kg body weight (STZVit.E) and 0.6 mg glibenclamide/kg body weight (STZG). Male albino wistar rats were used in the study and were injected intraperitonially with streptozotocin (STZ) (45 mg/kg body weight) in citrate buffer. The degrees of serum and tissue peroxidation, alanine and aspartate aminotransferase activity were investigated. MMPT pore was assessed as mitochondrial swelling and was monitored spectrophotometrically as changes in absorbance at 540 nm under succinate-energized condition. There was significant increase in serum glucose level, degree of tissue peroxidation, alanine and aspartate aminotransferase activity, cholesterol and triglycerides values in the diabetic control rats following streptozotocin induction. All the treatment had effect on the damage caused by streptozotocin. Quercetin exhibited the highest chemopreventive activity. Quercetin and vitamin E significantly reduced the blood glucose level, degree of tissue peroxidation and alanine and aspartate amino transferase activity. In vivo rat liver MMPT pore was opened in diabetic control rats and significantly inhibited in STZQ, STZV and STZG treated groups by 72.3%, 58.5% and 87.5% respectively. The activity of quercetin and vitamin E were substantiated by histopathological evaluation. Our study suggests that quercetin is an effective therapeutic agent for preventing hepatic tissues from oxidative stress resulting from streptozotocin-induced diabetes by inhibiting apoptotic processes in their target cells.


Assuntos
Mitocôndrias Hepáticas/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Quercetina/farmacologia , Vitamina E/química , Vitamina E/farmacologia , Administração Oral , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Glucose/química , Glibureto/administração & dosagem , Peroxidação de Lipídeos , Fígado/efeitos dos fármacos , Masculino , Mitocôndrias Hepáticas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Estresse Oxidativo , Permeabilidade , Ratos , Ratos Wistar , Estreptozocina , Fatores de Tempo
11.
J Biochem Mol Toxicol ; 32(11): e22216, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30152904

RESUMO

Brain tissue manganese (Mn) accumulation is a cirrhosis-associated complication. Cellular mitochondria are among the potential targets for Mn-induced cytotoxicity. Taurine is one of the most abundant amino acids with high concentrations in human brain tissue. Several pharmacological properties including regulation of mitochondrial function are attributed to taurine. The current investigation was designed to evaluate the effect of taurine on Mn-induced mitochondrial impairment in isolated mice brain mitochondria. The brain mitochondria were exposed to increasing concentrations of Mn (0.1-10 mM). Taurine (0.1, 1, and 10 mM) was added as the protective agent. The severe collapse of mitochondrial membrane potential, decreased mitochondrial dehydrogenases activity, mitochondrial swelling, and depleted mitochondrial adenosine triphosphate (ATP) were evident in Mn-exposed mitochondria. It was found that taurine administration preserved mitochondrial ATP, prevented mitochondrial depolarization and swelling, and increased mitochondrial dehydrogenases activity. These data suggest mitochondrial protection as an underlying mechanism for the protective effects of taurine against Mn toxicity.


Assuntos
Encéfalo/efeitos dos fármacos , Manganês/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Dilatação Mitocondrial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Taurina/farmacologia , Trifosfato de Adenosina/agonistas , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Encéfalo/metabolismo , Encéfalo/patologia , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/patologia , Cinética , Masculino , Manganês/efeitos adversos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Membranas Mitocondriais/química , Membranas Mitocondriais/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Oxirredutases/química , Oxirredutases/metabolismo , Permeabilidade/efeitos dos fármacos , Taurina/uso terapêutico
12.
Chin J Integr Med ; 24(11): 835-843, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30090975

RESUMO

OBJECTIVE: To investigate the neuro-protective effects of Acanthopanax senticosus Harms (EAS) on mesencephalic mitochondria and the mechanism of action, using a mouse model of Parkinson's disease (PD). METHODS: The chemical fingerprint analysis of the extract of Acanthopanax senticosus Harms (EAS) was performed using the ultra performance liquid chromatograph and time of flight mass spectrometry. Thirty mice were randomly divided into the control group, the MPTP model group, and the EAS treated group with MPTP (MPTP+EAS group, 10 in each group). The MPTP model group and the MPTP+EAS group received MPTP-HCl (30 mg/kg i.p) once a day for 5 days. The control group received an equal volume of saline (20 mL/kg i.p) once a day for 5 days. Induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride daily (MPTP-HCl, 30 mg/kg) for 5 days, the PD mice were treated with EAS at 45.5 mg/kg daily for 20 days. The behavioral testing of mice was carried out using the pole-climbing test. The integrity and functions of neurons were examined in mesencephalic mitochondria in a PD mouse model, including nicotinamide adenine dinucleotide dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 1 (MT-ND1), succinate dehydrogenase complex subunit A (SDHA), and succinate dehydrogenase cytochrome b560 subunit (SDHC). RESULTS: After treatment with EAS, the behavioral changes induced by MPTP were attenuated significantly (P<0.05). EAS protected the mesencephalic mitochondria from swelling and attenuated the decreases in their membrane potential (both P<0.05), which was supported by an ultra-structural level analysis. The changes in reactive oxygen species (ROS), malonic dialdehyde (MDA), oxidative phosphorylation (OXPHOS) system 4 subunits levels and PD-related proteins expressions (parkin, Pink1, DJ-1, α-synuclein, and Lrrk2) reverted to near normal levels (all P<0.05), based on the results of immune-histological and Western blotting observations. CONCLUSIONS: The neuro-protective effects of EAS are linked to protecting mice against MPTP-induced mitochondrial dysfunction and structural damage. Therefore, EAS is a promising candidate for the prevention or treatment of mitochondrial neurodegenerative disorders, such as PD.


Assuntos
Eleutherococcus , Intoxicação por MPTP/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Dilatação Mitocondrial/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/uso terapêutico
13.
Biochim Biophys Acta Bioenerg ; 1859(12): 1313-1326, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30031690

RESUMO

We investigated the properties of the permeability transition pore (PTP) in Saccharomyces cerevisiae in agar-embedded mitochondria (AEM) and agar-embedded cells (AEC) and its role in yeast death. In AEM, ethanol-induced pore opening, as indicated by the release of calcein and mitochondrial membrane depolarization, can be inhibited by CsA, by Cpr3 deficiency, and by the antioxidant glutathione. Notably, the pore opening is inhibited, when mitochondria are preloaded by EGTA or Fluo3 to chelate matrix Ca2+, or are pretreated with 4-Br A23187 to extract matrix Ca2+, prior to agar-embedding, or when pore opening is induced in the presence of EGTA; opened pores are re-closed by sequential treatment with CsA, 4-Br A23187 plus EGTA and NADH, indicating endogenous matrix Ca2+ involvement. CsA also inhibits the pore opening with low conductance triggered by exogenous Ca2+ transport with ETH129. In AEC, the treatment of tert-butylhydroperoxide, a pro-oxidant that triggers transient pore opening in high conductance in AEM, induces yeast death, which is also dependent on CsA and Cpr3. Furthermore, AEMs from mutants lacking three ADP/ATP carrier (AAC) isoforms and with defective ATP synthase dimerization exhibit high and low conductance pore openings with CsA sensitivity, respectively. Collectively, these data show that the yeast PTP is regulated by Cpr3, endogenous matrix Ca2+, and reactive oxygen species, and that it is involved in yeast death; furthermore, ATP synthase dimers play a key role in CsA-sensitive pore formation, while AACs are dispensable.


Assuntos
Cálcio/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Cátions Bivalentes/farmacologia , Morte Celular/efeitos dos fármacos , Ciclosporina/farmacologia , Etanol/farmacologia , Mitocôndrias/efeitos dos fármacos , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Permeabilidade , Peróxidos/farmacologia
14.
Int J Mol Sci ; 19(6)2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29882895

RESUMO

Excessive generation of reactive oxygen species (ROS) in mitochondria and the opening of the nonselective mitochondrial permeability transition pore are important factors that promote cardiac pathologies and dysfunction. The hormone melatonin (MEL) is known to improve the functional state of mitochondria via an antioxidant effect. Here, the effect of MEL administration on heart mitochondria from aged rats with acute cardiac failure caused by isoprenaline hydrochloride (ISO) was studied. A histological analysis revealed that chronic intake of MEL diminished the age-dependent changes in the structure of muscle fibers of the left ventricle, muscle fiber swelling, and injury zones characteristic of acute cardiac failure caused by ISO. In acute heart failure, the respiratory control index (RCI) and the Ca2+ retention capacity in isolated rat heart mitochondria (RHM) were reduced by 30% and 40%, respectively, and mitochondrial swelling increased by 34%. MEL administration abolished the effect of ISO. MEL partially prevented ISO-induced changes at the subunit level of respiratory complexes III and V and drastically decreased the expression of complex I subunit NDUFB8 both in control RHM and in RHM treated with ISO, which led to the inhibition of ROS production. MEL prevents the mitochondrial dysfunction associated with heart failure caused by ISO. It was shown that the level of 2',3'-cyclicnucleotide-3'-phosphodiasterase (CNPase), which is capable of protecting cells in aging, increased in acute heart failure. MEL also retained the CNPase content in RHM both in control experiments and after ISO-induced heart damage. We concluded that an increase in the CNPase level promotes cardioprotection.


Assuntos
Envelhecimento/patologia , Insuficiência Cardíaca/metabolismo , Melatonina/farmacologia , Mitocôndrias Cardíacas/metabolismo , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Animais , Cálcio/metabolismo , Respiração Celular/efeitos dos fármacos , Crioultramicrotomia , Transporte de Elétrons/efeitos dos fármacos , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Isoproterenol/farmacologia , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Canais de Ânion Dependentes de Voltagem/metabolismo
15.
Chem Biol Interact ; 291: 192-201, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29935161

RESUMO

Brominated flame retardants are used in consumer goods to increase product resistance to fire and/or high temperatures. Polybrominated diphenyl ethers (PBDEs) are the most commonly employed class of brominated flame retardants because they are inexpensive and can effectively prevent flame from spreading. PBDEs are persistent, can bioaccumulate, are transported over long distances, and display toxicity. However, their toxic mechanisms of action have not been well established. Because mitochondria are recognized as the main energy-producing cell organelle and play a vital role in cellular function maintenance, here we apply mitochondria as an experimental model to evaluate the toxic effects of the PBDE congener BDE-153 (Hexa-BDE) at concentrations ranging from 0.1 to 25 µM. We also assess BDE-153 cytotoxicity to HepG2 cells in order to elucidate its mechanisms of toxicity. Exposure to BDE-153 affects isolated mitochondria: this congener can interact with the mitochondrial membrane, to dissipate the membrane potential and to induce significant ATP depletion. Furthermore, BDE-153 can diminish MTT reduction and cell proliferation and can interfere in cell cycle, as evaluated in cell cultures. These cytotoxic effects are related to mitochondrial dysfunction due to mitochondrial membrane potential dissipation and reactive oxygen species accumulation. These effects result in apoptotic cell death, as demonstrated by phosphatidylserine maintenance on the cell membrane external surface, nuclear condensation and fragmentation, and presence of pro-apoptotic factors such as cytochrome c and Apoptosis-inducing Factor (AIF) plus caspase 3 activation in the cytosol. Together, our results show PBDEs can induce cytotoxicity, reinforcing the idea that these compounds pose a risk to the exposed population.


Assuntos
Apoptose/efeitos dos fármacos , Fígado/patologia , Mitocôndrias Hepáticas/patologia , Bifenil Polibromatos/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
16.
Med Sci Monit ; 24: 2832-2840, 2018 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-29730669

RESUMO

BACKGROUND Worldwide, epilepsy is an important chronic neurological condition. The aim of this study was to evaluate the effects of corilagin, an ellagitannin extracted from medicinal plants, on the frequency of seizures and cognitive function in a rat model of chronic epilepsy. MATERIAL AND METHODS Chronic epilepsy was induced in male Wistar rats by intraperitoneal (IP) injection of pentylenetetrazol (PTZ) for 36 days. Corilagin, 10 mg/kg and 20 mg/kg, was injected IP into treated rats, 24 days before the start of PTZ treatment, until the end of the protocol. The effects of corilagin were assessed by the pattern of epileptic seizures; cognitive function was assessed using the Morris water maze (MWM) navigation test. The mechanism of action of corilagin was investigated by measuring cytokine levels and oxidative stress parameters, including reactive oxygen species (ROS) production, and carbonic anhydrase inhibitory (CAI) activity. Histological analysis of fixed brain tissue sections included cresyl violet acetate staining (Nissl staining) for Nissl substance in the neuronal cytoplasm. RESULTS The corilagin-treated rats, compared with the control group, showed a significantly lower rate of epileptic events, improved cognitive function, reduced level of cytokines, reduced ROS production reduced CAI activity in the brain tissues (P<0.01). Histology of the rat brain tissues study showed that corilagin treatment maintained the neuronal cellular structure and number of surviving cells compared with the control group of rats. CONCLUSIONS The findings of this study showed that corilagin reduced the frequency of seizures and improved the cognitive function in a rat model of chronic epilepsy.


Assuntos
Cognição , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Glucosídeos/uso terapêutico , Taninos Hidrolisáveis/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Animais , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/patologia , Anidrases Carbônicas/metabolismo , Catalase/metabolismo , Contagem de Células , Doença Crônica , Cognição/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Dilatação Mitocondrial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Corpos de Nissl/efeitos dos fármacos , Corpos de Nissl/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pentilenotetrazol , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
17.
J Bioenerg Biomembr ; 50(4): 297-305, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29770896

RESUMO

In this work, the effects of two non-ionic, non-hydroxyl organic solvents, dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF) on the morphology and function of isolated rat hepatic mitochondria were investigated and compared. Mitochondrial ultrastructures impaired by DMSO and DMF were clearly observed by transmission electron microscopy. Spectroscopic and polarographic results demonstrated that organic solvents induced mitochondrial swelling, enhanced the permeation to H+/K+, collapsed the potential inner mitochondrial membrane (IMM), and increased the IMM fluidity. Moreover, with organic solvents addition, the outer mitochondrial membrane (OMM) was broken, accompanied with the release of Cytochrome c, which could activate cell apoptosis signaling pathway. The role of DMSO and DMF in enhancing permeation or transient water pore formation in the mitochondrial phospholipid bilayer might be the main reason for the mitochondrial morphology and function impaired. Mitochondrial dysfunctions induced by the two organic solvents were dose-dependent, but the extents varied. Ethanol (EtOH) showed the highest potential damage on the mitochondrial morphology and functions, followed by DMF and DMSO.


Assuntos
Dimetil Sulfóxido/toxicidade , Dimetilformamida/toxicidade , Mitocôndrias/ultraestrutura , Animais , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Etanol/toxicidade , Membranas Intracelulares/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Dilatação Mitocondrial/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Ratos
18.
Physiol Rep ; 6(7): e13667, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29611340

RESUMO

Kidney proximal tubules (PTs) contain a high density of mitochondria, which are required to generate ATP to power solute transport. Mitochondrial dysfunction is implicated in the pathogenesis of numerous kidney diseases. Damaged mitochondria are thought to produce excess reactive oxygen species (ROS), which can lead to oxidative stress and activation of cell death pathways. MitoQ is a mitochondrial targeted anti-oxidant that has shown promise in preclinical models of renal diseases. However, recent studies in nonkidney cells have suggested that MitoQ might also have adverse effects. Here, using a live imaging approach, and both in vitro and ex vivo models, we show that MitoQ induces rapid swelling and depolarization of mitochondria in PT cells, but these effects were not observed with SS-31, another targeted anti-oxidant. MitoQ consists of a lipophilic cation (Tetraphenylphosphonium [TPP]) joined to an anti-oxidant component (quinone) by a 10-carbon alkyl chain, which is thought to insert into the inner mitochondrial membrane (IMM). We found that mitochondrial swelling and depolarization was also induced by dodecyltriphenylphosphomium (DTPP), which consists of TPP and the alkyl chain, but not by TPP alone. Surprisingly, MitoQ-induced mitochondrial swelling occurred in the absence of a decrease in oxygen consumption rate. We also found that DTPP directly increased the permeability of artificial liposomes with a cardiolipin content similar to that of the IMM. In summary, MitoQ causes mitochondrial swelling and depolarization in PT cells by a mechanism unrelated to anti-oxidant activity, most likely because of increased IMM permeability due to insertion of the alkyl chain.


Assuntos
Antioxidantes/toxicidade , Túbulos Renais Proximais/efeitos dos fármacos , Dilatação Mitocondrial/efeitos dos fármacos , Compostos Organofosforados/toxicidade , Ubiquinona/análogos & derivados , Animais , Células Cultivadas , Túbulos Renais Proximais/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Gambás , Ubiquinona/toxicidade
19.
Int J Antimicrob Agents ; 52(2): 185-194, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29635008

RESUMO

The development of HIV aspartyl peptidase inhibitors (HIV-PIs) and their introduction into AIDS therapy preceded a significant decrease in the incidence, morbidity and mortality of relevant protozoan co-infections. However, few data are available about how HIV-PIs act on pathogenic parasites, such as Trypanosoma cruzi, the etiological agent of Chagas disease. Therefore, the aim of the present work was to evaluate different physiological aspects of the treatment of the infective trypomastigote forms of T. cruzi with the HIV-PIs, nelfinavir and lopinavir. At the LD50/4 h doses, both HIV-PIs significantly reduced the trypomastigote size and markedly increased the granularity/complexity. Transmission electron microscopy analysis associated to biochemical assays permitted definition of the main HIV-PIs targets in the parasite. Lopinavir and nelfinavir induced (i) plasma membrane shedding, particularly in the flagellar region, which drastically affected parasite integrity; (ii) strong mitochondrial swelling with rare matrix fragmentation, which were linked to severely reduced hydrolytic activity of dehydrogenases and organelle membrane depolarization; (iii) increased generation of reactive oxygen species (ROS); (iv) dilation of both nuclear envelope (without DNA disruption) and endoplasmic reticulum (with formation of autophagosomes), and (v) accumulation of intracellular lipid droplets, revealing a typical lipid metabolism disorder. Collectively, our study demonstrated that nelfinavir and lopinavir target vital cellular structures of trypomastigotes, culminating in irreversible metabolic injuries that lead to T. cruzi death.


Assuntos
Inibidores da Protease de HIV/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Lopinavir/farmacologia , Mitocôndrias/efeitos dos fármacos , Nelfinavir/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/patologia , Flagelos/efeitos dos fármacos , Flagelos/ultraestrutura , Gotículas Lipídicas/efeitos dos fármacos , Mitocôndrias/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/ultraestrutura
20.
Biol Pharm Bull ; 41(3): 319-325, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29491208

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and pain. In the present study, we examined the effects of celecoxib, a cyclooxygenase-2 (COX-2)-selective NSAID, on rat liver mitochondrial function. Celecoxib dose-dependently induced mitochondria swelling, which was not suppressed by cyclosporine A (CsA). The oxygen consumption rate in mitochondria-suspended solution was facilitated by the addition of celecoxib, and its uncoupling activity was observed. Celecoxib also suppressed SF6847-induced uncoupling, and appeared to exert inhibitory effects on the electron transport chain. Celecoxib suppressed the state 3 oxygen consumption rate in the presence of ADP. Protein release from the mitochondrial matrix was detected following the addition of celecoxib, and aldehyde dehydrogenase 2 (ALDH2) and hydroxymethylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2) bands were confirmed in a Western blot analysis. On the other hand, protein release of cytochrome C (CytC), which is an inducer of apoptosis, from the intermembrane space was not observed. Celecoxib enhanced the membrane permeability of human erythrocytes and synthesized liposomes dose-dependently. It then induced the membrane-involving mitochondrial swelling and suppressed mitochondrial function.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Mitocôndrias/efeitos dos fármacos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transporte de Elétrons/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hidroximetilglutaril-CoA Sintase/metabolismo , Técnicas In Vitro , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Dilatação Mitocondrial/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar
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