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1.
Life Sci ; 240: 116857, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521691

RESUMO

AIMS: Daphnetin (DAP) is a traditional Chinese drug usually used to treat cardiovascular diseases. Studies have confirmed the anti-inflammatory, antioxidant, anti-bacterial and insecticidal, anti-tumor and neuro-protective effects of DAP. However, its anti-arthritic potential remains unexplored. The aim of this study is to investigate the in vitro and in vivo chondroprotective effects of DAP. MAIN METHODS: The effect of DAP on primary rabbit chondrocytes was examined using recombinant human IL-1ß for 24 h. For the in vivo studies, rabbits were randomly divided into groups: a normal control group and osteoarthritis (OA) groups. The OA groups received three different doses of DAP for 4 or 8 weeks. The anti-arthritic effect of DAP was assessed using histopathological examinations, qRT-PCR, western blotting and immunohistochemical analysis. KEY FINDINGS: Both in vitro and in vivo results indicate that DAP exerts a protective effect against IL-1ß in chondrocytes. In vitro, DAP inhibits the expression of IL-6, IL-12, MMP-3, MMP-9 and MMP-13, induced by IL-1ß in rabbit chondrocytes, and stimulates the production of IL-10. The inhibitory effect of DAP on the MMPs is partially regulated by the inhibition of the PI3K/AKT, MAPK and NF-κB signaling pathways. The effect of DAP on OA may be attributed to the suppression of inflammatory factor secretion, chondrocyte apoptosis observed by the decrease in pro-apoptotic Caspase-3 and BAX, and the activation of anti-apoptotic BCL-2. SIGNIFICANCE: DAP has a broad range of prospects in the treatment of OA, which provides a novel therapeutic strategy for OA.


Assuntos
Antirreumáticos/uso terapêutico , Condrócitos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Umbeliferonas/uso terapêutico , Animais , Antirreumáticos/efeitos adversos , Apoptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Sobrevivência Celular , Condrócitos/patologia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Interleucina-1beta/farmacologia , Masculino , Osteoartrite/patologia , Cultura Primária de Células , Coelhos , Transdução de Sinais/efeitos dos fármacos , Umbeliferonas/efeitos adversos
2.
Cell Prolif ; 52(6): e12692, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560411

RESUMO

OBJECTIVES: Interleukin (IL)-37 is a natural suppressor of innate inflammation. This study was conducted to explore the anti-inflammatory effects of IL-37 in temporomandibular joint (TMJ) inflammation. MATERIALS AND METHODS: The expression of IL-37 in the TMJ was measured using ELISA and IHC. Human TMJ chondrocytes were treated with IL-37b and IL-1ß, and inflammation-related factors were detected. siRNA-IL-1R8 was transfected into chondrocytes, and the affected pathways were detected. IL-37b was used in disc-perforation-induced TMJ inflammation in SD rats. Micro-CT, IHC, real-time PCR and histological staining were used to quantify the therapeutic effect of IL-37b. RESULTS: IL-37 was expressed in the synovium and the disc of patients with osteoarthritis (OA) and in the articular cartilage of condylar fracture patients. IL-37 was highly expressed in synovial fluid of patients with synovitis than in those with OA and disc displacement and was closely related to visual analogue scale (VAS) score. In vitro, IL-37b suppressed the expression of pro-inflammatory factors. In addition, IL-37b exerted anti-inflammatory effects via IL-1R8 by inhibiting the p38, ERK, JNK and NF-κB activation, while silencing IL-1R8 led to inflammation and upregulation of these signals. In disc-perforation-induced TMJ inflammation in SD rats, IL-37b suppressed inflammation and inhibited osteoclast formation to protect against TMJ. CONCLUSIONS: IL-37b may be a novel therapeutic agent for TMJ inflammation.


Assuntos
Inflamação/tratamento farmacológico , Interleucina-1/farmacologia , Interleucina-1beta/farmacologia , Osteoartrite/tratamento farmacológico , Articulação Temporomandibular/efeitos dos fármacos , Adulto , Idoso , Animais , Cartilagem Articular/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
3.
Cell Prolif ; 52(6): e12629, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31468648

RESUMO

OBJECTIVES: Endothelial cells undergo TGF-ß-driven endothelial-mesenchymal transition (EndMT), representing up to 25% of cardiac myofibroblasts in ischaemic hearts. Previous research showed that conditioned medium of adipose tissue-derived stromal cells (ASC-CMed) blocks the activation of fibroblasts into fibrotic myofibroblasts. We tested the hypothesis that ASC-CMed abrogates EndMT and prevents the formation of adverse myofibroblasts. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were treated with IL-1ß and TGF-ß2 to induce EndMT, and the influence of ASC-CMed was assessed. As controls, non-treated HUVEC or HUVEC treated only with IL-1ß in the absence or presence of ASC-CMed were used. Gene expression of inflammatory, endothelial, mesenchymal and extracellular matrix markers, transcription factors and cell receptors was analysed by RT-qPCR. The protein expression of endothelial and mesenchymal markers was evaluated by immunofluorescence microscopy and immunoblotting. Endothelial cell function was measured by sprouting assay. RESULTS: IL-1ß/TGF-ß2 treatment induced EndMT, as evidenced by the change in HUVEC morphology and an increase in mesenchymal markers. ASC-CMed blocked the EndMT-related fibrotic processes, as observed by reduced expression of mesenchymal markers TAGLN (P = 0.0008) and CNN1 (P = 0.0573), as well as SM22α (P = 0.0501). The angiogenesis potential was impaired in HUVEC undergoing EndMT and could not be restored by ASC-CMed. CONCLUSIONS: We demonstrated that ASC-CMed reduces IL-1ß/TGF-ß2-induced EndMT as observed by the loss of mesenchymal markers. The present study supports the anti-fibrotic effects of ASC-CMed through the modulation of the EndMT process.


Assuntos
Meios de Cultivo Condicionados/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Interleucina-1beta/farmacologia , Células Estromais/efeitos dos fármacos , Fator de Crescimento Transformador beta2/farmacologia , Tecido Adiposo/efeitos dos fármacos , Células Cultivadas , Transição Epitelial-Mesenquimal/genética , Humanos , Interleucina-1beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Paediatr Drugs ; 21(5): 389-395, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31463794

RESUMO

INTRODUCTION: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by interleukin (IL)-1 overproduction. Colchicine is the mainstay drug in the treatment of FMF; however, a minority of patients do not respond despite the highest tolerated doses. We aimed to share our experience with canakinumab, a human monoclonal antibody against IL-1ß, in pediatric FMF patients. METHODS: This historical, single-cohort study retrospectively evaluated the disease characteristics, indications, and treatment responses of 14 pediatric FMF patients treated with canakinumab in our pediatric rheumatology department. RESULTS: The median age at onset and diagnosis of 14 FMF patients (9 females, 5 males), were 3.5 (range 0.5-10) years and 6 (range 3-16) years, respectively. Indications for canakinumab treatment were renal amyloidosis (n = 1), colchicine resistance (n = 11), and persistent arthritis (n = 2). Only two (14.3%) patients had colchicine intolerance. Complete response was obtained in 10/14 (71.5%) among all patients and 10/12 (86%) in patients with typical phenotype. The patient with chronic oligoarthritis had a complete response, whereas the patient with rheumatoid factor (RF)-positive polyarthritis demonstrated an initial partial response to canakinumab treatment. We found that attack frequency, proteinuria, and acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein, were significantly decreased after canakinumab treatment in children with FMF. CONCLUSION: Canakinumab may be an effective treatment option for pediatric FMF patients with colchicine resistance, renal amyloidosis, and chronic oligoarthritis. Further studies are needed to clarify the efficacy of canakinumab in patients with a second disease, RF-positive polyarticular juvenile idiopathic arthritis.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Interleucina-1beta/uso terapêutico , Adolescente , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Estudos de Coortes , Febre Familiar do Mediterrâneo/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-1beta/farmacologia , Masculino , Estudos Retrospectivos , Resultado do Tratamento
5.
Artif Cells Nanomed Biotechnol ; 47(1): 2972-2979, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31322005

RESUMO

Background/Aim: Ginsenoside Rg1 exerts a beneficial effect in many kidney diseases. But little work has been done to confirm whether ginsenoside Rg1 could also exert a protective effect on anti-glomerular basement membrane (anti-GBM) glomerular nephritis (GN). We aimed to explore the role of ginsenoside Rg1 in attenuating anti-GBM GN in vitro and in vivo and investigate the mechanism under its action. Methods: Interleukin-1ß (IL-1ß) treated podocytes were used as a cell model. A total of 20 mice were used to build the Anti-GBM GN mice model. Real-time PCR analysis (RT-PCR), Western blot analysis and ELISA assay were conducted to detect related indicators in this study. The statistical analysis was performed using GraphPad Prism software 6.0. Results: Ginsenoside Rg1 attenuates IL-1ß-induced inflammation and apoptosis in podocytes. NRF2 expression can be inhibited by IL-1ß, whereas reversed by ginsenoside Rg1. NRF2 inhibitor ML385 can significantly reverse the effects of ginsenoside Rg1 on inflammation and apoptosis induced by IL-1ß, and block the inhibitory effect of ginsenoside Rg1 on IL-1ß activated MAPK pathway. In addition, ginsenoside Rg1 could improve anti-GBM GN injury in vivo. Conclusion: Ginsenoside Rg1 inhibits the anti-GBM GN damage through regulating NRF2 pathway in vitro and in vivo. Our findings provide new insight and mechanism of ginsenoside Rg1 to prevent anti-GBM GN.


Assuntos
Autoanticorpos/imunologia , Ginsenosídeos/farmacologia , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glomerulonefrite/imunologia , Glomerulonefrite/metabolismo , Interleucina-1beta/farmacologia , Masculino , Camundongos , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologia
6.
Invest Ophthalmol Vis Sci ; 60(8): 2895-2903, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266061

RESUMO

Purpose: The proinflammatory cytokine interleukin (IL)-1 is implicated in corneal ulceration and promotes collagen degradation by corneal fibroblasts cultured in a three-dimensional (3D) collagen gel. Epigallocatechin-3-gallate (EGCG), the principal polyphenol in extracts of green tea, has various beneficial health effects, some of which appear to be mediated through direct or indirect inhibition of protease activity. We therefore examined the effect of EGCG on IL-1ß-induced collagen degradation by corneal fibroblasts embedded in a collagen gel. Methods: Human corneal fibroblasts were cultured in a type I collagen gel. Collagen degradation was assessed by measurement of hydroxyproline in acid hydrolysates of culture supernatants. The expression of urokinase-type plasminogen activator (uPA) was examined by real-time and RT-PCR analysis and by fibrin zymography, and that of the collagenase matrix metalloproteinase 1 (MMP1) was detected by immunoblot analysis. Results: EGCG inhibited IL-1ß-induced, plasminogen-dependent collagen degradation by corneal fibroblasts in a concentration-dependent manner. It also attenuated the IL-1ß-induced expression of uPA at both mRNA and protein levels. EGCG inhibited the IL-1ß-induced conversion of exogenous plasminogen to plasmin as well as the plasminogen-dependent activation of pro-MMP1 in the 3D cultures without a substantial effect on pro-MMP1 abundance. Conclusions: EGCG inhibits IL-1ß-induced collagen degradation by corneal fibroblasts, with this effect likely being mediated by suppression of the upregulation of uPA, the uPA-mediated conversion of plasminogen to plasmin, and the plasmin-mediated activation of pro-MMP1. EGCG thus warrants further investigation as a potential treatment for corneal ulcer.


Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Colágeno/metabolismo , Ceratócitos da Córnea/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/genética , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ceratócitos da Córnea/metabolismo , Relação Dose-Resposta a Droga , Fibrina/metabolismo , Fibrinolisina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Hidroxiprolina/metabolismo , Interleucina-1beta/farmacologia , Metaloproteinase 1 da Matriz/metabolismo , NF-kappa B/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
7.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(3): 300-306, 2019 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-31282322

RESUMO

Objective To investigate the effects of different inflammatory factors on hepatocyte kinase receptor(Eph)and ligand(ephrin)in human periodontal ligament fibroblasts(hPDLFs).Methods hPDLFs were stimulated with either 10 ng/ml tumor necrosis factor-α(TNF-α)or 10 ng/ml interleukin(IL)-1ß,and then the expressions of Eph and ephrin at both mRNA and protein levels were determined at 0,1,2,6,12,and 24 hours.Results The levels of Eph receptors and ephrin ligand changed in a time-dependent manner in human periodontal ligament fibroblasts after treatment with TNF-α or IL-1ß. The expression of ephrinA2 significantly increased in both groups within 24 hours(all P<0.05). In the TNF-α group,the mRNA expression of ephrinA2 significantly increased at 1 h and was significant higher that in the IL-1ß group at 24 h(P<0.05). EphB4 showed a time-dependent decline after a short period of high expression.Conclusions Both TNF-α and IL-1ß can cause changes in the expressions of Eph receptors and ephrin ligands in hPDLFs. The changes induced by both are consistent,although the effect of TNF-α is more pronounced.


Assuntos
Efrinas/metabolismo , Fibroblastos , Ligamento Periodontal/citologia , Receptores da Família Eph/metabolismo , Células Cultivadas , Humanos , Interleucina-1beta/farmacologia , Ligantes , Fator de Necrose Tumoral alfa/farmacologia
8.
Chem Biol Interact ; 310: 108730, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260663

RESUMO

The present study shows the basis for the anti-inflammatory effects of statins in interleukin 1ß (IL-1ß) induced SW1353 chondrosarcoma cell-line. The cells were pre-treated with simvastatin (5 µM, 10 µM, and 50 µM), followed by IL-1ß (5 ng/mL) stimulation. Effects of simvastatin on cell viability and cytotoxicity of chondrocytes were measured with WST-1 and lactate dehydrogenase (LDH) assays, respectively. Under inflammatory conditions, in the absence/presence of simvastatin, the changes in matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression levels were examined. Expression levels of MMP-1, -2, -3, -9, -13, and TIMP-1 and -2 were examined by qPCR. MMP-1, -9, -13, TIMP-1, and -2 levels were also determined by Western blotting. Gelatin zymography was performed to analyze the released and intracellular MMP-2 and MMP-9 activity levels. The results showed that simvastatin downregulated the degradation related genes MMP-3, MMP-13, MMP-2, MMP-9 and TIMP-2 in a dose-dependent manner.


Assuntos
Condrócitos/citologia , Condrossarcoma/patologia , Metaloproteinases da Matriz/metabolismo , Sinvastatina/farmacologia , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Citotoxinas/farmacologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/farmacologia , Metaloproteinases da Matriz/efeitos dos fármacos , Inibidores Teciduais de Metaloproteinases/metabolismo
9.
Cytogenet Genome Res ; 158(1): 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31261155

RESUMO

Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1ß stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1ß promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1ß, inhibits IL-1ß-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Butadienos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Nitrilos/farmacologia , Inibidores de Proteínas Quinases/farmacologia
10.
Mol Med Rep ; 20(2): 1523-1530, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257459

RESUMO

Intervertebral disc degeneration (IVDD) is the main pathological basis of spinal degenerative diseases, and aberrant apoptosis of nucleus pulposus cells (NPCs) is the main cellular process that causes IVDD. In our previous studies, 17ß­estradiol (E2) was demonstrated to protect rat NPCs from interleukin­1ß (IL­1ß)­induced apoptosis via the PI3K/Akt signaling pathway. However, the downstream signaling pathway of PI3K/Akt is currently unclear. The present study aimed to explore the signaling pathways that are downstream of the PI3K/Akt pathway, including mTOR, NF­κB and glycogen synthase kinase­3ß (GSK­3ß). Annexin V/propidium iodide double staining was used to determine the incidence of apoptosis. Cell Counting kit­8 and MTS assays were used to determine the proliferation and viability of NPCs, respectively. Cellular binding was evaluated using a cell­collagen binding assay. Western blotting was used to determine the protein expression levels of mTOR, NF­κB and GSK­3ß, and their phosphorylation levels, as well as the expression levels of active caspase­3. The results revealed that IL­1ß induced NPC apoptosis and increased the early apoptotic rate of NPCs. However, E2 reduced the early apoptosis of NPCs induced by IL­1ß. In addition, E2 suppressed the decrease in cell viability and binding ability caused by IL­1ß cytotoxicity. Western blotting revealed that E2 also reduced the expression of activated caspase­3, and increased the expression of activated mTOR. As a specific inhibitor of mTOR, rapamycin effectively attenuated the effects of E2. These findings indicated that E2 protected NPCs against apoptosis via activation of the mTOR/caspase­3 pathway.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/genética , Condrócitos/efeitos dos fármacos , Estradiol/farmacologia , Interleucina-1beta/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Animais , Apoptose/genética , Caspase 3/metabolismo , Condrócitos/citologia , Condrócitos/metabolismo , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-1beta/farmacologia , Masculino , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
11.
Life Sci ; 230: 208-217, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152815

RESUMO

Mushroom Phellinus linteus ("Sanghuang" in Chinese) is a popular medicinal polypore used to treat several disorders through its various biological functions. Inonotus sanghuang is claimed to produce general immune-potentiating and strengthening, anti-inflammatory, anti-tumor and anti-microbial properties, but its effect on acute lung inflammation and oxidative stress are not clearly understood. To determine the effect and mechanism of the polyphenols-rich ethyl acetate fraction from wild I. sanghuang extract (ISE) on acute lung injury (ALI) induced by bleomycin (BLM), female C57BL/6 mice were fed ISE (0%, 0.15% or 0.6% in diet) for 4 weeks prior to challenge with BLM. Bronchoalveolar lavage fluid (BALF) from lung, spleen and lung tissues were collected on day 3 after BLM challenge for histological, oxidative stress, molecular and biochemical analysis. ISE supplementation improved pathological features in lung injury scores and reduced lung wet-to-dry ratios. Moreover, ISE reduced inflammatory cell infiltration and the pro-inflammatory cytokines including IL-1ß, IL-6 and TNF-α in BALF, decreased the MPO activity and the MDA level and increased the SOD, CAT and GSH-Px activities in lung tissue homogenates. Further mechanism analysis demonstrated that dietary ISE inhibited NF-κB signal. Finally, peripheral immune function analysis showed that ISE had less effect on immune response including splenocyte producing inflammatory cytokines and T cell proliferation except for IL-1ß and IL-2. Our findings indicate the possibility that dietary ISE attenuates ALI induced by BLM through correcting the inflammation and oxidation balance at least in part via inhibiting NF-κB signal in vivo, suggesting that ISE might be a valuable medicinal food effective in improving lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Extratos Vegetais/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Agaricales/isolamento & purificação , Agaricales/metabolismo , Animais , Antioxidantes/farmacologia , Bleomicina/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Feminino , Inflamação/patologia , Interleucina-1beta/farmacologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/isolamento & purificação , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
12.
Artif Cells Nanomed Biotechnol ; 47(1): 2612-2617, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237151

RESUMO

Aging-related osteoarthritis (OA) is the most common type of arthritis. Chondrocyte senescence has been linked with the pathogenesis of OA. Here, we examined the expression of GPR39 in chondrocytes and its modulatory effect on IL-1ß-induced cellular senescence. We show that GPR39 is moderately expressed in human chondrocytes and its expression is repressed by the pro-inflammatory cytokine IL-1ß. The GPR39 agonist TC-G 1008 mitigates IL-1ß-induced chondrocyte senescence. Mechanistically, we show that TC-G 1008 mitigates IL-1ß-induced cell cycle arrest at G1 phase by suppressing the expression of p53, p21, PAI-1, and K382 acetylation of p53. Moreover, we show that TC-G 1008 treatment restores IL-1ß-induced inhibition of SIRT1 and the silencing of SIRT1 abolishes the function of TC-G 1008 on p53 acetylation and senescence, suggesting that the function of GPR39 signaling is mediated by SIRT1 in chondrocytes. Altogether, our findings implicate that the activation of GPR39 signaling ameliorates IL-1ß-induced chondrocyte senescence and the GPR39 agonist TC-G 1008 could have the potential to modulate aging-associated OA.


Assuntos
Senescência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Interleucina-1beta/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Sulfonamidas/farmacologia , Acetilação/efeitos dos fármacos , Linhagem Celular , Condrócitos/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo
13.
Artif Cells Nanomed Biotechnol ; 47(1): 2139-2145, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31146598

RESUMO

Osteoarthritis (OA) is a common joint disease for which a safe and reliable treatment has yet to be developed. Here, we demonstrated the potential benefit of treatment with paeonol, a derivative of Paeonia suffruticosa, in the treatment and prevention of OA. Chondrogenic cell line ATDC5 cells were cultured with IL-1ß and the effects of paeonol were assessed through qRT-PCR, western blot analysis, MTT, ELISA, and NF-κB luciferase reporter gene assay. Our findings demonstrate a novel ability of paeonol to inhibit numerous factors of OA, including expressions of IL-6, TNF-α, NOX2, PTGS2, NUCB2/nesfatin-1, ICAM-1, VCAM-1, MMP-3/13, degradation of type II collagen, and NF-κB activation through the rescue of IκBα. Additionally, we assessed the effects of paeonol on cell viability to confirm its safety. These findings implicate a valuable potential role of paeonol in the treatment and prevention of OA.


Assuntos
Acetofenonas/farmacologia , Condrócitos/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Interleucina-1beta/farmacologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Proteólise/efeitos dos fármacos , Acetofenonas/uso terapêutico , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Ciclo-Oxigenase 2/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , NADPH Oxidase 2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteoartrite/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
14.
Int J Mol Sci ; 20(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185608

RESUMO

Neuroinflammation is characterized by the elevated expression of various inflammatory proteins, including matrix metalloproteinases (MMPs), induced by various pro-inflammatory mediators, which play a critical role in neurodegenerative disorders. Interleukin-1ß (IL-1ß) has been shown to induce the upregulation of MMP-9 through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-reactive oxygen species (ROS)-dependent signaling pathways. N-(2-cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2-2-difluoropropanamide (RTA 408), a novel synthetic triterpenoid, has been shown to possess anti-oxidant and anti-inflammatory properties in various types of cells. Here, we evaluated the effects of RTA 408 on IL-1ß-induced inflammatory responses by suppressing MMP-9 expression in a rat brain astrocyte (RBA-1) line. IL-1ß-induced MMP-9 protein and mRNA expression, and promoter activity were attenuated by RTA 408. The increased level of ROS generation in RBA-1 cells exposed to IL-1ß was attenuated by RTA 408, as determined by using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and CellROX. In addition, the inhibitory effects of RTA 408 on MMP-9 expression resulted from the suppression of the IL-1ß-stimulated activation of Pyk2 (proline-rich tyrosine kinase), platelet-derived growth factor receptor ß (PDGFRß), Akt, ROS, and mitogen-activated protein kinases (MAPKs). Pretreatment with RTA 408 attenuated the IL-1ß-induced c-Jun phosphorylation, mRNA expression, and promoter activity. IL-1ß-stimulated nuclear factor-κB (NF-κB) p65 phosphorylation, translocation, and promoter activity were also attenuated by RTA 408. Furthermore, IL-1ß-induced glial fibrillary acidic protein (GFAP) protein and mRNA expression, and cell migration were attenuated by pretreatment with RTA 408. These results provide new insights into the mechanisms by which RTA 408 attenuates IL-1ß-mediated inflammatory responses and exerts beneficial effects for the management of brain diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , NF-kappa B/metabolismo , Triterpenos/farmacologia , Animais , Astrócitos/metabolismo , Encéfalo/citologia , Linhagem Celular , Interleucina-1beta/farmacologia , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/genética , Ratos , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
15.
Eur J Pharmacol ; 859: 172481, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31228458

RESUMO

Osteoarthritis (OA) is a frequently seen arthropathy that features cartilage loss and destruction. Vanillic acid (VA), is a well-known flavonoid, which possesses various pharmacological activities. However, the effects of Vanillic acid on articular cartilage destruction and the pathogenesis of OA remain unknown. The present study observed that VA attenuated OA progression in vivo and vitro. VA inhibited the expression of inflammation responses, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs) and aggrecanase -2(ADAMTS5). Moreover, the major markers of hypertrophic chondrocytes such as Collagen X, Runt related transcription factor 2 (Runx2) and Vascular endothelial growth factor (VEGFA) were also reduced by VA. In addition, the interleukin-1ß (IL-1ß) -stimulated collagen 2 and aggrecan destruction were suppressed by VA. Moreover, VA concentration -dependently inhibited IL-1ß induced production of High-mobility group box 1 (HMGB1), a classic damage-associated molecular pattern (DAMP) molecule with strong pro-inflammatory effects in OA. Meanwhile, we revealed that VA suppressed the IL-1ß induced activation of MAPK and PI3K/AKT/NF-κB pathways. In vivo, VA alleviated osteoarthritis progression in a rat OA model. Collectively, our results demonstrate that VA could potentially be a new candidate for OA therapy.


Assuntos
Cartilagem/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ácido Vanílico/farmacologia , Animais , Cartilagem/metabolismo , Cartilagem/patologia , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Hipertrofia/patologia , Interleucina-1beta/farmacologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Ratos Sprague-Dawley , Ácido Vanílico/uso terapêutico
16.
Eur J Pharmacol ; 858: 172445, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31211985

RESUMO

Osteoarthritis (OA) is an age-related arthropathy which has been considered to be associated with inflammatory damage and cartilage degradation. Liquiritigenin (LG), the main bioactive component of the rhizomes of Glycyrrhiza uralensis, has exhibited promising anti-inflammatory and anti-oxidative potential in numerous inflammatory diseases. However, the effects of LG on OA remain unclear. In this study, the therapeutic effects as well as the underlying mechanisms of LG on interleukin-1ß (IL-1ß)-treated rat chondrocytes had been investigated. Our results showed that LG could inhibit the IL-1ß-induced expression of nitic oxide (NO) and prostaglandin E2 (PGE2). In consist with these findings, the IL-1ß-induced production of inducible nitic oxide synthase (iNOS) and cyclooxygenase-2 (COX2) could also be decreased by LG. Meanwhile, LG could suppress the IL-1ß-induced upregulation of cartilage matrix catabolic enzymes including aggrecanase-2 (ADAMTS5) and matrix metalloproteinases (MMPs). Besides, the IL-1ß-induced degradation of collagen II and aggrecan could be alleviated by LG. Moreover, LG prevented cartilage damage in IL-1ß-treated rat cartilage explants. Mechanistically, LG functioned by inhibiting mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways activation. In general, this study reveals the anti-inflammatory properties of LG on IL-1ß-treated rat chondrocytes and the possible mechanisms behind it, which may provide new ideas for OA therapy.


Assuntos
Anti-Inflamatórios/farmacologia , Cartilagem/patologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Flavanonas/farmacologia , Interleucina-1beta/farmacologia , Proteína ADAMTS5/metabolismo , Agrecanas/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Cartilagem/efeitos dos fármacos , Condrócitos/patologia , Colágeno Tipo II/metabolismo , Dinoprostona/metabolismo , Flavanonas/uso terapêutico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Metaloproteinases da Matriz/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
17.
Cells ; 8(6)2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207939

RESUMO

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide.


Assuntos
Diabetes Mellitus Experimental/patologia , Endotélio/patologia , Liraglutida/farmacologia , Mesoderma/patologia , Neointima/patologia , Adenilato Quinase/metabolismo , Animais , Artérias/efeitos dos fármacos , Artérias/lesões , Artérias/patologia , Biomarcadores/metabolismo , Endotélio/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Interleucina-1beta/farmacologia , Mesoderma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estreptozocina
18.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067826

RESUMO

The temporomandibular joint (TMJ), which differs anatomically and biochemically from hyaline cartilage-covered joints, is an under-recognized joint in arthritic disease, even though TMJ damage can have deleterious effects on physical appearance, pain and function. Here, we analyzed the effect of IL-1ß, a cytokine highly expressed in arthritic joints, on TMJ fibrocartilage-derived cells, and we investigated the modulatory effect of mechanical loading on IL-1ß-induced expression of catabolic enzymes. TMJ cartilage degradation was analyzed in 8-11-week-old mice deficient for IL-1 receptor antagonist (IL-1RA-/-) and wild-type controls. Cells were isolated from the juvenile porcine condyle, fossa, and disc, grown in agarose gels, and subjected to IL-1ß (0.1-10 ng/mL) for 6 or 24 h. Expression of catabolic enzymes (ADAMTS and MMPs) was quantified by RT-qPCR and immunohistochemistry. Porcine condylar cells were stimulated with IL-1ß for 12 h with IL-1ß, followed by 8 h of 6% dynamic mechanical (tensile) strain, and gene expression of MMPs was quantified. Early signs of condylar cartilage damage were apparent in IL-1RA-/- mice. In porcine cells, IL-1ß strongly increased expression of the aggrecanases ADAMTS4 and ADAMTS5 by fibrochondrocytes from the fossa (13-fold and 7-fold) and enhanced the number of MMP-13 protein-expressing condylar cells (8-fold). Mechanical loading significantly lowered (3-fold) IL-1ß-induced MMP-13 gene expression by condylar fibrochondrocytes. IL-1ß induces TMJ condylar cartilage damage, possibly by enhancing MMP-13 production. Mechanical loading reduces IL-1ß-induced MMP-13 gene expression, suggesting that mechanical stimuli may prevent cartilage damage of the TMJ in arthritic patients.


Assuntos
Artrite Juvenil/metabolismo , Condrócitos/efeitos dos fármacos , Interleucina-1beta/farmacologia , Côndilo Mandibular/metabolismo , Metaloproteinase 13 da Matriz/genética , Articulação Temporomandibular/metabolismo , Proteína ADAMTS4 , Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Animais , Células Cultivadas , Condrócitos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Interleucina-1beta/metabolismo , Côndilo Mandibular/patologia , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Estresse Mecânico , Suínos , Articulação Temporomandibular/patologia
19.
Pathol Res Pract ; 215(7): 152423, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31085006

RESUMO

OBJECTIVES: Expression of miR-671 was reported to be downregulated in articular cartilage of patients with OA compared to healthy individuals, indicating it may serve as potential biomarker for OA. However, the mechanism by which miR-671 regulates the progression of OA remains unclear. Here, we aimed to investigate the role of miR-671 in cartilage from patients with OA. METHODS: The expression of miR-671 and inflammation mediators in cartilage from patients with OA was analyzed by RT-PCR. In vitro, chondrocytes CHON-001 were stimulated with IL-1ß for 24 h for OA model establishment. Protein expression of MMP-13, aggrecan, and collagen II was measured by western blot. In vivo, the severity of OA in mice was determined by histological analysis. RESULTS: We found that the level of miR-671 was downregulated in OA tissues, plasma and IL-1ß treated CHON-001 cells, compared with control. MiR-671 mimics ameliorated IL-1ß-induced proliferation inhibition and apoptosis stimulation, as well as decreased protein levels of collagen II and aggrecan in CHON-001 cells. In vivo study showed miR-671 mimics alleviated the progression of OA in mice. CONCLUSION: These results indicated miR-671 play an important role during the pathogenesis of OA. Therefore, miR-671 may serve as a potential therapeutic target for the treatment of OA.


Assuntos
Artrite Experimental/patologia , Cartilagem Articular/patologia , Condrócitos/metabolismo , MicroRNAs/metabolismo , Osteoartrite/patologia , Agrecanas/metabolismo , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Colágeno Tipo II/metabolismo , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Interleucina-1beta/farmacologia , Camundongos , MicroRNAs/genética , Osteoartrite/genética , Osteoartrite/metabolismo
20.
Artif Cells Nanomed Biotechnol ; 47(1): 1995-2002, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31106593

RESUMO

Retinal endothelial cells (RECs) are involved in many ocular diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. Salicin is the major ingredient of willow bark extract, and it has been shown to be a potent anti-inflammatory agent. We aim to explore whether salicin has a vascular protective effect in RECs. Our data indicate that the presence of salicin in RECs culture media ameliorates interleukin-1ß (IL-1ß)-induced cellular reactive oxygen species (ROS) production and NADPH oxidase 4 (NOX-4) expression. At the cellular level, salicin attenuates IL-1ß-induced mitochondrial injury as revealed by its preservation on mitochondrial membrane potential (MMP). Furthermore, salicin inhibits IL-1ß-induced production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), vascular adhesion molecules such as intercellular cell adhesion molecule-1 (iCAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and high-mobility group protein 1 (HMGB-1). On the other hand, salicin recovers IL-1ß-induced reduction of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) release. The presence of salicin significantly reduces the IL-1ß-induced release of lactate dehydrogenase (LDH), indicating that it mitigates cytokine caused cytotoxicity. Mechanistically, we show that salicin suppresses IL-1ß-induced activation of the nuclear factor-kappa B (NF-κB) signaling as revealed by its suppression on nuclear p65 protein and transfected NF-κB promoter. Collectively, our study demonstrates by multiple facets of its mechanisms that salicin is a protective agent in retinal endothelial cells. These results imply its potential use in therapeutic usage of retinal disease.


Assuntos
Álcoois Benzílicos/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Glucosídeos/farmacologia , Interleucina-1beta/farmacologia , Retina/citologia , Vasos Sanguíneos/citologia , Linhagem Celular , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína HMGB1/biossíntese , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
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