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1.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3441-3447, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602907

RESUMO

To observe the effect of Tripterygium Glycosides Tablets on angiogenesis of rats with type Ⅱ collagen-induced arthritis( CIA) and on the tube formation of human umbilical vein endothelial cells( HUVEC) in vitro. The HUVEC were induced by 20 µg·L-1 vascular endothelial growth factor( VEGF) in vitro,and were treated with 0. 1,1,10 mg·L-1 Tripterygium Glycosides Tablets continuously for 7 hours. The numbers of branches of tube formation were measured. SD rats were immunized to establish CIA. CIA rats were treated with 9,18,36 mg·kg-1·d-1 Tripterygium Glycosides Tablets for 42 days. Histopathological examination( HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joints. Immunohistochemistry and immunofluorescence were performed to observe the expression of platelets-endothelial cell adhesion molecule( CD31) and αsmooth muscle actin( αSMA) in synovial membrane. Immunohistochemistry and Western blot were performed to observe the expression of hypoxia-inducible factors 1α( HIF1α) and angiotensin 1( Ang1) in the synovial tissue. The results showed that the numbers of branches of tube formation of HUVEC induced by VEGF were improved,and declined significantly after treated by Tripterygium Glycosides Tablets. Compared with the normal group,the vascular density,CD31 positive expression,CD31 +/αSMA-immature and total vascular positive expression in the synovial membrane of the model group were significantly increased,and so as HIF1α and Ang1 in the synovium. Tripterygium Glycosides Tablets reduced the synovial vascular density and inhibited the positive expression of CD31,CD31+/αSMA-immature blood vessels and total vascular,but has no effect on CD31+/αSMA+mature blood vessels. Tripterygium Glycosides Tablets also inhibited the expression of HIF1α and Ang1 in synovial membrane of inflammatory joints. Our results demonstrated that Tripterygium Glycosides Tablets could inhibit the angiogenesis of synovial tissue in CIA rats and the tube formation of HUVEC,which is related to the down-regulation of HIF1α/Ang1 signal axis.


Assuntos
Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Glicosídeos/farmacologia , Tripterygium/química , Inibidores da Angiogênese/farmacologia , Angiotensina I/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Membrana Sinovial/efeitos dos fármacos , Comprimidos , Fator A de Crescimento do Endotélio Vascular
2.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3486-3493, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602913

RESUMO

The aim of this paper was to observe the toxic effect of Tripterygium Glycosides Tablets( TG) on the reproductive system of Ⅱ type collagen induced arthritis( CIA) male rats,and to explore the toxic mechanism preliminarily. Fifty SD rats were randomly divided into normal control group( Con),model group( CIA),Tripterygium Glycosides Tablets clinical equivalent dose groups of 1,2,4 times( 9,18,36 mg·kg-1),10 rats in each group,and were given by gavage once a day for 42 days after the first immunization.The organ indexes of uterine and ovarian were calculated on days 21 and 42. Histopathological and morphological changes of uterine and ovarian were observed under optical microscope. The concentration of estradiol( E2),follicle-stimulating hormone( FSH),luteinizing hormone( LH),17α-hydroxylase( CYP17 A1) and cytochrome P450 19 A1( CYP19 A1) in serum were detected by ELISA. Immunohistochemistry was used to observe the expression of Bax and Bcl-2 related proteins in the apoptosis pathway of uterus and ovary. The results showed that compared with the Con group,CIA group could reduce the number of uterine glands( P<0.05),but no significant changes were observed in other groups. Compared with the CIA group,there were no significant changes in the coefficients of uterus and ovary in the Tripterygium Glycosides Tablets groups. The number of uterine glands,total follicles in the ovary,mature follicles and corpus luteum,the distribution of blood vessels and mitochondria had a certain inhibitory trend,and also slightly increased the number of atresia follicles,but the histopathological quantitative indicators were not statistically different. Except that 2 times clinical dose of Tripterygium Glycosides Tablets could significantly reduce the content of CYP19 A1( P<0. 05) after 42 d administration,there were no significant changes in serum estrogen E2,FSH,LH and estrogen synthesis key enzymes CYP17 A1 in each administration group. Medium and high doses of Tripterygium Glycosides Tablets could increase the expression of apoptotic protein Bax in uterine and ovarian tissues( P<0. 05,P<0. 01),and all the administration groups could inhibit the expression of apoptotic inhibiting protein Bcl-2( P <0. 05,P<0. 01,P<0.001),42 d was more obvious than 21 d. In conclusion,4 times and less than 4 times Tripterygium Glycosides Tablets did not cause obvious toxicity and histopathological changes in the reproductive organs of CIA rats,but it could reduce the level of serum estrogen synthesis key enzyme CYP19 A1 and affect the content of apoptosis-related proteins Bax and Bcl-2 in uterus and ovary tissues. The relevant mechanism needs further study.


Assuntos
Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/toxicidade , Genitália Feminina/efeitos dos fármacos , Glicosídeos/toxicidade , Tripterygium/química , Animais , Apoptose , Aromatase/metabolismo , Artrite Experimental/induzido quimicamente , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Glicosídeos/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Comprimidos
3.
Life Sci ; 236: 116860, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518605

RESUMO

AIMS: Intrathecal injection of morphine presents analgesic and antiedematogenic effects in rats. However, it is unknown whether tramadol, which possess a mixed mechanism of action, can also produce analgesic and antiedematogenic effects similarly. MAIN METHODS: Male Wistar rats received carrageenan and LPS in the right knee joint. Tramadol (10 µg) was injected intrathecally 20 min before articular LPS injection. Incapacitation and articular edema were measured 5 h after LPS stimulation. Synovial fluid was collected for leukocyte counting and western blot analysis. Whole joint and lumbar spinal cord were also collected for histology and immunohistochemistry, respectively. Intrathecal pretreatments groups were with the NKCC1 blocker bumetanide, TRPV1 agonist resiniferatoxin, µ-opioid receptor antagonist CTOP and serotonergic neurotoxin 5,7-DHT, all previously to tramadol. KEY FINDINGS: Tramadol treatment caused the reduction of incapacitation and edema. It also reduced c-Fos protein expression in the spinal cord dorsal horn and slightly reduced TNF-α levels in synovial fluid, but neither reduced cell migration nor tissue damage. Bumetanide and resiniferatoxin prevented the analgesic and antiedematogenic effects of tramadol. CTOP prevented the analgesic and the antiedematogenic effects, but 5,7-DHT prevented only tramadol-induced analgesia. SIGNIFICANCE: Spinal NKCC1 cotransporter and peptidergic peripheral afferents seem to be important for the analgesic and antiedematogenic effects of tramadol, as well as µ-opioid receptor. However, the monoamine uptake inhibition effect of tramadol seems to be important only to the analgesic effect.


Assuntos
Analgésicos Opioides/administração & dosagem , Artralgia/prevenção & controle , Artrite Experimental/complicações , Artrite Reativa/complicações , Edema/prevenção & controle , Lipopolissacarídeos/toxicidade , Tramadol/administração & dosagem , Animais , Artralgia/etiologia , Artralgia/patologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/fisiopatologia , Artrite Reativa/induzido quimicamente , Artrite Reativa/fisiopatologia , Modelos Animais de Doenças , Edema/etiologia , Edema/patologia , Injeções Espinhais , Masculino , Ratos , Ratos Wistar
4.
Zhongguo Zhong Yao Za Zhi ; 44(7): 1457-1463, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090305

RESUMO

To observe the effect of Fengshi Qutong Capsules(FSQTC) on angiogenesis of rat aortarings and in knee joint synovium of type Ⅱ collagen-induced arthritis(CIA) rats. The blood vessel of aorta rings of normal SD rats were induced by vascular endothelial growth factor(VEGF) 20 µg·L~(-1 )in vitro, and were treated with FSQTC(0.02, 0.1 and 0.5 µg·L~(-1)) continuously for 9 days. The number, length and area of neovascularization of the vascular ring were measured. SD rats were immunized to establish collagen-induced arthritis. CIA rats were treated with FSQTC(0.25, 0.5, 1 g·kg~(-1)·d~(-1)) and methotrexate(0.2 mg·kg~(-1)·d~(-1)) daily for 19 days. Histopathological examination(HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joint. Immunohistochemistry was performed to observe the expression of platelets-endothelial cell adhesion molecule(CD31), VEGF and VEGF receptor 2(VEGFR_2)in the synovium. Immunofluorescence was performed to observe the expression of CD31 and α smooth muscle actin(αSMA) in synovial membrane.TGF-ß, PDGF and VEGFR_2 in serum were detected by enzyme-linked immunosorbent assay. The number, branch length and area of blood vessels of aorta rings were significantly increased induced by VEGF, and FSQTC could significantly reduce the number, branch length and area of blood vessels. Compared with the normal group, the vascular density, CD31 positive expression, CD31~+/αSMA~- immature and total vascular positive expression in the synovial membrane of the model group were significantly increased, and so as VEGF and VEGFR_2 in the synovium. The VEGFR_2, TGF-ß and PDGF in sera were also significantly increased in model group. FSQTC reduced the synovial vascular density and inhibited the positive expression of CD31, CD31~+/αSMA~- immature blood vessels and total vascular. FSQTC has no significant effect on CD31~+/αSMA~+mature blood vessels. FSQTC also negatively inhibited the expression of VEGF, VEGFR_2, TGF-ß and PDGF in synovial membrane and/or sera. The effect of methotrexate is similar with to the high dose group. Our results demonstrated that FSQTC could inhibit the angiogenesis of synovial tissue in CIA rats and of aortaring in rats, which is related to the reduction of angiogenesis regulatory factor.


Assuntos
Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neovascularização Patológica/tratamento farmacológico , Animais , Aorta , Artrite Experimental/induzido quimicamente , Cápsulas , Colágeno Tipo II , Ratos , Ratos Sprague-Dawley , Membrana Sinovial/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular
5.
J Immunol Res ; 2019: 7026067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949517

RESUMO

Aim: The RelB gene plays an important role in guiding the progression of arthritis. We have previously demonstrated that the expression of the RelB gene is decreased significantly in bone marrow DCs of CD38-/- mice. In this study, we demonstrate that the cluster of the differentiation (CD38) gene could be a potentially therapeutic target for autoimmune arthritis. Method: Collagen-induced arthritis (CIA) models were generated with both the wild-type (WT) C57BL/6 and CD38-/- mice. The expression of the RelB gene and maturation of bone marrow-derived dendritic cells (DCs) from the WT and CD38-/- mice were detected. Antigen-specific T cell responses, joint damage, and expression of proinflammatory cytokines were assessed. The effects of the Nuclear Factor Kappa B (NF-κB) transcription factor and its mechanisms were characterized. Results: We demonstrated that in CD38-/- mice, the expression of the RelB gene and major histocompatibility complex II (MHC II) was decreased, accompanied with the inhibited T cell reaction in a mixed lymphocyte reaction (MLR) in bone marrow-derived DCs. Compared to the serious degeneration of the cartilage and the enlarged gap of the cavum articular in WT CIA mice, joint pathological changes of the CD38-/- CIA mice revealed marked attenuation, while the joint structures were well preserved. The preserved effects were observed by the inhibition of proinflammatory cytokines and promotion of anti-inflammatory cytokines. Furthermore, decreased phosphorylation of NF-κB was also observed in CD38-/- CIA mice. Conclusion: We demonstrate that CD38 could regulate CIA through NF-κB and this regulatory molecule could be a novel target for the treatment of autoimmune inflammatory joint disease.


Assuntos
ADP-Ribosil Ciclase 1/genética , Artrite Experimental/fisiopatologia , Glicoproteínas de Membrana/genética , NF-kappa B/metabolismo , Transdução de Sinais , ADP-Ribosil Ciclase 1/imunologia , Animais , Artrite Experimental/induzido quimicamente , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Diferenciação Celular , Colágeno , Citocinas/imunologia , Regulação para Baixo , Genes MHC da Classe II , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , Fosforilação , Linfócitos T/imunologia , Fator de Transcrição RelB/genética , Fator de Transcrição RelB/imunologia
6.
Contrast Media Mol Imaging ; 2019: 2353658, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015824

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic, symmetrical, and erosive synovitis. RA is one of the most common disabling diseases in the clinic. The main clinical intervention strategies are early diagnosis and early treatment. This study aims to predict the diagnostic value of 68Ga-citrate and 18F-FDG PET/CT in RA by comparing and analyzing the value of 68Ga-citrate and 18F-FDG PET/CT for diagnosing type II collagen-induced arthritis (CIA) in rats. Some CIA models were established. Normal rats were selected as the control group, and 23 days and 40 days were selected as the early and late time points of arthritis, respectively. The semiquantitative analysis of CIA rats was carried out with 68Ga-citrate PET/CT and 18F-FDG PET/CT, and the ratio of the maximum standardized uptake (SUVmax) values in the regions of interest (ROIs) of the hind foot ankle joint and thigh muscle was calculated and statistically analyzed. The distribution of CIA rats in vivo at the 68Ga-citrate 90 min time point was studied, and the ankle tissues were evaluated with hematoxylin and eosin (HE) staining. 68Ga-citrate PET/CT is obviously superior to 18F-FDG PET/CT for CIA imaging, and the statistical results show that the difference between the two examination methods is statistically significant (P < 0.001). The uptake of these two radiopharmaceuticals showed the same trend in arthritis rats with different scores. The distribution of 68Ga-citrate at 90 min is consistent with the trend shown by 68Ga-citrate PET/CT. 68Ga-citrate PET/CT can reflect the inflammatory activity of affected joints in CIA rats earlier and more sensitively than 18F-FDG PET/CT, and this imaging advantage continues until the later stage of inflammation. Therefore, 68Ga-citrate PET/CT is worthy of further promotion and application in the clinical diagnosis of RA.


Assuntos
Artrite Experimental/induzido quimicamente , Artrite Experimental/diagnóstico por imagem , Colágeno Tipo II/toxicidade , Fluordesoxiglucose F18/análise , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Animais , Citratos/análise , Feminino , Gálio/análise , Ratos , Ratos Sprague-Dawley
7.
Eur J Pharmacol ; 853: 264-274, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951714

RESUMO

Methotrexate (MTX) efficacy in autoimmune arthritis is variable and unpredictable resulting in the need for the identification of biomarkers to guide drug therapy. This study utilizes the collagen-induced arthritis mouse model to investigate erythrocyte MTX disposition and anti-folate activity as biochemical markers of efficacy in autoimmune arthritis. Following induction of arthritis, DBA/1J mice were treated with once-weekly subcutaneous MTX at varying doses over a period of 40 days. At the completion of the study tissue samples were analyzed for MTX and folate content and assessed for their relationship with MTX efficacy. MTX treatment resulted in a reduction in disease activity that was variable and dose-dependent. Erythrocyte accumulation of MTX and its polyglutamate metabolites were dose proportionate, however, polyglutamate metabolites represented a mean ±â€¯S.E.M. of 8.9 ±â€¯0.4% of total erythrocyte MTX, which is markedly lower than previously observed in humans and failed to display any significant association with MTX efficacy. MTX treatment resulted in reductions in erythrocyte 5-methyl-tetrahydrofolate (5mTHF) levels that were similar to those previously observed in human studies. Disease induction was associated with a decrease in liver 5mTHF and increased formyl-tetrahydrofolate (fTHF) that was normalized in MTX treated mice. MTX efficacy was associated with reductions in erythrocyte 5mTHF (P = 0.04) and increases in liver 5mTHF (P = 0.0001). Together, these findings demonstrate a relationship between alterations in tissue folate levels and MTX efficacy, and supports erythrocyte levels of 5mTHF as a marker of MTX efficacy in autoimmune arthritis.


Assuntos
Artrite Experimental/metabolismo , Colágeno/efeitos adversos , Antagonistas do Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/farmacologia , Ácido Fólico/metabolismo , Metotrexato/metabolismo , Metotrexato/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Modelos Animais de Doenças , Masculino , Camundongos , Ácido Poliglutâmico/metabolismo
8.
Nutrients ; 11(4)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959746

RESUMO

Lactobacillus strains have shown efficacy in attenuating inflammation. This study evaluated the potential of Lactobacillus fermentum PC1 for the treatment of rheumatoid arthritis (RA) using a murine model of collagen-induced arthritis. On Day 1, healthy DBA/1 mice (six to eight weeks of age) were immunized, with 100 µg of Chicken Type 11 collagen emulsified in complete Freund's adjuvant (CFA) by intradermal injection, at the base of the tail. On Day 21, the mice were immunized intraperitoneally with 100 µg of Bovine Type11 collagen in phosphate buffered saline (PBS). On Day 28, the mice were immunized intraperitoneally with 50 µg of lipopolysaccharide (LPS). Viable L. fermentum PC1 (1 × 108 colony forming units) was given daily from Day two until the end of the experiment. From Day 21 onwards, the mice were monitored daily for clinical signs of arthritis. On Day 44, the experiment was terminated. Paws were obtained for histology and serum for cytokine assays. L. fermentum PC1-fed mice had significantly reduced paw inflammation as well as decreased synovial infiltration and less cartilage damage. Circulating serum cytokine profiles revealed decreased IL-12 and increased anti-inflammatory cytokines, namely IL-4 and IL-10. Thus, early administration of L. fermentum PC1 could prove to be a valuable therapeutic agent in the management of RA.


Assuntos
Artrite Experimental/induzido quimicamente , Colágeno Tipo II/toxicidade , Inflamação/tratamento farmacológico , Lactobacillus fermentum/fisiologia , Probióticos/farmacologia , Animais , Artrite Experimental/terapia , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA
9.
J Immunol Res ; 2019: 2641098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937315

RESUMO

The inflammatory and autoimmune events preceding clinical symptoms in rheumatoid arthritis (RA) and other autoimmune diseases are difficult to study in human patients. Therefore, animal models that share immunologic and clinical features with human RA, such as pristane-induced arthritis (PIA), are valuable tools for assessing the primordial events related to arthritis susceptibility. PIA-resistant HIII and susceptible LIII mice were injected i.p. with pristane, and peritoneal lavage fluid was harvested in the early (7 days) and late (35 days) preclinical phases of PIA. Chemokine and cytokine levels were measured in lavage supernatant with ELISA, peritoneal inflammatory leukocytes were immunophenotyped by flow cytometry, and gene expression was determined by qRT-PCR. Leukocyte recruitment was quantitatively and qualitatively divergent in the peritoneum of HIII and LIII mice, with an early increase of CC chemokines (CCL2/CCL3/CCL5/CCL12/CCL22) in the susceptible LIII strain. Also, cytokines such as IL-12p40, IL-23, and IL-18 were elevated in LIII mice while IL-6 was increased in HIII animals. The results show that an early peritoneal CC chemokine response is an important feature of arthritis susceptibility and defines potential biomarkers in this model.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Quimiocinas CC/imunologia , Inflamação , Peritônio/imunologia , Animais , Artrite Experimental/induzido quimicamente , Biomarcadores , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-6/imunologia , Masculino , Camundongos , Fenótipo , Terpenos/administração & dosagem
10.
Phytomedicine ; 58: 152825, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30831463

RESUMO

BACKGROUND: The seeds of Vitex negundo, with rich lignans metabolites, have been widely used as a traditional Chinese medicine and Ayurvedic herbal medicine for the treatment of rheumatism and joint inflammation. The total lignans of Vitex negundo seeds (TOV) were suggested to play an important role in the treatment of arthritis. PURPOSE: The aim of the study was designed to investigate the anti-arthritic effects of TOV on collagen-induced arthritis (CIA) in rats as well as its possible mechanisms. METHODS: TOV was prepared by combined macroporous resin and polyamide column chromatography, and constituents of TOV were analyzed by HPLC. CIA model in rats was established by immunization with chicken type II collagen and then the rats were intragastrically administrated with TOV for 30 days. Rat arthritis was evaluated by measurements of hind paw edema, arthritis index score, weight growth and indices of thymus and spleen, and by histological examination. Levels of serum MMP-2, MMP-3, MMP-9, IL-1ß, IL-6, IL-8, IL-10, IL-17A and TNF-α were also examined. In addition, the expression of COX-2, iNOS and IκB, p-IκB in synovial tissues was evaluated by western blotting. The analgesic and anti-inflammatory effects of TOV were also evaluated in acetic acid-induced writhing and xylene-induced ear edema in mice, respectively. In addition, acute toxicity test was employed to preliminarily assess the safety of TOV. RESULTS: TOV significantly inhibited the paw edema and decreased the arthritis index, with no influence on the body weight and the indices of thymus and spleen of CIA rats. Meanwhile, TOV dose-dependently reduced the infiltration of inflammatory cells, synovial hyperplasia and attenuated cartilage damage. Additionally, the serum levels of IL-1ß, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9 were markedly decreased, while the level of serum IL-10 was increased in TOV-treated rats. The significant reduction of the expression of COX-2, iNOS and p-IκB and the notable increase of IκB in synovial tissues were also observed in TOV-treated animals. TOV also significantly inhibited acetic acid-induced writhing and decreased xylene-induced ear edema in mice. Finally, the maximal tolerable dose (MTD) of TOV was determined to be 16.0 g/kg. CONCLUSION: These results suggest that TOV has significant anti-arthritic effects on collagen-induced arthritis in rats, which may be attributed to the inhibition of the levels of IL-1ß, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9, and the increase of IL-10 in serum as well as down-regulation of the protein expression of COX-2 and iNOS in synovial tissues via suppressing the phosphorylation and degradation of IκB. Due to its high efficacy and safety, TOV can be regarded as a promising drug candidate for rheumatoid arthritis treatment.


Assuntos
Artrite Experimental/tratamento farmacológico , Edema/tratamento farmacológico , Lignanas/farmacologia , Medicina Tradicional Chinesa , Vitex/química , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Galinhas , Colágeno Tipo II/efeitos adversos , Ciclo-Oxigenase 2/metabolismo , Citocinas/sangue , Edema/patologia , Feminino , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Sementes/química , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
11.
Toxicon ; 161: 4-11, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30825463

RESUMO

The aim of this study was to assess anti-inflammatory, anti-oxidant, anti-genotoxic and immunomodulatory effects of honey bee venom (HBV) on adjuvant-induced arthritis in rats. Thirty-five rats were equally divided into a negative control (NC), a positive control (PC) and low, moderate and high doses (2, 4 and 20 mg/kg, respectively) of HBV treatment groups. Freund's Complete Adjuvant (FCA) was given to the rats to form arthritis. The treatment groups were treated with HBV for 3 consecutive weeks. After the treatment, plasma IL-1ß, IL-6, TNF-α, IFN-γ and TGF-ß1, total oxidant status (TOS), total antioxidant status (TAS) and myeloperoxidase (MPO) activities and mononuclear leukocyte (MNL) DNA damage levels were measured. Oxidative stress index (OSI) was calculated. IL-1ß, IL-6, TNF-α, TGF-ß1, IFN-γ, TOS, OSI, DNA damage levels and MPO activities were significantly higher and TAS levels were lower in the PC group than the NC. After low-doses of HBV treatment IL-1ß, IL-6, TNF-α, TGF-ß1, TOS, OSI, MPO and MNL-DNA damage levels significantly decreased according to the PC, while IFN-γ and TAS levels increased. The differences in moderate and high-dose HBV treatment groups were not as significant as low HBV doses. Low-doses of HBV has been shown to treat RA with anti-inflammatory and antioxidant effects, by preventing DNA damage. However, these effects have not been observed as strong at higher doses of HBV. In summary, HBV may be an effective option to ameliorate RA, but the optimization of the therapeutic dose has a crucial role.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Venenos de Abelha/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Dano ao DNA , Edema/induzido quimicamente , Adjuvante de Freund , Radical Hidroxila/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
12.
Eur J Med Chem ; 169: 121-143, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875504

RESUMO

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized as reversible BTK inhibitors, and evaluated their kinase selectivity, anti-proliferation against the B-cell lymphoma cell lines (Ramos, Jeko-1) and cell line BTK enhanced (Daudi) in vitro. Among them, compound 28a exhibited the most excellent potency (IC50 = 3.0 nM against BTK enzyme, 8.52 µM, 11.10 µM and 7.04 µM against Ramos, Jeko-1, Daudi cells, respectively), good kinase selectivity and inhibited BTK Y223 auto-phosphorylation and PLCγ2 Tyr1217 phosphorylation. Importantly, 28a showed efficacy anti-arthritic effect on collagen-induced arthritis (CIA) model in vivo. 28a 60 mg/kg dose level once a day group displayed markedly reduced joint damage and cellular infiltration without any bone and cartilage morphology change.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Desenho de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Colágeno , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos DBA , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
13.
Res Vet Sci ; 124: 32-37, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30807910

RESUMO

OBJECTIVE: To determine antioxidant effects of prophylactic treatment with gold nanoparticles (AuNPs) in the early stage of collagen-induced arthritis (CIA). METHODS: The preventive treatment with 13 nm or 50 nm AuNPs injected intraarticularly (i.a.) was started at the induction day (0) of CIA and finished in the early stage of arthritis at the day 10. At the end of experiment blood indices (erythrocyte sedimentation rate, leukocyte and erythrocyte counts), pro-/antioxidant status of blood serum (the amount of malondialdehyde, catalase and total antioxidant activity), and internal organs' weight as well as the changes in the joint tissues and their microscopic structure were evaluated. RESULTS: Both 13 nm and 50 nm AuNPs showed antioxidant effect by increasing the level of catalase activity in the early stage of experimental arthritis. Preventive treatment with 50 nm more than with 13 nm AuNPs suppressed joint swelling. Histopathological asssesment revealed statistically significant reduction of synovial angiogenesis and erosion formation in the cartilage. Pilot transmission electron microscopy (TEM) analysis showed predominant accumulation of 13 nm in the synovial fibroblast lineage cells. CONCLUSIONS: Intraarticular injections of 13 nm or 50 nm AuNPs showed an antioxidant action significantly raising catalase activity without causing negative effects on hematological indices. Prophylactic treatment with 50 nm more than with 13 nm AuNPs suppressed joint swelling, synovial angiogenesis and cartilage erosion in the initial stage of arthritis.


Assuntos
Antioxidantes/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Colágeno/efeitos adversos , Ouro/farmacologia , Nanopartículas Metálicas , Animais , Artrite Experimental/induzido quimicamente , Masculino , Tamanho da Partícula , Distribuição Aleatória , Ratos , Ratos Wistar
14.
Inflammopharmacology ; 27(5): 997-1010, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30771056

RESUMO

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6'-O-benzene sulfonate (CP-25). PGE2 combined with tumor necrosis factor-α promoted DC maturation and activation through EP4-cAMP signaling. Treatment with CP-25 increased the endocytic capacity of DCs induced by PGE2. CP-25 inhibited the potency of DCs induced by the EP4 receptor agonist, CAY10598, to stimulate allogeneic T cells. Consistent with these findings, the CAY10598-induced upregulation of DC surface activation markers and production of IL-23 was significantly inhibited by CP-25 in a concentration-dependent manner. In vivo administration of CP-25 alleviated adjuvant arthritis (AA) in rats through inhibition of DC maturation and activation. Our results indicate that PGE2-EP4-cAMP signal hyperfunction can lead to abnormal activation of DC functions, which correlates with the course of disease in AA rats and provides a possible treatment target. The inhibition of DC maturation and activation by CP-25 interference of the PGE2-EP4 pathway may significantly contribute to the immunoregulatory profile of CP-25 when used to treat RA and other immune cell-mediated disorders.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Artrite Experimental/tratamento farmacológico , Células Dendríticas/efeitos dos fármacos , Dinoprostona/metabolismo , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adjuvantes Farmacêuticos/efeitos adversos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , AMP Cíclico/metabolismo , Células Dendríticas/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
15.
Phytomedicine ; 57: 271-281, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30802713

RESUMO

BACKGROUND: The stems of Tinospora sinensis (Lour.) Merr commonly named "Kuan-Jin-Teng" in Chinese, have been used to treat rheumatoid arthritis as a Tibetan medicine. PURPOSE: The effects of the EtOAc fraction of ethanolic extract from the stems of T. sinensis (KJT) on the pro-inflammatory cytokines and MAPK pathway were studied in collagen-induced arthritis (CIA) model. STUDY DESIGN: Anti-arthritic activity of KJT was investigated in CIA model. METHODS: The chemical constituents of KJT were analyzed by LC-MS and HPLC. The CIA model was established with injecting the bovine CII emulsified in Freund's adjuvant in Wistar rats. Several doses of KJT (50.0, 100.0 and 200.0 mg/kg) were administrated via oral gavage to CIA rats daily for 4 weeks. The anti-arthritic activity of KJT was investigated by clinical arthritis scoring, paw swelling inspection and hyperalgesia measurement, as well as radiological and histological analysis in CIA rats. The impacts of KJT on the activation of MAPK pathway, production of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-17) in ankle joints, serum, and spleen in CIA rats were examined by western blot, immunohistochemical staining, ELISA, and quantitative real-time PCR respectively. Lastly, the effects of KJT on production of the nitric oxide (NO) and pro-inflammatory cytokines as well as the regulation of the phosphorylation of p38 and Erk were detected in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells. RESULTS: KJT significantly alleviated the paw swelling, hyperalgesia and arthritic severity, and reduced the synovial tissue proliferation and inflammatory cell infiltration in the CIA rats. Moreover, KJT suppressed the production of TNF-α, IL-1ß, and IL-17 in ankle joints, serum, and spleen and reversed the up-regulation of the phosphorylation of p38 and Erk in CIA rats. KJT was also demonstrated to inhibit the production of NO and pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), and phosphorylation of p38 and Erk in LPS-stimulated RAW264.7 cells. CONCLUSION: These results suggest the mechanisms of KJT performing its anti-arthritis effect may be attributed to inhibiting the production of pro-inflammatory cytokines and down-regulating the MAPK signaling pathway.


Assuntos
Artrite Experimental/tratamento farmacológico , Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/tratamento farmacológico , Colágeno/toxicidade , Regulação para Baixo/efeitos dos fármacos , Edema/tratamento farmacológico , Edema/patologia , Adjuvante de Freund/efeitos adversos , Masculino , Medicina Tradicional Tibetana , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Ratos Wistar , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Tinospora/química
16.
BMC Complement Altern Med ; 19(1): 47, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755211

RESUMO

BACKGROUND: Libidibia ferrea (L. ferrea) has been used in folk medicine to treat several conditions and to prevent cancer. This study performed a chromatographic analysis of the crude aqueous extract of Libidibia ferrea (Mart. ex. Tul.) L.P. Queiroz (LfAE) leaves and evaluated its in vivo antioxidant and anti-inflammatory potential. METHODS: Polyphenols present in LfAE were characterized by high performance liquid chromatography (HPLC). Anti-inflammatory activity was studied in an experimental model of zymosan-induced intra-articular inflammation, conducted in Wistar rats treated with LfAE at the doses of 100, 200 and 300 mg/kg by gavage. Synovial fluid was collected for global leukocyte count, for spectrocopical UV/VIS analysis of myeloperoxidase (MPO) activity, total glutathione and malondialdehyde (MDA), and for quantification of inflammatory cytokines IL1-ß and TNF-α by enzyme-linked immunosorbent assay. Synovial membrane was collected for histological analysis. The level of statistical significance was p < 0.05. RESULTS: HPLC detected concentrations of 1.56 (0.77) %m/m for ellagic acid and 1.20 (1.38) %m/m for gallic acid in LfAE leaves. Treatment with LfAE at all doses significantly decreased the leukocyte influx into the synovial fluid (p < 0.001) and myeloperoxidase activity (p < 0.001), an important marker of neutrophils. LfAE at doses of 100 (p < 0.05), 200 and 300 mg/kg (p < 0.001) also reduced the levels of MDA. LfAE at doses of 200 and 300 mg/kg significantly decreased the levels of IL-1ß (p < 0.05) and TNF-α (p < 0.001). All doses of LfAE resulted in increased levels of total glutathione (p < 0.001). Histopathological findings confirmed a reduction of the inflammatory infiltrate in the rats treated with LfAE at a dose of 200 mg/kg (p < 0.05). CONCLUSION: LfAE has an important anti-oxidant and anti-inflammatory effect on intra-articular inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Caesalpinia/química , Inflamação/metabolismo , Extratos Vegetais/farmacologia , Animais , Antioxidantes/metabolismo , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Citocinas/metabolismo , Inflamação/induzido quimicamente , Masculino , Folhas de Planta/química , Ratos , Ratos Wistar , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Zimosan
17.
Int J Rheum Dis ; 22(4): 654-665, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30609267

RESUMO

OBJECTIVE: To determine if early supplemental intra-articular α2-macroglobulin (A2M) has a chondroprotective effect in a collagen II-induced arthritis (CIA) mice model. METHODS: DBA/1 mice were randomized into four groups (n = 15/group): (a) CIA + 1.2 µg of A2M; (b) CIA + 0.8 µg of A2M; (c) CIA + 0.4 µg of A2M; (d) vehicle + phosphate-buffered saline (PBS). A2M was injected into right ankles and PBS was injected into the left ankles simultaneously as internal control at days 36, 43 and 50. The CIA inflammation clinical score and ankle thickness were recorded every other day starting on day 21 until sacrifice. Changes in inflammation were monitored by in vivo fluorescence molecular tomography (FMT). Inflammation, cartilage and bone damage were assessed with X-ray, histology and immunohistochemistry. Cartilage and inflammation-related gene expression was quantified by real-time polymerase chain reaction (PCR). RESULTS: All mice showed ankle inflammation on day 33. After day 43, lower clinical scores, ankle thickness and Sharp/van der Heijde method scores in A2M-treated ankles compared with PBS-treated ankles. FMT data indicated that the inflammation markers MMPSense and ProSense were significantly elevated in the PBS-treated ankles than A2M-treated ankles. Histology and X-ray analyses indicated that A2M administration resulted in lower levels of inflammatory infiltration and synovial hyperplasia, as well as more typical cartilage and bone organization with increased COL II and Aggrecan staining when compared with PBS-treated ankles. In addition, real-time PCR showed that,matrix metalloproteinase-3, -9, -13, COL X and Runx2 were significantly less expressed in A2M-treated groups than PBS-treated animals. CONCLUSION: Early supplemental intra-articular A2M exerts an anti-inflammatory effect and attenuates cartilage and bone damage in a CIA model.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/prevenção & controle , Cartilagem Articular/efeitos dos fármacos , Colágeno Tipo II , Ossos do Pé/efeitos dos fármacos , Articulações do Pé/efeitos dos fármacos , alfa 2-Macroglobulinas Associadas à Gravidez/administração & dosagem , Agrecanas/genética , Agrecanas/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Remodelação Óssea/efeitos dos fármacos , Cartilagem Articular/imunologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrogênese/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Feminino , Ossos do Pé/imunologia , Ossos do Pé/metabolismo , Ossos do Pé/patologia , Articulações do Pé/imunologia , Articulações do Pé/metabolismo , Articulações do Pé/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Injeções Intra-Articulares , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos Endogâmicos DBA , Fatores de Tempo
18.
Phytomedicine ; 53: 70-78, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668414

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease which leads to bone and cartilage erosion. Oxidative stress and pro-inflammatory cytokines plays crucial role in the pathophysiology of RA. Cinnamaldehyde and eugenol have a long history of medical use in various inflammatory disorders. PURPOSE: The drugs available for the treatment of RA are associated with various side effects. The present study was conducted to evaluate the anti-arthritic effects of cinnamaldehyde and eugenol in rat model of arthritis. METHODS: Type II collagen was intradermally injected to rats for the induction of arthritis. Cinnamaldehyde (10 and 20 mg/kg/day) and eugenol (10 and 20 mg/kg/day) were given orally for 15 days, starting from day 21 to 35. Dexamethasone treated rats served as positive control. Histological, radiological and scanning electron microscopic analysis were done to monitor the effect of compounds on collagen induced arthritis (CIA). Reactive oxygen species (ROS) formation, nitric oxide and antioxidant status were also determined. The markers of biomolecular oxidation (protein, lipid and DNA) and activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, catalase and glutathione reductase) were also evaluated in the joint homogenate and plasma of rats. For detecting inflammation, levels of TNF-α, IL-6 and IL-10 were monitored by ELISA. RESULTS: Our results showed anti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol in arthritic rats. Scanning electron microscopy, histopathological and radiological findings also confirmed the anti-arthritic effects of cinnamaldehyde and eugenol. Both the compounds were effective in bringing significant decrease in the levels of ROS, nitric oxide, markers of biomolecular oxidation and increase in enzymatic and non-enzymatic antioxidants. The levels of TNF-α, IL-6 and IL-10 were also ameliorated by cinnamaldehyde and eugenol treatment. Between the two phytochemicals used, eugenol was found to be more effective than cinnamaldehyde in reducing the severity of arthritis. CONCLUSION: Cinnamaldehyde and eugenol were effective in ameliorating oxidative stress and inflammation in arthritic rats. These findings indicate that cinnamaldehdye and eugenol have a great potential to be used as an adjunct in the management of RA.


Assuntos
Acroleína/análogos & derivados , Artrite Experimental/tratamento farmacológico , Citocinas/metabolismo , Eugenol/farmacologia , Acroleína/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Colágeno Tipo II/toxicidade , Feminino , Radicais Livres/metabolismo , Inflamação/tratamento farmacológico , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
19.
BMC Musculoskelet Disord ; 20(1): 8, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611247

RESUMO

BACKGROUND: Osteoarthritis (OA) is a common joint disease in aging societies, which is accompanied by chronic inflammation and degeneration of the joint structure. Inflammation of the infrapatellar fat pad (IFP) and synovial membrane (IFP surface) plays essential roles in persistent pain development in patients with OA. To identify the point during the inflammatory process critical for persistent pain development, we performed a time course histological analysis in a rat arthritis model. METHODS: Wistar rats received single intra-articular injection of monoiodoacetic acid (MIA, 0.2 or 1.0 mg/30 µL) in the right knees or phosphate-buffered saline (PBS, 30 µL) as a control in the left knees. Pain avoidance behaviors (weight-bearing asymmetry and tactile hypersensitivity of the plantar surface of the hind paw) were evaluated on days 0, 1, 3, 5, 7, and 14 after injection. Histological assessments of the knee joint were performed on days 0, 1, 3, 5, and 7 after MIA injection. RESULTS: Weight-bearing asymmetry was observed along with the onset of acute inflammation in both the low- (0.2 mg) and high-dose (1.0 mg) groups. In the low-dose group, weight-bearing asymmetry was completely reversed on day 10, indicating that joint pain seemed to alleviate between days 7 and 10. In contrast, we observed persistent joint pain after day 10 in the high-dose group. Histological assessments of the high-dose group indicated that the initial sign of inflammatory responses was observed in the perivascular region inside the IFP. Inflammatory cell infiltration from the perivascular region to the parenchymal region of the IFP was observed on day 3 and reached the IFP surface (synovial membrane) on day 7. Extensive fibrosis throughout the IFP was observed between days 5 and 7 after MIA injection. CONCLUSION: Our data indicated that acute joint pain occurs along with the onset of acute inflammatory process. Irreversible structural changes in the IFP, such as extensive fibrosis, are observed prior to persistent pain development. Thus, we consider that this process may play important roles in persistent pain development.


Assuntos
Tecido Adiposo/patologia , Artralgia/patologia , Artrite Experimental/patologia , Osteoartrite/patologia , Membrana Sinovial/patologia , Tecido Adiposo/fisiopatologia , Animais , Artralgia/induzido quimicamente , Artralgia/fisiopatologia , Artralgia/psicologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/fisiopatologia , Artrite Experimental/psicologia , Comportamento Animal , Progressão da Doença , Fibrose , Ácido Iodoacético , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/fisiopatologia , Osteoartrite/psicologia , Percepção da Dor , Limiar da Dor , Ratos Wistar , Membrana Sinovial/fisiopatologia , Fatores de Tempo , Suporte de Carga
20.
Life Sci ; 218: 284-291, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611783

RESUMO

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease which poses a need to explore effective yet safe pharmacotherapeutic options. The current work aimed to study the therapeutic role of nicorandil in controlling RA. EXPERIMENTAL APPROACH: Complete Freund's adjuvant (CFA)-induced arthritis model was applied by injecting 400 µL of CFA in the right hind paw at day 0 and day 7. Four groups of rats were used as follows: normal-control (CTRL), CFA-induced arthritis (ART), CFA-induced arthritis treated with diclofenac (DIC) and CFA-induced arthritis treated with nicorandil (NIC). Both NIC and DIC were administered at day 14 for two weeks. Paw volume, knee joint diameter, pain behavior assessment as well as body weight were all periodically recorded throughout the experimental period. Following the sacrifice of animals at day 28, gene expressions of TLR-4, MyD88 and TRAF6 as well as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor Kappa B (NF-κB) were quantified in hind paws tissue. Finally, the serum levels of the inflammatory biomarkers (tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) together with the histopathological examination of sections in the rat hind paw were recorded. RESULTS: Both NIC and DIC proved promising anti-arthritic potential mediated, at least in part through switching off TLR4-MyD88-TRAF6 axis as well as downstream TRAF6 dependent activated MAP kinases and NF-κB. CONCLUSION AND IMPLICATIONS: Nicorandil, via interfering with TLR4 signaling, sheds light on a potential clinical role of the drug in pursuit for safe and effective regimens for RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Adjuvante de Freund/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , Nicorandil/farmacologia , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo , Adjuvantes Imunológicos/toxicidade , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Masculino , Fator 88 de Diferenciação Mieloide/genética , Medição da Dor , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/genética , Receptor 4 Toll-Like/genética , Vasodilatadores/farmacologia
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