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1.
PLoS Pathog ; 16(5): e1008516, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32413091

RESUMO

Lyme disease, caused by Borrelia burgdorferi, B. afzelii and B. garinii, is a chronic, multi-systemic infection and the spectrum of tissues affected can vary with the Lyme disease strain. For example, whereas B. garinii infection is associated with neurologic manifestations, B. burgdorferi infection is associated with arthritis. The basis for tissue tropism is poorly understood, but has been long hypothesized to involve strain-specific interactions with host components in the target tissue. OspC (outer surface protein C) is a highly variable outer surface protein required for infectivity, and sequence differences in OspC are associated with variation in tissue invasiveness, but whether OspC directly influences tropism is unknown. We found that OspC binds to the extracellular matrix (ECM) components fibronectin and/or dermatan sulfate in an OspC variant-dependent manner. Murine infection by isogenic B. burgdorferi strains differing only in their ospC coding region revealed that two OspC variants capable of binding dermatan sulfate promoted colonization of all tissues tested, including joints. However, an isogenic strain producing OspC from B. garinii strain PBr, which binds fibronectin but not dermatan sulfate, colonized the skin, heart and bladder, but not joints. Moreover, a strain producing an OspC altered to recognize neither fibronectin nor dermatan sulfate displayed dramatically reduced levels of tissue colonization that were indistinguishable from a strain entirely deficient in OspC. Finally, intravital microscopy revealed that this OspC mutant, in contrast to a strain producing wild type OspC, was defective in promoting joint invasion by B. burgdorferi in living mice. We conclude that OspC functions as an ECM-binding adhesin that is required for joint invasion, and that variation in OspC sequence contributes to strain-specific differences in tissue tropism displayed among Lyme disease spirochetes.


Assuntos
Borrelia burgdorferi/metabolismo , Dermatan Sulfato/metabolismo , Matriz Extracelular/metabolismo , Artropatias/metabolismo , Articulações/metabolismo , Doença de Lyme/metabolismo , Animais , Antígenos de Bactérias , Aderência Bacteriana , Proteínas da Membrana Bacteriana Externa , Borrelia burgdorferi/genética , Borrelia burgdorferi/patogenicidade , Dermatan Sulfato/genética , Matriz Extracelular/genética , Matriz Extracelular/microbiologia , Matriz Extracelular/patologia , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Artropatias/genética , Artropatias/microbiologia , Artropatias/patologia , Articulações/microbiologia , Articulações/patologia , Doença de Lyme/genética , Doença de Lyme/microbiologia , Doença de Lyme/patologia , Camundongos , Camundongos SCID , Mutação , Especificidade de Órgãos
2.
Nat Rev Rheumatol ; 16(5): 268-281, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32273577

RESUMO

Research into the molecular genetics of osteoarthritis (OA) has been substantially bolstered in the past few years by the implementation of powerful genome-wide scans that have revealed a large number of novel risk loci associated with the disease. This refreshing wave of discovery has occurred concurrently with epigenetic studies of joint tissues that have examined DNA methylation, histone modifications and regulatory RNAs. These epigenetic analyses have involved investigations of joint development, homeostasis and disease and have used both human samples and animal models. What has become apparent from a comparison of these two complementary approaches is that many OA genetic risk signals interact with, map to or correlate with epigenetic mediators. This discovery implies that epigenetic mechanisms, and their effect on gene expression, are a major conduit through which OA genetic risk polymorphisms exert their functional effects. This observation is particularly exciting as it provides mechanistic insight into OA susceptibility. Furthermore, this knowledge reveals avenues for attenuating the negative effect of risk-conferring alleles by exposing the epigenome as an exploitable target for therapeutic intervention in OA.


Assuntos
Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Articulações/metabolismo , Osteoartrite/genética , Alelos , Animais , Condrócitos/metabolismo , Metilação de DNA/genética , Expressão Gênica , Código das Histonas/genética , Homeostase/genética , Homeostase/fisiologia , Humanos , Articulações/crescimento & desenvolvimento , Camundongos , Modelos Animais , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Ribonucleico/genética , Fatores de Risco
3.
Chem Biol Interact ; 319: 108984, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061742

RESUMO

OBJECTIVES: As one of the main active ingredients of Chinese herbal medicine Andrographis paniculate, andrographolide is used in domestic clinical treatment for respiratory infections and inflammation. This study was designed to investigate the effects of andrographolide as an antioxidant on the level of oxidative stress, neutrophil accumulation and infiltration in joints and synovial tissue of arthritis rats induced by complete freund's adjuvant. METHODS: A rat model of rheumatoid arthritis was induced by subcutaneous injection of complete Freund's adjuvant in the footpad. The model was established 14 days after induction. The treatment was performed from 14th day to 35th day with different doses of andrographolide (25, 50, 100 mg/kg) and positive control methotrexate (3 mg/kg). The effects of andrographolide on oxidative stress, neutrophil accumulation and infiltration were measured by the paw swelling, arthritis score, the hot plate test, biochemical analysis, and histology. RESULTS: The medium and high-dose andrographolide (50, 100 mg/kg) group declined the levels of tumor necrosis factor-α, interleukin-6 and CXC chemokine ligand2, articular elastase and myeloperoxidase, and increased the levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione. The activity of malondialdehyde and nitrite/nitrate in andrographolide (50, 100 mg/kg) group was weakened than the model group. The degree of swelling and arthritis score of andrographolide group was lower than the model group. The results of hot plate test showed that high dose of andrographolide significantly improved the anti-injury ability of rats; Radiological and histological results showed that the joint osteoporosis, inflammatory cell infiltration, synovial hyperplasia and other phenomena in the andrographolide group were significantly improved. CONCLUSIONS: Andrographolide acts as a protective agent for the treatment of complete freund's adjuvant induced rheumatoid arthritis by inhibiting lipid peroxidation and nitrite/nitrate levels in a dose-dependent manner, enhancing antioxidant enzyme activity, reducing levels of chemokines and inflammatory factors, preventing neutrophil accumulation and infiltration.


Assuntos
Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Diterpenos/farmacologia , Adjuvante de Freund/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Catalase/metabolismo , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Glutationa/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Masculino , Metotrexato/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Ann Rheum Dis ; 79(1): 112-122, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31662319

RESUMO

OBJECTIVES: This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis. METHODS: Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and µCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis. RESULTS: R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice. CONCLUSIONS: Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.


Assuntos
Cartilagem Articular/patologia , Quimiocina CXCL12/metabolismo , Macrófagos/metabolismo , Osteoartrite/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores CXCR/genética , Sinovite/genética , Animais , Quimiotaxia/genética , Marcha , Regulação da Expressão Gênica , Humanos , Articulações/metabolismo , Articulações/patologia , Camundongos , Camundongos Knockout , Monócitos/metabolismo , Células Mieloides , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores CXCR/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Sinovite/patologia
5.
Immunology ; 159(1): 109-120, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606893

RESUMO

Serpins are evolutionarily conserved serine protease inhibitors that are widely distributed in animals, plants and microbes. In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin-a and HlSerpin-b, from the hard tick Haemaphysalis longicornis of China. Recombinant HlSerpin-a and HlSerpin-b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin-a and HlSerpin-b suppressed the expression of inflammatory cytokines such as TNF-α, interleukin (IL)-6 and IL-1ß from lipopolysaccharide-stimulated mouse bone-marrow-derived macrophages (BMDMs) or mouse bone-marrow-derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin-a, named SA-RCL, showed similar biological activities as HlSerpin-a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full-length HlSerpin-a and SA-RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA-RCL are dependent on their protease inhibitory activity. Finally, we showed that both full-length HlSerpins and SA-RCL can relieve the joint swelling and inflammatory response in collagen-induced mouse arthritis models. These results suggested that HlSerpin-a and HlSerpin-b are two functional arthropod serpins, and the minimal reactive peptide SA-RCL is a potential candidate for drug development against inflammatory diseases.


Assuntos
Artrite Experimental/prevenção & controle , Proteínas de Artrópodes/farmacologia , Células Dendríticas/efeitos dos fármacos , Imunossupressores/farmacologia , Ixodidae/metabolismo , Articulações/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Serpinas/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/isolamento & purificação , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunossupressores/isolamento & purificação , Ixodidae/genética , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Conformação Proteica , Células RAW 264.7 , Saliva/metabolismo , Serpinas/genética , Serpinas/isolamento & purificação , Relação Estrutura-Atividade
6.
Probl Radiac Med Radiobiol ; 24: 322-334, 2019 Dec.
Artigo em Inglês, Ucraniano | MEDLINE | ID: mdl-31841477

RESUMO

OBJECTIVE: establishing the types and frequency of disembriogenetic stigma in children with joint hypermobility given the clinical and laboratory features, genetic component and endocrine regulation of these disorders in a late period upon the accident. MATERIALS AND METHODS: Children (n = 109) inhabiting the radiologically contaminated territories and having the connective tissue dysplasia (CTD) signs were involved in the study. Diseases in family history, ossalgia complaints, fractures in a personal history, bone disembriogenetic stigma, joint hypermobility, type of somatic diseases, blood serum biochemical parameters (namely calcium, alkaline phosphatase, total protein, cholesterol, creatinine, iron, ferritin content), serum cortisol, free thyroxine, pituitary thyroid-stimulating hormone (TSH) levels, free amino acid composition in urine and radiation dose were considered. RESULTS: Radiation doses in children having the CTD ranged from (0.37 ± 0.11) mSv to (0.56 ± 0.10) mSv with no difference from that in those without CTD. Joint hypermobility (JHM) correlated with cancer in family history (rs = 0.53) and lower extremity varicose vein disease (rs = 0.40) (p < 0.05). Incidence of ossalgia, easy fatigability, and bone fractures was higher in children with CTD. Anomalies of the dentofacial system were first in line (38.5 %) in these children. Proportion of children with grade II JHM and platypodia was lower (rs = 0.42), but with lower extremity deformations was higher (rs = 0.68) (p < 0.05) vs. in the control group. Iron and ferritin deficiencies both with lymphocytosis were more common in children with CTD than in the comparison group (p < 0.05). The increased content of oxyproline, lysine, proline both with glycine deficiency were detected in children having the CTD, i.e. an imbalance of amino acids from the collagen content was observed featuring a predominance of catabolic processes over anabolic ones. There was a direct correlation between the TSH level and the JHM grade (rs = 0.49), although the values of hormone concentration in these children did not exceed the reference range (maximum values were 3.3 µIU/ml). CONCLUSIONS: The revealed abnormalities in amino acid content, ferrokinetics, and thyroid function indices can affect the collagen formation, organic matrix structure of bone tissue and significantly deregulate the hemato- poiesis. The later can underlie the pathways of haematologic malignancy development.


Assuntos
Acidente Nuclear de Chernobyl , Fadiga/fisiopatologia , Fraturas Ósseas/fisiopatologia , Instabilidade Articular/fisiopatologia , Exposição à Radiação/efeitos adversos , Fosfatase Alcalina/sangue , Aminoácidos/urina , Cálcio/sangue , Estudos de Casos e Controles , Criança , Colesterol/sangue , Creatinina/sangue , Fadiga/sangue , Fadiga/etiologia , Fadiga/patologia , Feminino , Ferritinas/sangue , Fraturas Ósseas/sangue , Fraturas Ósseas/etiologia , Fraturas Ósseas/patologia , Humanos , Hidrocortisona/sangue , Ferro/sangue , Instabilidade Articular/sangue , Instabilidade Articular/etiologia , Instabilidade Articular/patologia , Articulações/metabolismo , Articulações/patologia , Articulações/efeitos da radiação , Masculino , Doses de Radiação , Índice de Gravidade de Doença , Tireotropina/sangue , Tiroxina/sangue
7.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3576-3581, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602925

RESUMO

To detect the concentration of triptolide in skin and joint after percutaneous administration,an HPLC-MS/MS method and skin and joint micro-dialysis( MD) method of triptolide were established in this study. The separation was achieved on triple quadrupole( AB QTRAP4500) and phenomenex-C18( 4. 6 mm×150 mm,5 µm,luna) column with acetonitrile-water with 0. 1% formic acid( 65 ∶35) as the mobile phase at a flow rate of 0. 7 m L·min-1. An electrospray ionization( ESI) source was applied and operated in the positive multiple reaction monitoring( MRM) mode. The fragment ion for triptolide was m/z 361. 1→145. 0. The effects of different perfusion [Ringer's,PBS( p H 7. 4),30% ethanol saline]drug concentrations and flow rates on the recovery rate,as well as the relationship between the recovery rate and the loss rate were determined by incremental( dialysis) and reduction( retrodialysis) methods.The reduction method was applied in the in vivo study to investigate and determine the stability of the probe recovery rate in 10 h. The results of HPLC-MS/MS detection method conformed to the requirements of biological samples. The perfusion fluid was 30% ethanol saline. The recovery rate of skin and joint probes in vitro of triptolide increased within the flow rate of 0. 5-2. 5 µL·min-1. In order to increase the timeliness of data and the accuracy,the flow rate was determined to be 1 µL·min-1,and the sample interval was determined to be 0. 5 h. The recovery rate of triptolide in skin and joint probes in vitro and the loss rate were stable and equal despite of change of triptolide concentration within 10-200 µg·L-1. This indicated that the effect of drug concentration on the MD probe recovery rate was small,and the recovery rate could be replaced by the loss rate. The loss rate in vivo using MD method was measured at 10 h,indicating that the transfer rate of triptolide was stable within 10 h. The established method of triptolide in MD and HPLC-MS/MS can be applied to investigate the kinetic in skin and joint after percutaneous administration of triptolide.


Assuntos
Diterpenos/farmacocinética , Articulações/metabolismo , Fenantrenos/farmacocinética , Pele/metabolismo , Cromatografia Líquida de Alta Pressão , Compostos de Epóxi/farmacocinética , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
8.
Adv Mater ; 31(46): e1904535, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31549776

RESUMO

Osteoarthritis (OA) is a common joint degenerative disease that causes pain, joint damage, and dysfunction. External hyaluronic acid (HA) supplement is a common method for the management of osteoarthritis which requires multi-injections. It is demonstrated that biodegradable mesoporous silica nanoparticles successfully deliver an enzyme, hyaluronan synthase type 2 (HAS2), into synoviocytes from the temporomandibular joint (TMJ) and generate endogenous HA with high molecular weights. In a rat TMJ osteoarthritis inflammation model, this strategy promotes endogenous HA production and inhibits the synovial inflammation of OA for more than 3 weeks with one-shot administration. Such nanotherapy also helps repairing the bone defects in a rat OA bone defect model.


Assuntos
Hialuronan Sintases/farmacologia , Ácido Hialurônico/biossíntese , Articulações/efeitos dos fármacos , Articulações/metabolismo , Nanomedicina/métodos , Osteoartrite/tratamento farmacológico , Animais , Linhagem Celular , Humanos , Hialuronan Sintases/química , Hialuronan Sintases/metabolismo , Hialuronan Sintases/uso terapêutico , Ácido Hialurônico/química , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Peso Molecular , Nanopartículas/química , Osteoartrite/metabolismo , Osteoartrite/patologia , Porosidade , Ratos , Dióxido de Silício/química , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Sinoviócitos/patologia
9.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491879

RESUMO

The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Medicamentos Biossimilares/uso terapêutico , Articulações/patologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Artrite Reumatoide/metabolismo , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/efeitos adversos , Humanos , Articulações/metabolismo , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Inibidores do Fator de Necrose Tumoral/efeitos adversos
10.
Artif Cells Nanomed Biotechnol ; 47(1): 3391-3398, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31394949

RESUMO

Nimbolide, a triterpenoid isolated from flower of neem tree possess various therapeutic properties. The objective of the study was to assess the anti-arthritic activity of nimbolide in arthritis induced rats. Nimbolide (20 mg/kg per day) was given orally to arthritic rats induced with Complete Freund's Adjuvant and changes in paw volume, body weight, organ indices (thymus and spleen), arthritic score, biochemical parameters and proinflammatory cytokines levels were determined. Histopathological analysis was also performed. Western blot analysis was also performed. Rats treated with nimbolide displayed marked reduction in arthritic score, organ indices, volume of paw, edema formation, along with substantial enhancement in body weight. Histopathological findings showed significant reduction in destruction of joints and inflammation following nimbolide treatment. The protective action of arthritic rats treated with nimbolide was also substantiated by molecular and biochemical studies. The results of the study show that nimbolide treatment has markedly enhanced health and reduced inflammation via lessening the proinflammatory cytokines expression in arthritic rats. Hence, nimbolide may be used as a potent therapeutic drug in treating rheumatoid arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Adjuvante de Freund/efeitos adversos , Limoninas/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Peso Corporal/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase I-kappa B/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Limoninas/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos
11.
Nutrients ; 11(7)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262076

RESUMO

Rice porridge containing Allium fistulosum (Welsh onion) root water extract (RAFR) has anti-inflammatory bioactive compounds. We examined whether the long-term administration of rice porridge with RAFR would prevent or delay the progression of osteoarthritis and menopausal symptoms in estrogen-deficient animals by ovariectomy. The rats consumed 40% fat energy diets containing 250 mg RAFR (rice: Allium fistulosum root = 13:1)/kg body weight (bw) (OVX-OA-RAFR-Low), 750 mg RAFR/kg bw (OVX-OA-RAFR-High) and 750 mg starch and protein/kg bw(OVX), respectively. After consuming the assigned diets for eight weeks, monoiodoacetate (OVX-OA) or saline (OVX) were injected into the knee joints of the rats for an additional three weeks. Sham rats were administered saline injections (normal-control). OVX-OA-RAFR improved oral glucose tolerance and also protected against decreases in bone mineral density and lean body mass in the legs and increases in fat mass in the abdomen, compared to the OVX and OVX-OA. OVX-OA-RAFR improved swelling and limping scores, normalized weight distribution between the osteoarthritic and normal limbs, and increased maximum running speeds compared to the OVX-OA. The OVX-OA deteriorated the articular cartilage by reducing the articular matrix and bone loss in the knee joint and it prevented knee joint deterioration when compared to the OVX. The improvement in osteoarthritis symptoms in OVX-OA-RAFR decreased the mRNA expression of matrix metallo-proteinase-1 and matrix metalloproteinase-13, tumor necrosis factor-α, and interleukin-1ß and interleukin-6 in the articular cartilage compared to OVX-OA rats. In conclusions, RAFR is effective in treating osteoarthritis symptoms and it may be used for a therapeutic agent in osteoarthritis-induced menopausal women.


Assuntos
Artrite Experimental/dietoterapia , Comportamento Animal , Glicemia/metabolismo , Densidade Óssea , Fêmur/fisiopatologia , Articulações/fisiopatologia , Cebolas , Oryza , Extratos Vegetais/farmacologia , Raízes de Plantas , Ração Animal , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Biomarcadores/sangue , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Ingestão de Energia , Feminino , Fêmur/metabolismo , Fêmur/patologia , Articulações/metabolismo , Articulações/patologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Atividade Motora , Valor Nutritivo , Ratos Sprague-Dawley , Fatores de Tempo
12.
ACS Appl Mater Interfaces ; 11(28): 24984-24998, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31264830

RESUMO

The aim of this study was to design a click-crosslinked hyaluronic acid (HA) (Cx-HA) depot via a click crosslinking reaction between tetrazine-modified HA and trans-cyclooctene-modified HA for direct intra-articular injection into joints affected by rheumatoid arthritis (RA). The Cx-HA depot had significantly more hydrogel-like features and a longer in vivo residence time than the HA depot. Methotrexate (MTX)-loaded Cx-HA (MTX-Cx-HA)-easily prepared as an injectable formulation-quickly formed an MTX-Cx-HA depot that persisted at the injection site for an extended period. In vivo MTX biodistribution in MTX-Cx-HA depots showed that a high concentration of MTX persisted at the intra-articular injection site for an extended period, with little distribution of MTX to normal tissues. In contrast, direct intra-articular injection of MTX alone or MTX-HA resulted in rapid clearance from the injection site. After intra-articular injection of MTX-Cx-HA into rats with RA, we noted the most significant RA reversal, measured by an articular index score, increased cartilage thickness, extensive generation of chondrocytes and glycosaminoglycan deposits, extensive new bone formation in the RA region, and suppression of tumor necrosis factor-α or interleukin-6 expression. Therefore, MTX-Cx-HA injected intra-articularly persists at the joint site in therapeutic MTX concentrations for an extended period, thus increasing the duration of RA treatment, resulting in an improved relief of RA.


Assuntos
Artrite Reumatoide , Condrócitos , Hidrogéis , Articulações , Metotrexato , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Glicosaminoglicanos/metabolismo , Humanos , Hidrogéis/síntese química , Hidrogéis/química , Hidrogéis/farmacocinética , Hidrogéis/farmacologia , Injeções Intra-Articulares , Interleucina-6/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Metotrexato/química , Metotrexato/farmacocinética , Metotrexato/farmacologia , Camundongos , Células RAW 264.7 , Ratos , Distribuição Tecidual , Fator de Necrose Tumoral alfa/metabolismo
13.
Acta Histochem ; 121(6): 742-749, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31279484

RESUMO

Rheumatoid arthritis (RA) is a complicated chronic multisystem autoimmune disease, wherein the inflammatory cascade leads to vasospasm and osteoclastogenesis, which ultimately results in bone and cartilage destruction. In this study, we investigated the expression and localization of the alpha-7 nicotinic receptor (α7nAchR) gene CHRNA7 in the heart, liver, spleen, lung, kidney, and joints of the collagen-induced arthritis (CIA) rat model. The CHRNA7 mRNA and protein expression levels in these tissues of rats from CIA and normal groups were analyzed via real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. The cellular localization of CHRNA7 protein was determined via immunohistochemistry (IHC) assays. CHRNA7 was expressed at varying levels in different tissues of rats from the groups, among which joints showed significantly higher CHRNA7 expression levels than other tissues (P < 0.05). CIA rats had significantly higher CHRNA7 expression levels in the spleen and joints than the control group rats (P < 0.05). Positive expression signals for CHRNA7 were detected in various tissues of CIA and control group rats, among which strong positive signals were detected in joint fibroblast-like synoviocytes (FLSs), endothelial cells, stromal cells, and macrophages. Our results further confirmed the involvement of the CAP in the onset and development of inflammatory responses in RA, suggesting that CHRNA7 may be a new therapeutic target for RA. This study is of great clinical and theoretical significance for understanding the differential expression of CHRNA7 in various tissues and cholinergic anti-inflammatory pathway (CAP)-targeted treatment of RA.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Regulação da Expressão Gênica , Articulações/metabolismo , Sinoviócitos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/biossíntese , Animais , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Feminino , Articulações/patologia , Ratos , Ratos Wistar , Sinoviócitos/patologia
14.
PLoS One ; 14(7): e0219980, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31339920

RESUMO

There is an increasing demand for accurate endotyping of patients according to their pathogenesis to allow more targeted treatment. We explore a combination of blood-based joint tissue metabolites (neoepitopes) to enable patient clustering through distinct disease profiles. We analysed data from two RA studies (LITHE (N = 574, follow-up 24 and 52 weeks), OSKIRA-1 (N = 131, follow-up 24 weeks)). Two osteoarthritis (OA) studies (SMC01 (N = 447), SMC02 (N = 81)) were included as non-RA comparators. Specific tissue-derived neoepitopes measured at baseline, included: C2M (cartilage degradation); CTX-I and PINP (bone turnover); C1M and C3M (interstitial matrix degradation); CRPM (CRP metabolite) and VICM (macrophage activity). Clustering was performed to identify putative endotypes. We identified five clusters (A-E). Clusters A and B were characterized by generally higher levels of biomarkers than other clusters, except VICM which was significantly higher in cluster B than in cluster A (p<0.001). Biomarker levels in Cluster C were all close to the median, whilst Cluster D was characterised by low levels of all biomarkers. Cluster E also had low levels of most biomarkers, but with significantly higher levels of CTX-I compared to cluster D. There was a significant difference in ΔSHP score observed at 52 weeks (p<0.05). We describe putative RA endotypes based on biomarkers reflecting joint tissue metabolism. These endotypes differ in their underlining pathogenesis, and may in the future have utility for patient treatment selection.


Assuntos
Artrite Reumatoide/sangue , Articulações/metabolismo , Adulto , Idoso , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Biomarcadores/sangue , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cartilagem/metabolismo , Cartilagem/patologia , Feminino , Humanos , Articulações/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade
15.
Eur J Pharmacol ; 859: 172558, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325437

RESUMO

Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) is related to inflammation. In this study, we investigated the function of PSTPIP2 in adjuvant-induced arthritis (AIA) by using adeno-associated virus (AAV) to overexpress PSTPIP2 in rat. AIA rats were developed by injecting Lewis rats with complete Freund's adjuvant (CFA) on day 0. AAV-empty or AAV-PSTPIP2, or PBS was administered intraarticularly into each knee joint on day 8 postinduction. All animals were killed at day 18 after adjuvant injection. WB was used to detect the expression of PSTPIP2 in rat synovial tissues. Fluorescence microscopy showed the transduction efficiency in synovial tissue. The morphology of arthritic joints was examined by HE, safranin O/fast green, or Toluidine blue staining. The bone destruction was examined via X-ray and micro-CT analysis. Immunohistochemical analysis or TRAP staining were used to investigate the role of PSTPIP2 in osteoclasts and the expression of PSTPIP2 in synovial tissue. RT-qPCR and ELISA were used to examine the expression of pro-inflammatory cytokines in synovial tissue or serum. AIA rats were found to have decreased PSTPIP2 expression and AIA-associated bone loss and inflammatory infiltration. We showed that administration of AAV-PSTPIP2 before arthritis onset significantly reduces the severity of AIA. PSTPIP2 was highly expressed in synovial cells. In addition, inflammatory responses and the number of osteoclasts were reduced with AAV-PSTPIP2 treatment. These findings demonstrate that PSTPIP2 may improve the severity of AIA by inhibiting the function of fibroblast-like synoviocytes, suppressing inflammation and reducing the number of osteoclasts.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Articulações/patologia , Animais , Contagem de Células , Articulações/metabolismo , Osteoclastos/patologia , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Ratos
16.
Toxicol Lett ; 314: 18-26, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299270

RESUMO

Epidemiological investigations indicate that effects related to prenatal adverse environments on the organs of the offspring could continue to adulthood. This study intends to confirm that prenatal nicotine exposure (PNE) increases the susceptibility of osteoarthritis (OA) in the male offspring, and to explore the potential intrauterine programming mechanism. During pregnancy, rats were divided into a PNE group and a control group. After birth, rats were given a high-fat diet for 6 months and long-distance running for 6 weeks. The rats were euthanized at 18 months after birth (PM18) and on gestational day 20 (GD20), respectively. Knee joints were collected for histochemistry, immunohistochemistry, and quantitative polymerase chain reaction (qPCR) assays. Histological analyses and the Mankin's score showed increased cartilage destruction and accelerated OA progression in adult offspring from the PNE group. Immunohistochemistry results showed decreased expression of transforming growth factor beta (TGFß) signaling pathway. Furthermore, the expression of apoptosis factors (caspase-3 and caspase-8), inflammatory factors [interleukin (IL)-1, IL-6] and matrix degradation enzymes [matrix metalloproteinase (MMP)-3, MMP-13] were also significantly increased. Traced back to the intrauterine period, it was found that the number of chondrocytes and the contents of Col2A1 and aggrecan in the matrix in the PNE group were decreased. And, the expression of the TGFß signaling pathway was inhibited. These results suggested that PNE enhanced the susceptibility of OA in male elderly offspring rats by down-regulating TGFß signaling, which increased articular cartilage local inflammation, matrix degradation, and cell apoptosis. This study confirmed the developmental origin of OA, and clarified the congenital and the living environment impact on the occurrence and development of OA. Our findings provide a theoretical and experimental basis for OA early prevention.


Assuntos
Articulações/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Osteoartrite/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fatores Etários , Agrecanas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Condrogênese/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Feminino , Idade Gestacional , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Exposição Materna , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Gravidez , Ratos Wistar , Fatores de Risco , Fatores Sexuais
17.
Pharmacology ; 104(3-4): 187-195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31344704

RESUMO

BACKGROUND/AIMS: Tangeretin (TAN), a major phytochemical in tangerine peels and an important Chinese herb, has multiple biological properties, especially antioxidative and anti-inflammatory effects. However, the mechanisms remain unclear. Based on these findings, the aim of the present study was to assess the antioxidant and anti-inflammatory properties of TAN in bovine type II collagen-induced arthritis rats. METHODS: TAN (50 mg/kg) was given orally once daily for 14 days. The effects of treatment were evaluated by biochemical assay (articular elastase, myeloperoxidase, end products of lipid peroxidation [MDA], antioxidant enzyme, such as superoxide dismutase, catalase, glutathione), nitric oxide, and inflammatory cytokines (interleukin-1ß [IL-1ß], -IL-10, tumor necrosis factor-alpha [TNF-α], interferon-γ [IFN-γ], and prostaglandin E2 [PGE2]). The protective effects of TAN against rheumatoid arthritis (RA) were evident from the decrease in arthritis scoring. Furthermore, the Nrf-2 signaling pathway was assessed to illustrate the molecular mechanism. RESULTS: TAN had therapeutic effects on RA by decreasing the oxidative stress damage and regulating inflammatory cytokine expression, including suppression of the accumulation of MDA products, decreasing the IL-1ß, TNF-α, IFN-γ, and PGE2 levels, enhancing the IL-10 and the activity of antioxidant enzymes, which was through upregulating Nrf-2 signaling pathway. CONCLUSION: TAN might have potential as a therapeutic agent for the treatment of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Colágeno/farmacologia , Flavonas/farmacologia , Inflamação/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Artrite Experimental/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Catalase , Citocinas/metabolismo , Dinoprostona/metabolismo , Glutationa/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
Int J Rheum Dis ; 22(7): 1247-1254, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155849

RESUMO

AIM: The purpose of our investigation is to evaluate the anti-arthritic potential of isolated rosmarinic acid from the rind of Punica granatum. METHOD: Rosmarinic acid was isolated by bioactivity-guided isolation from butanolic fraction of Punica granatum and acute toxicity of rosmarinic acid was carried out. The experiment was conducted at doses of 25 and 50 mg/kg, in Freund's complete adjuvant (FCA)-induced arthritic rats. Various parameters, that is arthritic score, paw volume, thickness of paw, hematological, antioxidant and inflammatory parameters such as glutathione (GSH), superoxide dismutase (SOD), malonaldehyde (MDA) and tumor necrosis factor-α (TNF-α) were also estimated. RESULTS: Rosmarinic acid significantly decreased the arthritic score, paw volume, joint diameter, white blood cell count and erythrocyte sedimentation rate. It also significantly increased body weight, hemoglobin and red blood cells. The significantly decreased levels of TNF-α were observed in treated groups as compared to arthritic control rats (P < 0.001). At the same time antioxidant parameters (like GSH and SOD) were increased significantly while levels of MDA were significantly decreased (P < 0.001). CONCLUSION: The outcome of the present research concludes that rosmarinic acid showed significant anti-arthritic potential in FCA-induced arthritis in Wistar rats. This study represented the therapeutic role of rosmarinic acid from Punica granatum for the management of arthritis/rheumatoid arthritis/osteoarthritis and related inflammatory complications with negligible side effects which was still far from complete mitigation with available conventional medicines.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/prevenção & controle , Cinamatos/farmacologia , Depsídeos/farmacologia , Adjuvante de Freund , Articulações/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Glutationa/metabolismo , Mediadores da Inflamação/sangue , Articulações/metabolismo , Articulações/patologia , Malondialdeído/metabolismo , Ratos Wistar , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/sangue
19.
Inflammopharmacology ; 27(4): 845-856, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165333

RESUMO

Previously, ginsenoside metabolite compound K (C-K) was able to reduce B cell proliferation and serum anti-type II collagen (anti-CII) antibody to normal levels in mice with collagen-induced arthritis (CIA); however, the mechanism by which C-K restores B cell balance is unclear. In the present work, C-K treatment not only alleviated the polyarthritis index, swollen joint count, pathological scores of spleen and joints, spleen index, B cell proliferation and the level of serum antibodies (IgG1, IgG2a and anti-collagen II), but C-K treatment also restored B cell subsets including regulatory B cells, plasma cells, memory B cells, mature B cells, and follicular B cells in CIA mice. Interestingly, C-K did not change the expression level of immunoglobulin D-type B-cell receptor (IgD-BCR) but promoted IgD-BCR endocytosis. C-K treatment enhanced ß-arrestin1 expression, facilitating the colocalization between IgD and ß-arrestin1, as well as colocalization between IgD and adaptor protein 2 (AP2). Inhibition of the ß-arrestin1-AP2 interaction with barbadin significantly reduced the ability of C-K to attenuate IgD-BCR plasma membrane localization. These results taken together depict that C-K ameliorates CIA in part by inhibiting B cell activation through the triggering of IgD-BCR internalization in a ß-arrestin1-AP2 dependent manner.


Assuntos
Artrite Experimental/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Imunoglobulina D/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Complexo 2 de Proteínas Adaptadoras/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Linfócitos B/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Colágeno/farmacologia , Imunoglobulina G/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Baço/efeitos dos fármacos , Baço/metabolismo , beta-Arrestina 1/metabolismo
20.
PLoS One ; 14(6): e0218090, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31173610

RESUMO

BACKGROUND: Sphingosine-1-phosphate receptor 3 (S1P3) is one of five receptors for sphingosine-1-phosphate (S1P). S1P/S1P3 signaling is involved in numerous physiological and pathological processes including bone metabolism, sepsis, cancer, and immunity. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) are activated by several factors and promote abundant proinflammatory cytokine production and bone destruction. The aim of this study was to investigate whether S1P3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs. METHODS: Wild-type (WT) and S1P3 knockout (S1P3-KO) collagen-induced arthritis (CIA) mice were evaluated with respect to clinical and histological disease severity, along with the levels of anti-collagen antibodies and expression of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). S1P3 expression in the synovium was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. FLSs isolated from CIA mice were activated with TNFα and S1P3 expression was analyzed by real-time RT-PCR. The role of S1P/S1P3 signaling in activated and non-activated FLSs was investigated by measuring cell proliferation and cyto/chemokine production by real-time RT-PCR and/or enzyme-linked immunosorbent assay. RESULTS: Clinical and histological scores, and synovial IL-6 expression were significantly lower in S1P3-KO mice with CIA than in WT mice. Arthritic synovia had higher S1P3 expression than intact synovia and FLSs in arthritic joints expressed S1P3 in vivo. Primary cultured FLSs produced IL-6 in a time-dependent manner in response to S1P stimulation and exhibited higher levels of S1P3 expression after activation with TNFα. S1P3-induced production of IL-6 and MMP-3 was increased in FLSs pre-activated with TNFα. CONCLUSION: In this study, we demonstrated that S1P3 expression is associated with the development of autoimmune arthritis via inflammation-induced increases in S1P/S1P3 signaling that increase production of IL-6 in FLSs. Inhibition of S1P/S1P3 signaling could open the door to the development of new therapies for RA.


Assuntos
Artrite Experimental/metabolismo , Fibroblastos/metabolismo , Interleucina-6/biossíntese , Receptores de Esfingosina-1-Fosfato/metabolismo , Sinoviócitos/metabolismo , Regulação para Cima , Animais , Artrite Experimental/patologia , Proliferação de Células , Fibroblastos/patologia , Mediadores da Inflamação/metabolismo , Articulações/metabolismo , Articulações/patologia , Lisofosfolipídeos , Masculino , Camundongos Knockout , Transdução de Sinais , Esfingosina/análogos & derivados , Sinoviócitos/patologia , Fator de Necrose Tumoral alfa/metabolismo
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