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1.
BMC Complement Altern Med ; 19(1): 310, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718640

RESUMO

BACKGROUND: Heracleum moellendorffii roots (HM-R) have been long treated for inflammatory diseases such as arthritis, backache and fever. However, an anti-inflammatory effect and the specific mechanism of HM-R were not yet clear. In this study, we for the first time explored the anti-inflammatory of HM-R. METHODS: The cytotoxicity of HM-R against RAW264.7 cells was evaluated using MTT assay. The inhibition of NO and PGE2 production by HM-R was evaluated using Griess reagent and Prostaglandin E2 ELISA Kit, respectively. The changes in mRNA or protein level following HM-R treatment were assessed by RT-PCR and Western blot analysis, respectively. RESULTS: HM-R dose-dependently blocked LPS-induced NO and PGE2 production. In addition, HM-R inhibited LPS-induced overexpression of iNOS, COX-2, IL-1ß and IL-6 in RAW264.7 cells. HM-R inhibited LPS-induced NF-κB signaling activation through blocking IκB-α degradation and p65 nuclear accumulation. Furthermore, HM-R inhibited MAPK signaling activation by attenuating the phosphorylation of ERK1/2, p38 and JNK. HM-R increased nuclear accumulation of Nrf2 and HO-1 expression. However, NAC reduced the increased nuclear accumulation of Nrf2 and HO-1 expression by HM-R. In HPLC analysis, falcarinol was detected from HM-R as an anti-inflammatory compound. CONCLUSIONS: These results indicate that HM-R may exert anti-inflammatory activity by inhibiting NF-κB and MAPK signaling, and activating ROS/Nrf2/HO-1 signaling. These findings suggest that HM-R has a potential as a natural material for the development of anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/imunologia , Heracleum/química , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Espécies Reativas de Oxigênio/imunologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Heme Oxigenase-1/genética , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Raízes de Plantas/química , Células RAW 264.7
2.
J Med Food ; 22(9): 885-895, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274380

RESUMO

We have previously demonstrated the hepatoprotective effect of Schisandra chinensis polysaccharides (SCP) against the liver injury induced by alcohol, high-fat diet, and carbon tetrachloride in mice. In this study, we investigated the effect of SCP against the immunological liver injury induced by concanavalin A (Con A) in mice. The results showed that SCP could significantly reduce the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in the serum of mice with immunological liver injury. SCP could significantly decrease the content of malondialdehyde (MDA) and nitric oxide (NO) and increase the activity of superoxide dismutase (SOD) and glutathione (GSH) in the liver tissue. SCP could significantly increase the number of CD4+ and decrease the number of CD8+ in the peripheral blood, and elevate the ratio of CD4+/CD8+. SCP could significantly downregulate the expression of Kelch-like ECH-associated protein 1 (Keap1) and upregulate the expression of nuclear factor-erythroid 2-related factor2 (Nrf2) and downstream gene heme oxygenase-1 (HO-1), and downregulate the expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), and nuclear factor-kappa B (NF-κB) proteins. This study indicates that SCP can reduce the release of a large number of inflammatory factors to inhibit the oxidative stress in mice with the immunological liver injury induced by Con A, and its mechanism is closely related to the regulation of Nrf2/antioxidant response element and TLR4/NF-κB signaling pathways.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Hepatopatias/prevenção & controle , Fígado/lesões , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Polissacarídeos/administração & dosagem , Substâncias Protetoras/administração & dosagem , Schisandra/química , Receptor 4 Toll-Like/imunologia , Animais , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatias/genética , Hepatopatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Óxido Nítrico/imunologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
3.
J Food Sci ; 84(7): 1920-1928, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31264720

RESUMO

Vanillin, a kind of phenolic compound, is naturally found in food and beverage and widely used as a flavoring agent. In view of the safety and universality of vanillin, exploring the functions of vanillin on human is of great value. Thus, lipopolysaccharide (LPS)-activated THP-1 cells were selected as the cell model to evaluate the anti-inflammatory effect of vanillin in this study. On the basis of the results, vanillin markedly suppressed the expression of inflammatory cytokines (that is, TNF-α, IL-1ß, IL-6, and IL-8), mediators (NO, iNOS, PGE2, and COX-2), and NLRP3 inflammasome (that is, NLRP3, ASC, and caspase-1), blocked the LPS-induced activation of the NF-κB/IκBα/AP-1 signaling pathway, and activated the gene expression of the Nrf2/HO-1 signaling pathway. In addition, it was confirmed that vanillin was unable to react with LPS due to the results of quantification by HS-SPME-GC-MS. Hence, vanillin could effectively attenuate LPS-induced inflammatory response by regulating the expression of intracellular signaling pathways in THP-1 cells. It is a potent anti-inflammatory component found in food and beverage. These findings might contribute to the overall understanding of the potential health benefits of vanillin for food application. PRACTICAL APPLICATION: In this study, the anti-inflammatory effect of vanillin (VA) was evaluated by ELISA, real-time PCR, and western blot in LPS-induced THP-1 cells. The hypothesis that VA could react with LPS was excluded due to the results of quantification by HS-SPME-GC-MS. On the basis of the result, vanillin could effectively attenuate LPS-induced inflammatory response in THP-1 cells and was a potent anti-inflammatory component natural in food and beverage. These findings might contribute to the overall understanding of the potential health benefits of vanillin for food application.


Assuntos
Anti-Inflamatórios/farmacologia , Benzaldeídos/farmacologia , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/imunologia , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/imunologia , Monócitos/imunologia , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Células THP-1
4.
Mol Med Rep ; 20(2): 1761-1771, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257541

RESUMO

Atopic dermatitis (AD), a chronic inflammatory skin disease, is characterized by intense itching and recurrent eczematous lesions. Sulforaphane is known to attenuate oxidative stress, and tissue or cell damage in cerebral ischemia, brain inflammation and intracerebral hemorrhage. In the present study, a 2,4­dinitrochlorobenzene (DNCB)­induced AD mouse model was developed, and ear thickness, dermatitis score, eosinophil count, mast cell infiltration, and serum IgE levels were measured in DNCB­induced AD and sulforaphane­treated groups to demonstrate the therapeutic effects of sulforaphane. AD symptoms of DNCB­induced mice were attenuated by sulforaphane treatment compared with those of negative control mice; furthermore, eosinophil count, mast cell infiltration and serum IgE levels were also reduced by sulforaphane treatment in DNCB­induced AD mice. Western blot assays revealed that the expression levels of nuclear factor­E2­related factor 2 (Nrf2) and heme oxygenase-1 (HO­1), which exhibit oxidation resistance, were increased by sulforaphane treatment in DNCB­induced AD mice. The present study suggested that sulforaphane exerted a therapeutic effect in the AD mouse model through the activation of the Nrf2/HO­1 axis as well as the suppression of Janus kinase 1/STAT3 signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Heme Oxigenase-1/imunologia , Isotiocianatos/uso terapêutico , Fator 2 Relacionado a NF-E2/imunologia , Animais , Antioxidantes/uso terapêutico , Dermatite Atópica/imunologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
5.
Int Immunopharmacol ; 74: 105658, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177016

RESUMO

The acute respiratory distress syndrome (ARDS), a devastating clinical syndrome, is one of the most severe complications of acute lung injury (ALI). Despite of decades of clinical trials and supportive ventilation strategies, the incidence and mortality of ALI/ARDS remain high. DL-3-n-butylphthalide (NBP) is a synthesized raceme of L-3-n-butylphthalide which has been approved to possess various activities. In the current study, we aimed to investigate the effect of NBP on ALI in lipopolysaccharide (LPS)-treated mice. We found that 10 mg/kg and 50 mg/kg NBP significantly prevented LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. Sirtuin 1 (SIRT1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was increased by NBP in lung of LPS-treated mice. Knockout of SIRT1 significantly aggravated LPS-induced ALI. Moreover, the absence of SIRT1 notably inhibited NBP-induced protective effects against LPS-induced increase of W/D ratio of lung, histological injury of lung, infiltration of inflammatory cells, release of pro-inflammatory cytokines and chemokines, and oxidative damage. However, knockout of SIRT1 did not completely inhibit NBP-induced upregulation of Nrf2 and attenuation of ALI. The results demonstrated that NBP could activate Nrf2 antioxidant signaling in a SIRT1-dependent and SIRT1-independent manner, resulting in the amelioration of oxidative stress, inflammation and pulmonary edema. The data highlights the importance of SIRT1/Nrf2 signaling in the protective effects of NBP.


Assuntos
Lesão Pulmonar Aguda/imunologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzofuranos/farmacologia , Fator 2 Relacionado a NF-E2/imunologia , Sirtuína 1/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Benzofuranos/uso terapêutico , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/imunologia , Edema Pulmonar/patologia , Sirtuína 1/genética
6.
Fish Shellfish Immunol ; 92: 489-499, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31220575

RESUMO

In this study, we cloned the full-length cDNA of the Kelch-like ECH-associated protein 1 (Keap1) from the scallops Chlamys farreri (C. farreri). Sequences alignment and phylogenetic analysis showed that CfKeap1 was highly specific in the scallops, and the amino acid sequence identity value is closer to that in zebrafish Keap1b and Nothobranchius furzeri Keap1b than Keap1a. The highest transcription level of CfKeap1 expression was detected in the digestive glands. The gene expressions of CfKeap1, NF-E2-related nuclear factor 2 (Nrf2), Superoxide Dismutase (SOD), Catalase (CAT) and Glutathione Peroxidase (GPx) in digestive glands were evaluated by quantitative real-time PCR (qRT-PCR) after being exposed to benzo(a)pyrene (BaP) (0.25, 1and 4 µg/L) for 15 days, which indicated that the activation of Nrf2 and Keap1 expression can be significantly induced under BaP exposure. RNA interference (RNAi) experiments were conducted to examine the expression profiles of CfKeap1, Nrf2, antioxidant genes (Cu/Zn-SOD, CAT and GPx), mitogen-activated protein kinase (MAPKs) and protein kinase C (PKC) signaling pathways key genes in digestive glands and gills when exposed to BaP. Results showed that the mRNA level of CfKeap1 was significantly decreased by 60.69% and59.485%. The changes of CfKeap1 and Nrf2 suggested that the enhancement of Keap1 expression stimulating Nrf2 degradation. Furthermore, the expression of antioxidant genes were consistent with the Nrf2 gene, which suggesting that Nrf2-Keap1 signaling pathway is required for the induction of antioxidant genes. Besides, the changes of PKC, c-Jun N-terminal kinase (JNK) and p38 genes expression suggested that PKC and MAPKs signaling pathways played a synergistic role with Nrf2-Keap1 signaling pathway in the anti-oxidative defense system of bivalve molluscs. In conclusion, these data demonstrated that Keap1 can sense nucleophilic or oxidative stress factors to regulate the Nrf2 signaling pathway together with Cul3-based E3 Ubiquitin Ligase (E3), and the Nrf2-Keap1 signaling pathway played an important role in modulating gene expression of antioxidant enzymes in bivalve mollusks.


Assuntos
Benzo(a)pireno/efeitos adversos , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/imunologia , Pectinidae/efeitos dos fármacos , Poluentes Químicos da Água/efeitos adversos , Sequência de Aminoácidos , Animais , Perfilação da Expressão Gênica , Proteína 1 Associada a ECH Semelhante a Kelch/química , Fator 2 Relacionado a NF-E2/química , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Pectinidae/genética , Pectinidae/imunologia , Filogenia , Alinhamento de Sequência , Transdução de Sinais
7.
Inflamm Res ; 68(6): 511-523, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037316

RESUMO

OBJECTIVE: Chicoric acid (CA) is a natural product with promising antioxidant and anti-inflammatory properties; however, its protective effect on methotrexate (MTX)-induced acute kidney injury (AKI) hasn't been reported. We investigated the effect of CA on MTX-induced AKI in rats, pointing to the role of NF-κB/NLRP3 inflammasome and Nrf2/ARE/HO-1 signaling. MATERIALS AND METHODS: Wistar rats received 25 mg/kg and 50 mg/kg CA for 15 days and a single injection of MTX at day 16. At day 19, the rats were killed, and samples were collected for analyses. RESULTS: MTX induced a significant increase in serum creatinine and urea, and kidney Kim-1, reactive oxygen species (ROS), malondialdehyde and nitric oxide levels. In addition, MTX-induced rats exhibited multiple histopathological alterations, diminished antioxidant defenses, and decreased expression of Nrf2, NQO-1 and HO-1. CA prevented histological alterations, ameliorated kidney function markers, attenuated ROS production and lipid peroxidation, and boosted antioxidant defenses. CA suppressed the expression of NF-κB p65, NLRP3, caspase-1 and IL-1ß in the kidney of MTX-induced rats. Furthermore, CA inhibited MTX-induced apoptosis as evidenced by the decreased expression of BAX and caspase-3, and increased Bcl-2 gene expression. CONCLUSIONS: CA prevented MTX-induced AKI through activation of Nrf2/ARE/HO-1 signaling, and attenuation of ROS-induced activation of NF-κB/NLRP3 inflammasome signaling.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/imunologia , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/uso terapêutico , Succinatos/farmacologia , Succinatos/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Elementos de Resposta Antioxidante/imunologia , Apoptose/efeitos dos fármacos , Antagonistas do Ácido Fólico , Heme Oxigenase (Desciclizante)/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Masculino , Metotrexato , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ratos Wistar , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
8.
J Agric Food Chem ; 67(19): 5552-5559, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042377

RESUMO

The present study was designed to investigate the role of the canonical and noncanonical inflammasome, MAPKs and NRF-2/HO-1, signaling pathways involved in the antioxidant and anti-inflammatory activities of oleocanthal in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. Isolated cells were treated with oleocanthal in the presence or absence of LPS (5 µg mL-1) for 18 h. Oleocanthal showed a potent reduction of reactive oxygen species (ROS) (25 µM, 50. 612 ± 0.02; 50 µM, 53. 665 ± 0.09; 100 µM, 52. 839 ± 0.02), nitrites (25 µM, 0.631 ± 0.07; 50 µM, 0.652 ± 0.07; 100 µM, 0.711 ± 0.08), and pro-inflammatory cytokines levels when compared with LPS-DMSO-treated control cells. In terms of enzymes protein expression, oleocanthal was able to downregulate iNOS (25 µM, 0.173 ± 0.02; 50 µM, 0.149 ± 0.01; 100 µM, 0.150 ± 0.01; p < 0.001), COX-2 (25 µM, 0.482 ± 0.08; 50 µM, 0.469 ± 0.05; 100 µM, 0.418 ± 0.06; p < 0.001), and mPGES-1 (25 µM, 0.185 ± 0.11; 50 µM, 0.218 ± 0.13; 100 µM, 0.161 ± 0.15; p < 0.001) as well as p38 (25 µM, 0.366 ± 0.11; 50 µM, 0.403 ± 0.13; 100 µM, 0.362 ± 0.15; p < 0.001), JNK (25 µM, 0.443 ± 0.11; 50 µM, 0.514 ± 0.13; 100 µM, 0.372 ± 0.15; p < 0.001), and ERK (25 µM, 0.294 ± 0.01; 50 µM, 0.323 ± 0.01; 100 µM, 0.274 ± 0.01; p < 0.001) protein phosphorylation, which was accompanied by an upregulation of Nrf-2 (25 µM, 1.57 ± 0.01; 50 µM, 1.54 ± 0.01; 100 µM, 1.63 ± 0.05; p < 0.05) and HO-1(25 µM, 2.12 ± 0,03; 50 µM, 2.24 ± 0.01; 100 µM, 1.92 ± 0.05; p < 0.01) expression in comparison with LPS-DMSO cells. Moreover, oleocanthal inhibited canonical and noncanonical inflammasome signaling pathways. Thus, oleocanthal might be a promising natural agent for future treatment of immune-inflammatory diseases.


Assuntos
Aldeídos/farmacologia , Heme Oxigenase-1/imunologia , Inflamassomos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Fenóis/farmacologia , Animais , Células Cultivadas , Feminino , Heme Oxigenase-1/genética , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fosforilação , Espécies Reativas de Oxigênio/imunologia
9.
Immunopharmacol Immunotoxicol ; 41(2): 337-348, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31056974

RESUMO

Objective: The isochroman-type fungal metabolite 3,7-dimethyl-1,8-hydroxy-6-methoxyisochroman (DMHM) was isolated from the extracts of a marine-derived fungal strain of Penicillium sp. SF-6013. In this study, we investigated the effect of DMHM on inflammatory response. Materials and methods: Anti-inflammatory effects of DMHM were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, qRT-PCR, and western blot analysis. Results: DMHM revealed that it suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) in LPS-stimulated RAW264.7 and BV2 cells. Furthermore, DMHM decreased the mRNA expression of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-6. Therefore, DMHM was further investigated to elucidate the mechanisms of its anti-inflammatory properties; the results indicated that its effect was mediated by the suppression of the nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK) MAPK pathways. Furthermore, the anti-inflammatory activity of DMHM correlated with its induction of heme oxygenase-1 (HO)-1 expression via activation of the nuclear factor erythroid 2-like 2 (Nrf2) pathway. Discussion and conclusions: Collectively, the results of this study suggest that DMHM inhibited several inflammatory pathways including the NF-κB and MAPK pathways, and induced Nrf2-mediated HO-1 expression, demonstrating its potential usefulness for treating inflammatory and neuroinflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Cromanos/farmacologia , Heme Oxigenase-1/imunologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Animais , Anti-Inflamatórios/química , Cromanos/química , Ciclo-Oxigenase 2/imunologia , Dinoprostona/imunologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Óxido Nítrico/imunologia , Penicillium/química , Células RAW 264.7
10.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925687

RESUMO

p300/CBP-associated factor (PCAF), a histone acetyltransferase, is involved in many cellular processes such as differentiation, proliferation, apoptosis, and reaction to cell damage by modulating the activities of several genes and proteins through the acetylation of either the histones or transcription factors. Here, we examined a pathogenic role of PCAF and its potential as a novel therapeutic target in the progression of renal tubulointerstitial fibrosis induced by non-diabetic unilateral ureteral obstruction (UUO) in male C57BL/6 mice. Administration of garcinol, a PCAF inhibitor, reversed a UUO-induced increase in the renal expression of total PCAF and histone 3 lysine 9 acetylation and reduced positive areas of trichrome and α-smooth muscle actin and collagen content. Treatment with garcinol also decreased mRNA levels of transforming growth factor-ß, matrix metalloproteinase (MMP)-2, MMP-9, and fibronectin. Furthermore, garcinol suppressed nuclear factor-κB (NF-κB) and pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6, whereas it preserved the nuclear expression of nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and levels of Nrf2-dependent antioxidants including heme oxygense-1, catalase, superoxide dismutase 1, and NAD(P)H:quinone oxidoreductase 1. These results suggest that the inhibition of inordinately enhanced PCAF could mitigate renal fibrosis by redressing aberrant balance between inflammatory signaling and antioxidant response through the modulation of NF-κB and Nrf2.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Terpenos/uso terapêutico , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Fibrose , Inflamação/imunologia , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Nefropatias/imunologia , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Terpenos/farmacologia , Fatores de Transcrição de p300-CBP/imunologia
11.
J Immunol ; 202(8): 2189-2194, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30850475

RESUMO

Neutrophils are essential during contact hypersensitivity (CHS), a common skin allergic disease. NF-E2-related factor-2 (Nrf2) is a key regulator of redox balance and skin homeostasis playing a protective role in CHS. In this study, we investigated Nrf2 role in neutrophil recruitment during the sensitization phase of CHS. Comparing wild-type and Nrf2 knockout mice, we demonstrated that Nrf2 regulated dinitrochlorobenzene-induced xenoinflammation, notably neutrophil recruitment to sensitized skin. Nrf2 protective role was associated with high expression of antioxidant genes (ho-1, gclc, nqo1…) and decreased chemokine production (CCL2, CCL4, CCL11). Interestingly, skin sensitization induced CD36 upregulation in skin-resident macrophages. In vitro results confirmed that the transcription of cd36 gene in macrophages was dependent on Nrf2 and led to an improved capacity to phagocyte-damaged neutrophils by efferocytosis. Nrf2 emerges as a critical target in the sensitization phase of CHS regulating neutrophil recruitment and accumulation in the skin through antioxidant-dependent and -independent mechanisms.


Assuntos
Dermatite de Contato/imunologia , Regulação da Expressão Gênica/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Pele/imunologia , Animais , Antioxidantes , Quimiocinas/genética , Quimiocinas/imunologia , Dermatite de Contato/genética , Dermatite de Contato/patologia , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Neutrófilos/patologia , Pele/patologia
12.
Fish Shellfish Immunol ; 87: 871-878, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30776542

RESUMO

Viral infection is often accompanied with alteration of intracellular redox state, especially an imbalance between reactive oxygen species (ROS) production and antioxidant cellular defenses. The previous studies showed that an antioxidant cellular defense system, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), played an important role against spring viraemia of carp virus (SVCV) infection in fish. To further reveal the mediated mechanism that Nrf2 active state was affected by protein kinase C (PKC), here we evaluated SVCV replication in host cells by treated with a strong activator of PKC phorbol-12-myristate-13-acetate (PMA) and an inhibitor staurosporine. Our results showed that PMA significantly repressed SVCV replication and viral-induced apoptosis in Epithelioma papulosum cyprini (EPC) cell, suggesting that PKC may exhibit an anti-SVCV effect. Likewise, PMA resulted in a higher phosphorylation levels of PKCε rather than PKCα/ß to participate in the activation of Nrf2, mainly involved in the activation of Nrf2 phosphorylation of Ser40 to favor Nrf2 translocation to nucleus. Furthermore, the data revealed that PMA up-regulated an antiviral response heme oxygenase-1 (HO1) gene expression that was confirmed as the key player against SVCV infection by HO1 specific siRNA. Overall, this study provided a new therapeutic target for the treatment of SVCV infection, and modulating PKC activity could be used for the prevention and treatment of SVCV.


Assuntos
Carpas/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Proteína Quinase C-épsilon/imunologia , Rhabdoviridae/fisiologia , Acetato de Tetradecanoilforbol/análogos & derivados , Animais , Antioxidantes/metabolismo , Carpas/genética , Linhagem Celular , Proteínas de Peixes/genética , Fator 2 Relacionado a NF-E2/genética , Proteína Quinase C-épsilon/genética , Espécies Reativas de Oxigênio/metabolismo , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Acetato de Tetradecanoilforbol/farmacologia
13.
J Immunol ; 202(5): 1331-1339, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30674574

RESUMO

The Keap1-Nrf2 system plays a pivotal role in the oxidative stress response by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. In this article, we investigated the role of the Keap1-Nrf2 pathway in ILC2 homeostasis and allergic inflammation using Nrf2 knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response and underwent hyperproliferation in response to a combined stimulation of IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of the wild-type but not of the Nrf2-deficient ILC2s. This effect on viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3-dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33 administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the number of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response by determining the survival and death of ILC2s, and these findings suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.


Assuntos
Alérgenos/imunologia , Diabetes Mellitus Tipo 2/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Pulmão/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Animais , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Feminino , Inflamação/patologia , Pulmão/patologia , Linfócitos/imunologia , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/deficiência
14.
BMC Complement Altern Med ; 19(1): 15, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630473

RESUMO

BACKGROUND: Asian traditional herbal remedies are typically a concoction of a major and several complementary herbs. While balancing out any adverse effect of the major herb, the complementary herbs could dilute the efficacy of the major herb, resulting in a suboptimal therapeutic effect of an herbal remedy. Here, we formulated Chung-Sang (CS) by collating five major herbs, which are used against inflammatory diseases, and tested whether an experimental formula composed of only major herbs is effective in suppressing inflammation without significant side effects. METHODS: The 50% ethanol extract of CS (eCS) was fingerprinted by HPLC. Cytotoxicity to RAW 264.7 cells was determined by an MTT assay and a flow cytometer. Nuclear NF-κB and Nrf2 were analyzed by western blot. Ubiquitinated Nrf2 was similarly analyzed following immunoprecipitation of Nrf2. Acute lung inflammation and sepsis were induced in C57BL/6 mice. The effects of eCS on lung disease were measured by HE staining of lung sections, a differential cell counting of bronchoalveolar lavage fluid, a myeloperoxidase (MPO) assay, a real-time qPCR, and Kaplan-Meier survival of mice. RESULTS: eCS neither elicited cytotoxicity nor reactive oxygen species. While not suppressing NF-κB, eCS activated Nrf2, reduced the ubiquitination of Nrf2, and consequently induced the expression of Nrf2-dependent genes. In an acute lung inflammation mouse model, an intratracheal (i.t.) eCS suppressed neutrophil infiltration, the expression of inflammatory cytokine genes, and MPO activity. In a sepsis mouse model, a single i.t. eCS was sufficient to significantly decrease mouse mortality. CONCLUSIONS: eCS could suppress severe lung inflammation in mice. This effect seemed to associate with eCS activating Nrf2. Our findings suggest that herbal remedies consisting of only major herbs are worth considering.


Assuntos
Anti-Inflamatórios/administração & dosagem , Fator 2 Relacionado a NF-E2/imunologia , Extratos Vegetais/administração & dosagem , Pneumonia/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Composição de Medicamentos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , NF-kappa B/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Pneumonia/genética , Pneumonia/imunologia , Células RAW 264.7
15.
Biochem Biophys Res Commun ; 509(3): 713-721, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30638656

RESUMO

Ischemic stroke is the second most common cause of death, a major cause of acquired disability in adults. However, the pathogenesis that contributes to ischemic stroke has not been fully understood. Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) is a MAP kinase phosphatase, playing important role in regulating various cellular processes, including oxidative stress and inflammation. However, its effects on cerebral ischemia/reperfusion (IR) are unclear. In the study, we found that DUSP14 expression was decreased responding to IR surgery. Over-expressing DUSP14 reduced the infarction volume of cerebral IR mice. Cognitive dysfunction was also improved in mice with DUSP14 over-expression. Promoting DUSP14 expression markedly reduced the activation of glial cells, as evidenced by the decreases in GFAP and Iba-1 expressions in mice with cerebral IR injury. In addition, inflammatory response induced by cerebral IR injury was inhibited in DUSP14 over-expressed mice, as proved by the reduced expression of tumor necrosis factor (TNF)-α and interleukin 1ß (IL-1ß). Furthermore, oxidative stress was markedly reduced by DUSP14 over-expression through elevating nuclear factor-erythroid 2 related factor 2 (Nrf-2) signaling pathway. Importantly, we found that DUSP14 could interact with Nrf-1, which thereby protected mice against cerebral IR injury. In vitro, we also found that repressing Nrf-2 expression abrogated DUSP14 over-expression-reduced inflammation and ROS generation. Consistent with the anti-inflammatory effect of DUSP14, reducing the production of reactive oxygen species (ROS) also down-regulated TNF-α and IL-1ß expressions. Collectively, elevated DUSP14 alleviated brain damage from cerebral IR injury through Nrf-2-regulated anti-oxidant signaling pathway, and the restraining of inflammatory response. These results suggested that DUSP14 might be a potential therapeutic target to prevent ischemic stroke.


Assuntos
Apoptose , Isquemia Encefálica/imunologia , Fosfatases de Especificidade Dupla/imunologia , Inflamação/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Traumatismo por Reperfusão/imunologia , Animais , Infarto Encefálico/imunologia , Infarto Encefálico/patologia , Isquemia Encefálica/patologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Traumatismo por Reperfusão/patologia
16.
J Agric Food Chem ; 67(4): 1230-1243, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30614688

RESUMO

4-Ethylguaiacol, a common aroma compound of baijiu (a traditional Chinese alcoholic beverage), was assessed for its potential anti-inflammatory effects in an LPS-induced THP-1 cell model. To characterize the effect of 4-ethylguaiacol on the LPS-induced inflammatory response, the mRNA and protein expression of the TLR4-MAPKs-NF-κB-IκBα-AP-1, Nrf2-HO-1, and AMPK-SIRT1 pathways were monitored by ELISA, real-time PCR, and Western blotting. On the basis of the result, 4-ethylguaiacol exerted anti-inflammatory effects at doses of 10, 100, and 500 µM (the concentration of 4-ethylguaiacol in gujinggong baijiu is in the range of 1044 ± 44 to 1661 ± 63 µg/L) and significantly mitigated LPS-induced inflammation via activation of the Nrf2-HO-1 and AMPK-SIRT1 pathways and inhibition of NF-κB and AP-1 activation, thereby markedly inhibiting the activation of inflammasomes and down-regulating the production of inflammatory cytokines. These results indicated that 4-ethylguaiacol could reverse LPS-induced inflammatory responses and is a natural, potent anti-inflammatory component in baijiu.


Assuntos
Bebidas Alcoólicas/análise , Anti-Inflamatórios/farmacologia , Guaiacol/análogos & derivados , Inflamação/imunologia , Lipopolissacarídeos/efeitos adversos , Guaiacol/farmacologia , Humanos , Inflamação/etiologia , Inflamação/genética , Lipopolissacarídeos/imunologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Células THP-1 , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia
17.
Mol Immunol ; 106: 143-152, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30610999

RESUMO

BACKGROUND: Electroacupuncture (EA) at ST-36 can attenuate acute experimental colitis, but the mechanisms are unclear. We investigated the role of macrophages in the anti-inflammatory effects of EA and its molecular mechanisms. METHODS: Male C57BL/6 mice were randomized into five groups: normal control, dextran sulfate sodium (DSS)-induced acute colitis (DSS), DSS with sham EA (SEA), DSS with high-frequency EA (HEA) and DSS with low-frequency EA (LEA). Body weight, colon length, DAI score and histological score were evaluated during colitis progression. Serum and colonic levels of pro- and anti-inflammatory cytokines were detected with ELISA, cytometric beads array, RT-PCR and western blotting analysis. Colonic macrophage subsets were determined using flow cytometry. Magnetic-activated cell sorting was applied to isolate colonic macrophages, and molecular mechanisms were explored with western blotting, RT-PCR and immunofluorescence. RESULTS: (1) Compared with the DSS group, HEA and LEA attenuated body weight loss and decreased DAI and histological scores. (2) Serum levels and colonic protein and mRNA levels of IL-1ß, TNFα, IL-6, IL-12 and IL17 were markedly decreased with HEA and LEA. IL-10 level was increased with HEA. (3) M1 macrophage percentage increased, while M2 macrophage percentage decreased in the DSS group; HEA and LEA reversed these proportions. (4) NLRP3/IL-1ß protein and mRNA levels in isolated macrophages decreased with HEA and LEA compared with the DSS treatment group; (5) HEA increased Nrf2/HO-1 levels compared with levels in DSS mice. CONCLUSION: The anti-inflammatory effects of EA on DSS-induced acute colitis may rely on regulating macrophage polarization, NLRP3/IL-1ß suppression and Nrf2/HO-1 promotion.


Assuntos
Colite , Sulfato de Dextrana/toxicidade , Eletroacupuntura , Heme Oxigenase-1/imunologia , Interleucina-1beta/imunologia , Macrófagos , Proteínas de Membrana/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Doença Aguda , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colite/terapia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos
18.
Mol Immunol ; 105: 165-172, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30513452

RESUMO

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by muscle disorders. We conducted this study to detect whether NF-E2-related factor 2 (Nrf2) pathway inhibit inflammatory infiltration by macrophage in experimental autoimmune myositis (EAM) rat model. METHODS: CD163 levels were examined by immunohistochemistry (IHC), while serum creatine kinase (CK), reactive oxygen species (ROS), and serum monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) levels were determined by enzyme linked immunosorbnent assay (ELISA), both in IIM patients and EAM rat. We also detected MCP-1, TNF-α, IL-6, and Nrf2 levels by Realtime quantitative PCR (RT-PCR) in patients' muscles, and MCP-1, TNF-α, IL-6, and Nrf2, HO-1, NQO-1 levels by RT-PCR and Western blot in EAM rats' muscles. EAM macrophages were separated, and Nrf2 over-expression macrophages were constructed. ROS level and cell migration were detected by flow cytometer and transwell assay respectively. Then, levels of MCP-1, TNF-α, IL-6, Nrf2, Heme oxygenase-1 (HO-1) and NAD(P)H: quinine oxidoreductase 1 (NQO-1) were detected by RT-PCR and Western blot. RESULTS: Results showed that EAM rats were histopathologically inflammatory cell infiltration. Levels of CD163, serum CK and ROS, serum/muscle MCP-1, TNF-α and IL-6 increased and muscle Nrf2 level decreased in IIM patients and EAM rats. Cell migration ability and levels of ROS, MCP-1, TNF-α, IL-6, and plasma Nrf2 were down-regulated, and total/nucleus Nrf2, HO-1, NQO-1 were up-regulated notably when Nrf2 over-expressed. CONCLUSION: Nrf2 inhibited EAM macrophage infiltration by activating Nrf2/ARE pathway which could induce ROS degradation and inhibit pro-inflammatory factors expression.


Assuntos
Movimento Celular/imunologia , Macrófagos Peritoneais/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Doença Autoimune do Sistema Nervoso Experimental/imunologia , Transdução de Sinais/imunologia , Adulto , Animais , Citocinas/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Heme Oxigenase (Desciclizante)/imunologia , Humanos , Macrófagos Peritoneais/patologia , Masculino , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/imunologia , Doença Autoimune do Sistema Nervoso Experimental/patologia , Ratos , Ratos Wistar
19.
Am J Respir Cell Mol Biol ; 60(5): 569-577, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30428271

RESUMO

The aim of this study was to assess the association between regional tidal volume (Vt), regional functional residual capacity (FRC), and the expression of genes linked with ventilator-induced lung injury. Two groups of BALB/c mice (n = 8 per group) were ventilated for 2 hours using a protective or injurious ventilation strategy, with free-breathing mice used as control animals. Regional Vt and FRC of the ventilated mice was determined by analysis of high-resolution four-dimensional computed tomographic images taken at baseline and after 2 hours of ventilation and corrected for the volume of the region (i.e., specific [s]Vt and specific [s]FRC). RNA concentrations of 21 genes in 10 different lung regions were quantified using a quantitative PCR array. sFRC at baseline varied regionally, independent of ventilation strategy, whereas sVt varied regionally depending on ventilation strategy. The expression of IL-6 (P = 0.04), Ccl2 (P < 0.01), and Ang-2 (P < 0.05) was associated with sVt but not sFRC. The expression of seven other genes varied regionally (IL-1ß and RAGE [receptor for advanced glycation end products]) or depended on ventilation strategy (Nfe2l2 [nuclear factor erythroid-derived 2 factor 2], c-fos, and Wnt1) or both (TNF-α and Cxcl2), but it was not associated with regional sFRC or sVt. These observations suggest that regional inflammatory responses to mechanical ventilation are driven primarily by tidal stretch.


Assuntos
Fenômenos Biomecânicos/imunologia , Regulação da Expressão Gênica/imunologia , Pulmão/imunologia , Respiração Artificial/métodos , Lesão Pulmonar Induzida por Ventilação Mecânica/genética , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL2/genética , Quimiocina CXCL2/imunologia , Tomografia Computadorizada Quadridimensional , Interpretação de Imagem Assistida por Computador , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/imunologia , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/imunologia , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/imunologia , Transdução de Sinais , Volume de Ventilação Pulmonar/genética , Volume de Ventilação Pulmonar/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Lesão Pulmonar Induzida por Ventilação Mecânica/diagnóstico por imagem , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologia , Proteína Wnt1/genética , Proteína Wnt1/imunologia
20.
Cell Physiol Biochem ; 51(4): 1830-1838, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504721

RESUMO

BACKGROUND/AIMS: Osteoarthritis (OA) is a multifactorial disease that is associated with inflammation in joints. The purpose of the present study was to investigate the anti-inflammatory activity and mechanism of morin on human osteoarthritis chondrocytes stimulated by IL-1ß. METHODS: The levels of NO and PGE2 were measured by the Griess method and ELISA. The levels of MMP1, MMP3, and MMP13 were also measured by ELISA. RESULTS: The results revealed that IL-1ß significantly increased the production of NO, PGE2, MMP1, MMP3, and MMP13. Additionally, the increases were significantly attenuated by treatment with morin. Furthermore, IL-1ß-induced NF-κB activation was suppressed by morin. In addition, the expression of Nrf2 and HO-1 were increased by morin and knockdown of Nrf2 could prevent the anti-inflammatory effects of morin. CONCLUSION: In conclusion, this study suggested that morin attenuated IL-1ß-induced inflammation by activating the Nrf2 signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Flavonoides/farmacologia , Interleucina-1beta/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Osteoartrite/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/imunologia , Condrócitos/patologia , Humanos , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 3 da Matriz/imunologia , Pessoa de Meia-Idade , Óxido Nítrico/imunologia , Osteoartrite/imunologia , Osteoartrite/patologia , Transdução de Sinais/efeitos dos fármacos
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