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1.
BMC Musculoskelet Disord ; 18(1): 254, 2017 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-28606072

RESUMO

BACKGROUND: Recent findings support a connection between mitochondrial dysfunction and activation of inflammatory pathways in articular cells. This study investigates in vivo in an acute model whether intra-articular administration of oligomycin, an inhibitor of mitochondrial function, induces an oxidative and inflammatory response in rat knee joints. METHODS: Oligomycin was injected into the rat left knee joint on days 0, 2, and 5 before joint tissues were obtained on day 6. The right knee joint served as control. Results were evaluated by macroscopy and histopathology and by measuring cellular and mitochondrial reactive oxygen species (ROS), 4-hydroxy-2-nonenal (4-HNE, a marker of lipid peroxidation), nuclear factor erythroid 2-related factor 2 (Nrf2), and CD68 (macrophages) and chemokine levels. The marker of mitochondrial mass COX-IV was also evaluated. RESULTS: The macroscopic findings showed significantly greater swelling in oligomycin-injected knees than in control knees. Likewise, the histological score of synovial damage was also increased significantly. Immunohistochemical studies showed high expression of IL-8, coinciding with a marked infiltration of polymorphonuclears and CD68+ cells in the synovium. Mitochondrial mass was increased in the synovium of oligomycin-injected joints, as well as cellular and mitochondrial ROS production, and 4-HNE. Relatedly, expression of the oxidative stress-related transcription factor Nrf2 was also increased. As expected, no histological differences were observed in the cartilage; however, cytokine-induced neutrophil chemoattractant-1 mRNA and protein expression were up-regulated in this tissue. CONCLUSIONS: Mitochondrial failure in the joint is able to reproduce the oxidative and inflammatory status observed in arthritic joints.


Assuntos
Artrite Experimental/patologia , Inibidores Enzimáticos/farmacologia , Articulação do Joelho/patologia , Mitocôndrias/efeitos dos fármacos , Osteoartrite/patologia , Idoso , Idoso de 80 Anos ou mais , Aldeídos/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Artrite Experimental/induzido quimicamente , Cartilagem Articular/patologia , Quimiocina CXCL1/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Injeções Intra-Articulares , Interleucina-8/metabolismo , Macrófagos/metabolismo , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Oligomicinas/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Membrana Sinovial/patologia
2.
Rheumatology (Oxford) ; 55(10): 1889-900, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27354682

RESUMO

OBJECTIVE: The present study aimed to determine the protective effects of dietary supplementation with resveratrol (RSV) in an acute antigen-induced arthritis (AIA) model. METHODS: Rats were randomly divided into three groups: control, AIA and RSV-treated AIA group. RSV (12.5 mg/kg/day) was given orally for 8 weeks before induction of AIA and until the end of the experiment (48 h after intra-articular injection). The control and AIA animals were administered 100 µl of water. Results were evaluated by macroscopic observation, histopathology and immunohistochemistry for anti-PCNA, macrophages (CD68), T lymphocytes (CD3), monocyte chemoattractant protein-1 and 8-oxo-7,8-dihydro-2'-deoxyguanine (a marker of DNA damage). Cytokine-induced neutrophil chemoattractant-1 in serum and peroxidase activity in synovial tissue were measured using commercial kits. RESULTS: At the end of the study, RSV significantly reduced knee swelling. Likewise, the histological score of synovial tissue also reduced significantly. The arthritis-protective effects were associated with a significant decrease in PCNA, CD68, CD3 and monocyte chemoattractant protein-1 staining, as well as a reduction in serum concentrations of cytokine-induced neutrophil chemoattractant-1. RSV treatment also decreased the level of the marker of DNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanine. Accordingly, peroxidase activity in the synovial tissue was up-regulated. CONCLUSION: Dietary supplementation with RSV lowers the main pathological hallmarks of RA disease in an acute model of AIA. RSV may represent a promising strategy in controlling the severity of RA.


Assuntos
Antioxidantes/farmacologia , Artrite Experimental/tratamento farmacológico , Estilbenos/farmacologia , Membrana Sinovial/patologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Hiperplasia/imunologia , Hiperplasia/prevenção & controle , Imunidade Celular , Peroxidase/antagonistas & inibidores , Distribuição Aleatória , Ratos Endogâmicos Lew , Resveratrol , Membrana Sinovial/imunologia
3.
Rheumatology (Oxford) ; 53(7): 1332-43, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24609059

RESUMO

OBJECTIVES: In RA, synoviocytes cause increased oxidative stress, leading to mitochondrial alterations that may participate in the pathogenesis of RA. Here we investigated whether mitochondrial dysfunction induces inflammatory responses in cultured normal human synoviocytes, a hallmark of RA. METHODS: Mitochondrial dysfunction was induced with the inhibitor oligomycin. The effects of mitochondrial dysfunction on cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and IL-8 expression; cellular and mitochondrial reactive oxygen species (ROS) production; nuclear factor-κB (NF-κB) activation and p65 translocation were studied. ROS scavengers (N-acetylcysteine and mitoTEMPO) and an NF-κB inhibitor (BAY-117085) were used to investigate the pathways involved. The natural anti-inflammatory antioxidant resveratrol was also tested. RESULTS: Mitochondrial dysfunction per se significantly stimulated mitochondrial ROS production as well as low-grade expressions of COX-2, PGE2 and IL-8. Interestingly, mitochondrial dysfunction induced by pretreatment of synoviocytes with oligomycin synergized with IL-1ß to increase the expression of these inflammatory mediators. The inflammatory effects of mitochondrial damage appeared to be dependent on ROS production and NF-κB activation since the inflammatory response was counteracted by both N-acetylcysteine and mitoTEMPO and it was also reduced by BAY-117085. Antimycin A and paraquat (inhibitors of mitochondrial function) also induced inflammatory responses. Furthermore, resveratrol significantly reduced the inflammatory response by decreasing ROS production and NF-κB activation. CONCLUSION: These data suggest that mitochondrial dysfunction could induce an inflammatory response in normal human synoviocytes and sensitize these cells, causing a significant amplification of the inflammatory response induced by IL-1ß. Resveratrol may represent a promising strategy in controlling the synovial inflammatory response.


Assuntos
Inibidores Enzimáticos/farmacologia , Inflamação/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Oligomicinas/farmacologia , Membrana Sinovial/patologia , Membrana Sinovial/fisiopatologia , Idoso , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-1beta/farmacologia , Interleucina-8/metabolismo , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol , Estilbenos/farmacologia , Membrana Sinovial/efeitos dos fármacos
4.
Mitochondrion ; 13(2): 106-18, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23333405

RESUMO

Inflammation has been linked to multiple degenerative and acute diseases as well as the aging process. Moreover, mitochondrial alterations play a central role in these processes. Mitochondria have an important role in pro-inflammatory signaling; similarly, pro-inflammatory mediators may also alter mitochondrial function. Both of these processes increase mitochondrial oxidative stress, promoting a vicious inflammatory cycle. Additionally, damage-associated molecular patterns derived from mitochondria could contribute to inflammasome formation and caspase-1 activation, while alterations in mitochondrial autophagy may cause inflammation. Strategies aimed at controlling excessive oxidative stress within mitochondria may represent both preventive and therapeutic interventions in inflammation.


Assuntos
Inflamação/patologia , Mitocôndrias/fisiologia , Humanos , Mitocôndrias/metabolismo , Estresse Oxidativo
5.
Arthritis Rheum ; 64(9): 2927-36, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22549761

RESUMO

OBJECTIVE: Alterations in mitochondria play a key role in the pathogenesis of osteoarthritis (OA). The role of inflammation in the progression of OA has also acquired important new dimensions. This study was undertaken to evaluate the potential role of mitochondrial dysfunction in increasing the inflammatory response of normal human chondrocytes to cytokines. METHODS: Mitochondrial dysfunction was induced by commonly used inhibitors. Interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNFα) were used as inflammatory mediators. IL-8 and cyclooxygenase 2 (COX-2) protein and messenger RNA (mRNA) expression and prostaglandin E(2) (PGE(2) ) levels were assessed. The chemotactic activity of neutrophils was assayed. Additionally, inhibitors of reactive oxygen species (ROS) and NF-κB were used to identify possible inflammatory response pathways induced by mitochondrial dysfunction, and the effects of the natural antioxidant resveratrol were tested. RESULTS: Pretreatment with antimycin A or oligomycin (inhibitors of mitochondrial respiratory chain complexes III and V, respectively) triggered a strong potentiation of IL-1ß-induced IL-8 mRNA and protein expression (mean ± SEM at 18 hours 5,932 ± 1,995 pg/50,000 cells for IL-1ß alone versus 16,241 ± 5,843 pg/50,000 cells for antimycin A plus IL-1ß and 20,087 ± 5,407 pg/50,000 cells for oligomycin plus IL-1ß; P < 0.05). Similar results were observed with TNFα or when expression of the inflammatory mediator COX-2 or PGE(2) production was assessed. Mitochondrial dysfunction increased the chemotactic activity induced by cytokines, and ROS and NF-κB inhibitors decreased the production of IL-8. Resveratrol significantly reduced the inflammatory response. CONCLUSION: Our findings indicate that mitochondrial dysfunction could amplify the responsiveness to cytokine-induced chondrocyte inflammation through ROS production and NF-κB activation. This pathway might lead to the impairment of cartilage and joint function in OA.


Assuntos
Condrócitos/metabolismo , Interleucina-1beta/farmacologia , Mitocôndrias/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Idoso , Antimicina A/farmacologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Feminino , Humanos , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Oligomicinas/farmacologia
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