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1.
Int J Exp Pathol ; 101(1-2): 55-64, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32459025

RESUMO

Rheumatoid arthritis is a disabling autoimmune disease with a high global prevalence. Treatment with disease-modifying anti-arthritic drugs (DIMARDs) has been routinely used with beneficial effects but with adverse long-term consequences; novel targeted biologics and small-molecule inhibitors are promising options. In this study, we investigated whether purified omega unsaturated fatty acids (ω-UFAs) and dialysable leukocyte extracts (DLEs) prevented the development of arthritis in a model of collagen-induced arthritis (CIA) in mice. We also investigated whether the transcription factor NF-κB and the NLRP3 inflammasome were involved in the process and whether their activity was modulated by treatment. The development of arthritis was evaluated for 84 days following treatment with nothing, dexamethasone, DLEs, docosahexaenoic acid, arachidonic acid, and oleic acid. Progression of CIA was monitored by evaluating clinical manifestations, inflammatory changes, and histological alterations in the pads' articular tissues. Both DLEs and ω-UFAs led to an almost complete inhibition of the inflammatory histopathology of CIA and this was concomitant with the inhibition of NF-kB and the inhibition of the activation of NLRP3. These data suggest that ω-UFAs and DLEs might have NF-κB as a common target and that they might be used as ancillary medicines in the treatment of arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Cartilagem Articular/efeitos dos fármacos , Extratos Celulares/farmacologia , Ácidos Graxos Insaturados/farmacologia , Leucócitos , Animais , Ácido Araquidônico/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Colágeno Tipo II , Diálise , Ácidos Docosa-Hexaenoicos/farmacologia , Feminino , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oleico/farmacologia
2.
PLoS One ; 15(4): e0231734, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294140

RESUMO

Osteoarthritis is a degenerative disease that causes substantial changes in joint tissues, such as cartilage degeneration and subchondral bone sclerosis. Chondroitin sulfate and glucosamine are commonly used products for the symptomatic treatment of osteoarthritis. The aim of the present study was to investigate the effects of these products when used as structure-modifying drugs on the progression of osteoarthritis in the rabbit temporomandibular joint. Thirty-six New Zealand rabbits were divided into 3 groups (n = 12/group): control (no disease); osteoarthritis (disease induction); and treatment (disease induction and administration of chondroitin sulfate and glucosamine). Osteoarthritis was induced by intra-articular injection of monosodium iodoacetate. Animals were killed at 30 and 90 days after initiation of therapy. The treatment was effective in reducing disease severity, with late effects and changes in the concentration of glycosaminoglycans in the articular disc. The results indicate that chondroitin sulfate and glucosamine may have a structure-modifying effect on the tissues of rabbit temporomandibular joints altered by osteoarthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Sulfatos de Condroitina/administração & dosagem , Glucosamina/administração & dosagem , Osteoartrite/tratamento farmacológico , Articulação Temporomandibular/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/diagnóstico , Artrite Experimental/patologia , Cartilagem Articular/citologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Humanos , Injeções Intra-Articulares , Injeções Subcutâneas , Ácido Iodoacético/administração & dosagem , Ácido Iodoacético/toxicidade , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/diagnóstico , Osteoartrite/patologia , Coelhos , Índice de Gravidade de Doença , Articulação Temporomandibular/patologia
3.
Chem Biol Interact ; 324: 109095, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289289

RESUMO

Rheumatoid Arthritis (RA) affects approximately 1% of the total world population. Despite incessant research and development of new therapeutic agents, management of RA is still a troublesome affair. Histone Deacetylase 1 (HDAC1) is an epigenetic regulator which play important role in pathogenesis of RA. In present study, we hypothesized that Phenethyl isothiocyanate (PEITC), a potent inhibitor of HDAC1, may ameliorate RA. Efficacy of PEITC was evaluated in Complete Freund's Adjuvant (CFA) induced arthritis model in rats. CFA (0.1 ml) was injected subplantarly in the left hind paw on day 0 to all the groups except normal control. The administration of test drug PEITC (10, 24 & 50 mg/kg) and standard drug Ibuprofen started simultaneously and was continued for 21 days. Paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion were evaluated. Further, radiographic studies, TNF-alpha as well as HDAC1 levels in synovial tissue homogenate and histological analysis were performed. Prophylactic treatment of PEITC attenuated paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion in dose dependent manner. Furthermore, there was significant decrease in TNF-alpha as well as HDAC1 levels in synovial tissue homogenate. Histological analysis revealed no cartilage damage, bone erosion, hyperplasia at synovial lining as well as infiltration of inflammatory cells in treatment group. Results of this study suggest potent anti-rheumatoid arthritis activity of Phenethyl isothiocyanate in CFA induced RA model in rats.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Isotiocianatos/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Animais , Artrite Experimental/induzido quimicamente , Edema/tratamento farmacológico , Pé/patologia , Articulações do Pé/patologia , Adjuvante de Freund , Ibuprofeno/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Dor/tratamento farmacológico , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
4.
PLoS One ; 15(3): e0230657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208438

RESUMO

BACKGROUND: High-grade inflammation may play a pivotal role in the pathogenesis of left ventricular (LV) dysfunction. Evidence to support a role of systemic inflammation in mediating impaired LV function in experimental models of rheumatoid arthritis (RA) remains limited. The aim of the present study was to determine the effects of high-grade systemic inflammation on LV diastolic and systolic function in collagen-induced arthritis (CIA). METHODS: To induce CIA, bovine type-II collagen emulsified in incomplete Freund's adjuvant was injected at the base of the tail into 21 three-month old Sprague Dawley rats. Nine-weeks after the first immunisation, LV function was assessed by pulsed Doppler, tissue Doppler imaging and Speckle tracking echocardiography. Cardiac collagen content was determined by picrosirius red staining; circulating inflammatory markers were measured using ELISA. RESULTS: Compared to controls (n = 12), CIA rats had reduced myocardial relaxation as indexed by lateral e' (early diastolic mitral annular velocity) and e'/a' (early-to-late diastolic mitral annular velocity) and increased filling pressures as indexed by E/e'. No differences in ejection fraction and LV endocardial fractional shortening between the groups were recorded. LV global radial and circumferential strain and strain rate were reduced in CIA rats compared to controls. Higher concentrations of circulating inflammatory markers were associated with reduced lateral e', e'/a', radial and circumferential strain and strain rate. Greater collagen content was associated with increased concentrations of circulating inflammatory markers and E/e'. CONCLUSION: High-grade inflammation is associated with impaired LV diastolic function and greater myocardial deformation independent of haemodynamic load in CIA rats.


Assuntos
Artrite Experimental/fisiopatologia , Função Ventricular Esquerda/fisiologia , Animais , Artrite Experimental/induzido quimicamente , Biomarcadores/sangue , Biomarcadores/metabolismo , Pressão Sanguínea , Peso Corporal , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Bovinos , Colágeno/análise , Colágeno Tipo II/toxicidade , Ecocardiografia Doppler de Pulso , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
5.
PLoS One ; 15(3): e0230719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218599

RESUMO

INTRODUCTION: Epidemiologically, cigarette smoking is a well-known risk factor for the pathogenesis of rheumatoid arthritis (RA). However, there has been few plausible explanations why cigarette smoking aggravated RA. We investigated the causal effect of smoking in experimental model of arthritis development. METHODS: During induction of experimental arthritis with collagen challenge, mice were exposed to a smoking environment with 3R4F cigarettes. Generated smoke was delivered to mice through a nose-only exposure chamber (ISO standard 3308). Human cartilage pellet was challenged by cigarette smoke extract to identify citrullinating potential in vitro. RESULTS: Cigarette smoke exacerbated arthritis in a collagen-induced arthritis (CIA) model. Exposure to smoke accelerated the onset of arthritis by 2 weeks compared to the conventional model without smoke. Citrullination of lung tissue as well as tarsal joints were revealed in smoke-aggravated CIA mice. Interestingly, tracheal cartilage was a core organ regarding intensity and area size of citrullination. The trachea might be an interesting organ in viewpoint of sharing cartilage with joint and direct smoke exposure. Anti-CCP antibodies were barely detected in the serum of CIA mice, they were significantly elevated in cigarette smoke group. Citrullinated antigens were increased in the serum of smoke-exposed mice. Lastly, a cigarette smoke extract enhanced human cartilage citrullination in vitro. CONCLUSIONS: Missing link of arthritic mechanism between smoke and RA could be partially explained by tracheal citrullination. To control tracheal cartilage citrullination may be beneficial for preventing arthritis development or aggravation if cigarette smoke is becoming a risk factor to pre-arthritic individual.


Assuntos
Artrite Experimental/induzido quimicamente , Fumar Cigarros/efeitos adversos , Animais , Artrite Experimental/patologia , Citrulinação/efeitos dos fármacos , Feminino , Camundongos , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia
6.
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
7.
Biochem Pharmacol ; 174: 113822, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987855

RESUMO

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease with complicated pathogenesis. IL-17-producing T helper cells (Th17) are important players in the RA process. Despite numerous researches have proven that microRNAs (miRNAs) are crucial to regulate autoimmune diseases including RA, the effect of miRNAs on Th17 cell differentiation and function in the RA progress is not clear. Here, our results showed that the expression of miRNA let-7g-5p was substantially lower in RA patients and CIA mice compared with healthy controls, accompanied by the increased Th17 cell population. Furthermore, the inhibition of let-7g-5p on Th17 cell differentiation and function were verified in vitro. Notably, the disease severity in CIA mice was significantly alleviated after the treatment of let-7g-5p mimics. In addition, let-7g-5p mimics treatment markedly down-regulated the frequency of Th17 cells in CIA mice. Taken together, our findings indicate that let-7g-5p can ameliorate CIA through blocking the differentiation of Th17 cells, which may be a novel strategy to treat autoimmune diseases such as RA.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Diferenciação Celular/fisiologia , MicroRNAs/biossíntese , Células Th17/metabolismo , Idoso , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Pessoa de Meia-Idade , Mimetismo Molecular/efeitos dos fármacos , Mimetismo Molecular/fisiologia , Células Th17/efeitos dos fármacos , Células Th17/patologia
8.
Int J Mol Sci ; 21(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936141

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was suppressor of cytokine signaling 3 (Socs3), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, Socs3, was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/prevenção & controle , Peptídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Colágeno , Modelos Animais de Doenças , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Food Chem Toxicol ; 135: 110958, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715307

RESUMO

Nerolidol is naturally occurring sesquiterpene has wide range of biological properties including anti-inflammatory activity. However, it has high volatility with low solubility in nature. The present study aimed to develop and characterized nano-encapsulated nerolidol and evaluated its activity on zymosan-induced arthritis model. Nano-capsules were produced by interfacial deposition of preformed polymer method and characterized by particle size, pH, polydispersity index (PDI), zeta potential, drug content and transmission electron microscopy (TEM). In vitro cytotoxicity of formulations was evaluated by alamar blue and MTT assays. In vivo neutrophils migration assay was performed on intra-articular zymosan-induced arthritis model in mice. Nano-encapsulated nerolidol suspensions presented adequate properties: mean diameter of particles 219.5 ±â€¯8.4 nm, pH: 6.84 ±â€¯0.5, PDI≤0.2, the zeta potential was -20.3 ±â€¯3.6 mV and drug content 71,2 ±â€¯1.3%. The formulations did not demonstrated cytotoxicity under the conditions assessed. Nerolidol 300 mg/kg inhibited neutrophils migration into joint cavity by 18.8% remains compared with control group, and nano-encapsulated nerolidol 3 mg/kg inhibited (26.7% remains) similar to free nerolidol 10 mg/kg (27.4% remains). Histological, quantification of pro-inflammatory and anti-inflammatory cytokines proves the same results. In conclusion the data suggests that nanoencapsulation of nerolidol improved its anti-inflammatory effect on arthritis in mice.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Portadores de Fármacos/química , Nanocápsulas/química , Sesquiterpenos/uso terapêutico , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/induzido quimicamente , Linhagem Celular Tumoral , Feminino , Camundongos , Tamanho da Partícula , Zimosan
10.
Antioxid Redox Signal ; 32(3): 161-172, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31873060

RESUMO

Aims: In this study, we investigate the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in autoimmune diseases. We focus on oxidative regulation at the interaction between antigen-presenting cells (APCs) and T cells, and consequent effect of ROS and RNS on type II collagen (CII)-induced arthritis (CIA) model in mice. Results: Mice deficient in ROS and peroxide, due to a mutation in Ncf1 gene, develop an exaggerated CIA and a stronger T cell response to CII. In contrast, nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was found to protect against CIA. The most pronounced protective effect was observed when L-NAME treatment started immediately after CII immunization. Ten days after immunization, the CII-reactive T cell-proliferative response was greater in Ncf1-mutant mice that were treated with L-NAME. T cells from L-NAME-treated mice, primed with CII, showed lower interleukin-2 secretion in response to CII in vitro. Moreover, inhibition of RNS production resulted in dysregulation of NOS1 (neuronal) expression in CII-reactive T cells. Innovation and Conclusion: The results support that deficiency of a paracrine factor as ROS and peroxide released by APC leads to pronounced activation of T cells and enhanced arthritis. An intrinsic factor might be RNS produced by NOS1, which likely enhanced T cell activation in an autocrine manner.


Assuntos
Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Colágeno Tipo II/farmacologia , Espécies Reativas de Nitrogênio/imunologia , Espécies Reativas de Oxigênio/imunologia , Linfócitos T/imunologia , Animais , Proliferação de Células/fisiologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , NG-Nitroarginina Metil Éster/imunologia
11.
Oxid Med Cell Longev ; 2019: 8564681, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827706

RESUMO

Osteoarthritis (OA) is a multifactorial and inflammatory disease characterized by cartilage destruction that can cause disability among aging patients. There is currently no effective treatment that can arrest or reverse OA progression. Kruppel-like factor 2 (KLF2), a member of the zinc finger family, has emerged as a transcription factor involved in a wide variety of inflammatory diseases. Here, we identified that KLF2 expression is downregulated in IL-1ß-treated human chondrocytes and OA cartilage. Genetic and pharmacological overexpression of KLF2 suppressed IL-1ß-induced apoptosis and matrix degradation through the suppression of reactive oxygen species (ROS) production. In addition, KLF2 overexpression resulted in increased expression of heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) through the enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Further, Nrf2 inhibition abrogated the chondroprotective effects of KLF2. Safranin O/fast green and TUNEL staining demonstrated that adenovirus-mediated overexpression of KLF2 in joint cartilage protects rats against experimental OA by inhibiting cartilage degradation and chondrocyte apoptosis. Immunohistochemical staining revealed that KLF2 overexpression significantly decreases MMP13 expression caused by OA progression in vivo. This in vitro and in vivo study is the first to investigate the antioxidative effect and mechanisms of KLF2 in OA pathogenesis. Our results collectively provide new insights into OA pathogenesis regulated by KLF2 and a rationale for the development of effective OA intervention strategies.


Assuntos
Elementos de Resposta Antioxidante/genética , Artrite Experimental/prevenção & controle , Fatores de Transcrição Kruppel-Like/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteoartrite/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Células Cultivadas , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ácido Iodoacético/toxicidade , Fatores de Transcrição Kruppel-Like/genética , Masculino , Fator 2 Relacionado a NF-E2/genética , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
12.
Pak J Pharm Sci ; 32(5): 1995-2001, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31813863

RESUMO

This study was to investigate the effect of methotrexate in combination therapy by the characteristic cytokine in Th17 cells and the frequency of Tregs, which involved in the induction and pathological progress of rheumatoid arthritis (RA). The collagen-induced arthritis rats were treated with methotrexate + prednisone, methotrexate + disease-modifying rheumatic drugs (DMARDs) and methotrexate + TNFi, respectively. The following parameters were observed to evaluate three treatments: the frequency and function of Th17 cells and Tregs, the scores of X-rays, H&E staining and immunohistochemistry. For rats starting methotrexate + prednisone (low doses), the frequency and suppressive function of Th17 cells decreased while the frequency of Tregs increased, which were the same in methotrexate + TNFi. Immunohistochemical in the pathological sections of ankle joint showed the same results. The effect of methotrexate + DMARDs treatment was slightly inferior to the other combination therapies. In summary, rats treated with methotrexate + prednisone can achieve high level of Tregs and low level of Th17 cells and IL-17. Low doses of glucocorticoid suggesting a critical role in the pathogenesis of rheumatoid arthritis may have the similar effect as DMARDs.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Colágeno/farmacologia , Metotrexato/farmacologia , Animais , Artrite Reumatoide/tratamento farmacológico , Terapia Combinada/métodos , Quimioterapia Combinada/métodos , Glucocorticoides/farmacologia , Masculino , Prednisona , Ratos , Ratos Sprague-Dawley , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos
13.
Drug Deliv ; 26(1): 1140-1154, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31736366

RESUMO

The current study aimed to encapsulate fluvastatin sodium (FVS), a member of the statins family possessing pleiotropic effects in rheumatoid arthritis (RA), into spanlastic nanovesicles (SNVs) for transdermal delivery. This novel delivery could surmount FVS associated oral encumbrances such as apparent first-pass effect, poor bioavailability and short elimination half-life, hence, accomplishing platform for management of RA. To consummate this objective, FVS-loaded SNVs were elaborated by thin film hydration method, utilizing either Span 60 or Span 80, together with Tween 80 or Brij 35 as an edge activator according to full factorial design (24). Applying Design-Expert® software, the influence of formulation variables on SNVs physicochemical properties and the optimized formulation selection were explored. Additionally, the pharmacokinetic studies were scrutinized in rats. Furthermore, in Freund's adjuvant-induced arthritis, rheumatoid markers, TNF-α, IL-10, p38 MAPK, and antioxidant parameters were measured. The optimum SNVs were nano-scaled spherical vesicles (201.54 ± 9.16 nm), having reasonable entrapment efficiency (71.28 ± 2.05%), appropriate release over 8 h (89.45 ± 3.64%) and adequate permeation characteristics across the skin (402.55 ± 27.48 µg/cm2). The pharmacokinetic study disclosed ameliorated bioavailability of the optimum SNVs gel by 2.79- and 4.59-fold as compared to the oral solution as well as the traditional gel, respectively. Moreover, it elicited a significant suppression of p38 MAPK expression and also significant improvement of all other measured biomarkers. Concisely, the foregoing findings proposed that SNVs can be auspicious for augmenting FVS transdermal delivery for management of RA.


Assuntos
Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Fluvastatina/administração & dosagem , Adjuvante de Freund/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pele/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Administração Cutânea , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Disponibilidade Biológica , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Tamanho da Partícula , Permeabilidade , Ratos , Ratos Wistar , Absorção Cutânea
14.
Int J Pharm ; 572: 118800, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678378

RESUMO

The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2 ±â€¯46.8 µg/cm2) and 1.2 times (502.92 ±â€¯24.0 µg/cm2) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔTg = -17.7 °C), which was proved by FTIR and 13C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch.


Assuntos
Analgésicos/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/prevenção & controle , Azepinas/administração & dosagem , Crotonatos/administração & dosagem , Cetoprofeno/administração & dosagem , Dor/prevenção & controle , Absorção Cutânea/efeitos dos fármacos , Toluidinas/administração & dosagem , Adesivo Transdérmico , Ácido Acético , Administração Cutânea , Analgésicos/química , Analgésicos/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Experimental/induzido quimicamente , Azepinas/química , Crotonatos/química , Crotonatos/farmacocinética , Combinação de Medicamentos , Composição de Medicamentos , Interações Medicamentosas , Liberação Controlada de Fármacos , Adjuvante de Freund , Ligação de Hidrogênio , Cetoprofeno/química , Cetoprofeno/farmacocinética , Masculino , Camundongos , Dor/induzido quimicamente , Permeabilidade , Coelhos , Ratos , Toluidinas/química , Toluidinas/farmacocinética
15.
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
16.
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
17.
Life Sci ; 238: 116956, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622607

RESUMO

AIMS: The aim of our study was to study the pathological mechanisms induced by the rheumatoid arthritis (RA) on the Enteric Nervous System (ENS). MAIN METHODS: We evaluated the effect of the chronic arthritis and its treatment with 50 mg/kg quercetin alone (AQ) and combined with 17.5 mg/kg ibuprofen (AIQ) for 60 days on neurons, glial cells and intestinal wall. Other groups were used: control (C), arthritic (A) and arthritic treated with 17.5 mg/kg ibuprofen (AI). After 60 days, the jejunum was removed and processed for immunohistochemical techniques. Immunostainings were performed for HuC/D and S100 (myenteric and submucosal plexuses), and GFAP (only myenteric plexus), while immunolabeling for CD45 and CD20 lymphocytes was performed using cryosections. Western blot was performed for GDNF, S100 and GFAP. KEY FINDINGS: A group yielded a remarkable density decrease of the neurons and glial cells with morphometric changes in the myenteric and submucosal plexuses, reduction of the GDNF expression and GFAP-related parameters (GFAP expression, occupancy area and GFAP-expressing glial cells) and intestinal inflammation and atrophy of the mucosa and intestinal wall. AQ group substantially reversed most of these effects, except for intestinal atrophy of the jejunum. The AI and AIQ groups displayed lower beneficial results than AQ for parameters related to the neurons and glial cells, although AIQ did not prevent the inflammation of the mucosa. SIGNIFICANCE: The severe chronic rheumatoid arthritis induced severe effects on ENS and mucosa, and quercetin treatment continues to be an important antioxidant supplement preventing the progression of the RA severity.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/complicações , Artrite Reumatoide/complicações , Inflamação/tratamento farmacológico , Jejuno/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Quercetina/farmacologia , Animais , Antioxidantes/farmacologia , Artrite Experimental/induzido quimicamente , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/patologia , Inflamação/etiologia , Inflamação/patologia , Jejuno/imunologia , Jejuno/patologia , Masculino , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Neuroproteção/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
PLoS One ; 14(10): e0223244, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31603905

RESUMO

The temporomandibular joint (TMJ) is a fibrocartilaginous tissue critical for chewing and speaking. In patients with temporomandibular disorders (TMDs), permanent tissue loss can occur. Recapitulating the complexity of TMDs in animal models is difficult, yet critical for the advent of new therapies. Synovial fluid from diseased human samples revealed elevated levels of tumor necrosis factor alpha (TNF-alpha). Here, we propose to recapitulate these findings in mice by subjecting murine TMJs with TNF-alpha or CFA (Complete Freund's Adjuvant) in mandibular condyle explant cultures and by local delivery in vivo using TMJ intra-articular injections. Both TNF-alpha and CFA delivery to whole mandibular explants and in vivo increased extracellular matrix deposition and increased cartilage thickness, while TNF-alpha treated explants had increased expression of inflammatory cytokines and degradative enzymes. Moreover, the application of TNF-alpha or CFA in both models reduced cell number. CFA delivery in vivo caused soft tissue inflammation, including pannus formation. Our work provides two methods of chemically induced TMJ inflammatory arthritis through a condyle explant model and intra-articular injection model that replicate findings seen in synovial fluid of human patients, which can be used for further studies delineating the mechanisms underlying TMJ pathology.


Assuntos
Artrite Experimental/imunologia , Cartilagem Articular/imunologia , Matriz Extracelular/imunologia , Transtornos da Articulação Temporomandibular/imunologia , Articulação Temporomandibular/imunologia , Proteína ADAMTS5/genética , Proteína ADAMTS5/imunologia , Adolescente , Adulto , Idoso , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/genética , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Colágeno Tipo II/genética , Colágeno Tipo II/imunologia , Colágeno Tipo X/genética , Colágeno Tipo X/imunologia , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Feminino , Adjuvante de Freund/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Interleucinas/genética , Interleucinas/imunologia , Masculino , Côndilo Mandibular/efeitos dos fármacos , Côndilo Mandibular/imunologia , Côndilo Mandibular/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Líquido Sinovial/imunologia , Articulação Temporomandibular/efeitos dos fármacos , Articulação Temporomandibular/patologia , Transtornos da Articulação Temporomandibular/genética , Transtornos da Articulação Temporomandibular/patologia , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/administração & dosagem
19.
Curr Med Sci ; 39(5): 784-793, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612397

RESUMO

Huai Qi Huang (HQH) exerts great effects in clinic, such as anti-inflammation, immune-regulation, anti-cancer, and so on. However, the mechanism by which HQH protects juvenile idiopathic arthritis (JIA) is obscure. Thus, we explored deeply the protective mechanisms in juvenile collagen-induced arthritis (CIA) rat model. Pyroptosis is Gasdermin D (GSDMD)-dependent programmed cell death, involved in many diseases, such as sepsis. We investigated whether GSDMD-induced pyroptosis take part in mechanisms of juvenile CIA arthritis. Juvenile Wistar rats (3-4 weeks) were injected intradermally with fully emulsified bovine type II collagen and complete Freund's adjuvant to establish CIA rat models. Later, the CIA rats received oral administration of HQH (4.16 g/kg) once a day from the day 21 of modeling, with the treatment lasting for 28 days. Varieties of indicators were measured for evaluation of anti-inflammation effect of HQH, including hind paw swelling, arthritis scores, micro CT, and histopathological changes and the level of pro-inflammatory cytokines in the serum, including tumor necrosis factor alpha (TNF-±) and interleukin-18 (IL-18). The expression of GSDMD and caspase-1 in the joint synovial tissues was detected. The results demonstrated that the expression of the pyroptotic protein GSDMD and its upstream caspase-1 was significantly increased in the synovial tissues of CIA rats. The treatment of HQH ameliorated the symptoms in CIA rats, reduced levels of pro-inflammatory cytokines and hind paw swelling, down-regulated the expression of GDSMD and caspase-1. GSDMD-induced pyroptosis participated in the pathogenesis of CIA rats. The study supported that HQH can effectively improve joints inflammation of juvenile collagen-induced arthritis rats by inhibiting pyroptosis pathway in the joint synovial tissues.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/genética , Artrite Experimental/imunologia , Caspase 1/genética , Caspase 1/imunologia , Bovinos , Colágeno Tipo II/administração & dosagem , Esquema de Medicação , Membro Posterior , Interleucina-18/genética , Interleucina-18/imunologia , Masculino , Piroptose/genética , Ratos , Ratos Wistar , Membrana Sinovial , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Microtomografia por Raio-X
20.
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
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