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1.
Sci Rep ; 11(1): 17971, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504248

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease associated with advanced joint dysfunction. Madhuca indica J. F. Gmel, from the family Sapotaceae, is an Indian medicinal plant reported to have an array of pharmacological properties. The aim of present investigation was to determine the anti-arthritic potential of an isolated phytoconstituent from methanolic leaf extract of Madhuca indica (MI-ALC) against FCA-induced experimental arthritis. Polyarthritis was induced in female rats (strain: Wistar) via an intradermal injection of FCA (0.1 mL) into the tail. Polyarthritis developed after 32 days of FCA administration. Then rats were treated orally with an isolated phytoconstituent from MI-ALC at doses of 5, 10, and 20 mg/kg. Findings suggested that High-Performance Thin-Layer Chromatography, Fourier-Transform Infrared Spectroscopy, and Liquid Chromatography-Mass Spectrometry spectral analyses of the phytoconstituent isolated from MI-ALC confirmed the structure as 3,5,7,3',4'-Pentahydroxy flavone (i.e., QTN). Treatment with QTN (10 and 20 mg/kg) showed significant (p < 0.05) inhibition of increased joint diameter, paw volume, paw withdrawal threshold, and latency. The elevated synovial oxidative stress (Superoxide dismutase, reduced glutathione, and malondialdehyde) and protein levels of Tumor necrosis factor-α (TNF-α) and Interleukin (ILs) were markedly (p < 0.05) reduced by QTN. It also effectively (p < 0.05) ameliorated cyclooxygenase-2 (COX-2), Nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kß) and its inhibitor-α (Ikßα), and ATP-activated P2 purinergic receptors (P2X7) protein expressions as determined by western blot analysis. In conclusion, QTN ameliorates FCA-induced hyperalgesia through modulation of elevated inflammatory release (NF-kß, Ikßα, P2X7, and COX-2), oxido-nitrosative stress, and pro-inflammatory cytokines (ILs and TNF-α) in experimental rats.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonoides/administração & dosagem , Madhuca/química , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Adjuvantes Imunológicos/efeitos adversos , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/isolamento & purificação , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Flavonoides/química , Flavonoides/isolamento & purificação , Adjuvante de Freund/efeitos adversos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
3.
Biomed Pharmacother ; 139: 111635, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243601

RESUMO

This study aimed to evaluate the anti-inflammatory effect of Auraptene (AUR) and Umbelliprenin (UMB) in a rat model of rheumatoid arthritis (RA) induced by using complete Freund's adjuvant (CFA). Paw swelling of adjuvant arthritis rats measured at various times after CFA injection. Over 15 days of RA induction, mediator/cytokine-mediated processes involved in managing the regulation and resolving RA's inflammation were also quantified with ELISA. Histopathological changes were also assessed under a microscope 15 days after the CFA injection. AUR at all doses and UMB administration only at a 16 mM /kg administration dose significantly reduced CFA-induced paw edema level compared to the control group. UMB (64 and 32 mM) and AUR (64, 32, and 16 mM) could reduce the PGE2 (p < .0001-.01) and NO (p < .0001-.05) levels in the treatment groups compared to the negative control group. However, these compounds showed no significant effect on the TNF-α, IFN-γ, TGF-ß, IL-4, and IL-10 levels than the control group (p > .05). Unlike indomethacin and prednisolone, treatment of rats with AUR (16, 32, and 64 mM/kg) and UMB (16 and 32 mM/kg) reduced the level of IL-2 (p < .0001). In all treatment groups, the serum level of IL-17 was significantly reduced compared to the CFA group (p < .001-0.05). We suggested AUR and UMB could diminish inflammation by reducing the serum level of IL-17 and could be considered a proper alternative in the treatment of IL-17 related inflammatory diseases such as rheumatoid arthritis. Given that AUR and UMB apply their anti-inflammatory effects by changing distinct cytokine release/inhibition patterns, their potential application in diverse inflammatory diseases seems different.


Assuntos
Artrite/tratamento farmacológico , Cumarínicos/farmacologia , Adjuvante de Freund/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Umbeliferonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Artrite/metabolismo , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar
4.
Sci Rep ; 11(1): 12516, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131243

RESUMO

We recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21-/-) (n = 16) and wild type C57BL/6 (p21+/+) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1ß stimulation was determined in vitro. Arthritis scores were higher in p21-/- mice than in p21+/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21-/- mice compared to p21+/+ mice. p21-/- mice expressed higher levels of IL-1ß, TNF-α, F4/80, CD86, p-IKKα/ß, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1ß-induced NF-kB signaling. IL-1ß stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/ß and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1ß, IL-6, and TNF-α.


Assuntos
Artrite Experimental/genética , Artrite Reumatoide/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Inflamação/genética , Interleucina-1beta/genética , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/patologia , Antígeno B7-2/genética , Proteínas de Ligação ao Cálcio/genética , Cartilagem/metabolismo , Cartilagem/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/efeitos adversos , Interleucina-1beta/farmacologia , Interleucina-6/genética , Articulação do Joelho , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Knockout , Receptores Acoplados a Proteínas G/genética , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/genética
5.
Food Funct ; 12(12): 5387-5398, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-33983361

RESUMO

Rheumatoid arthritis is emerging as a chronic autoimmune disease worldwide. In this study, the beneficial effects of tuna oil (TO) on collagen-induced arthritis (CIA) mice were investigated. Dietary administration of TO relieved arthritis severity and joint bone erosion, and ameliorated systemic inflammation. Furthermore, TO treatments regulated the phosphorylation of nuclear factor-kappa B (NF-κB) and Wnt1/ß-catenin signaling pathways in the joint, enhanced osteoblastogenesis biomarkers and suppressed osteoclastogenesis biomarkers, and subsequently re-balanced bone remodeling. Moreover, the impaired intestinal epithelial barrier was repaired after TO treatments, along with gut microbiota modulation. By employing fecal microbiota transplantation, we clarified that the beneficial effects of TO in CIA alleviation were mediated by the modulated gut microbiota. These results indicated that gut microbiota mediated the protective effects of tuna oil on collagen-induced arthritis in mice.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/terapia , Colágeno/efeitos adversos , Óleos de Peixe/farmacologia , Microbioma Gastrointestinal/fisiologia , Atum/metabolismo , Animais , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/patologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/patologia , Biomarcadores , Citocinas/análise , Transplante de Microbiota Fecal , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Proteína Wnt1 , beta Catenina
6.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805383

RESUMO

There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.


Assuntos
Artrite Experimental/prevenção & controle , Berberina/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/prevenção & controle , Linfócitos B , Berberina/uso terapêutico , Colágeno Tipo II/toxicidade , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos DBA , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Linfócitos T/imunologia
7.
Eur J Pharm Sci ; 163: 105856, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33882329

RESUMO

This work proposes new methotrexate (MTX) loaded drug delivery systems (DDS) to treat rheumatoid arthritis via the intra-articular route: a poloxamer based thermosensitive hydrogel (MTX-HG), oligochitosan and hypromellose phthalate-based polyelectrolyte complexes (MTX-PEC) and their association (MTX-PEC-HG). MTX-PEC showed 470 ± 166 nm particle size, 0.298 ± 0.108 polydispersity index, +26 ± 2 mV and 74.3 ± 5.8% MTX efficiency entrapment and particle formation was confirmed by infrared spectroscopy and thermal analysis. MTX-HG and MTX-PEC-HG gelled at 36.7°C. MTX drug release profile was prolonged for MTX-HG and MTX-PEC-HG, and faster for MTX-PEC and free MTX. The in vivo effect of the MTX-DDSs systems was evaluated in induced arthritis rats as single intra-articular dose. The assessed parameters were the mechanical nociceptive threshold, the plasmatic IL-1ß level and histological analysis of the tibiofemoral joint. MTX-HG and MTX-PEC-HG performance were similar to free MTX and worse than oral MTX, used as positive control. All DDSs showed some irritative effect, for which further studies are required. MTX-PEC was the best treatment on recovering cartilage damage and decreasing allodynia. Thus, MTX-PEC demonstrated potential to treat rheumatoid arthritis, with the possibility of decreasing the systemic exposure to the drug.


Assuntos
Artrite Reumatoide , Metotrexato , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Liberação Controlada de Fármacos , Hidrogéis , Polieletrólitos , Ratos
8.
Bull Cancer ; 108(6): 643-653, 2021 Jun.
Artigo em Francês | MEDLINE | ID: mdl-33902919

RESUMO

New anti-cancer therapeutics have been developed in the recent years and dramatically change prognosis and patient management. Either used alone or in combination, immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD1/PD-(L)1, act by removing T-cell inhibition to enhance their antitumor response. This change in therapeutic targets leads to a break in immune-tolerance and a unique toxicity profile resulting in immune complications. These side effects, called Immune-Related Adverse Events (IrAEs), can affect all organs, with a wide range of clinical and biological presentations and severity. Various rheumatic and musculoskeletal manifestations have been reported in the literature, ranging from mild arthralgia, polymyalgia rheumatica, to genuine serodefined rheumatoid arthritis and myositis. Tolerance studies suggest some correlations between IrAEs occurrence and tumor response. Assessment of patient musculoskeletal status prior to the start of the ICI is warranted. Management of rheumatic IrAEs does not usually request ICI discontinuation, exception for myositis or very severe forms where it should be discussed. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs) or low dose glucocortioids (<20mg per day). Dose should be adjusted according to severity. The use of disease modifying anti-rheumatic drugs (DMARDs), either conventional and/or biological should be very cautious and result from a shared decision between oncologist and rheumatologist to best manage dysimmunitary complications without hampering the antitumor efficacy of ICI.


Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artralgia/induzido quimicamente , Artralgia/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Glucocorticoides/administração & dosagem , Humanos , Miosite/induzido quimicamente , Miosite/tratamento farmacológico , Polimialgia Reumática/induzido quimicamente , Polimialgia Reumática/tratamento farmacológico , Linfócitos T/efeitos dos fármacos
9.
J Ethnopharmacol ; 273: 113988, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-33667569

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Shentong-Zhuyu decoction (STZYD) has been recognized by the Chinese National Administration of Traditional Chinese Medicine (TCM) as a classic TCM formula. Use of STZYD has shown a satisfactory clinical therapeutic outcome for rheumatoid arthritis (RA); despite this, its bioactive chemical composition and relevant mechanism(s) of this action have not been clearly elucidated. AIM OF THE STUDY: To explore the bioactive chemical composition of STZYD used for RA treatment and its possible mechanism(s) of action. MATERIALS AND METHODS: Serum pharmacochemistry mediated by the UPLC-Q-Exactive MS/MS method was employed to identify the absorbed phytochemical compounds in serum derived from STZYD, which were commonly considered as the potential bioactive compounds. And then, these components were used to construct a compound-target network for RA using a network pharmacology approach, to predict the possible biological targets of STZYD along with potential signaling pathways. Afterwards, we established a Complete Freund's adjuvant (CFA)-induced RA rat model, and observed the anti-RA effect of STZYD by a series of indexes, including foot swelling, ankle diameter, arthritis score, morphological and radiographic analysis, serum inflammatory factors, and histopathological analysis of synovial tissues. Particularly, the predicted pathway by the combination of serum pharmacochemistry and network pharmacology was further validated using RT-qPCR, Western blot, and immunohistochemical analyses in animal experiment. RESULTS: Totally, 38 compounds derived from STZYD have been identified by serum sample analysis. Based on it, 387 genes related to these identified compounds in STZYD and 3807 genes related to RA were collected by network pharmacology. Critically, KEGG analysis indicated that the PI3K/AKT signaling pathway was recommended as one of the main pathway related to anti-RA effect of STZYD. Experimentally, STZYD significantly alleviated CFA-induced arthritis without any visible side-effects. Compared to the RA model group without any treatment, the treatment of STZYD significantly reduced the expression of both mRNA and protein targets in the PI3K/AKT signaling pathway. Furthermore, this result was also corroborated by immunohistochemistry analysis. All these studies could effectively corroborate the predicted result as above, suggested that the feasibility of this integrated strategy. CONCLUSION: This study provided a useful strategy to identify bioactive compounds and the potential mechanisms for TCM formula by integrating serum pharmacochemistry and network pharmacology.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/tratamento farmacológico , Animais , Artrite Reumatoide/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Fitoterapia , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos
10.
Int J Nanomedicine ; 16: 133-145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33447032

RESUMO

Background: Rheumatoid arthritis (RA) is an autoimmune disease that underlies chronic inflammation of the synovial membrane. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat RA. However, a long list of adverse events associated with long-term treatment regimens with NSAIDs negatively influences patient compliance and therapeutic outcomes. Aim: The aim of this work was to achieve site-specific delivery of celecoxib-loaded spanlastic nano-vesicle-based delivery system to the inflamed joints, avoiding systemic administration of large doses. Methodology: To develop spanlastic nanovesicles for transdermal delivery of celecoxib, modified injection method was adopted using Tween 80 or Brij as edge activators. Entrapment efficiency, vesicle size, ex vivo permeation, and morphology of the prepared nano-vesicles were characterized. Carbopol-based gels containing the selected formulations were prepared, and their clarity, pH, rheological performance, and ex vivo permeation were characterized. Celecoxib-loaded niosomes and noisome-containing gels were developed for comparison. The in vivo efficacy of the selected formulations was evaluated in a rat model of Freund's complete adjuvant-induced arthritis. Different inflammatory markers including TNF-α, NF-кB and COX-2 were assessed in paw tissue before and after treatment. Results: The size and entrapment efficiency of the selected spanlastic nano-vesicle formulation were 112.5 ± 3.6 nm, and 83.6 ± 2.3%, respectively. This formulation has shown the highest transdermal flux and permeability coefficient compared to the other investigated formulations. The spanlastics-containing gel of celecoxib has shown transdermal flux of 6.9 ± 0.25 µg/cm2/hr while the celecoxib niosomes-containing gel and unprocessed celecoxib-loaded gel have shown 5.2 ± 0.12 µg/cm2/hr and 0.64 ± 0.09 µg/cm2/hr, respectively. In the animal model of RA, the celecoxib-loaded spanlastics-containing gel significantly reduced edema circumference and significantly suppressed TNF-α, NF-кB and COX-2 levels compared to the niosomes-containing gel, the marketed diclofenac sodium gel, and unprocessed celecoxib-loaded gel. Conclusion: The spanlastic nano-vesicle-containing gel represents a more efficient site-specific treatment for topical treatment of chronic inflammation like RA, compared to commercial and other conventional alternatives.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Celecoxib/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , NF-kappa B/metabolismo , Nanopartículas/química , Fator de Necrose Tumoral alfa/metabolismo , Administração Cutânea , Administração Tópica , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/genética , Celecoxib/farmacologia , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Adjuvante de Freund , Regulação da Expressão Gênica/efeitos dos fármacos , Cinética , Lipossomos , Masculino , Camundongos , NF-kappa B/genética , Tamanho da Partícula , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Reologia , Absorção Cutânea/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
11.
Diabetes Metab Syndr ; 15(1): 249-255, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33465685

RESUMO

BACKGROUND AND AIMS: Case reports have described occurrence of rheumatoid arthritis (RA) after initiation of Dipeptidyl Peptidase-4 Inhibitors (DPP4i), suggesting a possible adverse effect of the medications. However, the findings from subsequent cohort studies suggest the opposite as they indicate that T2DM patients who used DPP4i tended to have a lower risk of RA. We aimed to investigate the association between use of DPP4i and incident RA in patients with type 2 diabetes mellitus (T2DM) using systematic review and meta-analysis. METHODS: Potentially eligible studies were identified from Medline and EMBASE databases from inception to May 2020 using search strategy that comprised of terms for "Dipeptidyl peptidase-4 inhibitor" and "Rheumatoid arthritis". Eligible study must be cohort study consisting of one cohort of patients with T2DM who were DPP4i users and another cohort of comparators with T2DM who did not receive DPP4i. Then, the study must report effect estimates with 95% confidence intervals (95% CIs) comparing incident RA between DPP4i users versus comparators. Point estimates with standard errors retrieved from each study were combined together using the generic inverse variance method. RESULTS: A total of 709 articles were identified. After systematic review, four retrospective cohort studies met the eligibility criteria and were included into the meta-analysis. DPP4i users had a significantly lower risk of incident RA compared with comparators with the pooled hazard ratio of 0.72 (95% CI, 0.54-0.96; I2 75%). CONCLUSION: This systematic review and meta-analysis found a significant association between DPP4i use and a lower risk of incident RA.


Assuntos
Artrite Reumatoide/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Artrite Reumatoide/prevenção & controle , Estudos de Coortes , Humanos
12.
Sci Rep ; 11(1): 1995, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479267

RESUMO

The joint disease called pararamosis is an occupational disease caused by accidental contact with bristles of the caterpillar Premolis semirufa. The chronic inflammatory process narrows the joint space and causes alterations in bone structure and cartilage degeneration, leading to joint stiffness. Aiming to determine the bristle components that could be responsible for this peculiar envenomation, in this work we have examined the toxin composition of the caterpillar bristles extract and compared it with the differentially expressed genes (DEGs) in synovial biopsies of patients affected with rheumatoid arthritis (RA) and osteoarthritis (OA). Among the proteins identified, 129 presented an average of 63% homology with human proteins and shared important conserved domains. Among the human homologous proteins, we identified seven DEGs upregulated in synovial biopsies from RA or OA patients using meta-analysis. This approach allowed us to suggest possible toxins from the pararama bristles that could be responsible for starting the joint disease observed in pararamosis. Moreover, the study of pararamosis, in turn, may lead to the discovery of specific pharmacological targets related to the early stages of articular diseases.


Assuntos
Artrite Reumatoide/epidemiologia , Artropatias/epidemiologia , Lepidópteros/patogenicidade , Osteoartrite/epidemiologia , Toxinas Biológicas/toxicidade , Animais , Artrite Reumatoide/induzido quimicamente , Humanos , Inflamação/induzido quimicamente , Inflamação/epidemiologia , Artropatias/induzido quimicamente , Artropatias/patologia , Lepidópteros/química , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/epidemiologia , Osteoartrite/induzido quimicamente , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Toxinas Biológicas/isolamento & purificação , Peçonhas/efeitos adversos , Peçonhas/química
13.
Am J Ind Med ; 64(4): 245-250, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33512020

RESUMO

BACKGROUND: There is growing evidence that exposure to organic solvents can play a role in the etiology of rheumatoid arthritis (RA). This prospective cohort study aimed to investigate the association between RA and toluene exposure. METHODS: The study cohort consisted of Korea Occupational Safety and Health Agency data from male workers exposed to toluene who had undergone a toluene-associated special medical examination at least once between January 1, 2000 and December 31, 2004 (n = 148,870). The morbidity from RA based on hospital admission records was estimated from 2000 to 2005 using National Health Insurance Claim Data. The standardized admission ratio (SAR) for RA was calculated with reference to the general population. Levels of urinary hippuric acid (HA), a metabolite of toluene, were measured and used for exposure assessment. RESULTS: Toluene-exposed workers were at an elevated risk of seropositive rheumatoid arthritis (ICD-10 code M05) with an SAR of 2.38 (95% confidence interval [CI]: 1.14-4.37) and other rheumatoid arthritis (M06) with an SAR of 1.22 (95% CI: 0.91-1.59). When data were stratified according to the duration of toluene exposure and by tertiles of urinary HA level, no significant difference was apparent. CONCLUSION: SARs of the toluene-exposed workers are higher than that of the general reference population, indicating that exposure to toluene may contribute to an increased risk of RA. Further studies of toluene-exposed workers with longer follow-up are needed.


Assuntos
Artrite Reumatoide/epidemiologia , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Vigilância da População , Solventes/toxicidade , Tolueno/toxicidade , Adulto , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/urina , Hipuratos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/urina , Estudos Prospectivos , República da Coreia , Adulto Jovem
14.
Rheumatol Int ; 41(1): 33-42, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32743706

RESUMO

Immune checkpoint inhibitors (ICI) associate with a wide range of immune-related adverse events (Ir-AE), including musculoskeletal manifestations. We aimed at identifying all studies reporting musculoskeletal Ir-AE. An electronic (Medline, Scopus and Web of Science) search was performed using two sets of key words. The first set consisted of: arthritis, musculoskeletal, polymyalgia rheumatica and myositis. The second set consisted of: anti-PD-1, anti-PD-L1, anti-CTLA-4, ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab. We identified 3 prospective studies, 17 retrospective studies and 4 case series reporting 363 patients in total. Combined data from all three prospective studies provide a prevalence rate of 6.13%. Most patients were males (59.68%) and the vast majority (73%) were on programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors. Most studies report a median time of ≤ 12 weeks from first ICI administration to symptom onset. The main clinical phenotypes reported were: (a) inflammatory arthritis (57.57%), (b) myositis (14.04%) and (c) polymyalgia rheumatica (PMR) (12.12%). A total of 256 patients required steroids (70.52%) and 67 patients (18.45%) were treated with DMARDs. Positive auto-antibodies and family history of any autoimmune disease were present in 18.48% and 19.04% of cases, respectively. Only a few patients (19%) had to discontinue treatment due to musculoskeletal Ir-AE. Two prospective studies show that significantly more patients with musculoskeletal Ir-AE exhibit a favorable oncologic response compared to patients not exhibiting such manifestations whereas retrospective studies show that 77.22% of patients with musculoskeletal Ir-AE have a good tumor response. One out of 15 patients treated with ICI will develop musculoskeletal Ir-AE; in most cases the severity of these manifestations is mild/moderate and usually ICI may be continued. Rheumatologists should familiarize with this new clinical entity and develop relevant therapeutic algorithms.


Assuntos
Artrite Reumatoide/induzido quimicamente , Inibidores de Checkpoint Imunológico/efeitos adversos , Miosite/induzido quimicamente , Polimialgia Reumática/induzido quimicamente , Artrite Reumatoide/epidemiologia , Feminino , Humanos , Masculino , Miosite/epidemiologia , Polimialgia Reumática/epidemiologia , Prevalência
15.
Rheumatol Int ; 41(4): 795-797, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33196874

RESUMO

Hair dye (HD) and its component para-phenylenediamine (PPD) are commonly used to enhance beauty and youth. HD is associated with allergic contact reactions and the development of autoimmune phenomena. A 28-year-old woman presented to us complaining of pain and swelling affecting the small joints of the hands bilaterally lasting for 7 weeks. Laboratory evaluation was remarkable only for an increase of acute-phase reactants, while the rest of laboratory tests including serological tests for viruses, as well as immunological tests were negative or within normal limits. She noticed a close correlation between the onset of symmetrical polyarthritis and the use of HD product. Thus, after excluding other possibilities of inflammatory arthritides, the diagnosis of HD-induced arthritis was made. The patient was treated with naproxen, and after 3 weeks, she had a complete clinical response with decrease of acute-phase reactants. Thus, we review and discuss the relevant literature of cases related with the use of HD and arthritis development. This is the first described case of HD-induced arthritis. Physicians must be aware and recognize these symptoms and signs of patients exposed to HD and treat them appropriately.


Assuntos
Artrite Reumatoide/induzido quimicamente , Corantes/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Tinturas para Cabelo/efeitos adversos , Fenilenodiaminas/efeitos adversos , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Dermatite Alérgica de Contato/tratamento farmacológico , Feminino , Humanos , Hipersensibilidade/tratamento farmacológico , Naproxeno/uso terapêutico , Resultado do Tratamento
16.
Mol Immunol ; 129: 78-85, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33229071

RESUMO

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by the destruction of cartilage and bone. The present study aims to investigate the role of HtrA serine peptidase 2 (HtrA2) in the collagen-induced arthritis. The expressions of HtrA2 were determined in the database BioGPS and bone marrow-derived macrophages (BMDMs). The populations of myeloid and lymphoid cells were determined in wild type and HtrA2 knockout (HtrA2MKO) mice using flow cytometry. In addition, the expressions of pro-inflammatory cytokines (Il6, Tnf, and Il1ß) were determined in the activated BMDMs from wild type (WT) and HtrA2MKO mice. STRING database was used to predict the interactive proteins of HtrA2 and Co-Immunoprecipitation was used to confirm these interactions. A collagen-induced arthritis model was established to investigate the effects of HtrA2 on the arthritis symptoms. It was found that HtrA2 reduction was associated with the activation of myeloid cells. Interestingly, HtrA2 deficiency did not affect the development of myeloid and lymphoid cells. Further studies demonstrated that HtrA2 deficiency suppressed the production of pro-inflammatory cytokines in BMDMs induced by lipopolysaccharide or CpG. Co-Immunoprecipitation results demonstrated that HtrA2 enhanced the stability of TNF receptor-associated factor 2 (TRAF2). HtrA2 participated in the activation of the inflammatory response in a collagen-induced arthritis model. In summary, HtrA2 modulates inflammatory responses in BMDMs by controlling TRAF2 stability in a collagen-induced arthritis mouse model.


Assuntos
Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Colágeno/farmacologia , Serina Peptidase 2 de Requerimento de Alta Temperatura A/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/metabolismo , Osso e Ossos/metabolismo , Cartilagem/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo
17.
Bioorg Med Chem Lett ; 34: 127754, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33347967

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitise, and its pathogenesis is complicated. Sphingosine-1-phosphate (S1P) is a lipid produced by sphingosine kinase 1 and 2 (SphK1/2), which participate in some of most-spread skeletal diseases such as rheumatoid arthritis or osteoarthritis. To explore the anti-inflammatory activity of 2-epi-jaspine B analogs as SphKs inhibitors, we used LPS-induced rheumatoid arthritis fibroblast-like synovial cells (HFLS-RA) as the research object to evaluate the anti-inflammatory activity of 16 2-epi-jaspine B analogs and the newly synthesized salt CHJ01. We found that 2-epi-jaspine B analog CHJ01 in hydrochloride salt form has excellent SphK1 inhibitory effect and better anti-RA effect. CHJ01 showed an anti-inflammatory effect similar to that of MTX in vitro, its IC50 value is 8.64 µM. Moreover, the anti-RA effect of CHJ01 was also studied by using a Complete Freund's Adjuvant (CFA)-induced arthritis (AIA) in a rat mode. Pharmacological experiments show that CHJ01 can help to significantly improve the symptoms of rheumatoid arthritis by reducing the swelling volume, arthritis score, spleen index and the level of IL-1ß, TNF-α, IL-6 of AIA rats. Therefore, CHJ01 holds high potential for the treatment of RA.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Reumatoide/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Pirrolidinas/farmacologia , Esfingosina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/química , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Adjuvante de Freund , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirrolidinas/química , Ratos , Esfingosina/química , Esfingosina/farmacologia , Relação Estrutura-Atividade
18.
J Ethnopharmacol ; 269: 113749, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33359861

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aralia echinocaulis has been used in traditional medicines in China and exhibits good effects on rheumatoid arthritis (RA). AIM OF THE STUDY: Aralia echinocaulis is rich in polysaccharides and glycosides. This study aims to explore the effect of total polysaccharide and glycoside (TPG) from A. echinocaulis on an RA rat model and the role of alterations in gut microbes mediated by TPG. MATERIALS AND METHODS: In this study, a collagen-induced arthritis (CIA) rat model was constructed and used to evaluate the effects of TPG in vivo. 16S rRNA sequencing was used to detect the changes in the gut microbiota. A cooccurrence analysis was conducted by calculating Spearman's rank correlations. Microbial functions were predicted using PICRUSt with the KEGG and COG databases. RESULTS: The results showed that TPG from A. echinocaulis could inhibit arthritis, reduce serum IL-1ß and TNF-α levels, and improve synovial pathology in the RA rat model but failed to produce the same results in a pseudoaseptic RA rat model. 16S rRNA sequencing verified that TPG could modulate the gut microbiota community structure of RA rats. The cooccurrence analysis found 19 out of the 50 most abundant genera in a cooccurrence network, of which 16 showed a positive correlation and 3 showed a negative correlation. KEGG pathway and COG function analyses found that TPG-induced alterations in the gut microbiota might be correlated with the circulatory system, excretory system, metabolic diseases, signaling molecules and interactions, coenzyme transport and metabolism, and nucleotide transport and metabolism. CONCLUSIONS: TPG from A. echinocaulis had significant effects on the RA rat model, which are related to the modulation of the gut microbiota. These results are useful to better understanding the mechanisms of TPG in RA.


Assuntos
Aralia/química , Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Glicosídeos/farmacologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Artrite Experimental/sangue , Artrite Experimental/microbiologia , Artrite Reumatoide/induzido quimicamente , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fezes/microbiologia , Glicosídeos/isolamento & purificação , Glicosídeos/uso terapêutico , Interleucina-1beta/sangue , Masculino , Medicina Tradicional Chinesa , Redes e Vias Metabólicas/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Polissacarídeos/isolamento & purificação , Polissacarídeos/uso terapêutico , Substâncias Protetoras/farmacologia , RNA Ribossômico 16S/análise , Ratos Sprague-Dawley , Membrana Sinovial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
19.
Mol Pharm ; 18(1): 305-316, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33253580

RESUMO

DEK protein is critical to the formation of neutrophil extracellular traps (NETs) in rheumatoid arthritis (RA). Blocking DEK using the aptamer DTA via articular injection has been shown to have robust anti-inflammatory efficacy in a previous study. However, DTA is prone to nuclease degradation and renal clearance in vivo. RA is a systemic disease that involves multiple joints, and local injection is impractical in clinical settings. In this study, DTA was modified with methoxy groups on all deoxyribose sugar units and inverted deoxythymidine on the 3' end (DTA4) to enhance its stability against nuclease. DTA4 is stable for 72 h in 90% mouse serum and maintains a high binding affinity to DEK. DTA4 effectively inhibits the formation of NETs and the migration of HUVECs in vitro. DTA4 was then modified with cholesterol on its 5' end to form DTA6. DTA6 dramatically reduces DEK expression in inflammatory RAW264.7 cells. A hydrogel microneedle (hMN) was then fabricated for the transdermal delivery of DTA6. The hMN maintains morphological integrity after absorbing the aptamer solution, effectively pierces the skin, and rapidly releases DTA6 into the dermis. The DTA6-loaded hMN significantly attenuates inflammation and protects joints from cartilage/bone erosion in collagen-induced arthritis (CIA) mice.


Assuntos
Aptâmeros de Nucleotídeos/administração & dosagem , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Colágeno/farmacologia , Proteínas de Ligação a DNA/metabolismo , Hidrogéis/administração & dosagem , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Linhagem Celular , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Substâncias Protetoras/administração & dosagem , Células RAW 264.7
20.
Acta Pharmacol Sin ; 42(5): 755-766, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32855529

RESUMO

ß-arrestin2 (ß-arr2) is, a key protein that mediates desensitization and internalization of G protein-coupled receptors and participates in inflammatory and immune responses. Deficiency of ß-arr2 has been found to exacerbate collagen antibody-induced arthritis (CAIA) through unclear mechanisms. In this study we tried to elucidate the molecular mechanisms underlying ß-arr2 depletion-induced exacerbation of CAIA. CAIA was induced in ß-arr2-/- and wild-type (WT) mice by injection of collagen antibodies and LPS. The mice were sacrificed on d 13 after the injection, spleen, thymus and left ankle joints were collected for analysis. Arthritis index (AI) was evaluated every day or every 2 days. We showed that ß-arr2-/- mice with CAIA had a further increase in the percentage of plasma cells in spleen as compared with WT mice with CAIA, which was in accordance with elevated serum IgG1 and IgG2A expression and aggravating clinical performances, pathologic changes in joints and spleen, joint effusion, and joint blood flow. Both LPS stimulation of isolated B lymphocytes in vitro and TNP-LPS challenge in vivo led to significantly higher plasma cell formation and antibodies production in ß-arr2-/- mice as compared with WT mice. LPS treatment induced membrane distribution of toll-like receptor 4 (TLR4) on B lymphocytes, accordingly promoted the nuclear translocation of NF-κB and the transcription of Blimp1. Immunofluorescence analysis confirmed that more TLR4 colocalized with ß-arr2 in B lymphocytes in response to LPS stimulation. Depletion of ß-arr2 restrained TLR4 on B lymphocyte membrane after LPS treatment and further enhanced downstream NF-κB signaling leading to additional increment in plasma cell formation. In summary, ß-arr2 depletion exacerbates CAIA and further increases plasma cell differentiation and antibody production through inhibiting TLR4 endocytosis and aggravating NF-κB signaling.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Plasmócitos/metabolismo , beta-Arrestina 2/deficiência , Animais , Anticorpos Monoclonais/imunologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/patologia , Peso Corporal/fisiologia , Diferenciação Celular/fisiologia , Colágeno Tipo II/imunologia , Imunidade Humoral/fisiologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Ativação Linfocitária/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo
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