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1.
Toxicon ; 187: 116-121, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32882256

RESUMO

Analgesic mechanism of Botulinum toxin type A (BoNT/A) involves retrograde axonal transport to central nervous system, where it may interact with sensory neurons. Though, some authors suggested that BoNT/A antinociceptive action may also be associated with the inhibition intracellular factors and neuromodulators expressed by immune cells, especially by microglia. Antigen-induced arthritis in the temporomandibular joint (TMJ) of rats is signal by P2X7 receptor/Cathepsin S (CatS)/Fractalkine (FKN) microglia-activated pathway. Thus, we aimed to evaluate the possible modulatory effect of an intra-TMJ injection of BoNT/A on the P2X7/CatS/FKN microglia-activated pathway in the trigeminal subnucleus caudalis of rats with antigen-induced arthritis of the TMJ. A model of antigen-induced arthritis was used on Wistar rats (n = 40) by systemic injections of an emulsion containing complete Freund's adjuvant and methylated bovine serum albumin (mBSA) diluted in PBS. The arthritic condition was stablished by an intra-TMJ injection of mBSA (10 µg/TMJ/week) for 3 weeks. Then, animals were treated with an intra-TMJ injection of BoNT/A (onabotulinumtoxinA, Allergan®; 7U/kg) or vehicle saline. Animals were euthanized 24 h, 7 or 14 days after BoNT/A treatment and their trigeminal nucleus caudalis was harvested to evaluate the protein level of microglial purinergic P2X7 receptor and CX3 chemokine receptor 1 (CX3CR1) by Western blot, and to measure the protein level of microglial modulators CatS, FKN, and the pro-inflammatory cytokines tumor necrosis alfa (TNF-α) and interleukin 1ß (IL-1ß) by enzyme-linked immunosorbent assay (ELISA). The antigen-induced arthritis in the TMJ significantly increased the protein levels of P2X7, CatS, FKN, TNF-α and IL-1ß in the trigeminal subnucleus caudalis (P < 0.05). The intra-TMJ injection of BoNT/A reduced the protein levels of P2X7 in all time points tested. Additionally, BoNT/A significantly reduced the protein levels of CatS, FKN, and TNF-α 14 days after treatment. However, IL-1ß was significantly reduced just 24 h after the BoNT/A intra-TMJ treatment. Based on our results, we can suggest that the intra-TMJ injection of BoNT/A may promote a central effect by reducing the P2X7/CatS/FKN microglia-activated pathway in the trigeminal subnucleus caudalis.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Articulação Temporomandibular , Animais , Artrite Experimental/tratamento farmacológico , Quimiocina CX3CL1/metabolismo , Adjuvante de Freund , Injeções Intra-Articulares , Masculino , Microglia/metabolismo , Ratos , Ratos Wistar
2.
Life Sci ; 260: 118261, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795539

RESUMO

AIMS: Rheumatoid arthritis is an autoimmune systemic disorder causing pain, swelling, stiffness, and disability in various joints. This work was designed to evaluate the effect of sitagliptin and tofacitinib on Janus kinase (JAK)/signaling transducer and activator of transcription (STAT) and toll like receptor (TLR-4)/nuclear factor kappa B (NF-κB) signaling pathways in adjuvant induced arthritis in rats. MATERIALS AND METHODS: Severity of arthritis was evaluated and serum was analyzed for inflammatory mediators. The mRNA and protein expression level of the most important members of the two signaling pathways were determined. Lipid profile, transaminases and renal function parameters were assessed. KEY FINDINGS: Sitagliptin and tofacitinib significantly decreased the level of inflammatory parameters, the mRNA and protein expression level of the members of JAK/STAT and TLR-4/NF-κB pathways with more prominent effect of sitagliptin on TLR-4/NF-κB pathway and more expected obvious effect of tofacitinib on JAK/STAT pathway. The combination offered additional anti-inflammatory effect by inhibiting the cross talk between these pathways as inhibition of NF-κB activation decreased the serum level of IL-6 preventing the activation of STAT-3 in tibiotarsal tissues. SIGNIFICANCE: The combination of tofacitinib and sitagliptin normalized serum lipids and blood glucose level which could offer protection against cardiovascular diseases and caused partial reversal of serum transaminases and creatinine levels which can protect against tofacitinb's related hepato and nephrotoxicity. We could conclude that the combination of Sitagliptin with tofacitinib can offer synergistic anti-inflammatory effect and more protective action against side effects of tofacitinib.


Assuntos
Artrite Experimental/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios , Glicemia/análise , Sinergismo Farmacológico , Quimioterapia Combinada , Hipoglicemiantes , Interleucina-6/sangue , Janus Quinases/metabolismo , Lipídeos/sangue , Masculino , NF-kappa B/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/metabolismo
3.
Life Sci ; 259: 118250, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32791152

RESUMO

AIMS: Several microbial toll-like receptor (TLR) ligands, bacterial DNA and bacterial cell wall fragments have been identified in the synovium of rheumatoid arthritis (RA) patients, proving bacterial involvement in the pathogenesis of RA. The current study aimed to verify that low dose polymyxin B could prevent the development of chronic inflammatory arthritis. METHODS: Twelve days post adjuvant injection, Sprague-Dawley rats were treated twice weekly with methotrexate (0.5 mg/kg) or daily with polymyxin B (1 mg/kg) or with combination of both for 1 or 2 weeks. Arthritis progression was assessed by hind paw swelling, serum levels of tumor growth factor-1ß (TGF-1ß), tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (HS-CRP) and nuclear factor kappa B (NF-κB) were measured using ELISA. Cyclooxygenase-1 (Cox-1) and Cox-2 activities, as well as mRNA expression of TLR-2 and TLR-4 were determined. Histopathological examination of the ankle joint was performed as well as immunohistochemistry for anti-TLR-4. Histopathological assessment of toxic effects on the kidney was performed. KEY FINDINGS: Adjuvant arthritis led to a significant swelling of the hind paw and alteration in all serum parameters, TLR-2 and TLR-4 expression, as well as Cox-2 activity. These alterations were associated with histopathological changes of the joints. Polymyxin B reduced significantly all biomarkers of inflammation, showing better effect of the combination in most of the studied parameters, with minimal signs of nephrotoxicity. SIGNIFICANCE: In conclusion, results showed that polymyxin B possesses significant anti-arthritic activity which may be attributed to inhibition of the TLR-4, NF-κB and Cox-2 signaling pathway.


Assuntos
Artrite Experimental/tratamento farmacológico , Polimixina B/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/fisiopatologia , Artrite Reumatoide/tratamento farmacológico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/fisiologia , Adjuvante de Freund/farmacologia , Inflamação/tratamento farmacológico , Masculino , NF-kappa B/metabolismo , Polimixina B/metabolismo , Polimixina B/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/metabolismo , Receptores Toll-Like/metabolismo , Receptores Toll-Like/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
4.
Braz J Med Biol Res ; 53(6): e9489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401927

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease of knee joints involving pain and inflammation. Rhoifolin is a plant flavonoid known to have antioxidant and anti-inflammatory properties. This study was taken to identify the effect of rhoifolin on complete Freund's adjuvant (CFA)-induced arthritis in the rat model. Treatment with rhoifolin (10 and 20 mg/kg) showed a significant improvement in the overall health parameters such as paw edema and weight loss. This improvement in morphological parameters corroborated the findings with gross morphological changes observed in the histopathological analysis. Rhoifolin treatment also caused a significant decrease in oxidative stress, evident from changes in intracellular levels of glutathione, glutathione peroxidase, malondialdehyde, and superoxide dismutase in the articular cartilage tissue. Moreover, proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin(IL)-1ß, and IL-6 showed a significant downregulation of gene expression and intracellular protein concentration levels. The NF-κB pathway showed a significant attenuation as evident in the significant reduction in the levels of NF-κB p65 and p-IκB-α. These results indicated that rhoifolin can be a natural therapeutic alternative to the extant regimens, which include non-steroidal anti-inflammatory drugs and immunosuppressants. Additionally, the antioxidant and anti-inflammatory action of rhoifolin was probably mediated by the NF-κB pathway. However, the exact target molecules of this pathway need to be determined in further studies.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Citocinas/sangue , Dissacarídeos/administração & dosagem , Flavonoides/administração & dosagem , Adjuvante de Freund/administração & dosagem , Glicosídeos/administração & dosagem , NF-kappa B/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , NF-kappa B/metabolismo , Ratos , Fator de Necrose Tumoral alfa/sangue
5.
Exp Mol Pathol ; 115: 104454, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32422132

RESUMO

The pleiotropic effects of statins, including an antiarthritic potential, have been noted. This study aimed to determine the efficacy of statins on rheumatoid arthritis (RA) and clarify how statins affect its pathogenesis. Fluvastatin (500 µg/kg/day) or vehicle was given per os to env-pX rats, which carry the human T-cell leukemia virus type I env-pX gene and spontaneously develop destructive arthritis mimicking RA, for 30 days. Blood sampling and ultrasonography (US) of the ankle joints were conducted on days 0, 10, 20, and 30. On day 30, all rats were euthanized, and the ankle joints were subjected to histological analysis. To clarify how fluvastatin affects the pathogenesis of RA, comprehensive serum exosomal microRNA (miRNA) analysis was performed. Gene expression in the primary culture of synovial fibroblasts derived from arthritic rat and human and non-arthritic rat periarticular tissues was determined quantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). As a result, the development of arthritis in env-pX rats was significantly suppressed by fluvastatin, which was evident from the viewpoints of serology, US imaging, and histology. Comprehensive serum exosomal miRNA analysis suggested that the expression of Rho GTPase-activating protein 12 (Arhgap12) was decreased in arthritic env-pX rats but increased with the administration of fluvastatin. Corresponding results were obtained by quantitative RT- PCR using primary culture of synovial fibroblasts. The collective findings suggest that fluvastatin prevents the development of arthritis in env-pX rats via the up-regulation of ARHGAP12. This study suggests that ARHGAP12 can be a possible therapeutic target of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/prevenção & controle , Fluvastatina/uso terapêutico , Proteínas Ativadoras de GTPase/metabolismo , Regulação para Cima , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/patologia , Exossomos/efeitos dos fármacos , Exossomos/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fluvastatina/farmacologia , Proteínas Ativadoras de GTPase/genética , Humanos , Inflamação/patologia , Articulações/diagnóstico por imagem , Articulações/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Membrana Sinovial/patologia , Regulação para Cima/efeitos dos fármacos
6.
Phytomedicine ; 71: 153233, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32454348

RESUMO

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability. PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers. CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Propiofenonas/química , Propiofenonas/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Feminino , Flavonoides/farmacocinética , Adjuvante de Freund/efeitos adversos , Interleucina-6/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Micelas , Estresse Oxidativo/efeitos dos fármacos , Propiofenonas/farmacocinética , Ratos Wistar , Solubilidade , Fator de Necrose Tumoral alfa/metabolismo
7.
Life Sci ; 254: 117605, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278692

RESUMO

AIMS: Although chloroquine and diclofenac are not cardiovascular drugs, their chronic administration may trigger cardiotoxicity. We, therefore, evaluated the cardiotoxic impact of diclofenac in chloroquine-treated adjuvant arthritic rats and the protective role of Rho-kinase inhibitors. METHODS: 90 male rats were equally distributed into 9 groups including control. Arthritis was induced by S.C injection of Complete Freund's adjuvant in hind paw plantar surface. Arthritic rats were subdivided into 8 groups, orally treated with: no drug, chloroquine (50 mg/kg), diclofenac sodium (1 mg/kg) and chloroquine + diclofenac. To study the role of Rho-kinase in chloroquine/diclofenac-triggered cardiotoxicity, four arthritic groups were also co-treated with Rho-kinase inhibitors (fasudil or atorvastatin) along with diclofenac and chloroquine + diclofenac. KEY FINDINGS: All treatments significantly elevated serum cardiac injury and dysfunction markers as well as left ventricular malondialdehyde but depleted antioxidants with the greatest effect in the combination group. Chloroquine and/or diclofenac; in particular, their combination shifted the balance between left ventricular pro- and anti-apoptotic proteins towards myocardial apoptosis. Surprisingly, treatment with diclofenac or chloroquine/diclofenac markedly up-regulated cardiac RhoA and Rho-kinase1. Such up-regulation was coupled with a greater increase in cardiac oxidative damage biomarkers in the combination group than in individually-treated ones. However, Rho-kinase inhibition protected against diclofenac-induced increase in myocardial oxidative damage markers. SIGNIFICANCE: Diclofenac greatly amplified cardiac oxidative damage in chloroquine-treated arthritic rats via up-regulation of Rho-kinase1. However, Rho-kinase inhibitors provided cardioprotection against diclofenac toxicity. Overall, they could be used as safer adjuvants to diclofenac during the treatment of rheumatoid arthritis with chloroquine.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Artrite Experimental/tratamento farmacológico , Cloroquina/uso terapêutico , Diclofenaco/toxicidade , Coração/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Masculino , Estresse Oxidativo , Ratos
8.
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
9.
Toxicon ; 178: 33-40, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32250746

RESUMO

Chronic inflammatory pain is a serious clinical problem caused by inflammation of the joints and degenerative diseases and greatly affects patients' quality of life. Persistent pain states are thought to result from the central sensitization of nociceptive pathways in the spinal dorsal horn. Spinal microglia-mediated neuroinflammation plays a pivotal role in the development and maintenance of the central sensitization of chronic inflammatory pain. Botulinum toxin type A (BoNT/A) was recently reported to have analgesic and anti-inflammatory effects. However, the precise mechanism underlying its analgesic effect remains unclear. Although several studies have reported that BoNT/A could regulate neuroflammation, the reduction of neuroinflammation regulated by BoNT/A in chronic inflammatory pain in experimentally induced arthritis has not been reported. The aim of this study was to investigate whether BoNT/A could alleviate adjuvant-arthritis pain via modulating microglia-mediated neuroinflammation and intracellular molecular pathway. The pain behavioral tests were performed before and after CFA immunization as well as after BoNT/A injection. Western blotting and immunofluorescence staining were used to assess the changes of microglial activation markers (ionized calcium binding adaptor molecule 1, IBA-1) and phosphorylation of P38MAPK (P-p38MAPK) in the lumbar spinal cord. TNF-αand P2X4R gene expression were studied by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that (1) the activation of spinal microglia can be continued till 21 days after CFA injection, which suggested its role in the development and maintenance of chronic inflammatory pain. (2) The intra-articular administration of a single effective dose of BoNT/A (5U/10 U) on day 21 after CFA injection significantly reduced nociceptive behaviors and decreased protein overexpression and immunoreactivity for IBA-1 and P-p38MAPK in CFA induced rat. Simultaneously, BoNT/A (5 U) also inhibited the increase in TNF-α mRNA and P2X4R mRNA expression induced by CFA injection. These results suggested that BoNT/A is a potential therapeutic agent for relieving the neuroinflammation that occurs in chronic inflammatory pain by inhibiting the activation of microglial cells and the release of microglia-derived TNF-α. This effect is likely mediated by inhibiting the activation of the P2X4R-P38MAPK signaling pathways in spinal microglial cells.


Assuntos
Artrite Experimental/tratamento farmacológico , Toxinas Botulínicas Tipo A/uso terapêutico , Animais , Inflamação/tratamento farmacológico , Masculino , Ratos , Receptores Purinérgicos P2X4/genética , Receptores Purinérgicos P2X4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Life Sci ; 252: 117629, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32247619

RESUMO

AIMS: To analyze the prostatic compartments, extracellular matrix, microvascularization, transforming growth factor-beta (TGF-ß) and angiotensin II receptors type 1 (AT1) levels, and histopathology of the ventral prostate in a rat model for rheumatoid arthritis, and to evaluate the effect of angiotensin II AT1 receptor blocker (ARB) in the disease. MAIN METHODS: Fifteen male rats (90 days old) were divided into three groups (n = 5/group): control, adjuvant-induced arthritis without (AIA) or with AT1 receptor blocker (AIA + ARB). Animals were euthanized 60 days after immunization. The ventral prostate was collected, weighed, and processed for histological and immunohistochemical analysis. KEY FINDINGS: Our results show that AIA increases production of the prostatic epithelium and extracellular matrix, accompanied by a reduction in the number of tissue capillaries. ARB treatment promotes decreased production of extracellular matrix and increased TGF-ß and AT1 receptor immunostaining. SIGNIFICANCE: AIA may activate specific mechanisms that modify the prostatic environment; the use of ARB attenuates some altered prostate parameters in a rat model for arthritis.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Artrite Experimental/complicações , Artrite Reumatoide/complicações , Próstata/patologia , Doenças Prostáticas/prevenção & controle , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/fisiopatologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Matriz Extracelular/patologia , Masculino , Doenças Prostáticas/etiologia , Ratos , Ratos Wistar
11.
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
12.
Int J Radiat Biol ; 96(7): 857-867, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32216648

RESUMO

Purpose: Low dose radiation has been reported as an effective treatment for rheumatoid arthritis via multiple dose exposures. The present study was designed to increase the therapeutic efficacy of low dose radiation with the minimum exposure level in arthritic rats by concurrent administration of resveratrol (RSV) as an adjunctive therapy with anti-inflammatory properties.Materials and methods: Rats were rendered arthritic by sub-plantar injection of Freund's complete adjuvant (FCA) and exposed to low dose radiation at a total exposure level of 0.5 Gy (2 × 0.25). During the exposure course, RSV (50 mg/kg) was orally administered once daily for two weeks. Diclofenac (3 mg/kg) was administered as a standard anti-inflammatory drug. Paw volume was measured every 4 days. After 28 days of induction, rats were sacrificed and serum was collected for estimation of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), thiobarbituric acid reactive substances (TBARS), and total nitrate/nitrite (NOx). Furthermore, paws were dissected for histopathological examinations and immuno-histochemical estimation of nuclear factor-kappa B p65 (NF-κB p65) expression.Results: Administration of RSV during the low dose radiation exposure course produced a significant decrease in the paw swelling and a potentiated inhibition in the serum levels of TNF-α, IL-1ß, TBARs, and NOx. The dual treatment strategy alleviated the histopathological damage to a greater extent than that produced by each treatment. Moreover, a pronounced suppression of NF-κB p65 expression in the synovial tissue was observed in the combination group. The combination treatment showed a nearly similar potency to that observed in the diclofenac treated group.Conclusion: Administration of RSV augmented the modulatory activity of low dose radiation with minimum exposure level on the disease progression.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/radioterapia , Raios gama/uso terapêutico , Doses de Radiação , Resveratrol/farmacologia , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Articulação do Tornozelo/efeitos da radiação , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Terapia Combinada , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/sangue , Masculino , Dosagem Radioterapêutica , Ratos , Ratos Wistar , Resveratrol/uso terapêutico , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/sangue
13.
Ann Clin Lab Sci ; 50(1): 85-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32161016

RESUMO

The aim of the present study is to investigate the effect of cyclopamine, a hedgehog signaling pathway inhibitor, on adjuvant arthritis (AA), rat articular chondrocyte viability, and part mechanisms in vitro In this study, an AA rat model was established by Freund's complete adjuvant (FCA). The arthritis index (AI), secondary paw swelling degree, and HE staining were used to evaluate whether the model was successfully established. Chondrocytes of the ankle joint of AA rats were cultured and identified. Cyclopamine (0, 0.03, 0.1, 0.3, 1, 3, 10 and 30 mg/l) was administered to determine chondrocyte viability. Chondrocyte apoptosis was detected by Annexin V-FITC/PI double dye. The expression of hedgehog signaling pathway-related proteins Shh, Ptch1, and Gli1 in chondrocytes was detected by western blotting. The results show that AA was successfully induced by FCA since the AI of AA rats and secondary paw swelling degree increased and the cartilage tissue of the rats' ankle joint was damaged. Thus, the chondrocytes were successfully cultured in vitro following the identification of toluidine blue and type II collagen. Cyclopamine (0.03, 0.1, 0.3, 1, 3, 10 and 30 mg/l) could increase the viability of chondrocytes in vitro and reduce the apoptotic rate of chondrocytes. As compared with the control group, different doses of cyclopamine (0.3, 3 and 10 mg/l) significantly decreased the expression of Shh, Ptch1 and Gli1 proteins in AA chondrocytes. Therefore, an AA rat model was successfully established in the present study and cyclopamine improved the viability and inhibited the apoptosis of chondrocytes. This is an effect that may be associated with the inhibition of the chondrocyte hedgehog signaling pathway.


Assuntos
Artrite Experimental/tratamento farmacológico , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Alcaloides de Veratrum/farmacologia , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Sobrevivência Celular , Condrócitos/metabolismo , Condrócitos/patologia , Proteínas Hedgehog/metabolismo , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar
14.
Toxicol Appl Pharmacol ; 391: 114917, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32044269

RESUMO

The hyperplastic phenotype of fibroblast-like synoviocytes (FLSs) plays an important role for synovitis, chronic inflammation and joint destruction in rheumatoid arthritis (RA). Interleukin 17A (IL-17A), a signature pro-inflammatory cytokine effectively influences the hyperplastic transformation of FLS cells and synovial pannus growth. IL-17A cytokine signalling participates in RA pathology by regulating an array of pro-inflammatory mediators and osteoclastogenesis. Cyanidin, a key flavonoid inhibits IL-17A/IL-17 receptor A (IL-17RA) interaction and alleviates progression and disease severity of psoriasis and asthma. However, the therapeutic efficacy of cyanidin on IL-17A cytokine signalling in RA remains unknown. In the present study, cyanidin inhibited IL-17A induced migratory and proliferative capacity of FLS cells derived from adjuvant-induced arthritis (AA) rats. Cyanidin treatment reduced IL-17A mediated reprogramming of AA-FLS cells to overexpress IL-17RA. In addition, significantly decreased expression of IL-17A dependent cyr61, IL-23, GM-CSF, and TLR3 were observed in AA-FLS cells in response to cyanidin. At the molecular level, cyanidin modulated IL-17/IL-17RA dependent JAK/STAT-3 signalling in AA-FLS cells. Importantly, cyanidin activated PIAS3 protein to suppress STAT-3 specific transcriptional activation in AA-FLS cells. Cyanidin treatment to AA rats attenuated clinical symptoms, synovial pannus growth, immune cell infiltration, and bone erosion. Cyanidin reduced serum level of IL-23 and GM-CSF and expression of Cyr 61 and TLR3 in the synovial tissue of AA rats. Notably, the level of p-STAT-3 protein was significantly decreased in the synovial tissue of AA rats treated with cyanidin. This study provides the first evidence that cyanidin can be used as IL-17/17RA signalling targeting therapeutic drug for the treatment of RA and this need to be investigated in RA patients.


Assuntos
Antocianinas/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Interleucina-17/metabolismo , Transdução de Sinais/efeitos dos fármacos , Líquido Sinovial/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/patologia , Movimento Celular/efeitos dos fármacos , Progressão da Doença , Fibroblastos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Janus Quinases/biossíntese , Janus Quinases/genética , Masculino , Ratos , Ratos Wistar , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Membrana Sinovial/patologia , Sinoviócitos/patologia
15.
Pharmacol Rep ; 72(1): 104-114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016833

RESUMO

BACKGROUND: Astaxanthin (ATX), a natural xanthophyll carotenoid, has shown to exert significant protective effects against various diseases via its antioxidant and anti-inflammatory properties. However, its potential role in arthritis is still not reported. Therefore, the aim of the present study was to investigate the potential anti-arthritic properties of ATX against complete Freund's adjuvant (CFA)-induced arthritis rats. METHODS: Adjuvant arthritis was induced by single intraplantar injection of complete Freund's adjuvant (CFA) in the left hind paw of adult female Wistar rats. ATX (25, 50 and 100 mg/kg) and indomethacin (5 mg/kg) were given orally from days 14 to 28. The anti-arthritic activity was evaluated through various nociceptive behavioral tests (mechanical allodynia, mechanical hyperalgesia, cold allodynia, and thermal hyperalgesia), paw edema assessment, and arthritis scores. Serum tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and cyclic citrullinated peptide (CCP) antibody levels were assessed. Moreover, malondialdehyde (MDA), nitrite, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were also evaluated. RESULTS: Oral administration of ATX (50 and 100 mg/kg) exhibited significant anti-arthritic activity via enhancing the nociceptive threshold, reducing paw edema and improving arthritis scores. Moreover, ATX treatment also markedly suppressed inflammatory and oxidative mediators in adjuvant-administered rats. CONCLUSIONS: Our findings suggest that ATX possesses potential anti-arthritic activity, which could be attributed to its anti-inflammatory and antioxidant properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Antirreumáticos/administração & dosagem , Artrite Experimental/patologia , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Adjuvante de Freund , Indometacina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Xantofilas/administração & dosagem , Xantofilas/farmacologia
16.
Nat Commun ; 11(1): 745, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029712

RESUMO

Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC1, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1 leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC1 is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Receptor Tipo 1 de Melanocortina/agonistas , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Variação Genética , Humanos , Imidazóis/farmacologia , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor Tipo 1 de Melanocortina/deficiência , Receptor Tipo 1 de Melanocortina/genética , Receptores Notch/antagonistas & inibidores , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , alfa-MSH/farmacologia
17.
J Pharmacol Exp Ther ; 373(2): 302-310, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32029577

RESUMO

Cinnamaldehyde (Cin), a bioactive cinnamon essential oil from traditional Chinese medicine herb Cinnamomum cassia, has been reported to have multipharmacological activities including anti-inflammation. However, its role and molecular mechanism of anti-inflammatory activity in musculoskeletal tissues remains unclear. Here, we first investigated the effects and molecular mechanisms of Cin in human synoviocyte cells. Then in vivo therapeutic effect of Cin on collagen-induced arthritis (CIA) also studied. Cell Counting Kit CCK-8 assay was performed to evaluate the cell cytotoxicity. Proinflammatory cytokine expression was evaluated using quantitative polymerase chain reaction and ELISA. Protein expression was measured by western blotting. The in vivo effect of Cin (75 mg/kg per day) was evaluated in rats with CIA by gavage administration. Disease progression was assessed by clinical scoring, radiographic, and histologic examinations. Cin significantly inhibited interleukin (IL)-1ß-induced IL-6, IL-8, and tumor necrosis factor-α release from human synoviocyte cells. The molecular analysis revealed that Cin impaired IL-6-induced activation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 1 (STAT1), and STAT3 signaling pathway by inhibiting the phosphorylation of JAK2, STAT1, and STAT3, without affecting NF-κB pathway. Cin reduced collagen-induced swollen paw volume of arthritic rats. The anti-inflammation effects of Cin were associated with decreased severity of arthritis, joint swelling, and reduced bone erosion and destruction. Furthermore, serum IL-6 level was decreased when Cin administered therapeutically to CIA rats. Cin suppresses IL-1ß-induced inflammation in synoviocytes through the JAK/STAT pathway and alleviated collagen-induced arthritis in rats. These data indicated that Cin might be a potential traditional Chinese medicine-derived, disease-modifying, antirheumatic herbal drug. SIGNIFICANCE STATEMENT: In this study, we found that cinnamaldehyde (Cin) suppressed proinflammatory cytokines secretion in rheumatology arthritis synoviocyte cells by Janus kinase/signal transducer and activator of transcription pathway. The in vivo results showed that Cin ameliorated collagen-induced arthritis in rats. These findings indicate that Cin is a potential traditional Chinese medicine-derived, disease-modifying, antirheumatic herbal drug.


Assuntos
Acroleína/análogos & derivados , Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Janus Quinases/fisiologia , Fatores de Transcrição STAT/fisiologia , Sinoviócitos/efeitos dos fármacos , Acroleína/farmacologia , Acroleína/uso terapêutico , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/análise , Feminino , Humanos , Interleucina-1beta/farmacologia , NF-kappa B/metabolismo , Ratos , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacos
18.
Pharm Biol ; 58(1): 157-164, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037930

RESUMO

Context: Er Miao San (EMS) is a traditional Chinese medicine composed of Atractylodis Rhizoma and Phellodendri Cortex in a 1:1 weight ratio. EMS has been used to treat rheumatism in China for many years.Objective: To evaluate the anti-arthritic activity of EMS extract on adjuvant-induced arthritis (AA) in Sprague-Dawley rats and to clarify its mechanisms of action.Materials and methods: EMS (0.75, 1.5 and 3 g/kg, once daily) was orally administered from day 18 after immunization to day 31. The effects of EMS on AA rats were evaluated by histopathological examination, paw swelling and polyarthritis index. The proliferation of fibroblast-like synoviocyte (FLS) and T cells was detected by CCK-8. The percentages of Th17 cells and Treg cells in splenocytes were determined by flow cytometry. Levels of cytokines in serum were detected by ELISA.Results: EMS treatment significantly decreased the paw volume (from 1.20 to 0.81), polyarthritis index (from 9.56 to 4.46) and alleviated ankle joint histopathology in AA rats. EMS inhibited the proliferation of FLS and T cells. Furthermore, EMS treatment decreased Th17 cells (from 4.62 to 2.08%) and increased Treg cells (from 2.77 to 4.75%) in splenocytes. The levels of IL-17A, TNF-α and IL-6 were remarkably decreased in the serum of EMS-treated rats, whereas the levels of IL-10 and TGF-ß1 were significantly increased.Conclusions: EMS exhibits anti-arthritic activity in the AA model by regulating the balance of cytokines and the ratio of Th17 and Treg cells. These insights may provide an experimental basis for the clinical treatment of RA.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Antirreumáticos/administração & dosagem , Artrite Experimental/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Adjuvante de Freund , Masculino , Ratos , Ratos Sprague-Dawley , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo
19.
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
20.
J Dent Res ; 99(4): 446-455, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31977264

RESUMO

Severe inflammation, progressive cartilage, and bone destruction are typical pathologic changes in temporomandibular joint (TMJ) arthritis and lead to great difficulty for treatment. However, current therapy is inefficient to improve degenerative changes in progressive TMJ arthritis. This study investigated the therapeutic effects of human dental pulp stem cells (DPSCs) on severe inflammatory TMJ diseases. Progressive TMJ arthritis in rats was induced by intra-articular injection of complete Freund's adjuvant and monosodium iodoacetate. DPSCs were injected into the articular cavity to treat rat TMJ arthritis, with normal saline injection as control. Measurement of head withdrawal threshold, micro-computed tomography scanning, and histologic staining were applied to evaluate the severity of TMJ arthritis. Results showed that local injection of DPSCs in rats with TMJ arthritis relieved hyperalgesia and synovial inflammation, attenuated cartilage matrix degradation, and induced bone regeneration. Inflammatory factors TNF-α and IFN-γ were elevated in progressive TMJ arthritis and partially decreased by local injection of DPSCs. MMP3 and MMP13 were elevated in the arthritis + normal saline group and decreased in the arthritis + DPSCs group, which indicated amelioration of matrix degradation. The isolated primary synoviocytes were cocultured with DPSCs after inflammatory factors stimulated to explore the possible biological mechanisms. The expression of MMP3 and MMP13 in synoviocytes was elevated after TNF-α and IFN-γ stimulation and partially reversed by DPSC treatment in the in vitro study. The signal transducer and activator of transcription 1 (STAT1) was activated by inflammatory stimulation and suppressed by DPSC coculture. The upregulation of MMP3 and MMP13 triggered by inflammation was blocked by STAT1-specific inhibitor, suggesting that STAT1 regulated the expression of MMP3 and MMP13. In conclusion, this study demonstrated the possible therapeutic effects of local injection of DPSCs on progressive TMJ arthritis by inhibiting the expression of MMP3 and MMP13 through the STAT1 pathway.


Assuntos
Artrite Experimental , Transtornos da Articulação Temporomandibular , Animais , Artrite Experimental/tratamento farmacológico , Adjuvante de Freund , Humanos , Ratos , Fator de Transcrição STAT1 , Transdução de Sinais , Articulação Temporomandibular , Transtornos da Articulação Temporomandibular/tratamento farmacológico , Microtomografia por Raio-X
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