Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.506
Filtrar
1.
Biomed Res Int ; 2021: 5574282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497850

RESUMO

Programmed cell death 1 ligand (PD-L1) and its receptor (PD-1) are key molecules for immunoregulation and immunotherapy. PD-L1 binding PD-1 is an effective way to regulate T or B cell immunity in autoimmune diseases such as rheumatoid arthritis (RA). In our study, we overexpressed PD-L1 by constructing a recombinant of PD-L1-lentiviral vector, which was subsequently used to transfect mouse bone marrow mesenchymal stem cells (MBMMSCs) and significantly suppressed the development of collagen-induced arthritis (CIA) in DBA/1j mice. In addition, PD-L1-transfected MBMMSCs (PD-L1-MBMMSCs) ameliorated joint damage, reduced proinflammatory cytokine expression, and inhibited T and B cell activation. Furthermore, PD-L1-MBMMSCs decreased the number of dendritic cells and increased the numbers of regulatory T cells and regulatory B cells in joints of CIA mice. In conclusion, our results provided a potential therapeutic strategy for RA treatment with PD-L1-MBMMSC-targeted therapy.


Assuntos
Artrite Experimental/terapia , Artrite Reumatoide/terapia , Antígeno B7-H1/administração & dosagem , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Linfócitos T Reguladores/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Células Cultivadas , Modelos Animais de Doenças , Ativação Linfocitária , Masculino , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos DBA
2.
Life Sci ; 284: 119910, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453939

RESUMO

AIMS: Quercetin has been investigated as an agent to treat rheumatoid arthritis. At high doses it improves inflammation and the antioxidant status of arthritic rats, but it also exerts mitochondriotoxic and pro-oxidant activities. Beneficial effects of quercetin have not been found at low doses because of its chemical instability and low bioavailability. In the hope of overcoming these problems this study investigated the effects of long-term administration of quercetin-loaded pectin/casein microparticles on the oxidative status of liver and brain of rats with adjuvant-induced arthritis. MAIN METHODS: Particle morphology was viewed with transmission electron microscopy and the encapsulation efficiency was measured indirectly by X-ray diffraction. Quercetin microcapsules (10 mg/Kg) were orally administered to rats during 60 days. Inflammation indicators and oxidative stress markers were measured in addition to the respiratory activity and ROS production in isolated mitochondria. KEY FINDINGS: Quercetin was efficiently encapsulated inside the polymeric matrix, forming a solid amorphous solution. The administration of quercetin microparticles to arthritic rats almost normalized protein carbonylation, lipid peroxidation, the levels of reactive oxygen species as well as the reduced glutathione content in both liver and brain. The paw edema in arthritic rats was not responsive, but the plasmatic activity of ALT and the mitochondrial respiration were not affected by quercetin, indicating absence of mitochondriotoxic or hepatotoxic actions. SIGNIFICANCE: Quercetin-loaded pectin/casein microcapsules orally administered at a low dose improve oxidative stress of arthritic rats without a strong anti-inflammatory activity. This supports the long-term use of quercetin as an antioxidant agent to treat rheumatoid arthritis.


Assuntos
Artrite Experimental/patologia , Caseínas/química , Microesferas , Estresse Oxidativo , Pectinas/química , Quercetina/farmacologia , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Artrite Experimental/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Varredura Diferencial de Calorimetria , Respiração Celular/efeitos dos fármacos , Edema/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
3.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343136

RESUMO

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismo
4.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360655

RESUMO

Low-dose ozone acts as a bioregulator in chronic inflammatory diseases, biochemically characterized by high oxidative stress and a blocked regulation. During systemic applications, "Ozone peroxides" are able to replace H2O2 in its specific function of regulation, restore redox signaling, and improve the antioxidant capacity. Two different mechanisms have to be understood. Firstly, there is the direct mechanism, used in topical treatments, mostly via radical reactions. In systemic treatments, the indirect, ionic mechanism is to be discussed: "ozone peroxide" will be directly reduced by the glutathione system, informing the nuclear factors to start the regulation. The GSH/GSSG balance outlines the ozone dose and concentration limiting factor. Antioxidants are regulated, and in the case of inflammatory diseases up-regulated; cytokines are modulated, here downregulated. Rheumatoid arthritis RA as a model for chronic inflammation: RA, in preclinical and clinical trials, reflects the pharmacology of ozone in a typical manner: SOD (superoxide dismutase), CAT (catalase) and finally GSH (reduced glutathione) increase, followed by a significant reduction of oxidative stress. Inflammatory cytokines are downregulated. Accordingly, the clinical status improves. The pharmacological background investigated in a remarkable number of cell experiments, preclinical and clinical trials is well documented and published in internationally peer reviewed journals. This should encourage clinicians to set up clinical trials with chronic inflammatory diseases integrating medical ozone as a complement.


Assuntos
Antioxidantes/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo , Ozônio/administração & dosagem , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Catalase/metabolismo , Citocinas/metabolismo , Glutationa/metabolismo , Humanos , Inflamação/etiologia , Inflamação/patologia , Oxidantes Fotoquímicos/administração & dosagem , Oxirredução , Ratos
5.
Immunology ; 164(3): 617-636, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34351636

RESUMO

Proper regulation of B-cell function is essential for effective humoral immunity and maintenance of immune tolerance. Here, we found that FBW7 (F-box/WD40 repeat-containing protein 7) is highly expressed in germinal centre B and B1 cells, and confirmed that it has an intrinsic role in maintaining homeostasis of mature B cells and B-1 cells. FBW7 deletion led to an impairment of antibody response, and although germinal centre formation was not affected, antibody class-switch recombination and affinity maturation processes were defective. Likewise, memory immune response was severely impaired. Moreover, FBW7 ablation ameliorated the pathogenesis of an autoimmune disease model, collagen-induced arthritis, by reducing the production of anti-collagen II autoantibodies. Taken together, these data suggest that FBW7 may be an attractive target for developing new therapeutics for the treatment of autoimmune diseases.


Assuntos
Artrite Experimental/imunologia , Linfócitos B/imunologia , Proteína 7 com Repetições F-Box-WD/metabolismo , Animais , Artrite Experimental/diagnóstico , Artrite Experimental/patologia , Linfócitos B/metabolismo , Colágeno/administração & dosagem , Colágeno/imunologia , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Switching de Imunoglobulina/genética , Memória Imunológica , Masculino , Camundongos , Camundongos Knockout , Índice de Gravidade de Doença , Ubiquitinação/imunologia
6.
J Histochem Cytochem ; 69(8): 511-522, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34291686

RESUMO

Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice (n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV; (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue; and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction.


Assuntos
Artrite Experimental/patologia , Reabsorção Óssea/patologia , Cartilagem Articular/patologia , Modelos Animais de Doenças , Edema/patologia , Animais , Anticorpos Monoclonais/administração & dosagem , Artrite Experimental/induzido quimicamente , Artrite Experimental/diagnóstico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/patologia , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/diagnóstico , Cartilagem Articular/efeitos dos fármacos , Edema/induzido quimicamente , Edema/diagnóstico , Feminino , Membro Anterior/efeitos dos fármacos , Membro Anterior/patologia , Histocitoquímica , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/patologia , Índice de Gravidade de Doença , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia
7.
Front Immunol ; 12: 628065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220796

RESUMO

Objective: Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/ß2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis. Methods: Complete Freund's adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the ß2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization. Results: On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint. Conclusion and Significance: Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Artrite Experimental/prevenção & controle , Articulações/efeitos dos fármacos , Fentolamina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Terbutalina/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Combinação de Medicamentos , Adjuvante de Freund , Articulações/diagnóstico por imagem , Articulações/metabolismo , Articulações/patologia , Masculino , Ratos Endogâmicos Lew , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais
8.
Am J Physiol Cell Physiol ; 321(3): C569-C584, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34288720

RESUMO

Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on the expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice, treatment with a small molecule-specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pretreatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule-specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Colestanos/farmacologia , Células Supressoras Mieloides/imunologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Comunicação Celular , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Expressão Gênica , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/transplante , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/antagonistas & inibidores , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/imunologia , Índice de Gravidade de Doença , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia
9.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203838

RESUMO

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α-/-ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α-/-ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4+ subpopulations; and an increased number of CXCR5+ T cells in the draining lymph nodes of the p110α-/-ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α-/-ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α-/-ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases.


Assuntos
Artrite Experimental/enzimologia , Artrite Experimental/patologia , Domínio Catalítico , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Linfócitos T/enzimologia , Animais , Anticorpos/sangue , Artrite Experimental/sangue , Artrite Experimental/imunologia , Biomarcadores/metabolismo , Proliferação de Células , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Deleção de Genes , Imunidade , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-6/sangue , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Transdução de Sinais
10.
Biochem Biophys Res Commun ; 570: 26-34, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34271433

RESUMO

Hydroxysafflor yellow A (HSYA) from safflower (Carthamus tinctorius L.) possesses several medicinal properties. However, it is unknown whether HSYA is effective in the treatment of rheumatoid arthritis (RA). Hence, we investigated the effects of HSYA on the inflammation and synovial damage in rats with collagen-induced arthritis (CIA) by subjecting them to treatment with different doses of HSYA. Our results revealed that HSYA could significantly reduce paw swelling, pathological manifestations, and serum cytokine levels in rats with CIA. The HSYA-treated groups showed increased antioxidant enzyme activity in the serum and decreased expression of inflammatory mediators in the synovial tissues. Furthermore, HSYA treatment inhibited extracellular signal-regulated kinase (ERK) signalling pathway activation. Notably, the highest dose of HSYA (20 mg/kg) exhibited the best effects against RA symptoms. Therefore, our findings suggest that HSYA alleviates the inflammatory response and synovial damage in rats with CIA by inhibiting the ERK signalling pathway.


Assuntos
Artrite Experimental/tratamento farmacológico , Chalcona/análogos & derivados , Quinonas/uso terapêutico , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Bovinos , Chalcona/farmacologia , Chalcona/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Citocinas/sangue , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Oxirredução , Quinonas/farmacologia , Ratos Wistar , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
11.
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
12.
Front Immunol ; 12: 680073, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079556

RESUMO

Gut microbiota and their influence on metabolites are receiving increasing attentions in autoimmune diseases including rheumatoid arthritis (RA). Probiotics become a promising manipulator to prevent or attenuate the progression of arthritis, some evidences suggesting that lactobacilli treatment influence the responses to RA therapy but the underlying mechanisms are limited. By using a collagen-induced arthritis (CIA) rats, the study assessed the effects of two L. casei strains (CCFM1074, CCFM1075) on the immune responses, gut microbiota and plasma metabolites via an integrated cross-omics approach including fecal 16S rRNA high-throughput sequencing and plasma metabolomics. The genome of the two strains was analyzed and compared using whole-genome sequencing approach to further confirm biology functions. CCFM1074 reduced arthritic symptoms while CCFM1075 did not, though both strains down-regulated the plasma IL-6 and Th17 cells proportion. CCFM1074 enhanced the proportion of Treg cells in mesenteric lymph nodes which was significantly associated with SCFAs upregulation, as well as with genomic evidence that CCFM1074 possesses more functional genes involved in carbohydrate metabolism. Moreover, CCFM1074 regulated the gut microbiota, including modulating community structure, decreasing the abundance of Alistipes and Parabacteroides and increasing the abundance of Oscillibacter. The differential metabolites modulated by CCFM1074 including eicosapentaenoic acid and docosapentaenoic acid which involved in unsaturated fatty acids metabolism. Furthermore, alterations of gut microbial community were correlated with the plasma metabolome. In summary, L. casei CCFM1074 alleviated arthritis via rebalancing gut microbiota, immune responses and plasma metabolites.


Assuntos
Artrite Experimental/etiologia , Artrite Experimental/metabolismo , Microbioma Gastrointestinal , Lactobacillus casei/imunologia , Probióticos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Biodiversidade , Biomarcadores , Cromatografia Líquida , Biologia Computacional/métodos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Genômica/métodos , Metaboloma , Metabolômica/métodos , RNA Ribossômico 16S/genética , Ratos , Linfócitos T Reguladores/metabolismo , Espectrometria de Massas em Tandem , Células Th17/metabolismo
13.
Biomed Pharmacother ; 140: 111770, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34119929

RESUMO

Our study has renewed interest in the genus Jasmine for the treatment of chronic inflammatory conditions. Aerial parts of Jasminum grandiflorum L. subsp. floribundum total methanolic extract (JTME) were tested for its therapeutic potential as an anti-inflammatory agent using two experimental models in rats; acetic acid (AA) induced ulcerative colitis and adjuvant induced arthritis. The administration of JTME showed anti-inflammatory activity in a dose dependent manner. JTME, 400 mg/kg was like prednisolone, 2 mg/kg p.o. (the reference drug), since it improved the tissues of the colon clinically, macro and microscopically (ulcer index), and histopathological (scoring). It reduced the intestinal expression of pro-inflammatory cytokines in the colonic mucosa; IFNγ, TNFα, IL-6, IL-1, and MPO. It also preserved tight junctions in intestinal epithelial cells by counter-regulating claudin-5 and occludin levels additionally, it had a potent antioxidant activity. The expressions of NF-κB p65, TNF-α and caspase-3 in rats administered AA (2 mL of 4% solution, once, intrarectally) were significantly increased, where the lowest expression was scored in JTME, 400 mg/kg group. In the adjuvant induced model of rheumatoid arthritis, the TJME, 400 mg/kg reduced the levels of cathepsin D, iNOS, NO, RF, CRP, CPP and elevated the total antioxidant capacity of tissues. Additionally, it maintained bones without histopathological lesions, articular cartilage damage, and inflammation of the synovial membrane and periarticular tissues, in contrast to arthritic rats. Finally, we report a new detailed study to validate the medicinal importance of Jasminum for the chronic inflammatory disorders with immune dysfunction with anti-inflammatory and antioxidant effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Jasminum , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Artrite Experimental/patologia , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
14.
Nutrients ; 13(5)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068191

RESUMO

Short-chain fatty acids are gut-bacteria-derived metabolites that execute important regulatory functions on adaptive immune responses, yet their influence on inflammation driven by innate immunity remains understudied. Here, we show that propionate treatment in drinking water or upon local application into the joint reduced experimental arthritis and lowered inflammatory tissue priming mediated by synovial fibroblasts. On a cellular level, incubation of synovial fibroblasts with propionate or a physiological mixture of short-chain fatty acids interfered with production of inflammatory mediators and migration and induced immune-regulatory fibroblast senescence. Our study suggests that propionate mediates its alleviating effect on arthritis by direct abrogation of local arthritogenic fibroblast function.


Assuntos
Artrite Experimental/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Propionatos/uso terapêutico , Envelhecimento/efeitos dos fármacos , Animais , Artrite Experimental/patologia , Feminino , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Líquido Sinovial/citologia
15.
PLoS One ; 16(6): e0252590, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34086763

RESUMO

Conditions that resemble osteoarthritis (OA) were produced by injection of sodium monoiodoacetate (MIA) into the knee joints of mice. Bone marrow derived mast cells (BMMCs) injected into the OA knee joints enhanced spontaneous pain. Since no spontaneous pain was observed when BMMCs were injected into the knee joints of control mice that had not been treated with MIA, BMMCs should be activated within the OA knee joints and release some pain-inducible factors. Protease activated receptor-2 (PAR2) antagonist (FSLLRY-NH2) almost abolished the pain-enhancing effects of BMMCs injected into the OA knee joints, suggesting that tryptase, a mast cell protease that is capable of activating PAR2, should be released from the injected BMMCs and enhance pain through activation of PAR2. When PAR2 agonist (SLIGKV-NH2) instead of BMMCs was injected into the OA knee joints, it was also enhanced pain. Apyrase, an ATP degrading enzyme, injected into the OA knee joints before BMMCs suppressed the pain enhanced by BMMCs. We showed that purinoceptors (P2X4 and P2X7) were expressed in BMMCs and that extracellular ATP stimulated the release of tryptase from BMMCs. These observations suggest that ATP may stimulate degranulation of BMMCs and thereby enhanced pain. BMMCs injected into the OA knee joints stimulated expression of IL-1ß, IL-6, TNF-α, CCL2, and MMP9 genes in the infrapatellar fat pads, and PAR2 antagonist suppressed the stimulatory effects of BMMCs. Our study suggests that intermittent pain frequently observed in OA knee joints may be due, at least partly, to mast cells through activation of PAR2 and action of ATP, and that intraarticular injection of BMMCs into the OA knee joints may provide a useful experimental system for investigating molecular mechanisms by which pain is induced in OA knee joints.


Assuntos
Trifosfato de Adenosina/metabolismo , Artrite Experimental/terapia , Dor Crônica/patologia , Articulação do Joelho/patologia , Mastócitos/transplante , Receptor PAR-2/metabolismo , Trifosfato de Adenosina/análise , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Células da Medula Óssea/citologia , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/toxicidade , Dor Crônica/etiologia , Modelos Animais de Doenças , Articulação do Joelho/metabolismo , Masculino , Mastócitos/citologia , Mastócitos/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oligopeptídeos/administração & dosagem , Receptor PAR-2/agonistas , Receptor PAR-2/antagonistas & inibidores , Receptores Purinérgicos/metabolismo , Líquido Sinovial/metabolismo
16.
J Clin Invest ; 131(16)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34185706

RESUMO

TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPß activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.


Assuntos
Proteínas 14-3-3/imunologia , Macrófagos/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Proteínas 14-3-3/química , Proteínas 14-3-3/deficiência , Proteínas 14-3-3/metabolismo , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Autoimunidade , Humanos , Inflamação/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Complexos Multiproteicos/química , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Progranulinas/imunologia , Progranulinas/metabolismo , Células RAW 264.7 , Receptores Tipo II do Fator de Necrose Tumoral/química , Receptores Tipo II do Fator de Necrose Tumoral/deficiência , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/imunologia
17.
Front Immunol ; 12: 672752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34040613

RESUMO

Objective: We recently demonstrated that EBV DNA is correlated with proinflammatory responses in mice and in rheumatoid arthritis (RA) patients; hence, we utilized an RA mouse model to examine whether EBV DNA enhances the risk and severity of arthritis and to assess its immunomodulatory effects. Methods: C57BL/6J mice were treated with collagen (arthritis-inducing agent), EBV DNA 6 days before collagen, EBV DNA 15 days after collagen, Staphylococcus epidermidis DNA 6 days before collagen, EBV DNA alone, or water. Mice were then monitored for clinical signs and affected joints/footpads were histologically analysed. The relative concentration of IgG anti- chicken collagen antibodies and serum cytokine levels of IL-17A and IFNϒ were determined by ELISA. The number of cells co-expressing IL-17A and IFNϒ in joint histological sections was determined by immunofluorescence. Results: The incidence of arthritis was significantly higher in mice that received EBV DNA prior to collagen compared to mice that only received collagen. Similarly, increased clinical scores, histological scores and paw thicknesses with a decreased gripping strength were observed in groups treated with EBV DNA and collagen. The relative concentration of IgG anti-chicken collagen antibodies was significantly increased in the group that received EBV DNA 6 days prior to collagen in comparison to the collagen receiving group. On the other hand, the highest number of cells co-expressing IFNϒ and IL-17A was observed in joints from mice that received both collagen and EBV DNA. Conclusion: EBV DNA increases the incidence and severity of arthritis in a RA mouse model. Targeting mediators triggered by viral DNA may hence be a potential therapeutic avenue.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , DNA Viral/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Animais , Artrite Experimental/patologia , Artrite Experimental/virologia , Artrite Reumatoide/patologia , Artrite Reumatoide/virologia , Infecções por Vírus Epstein-Barr/complicações , Feminino , Herpesvirus Humano 4 , Incidência , Camundongos , Camundongos Endogâmicos C57BL
18.
Eur J Med Chem ; 221: 113514, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33992926

RESUMO

While anti-inflammatory properties of isocoumarins are known their PDE4 inhibitory potential was not explored previously. In our effort the non-PDE4 inhibitor isocoumarins were transformed into the promising inhibitors via introducing an aminosulfonyl/aminocarboxamide moiety to the C-3 benzene ring attached to the isocoumarin framework. This new class of isocoumarins were synthesized via a PdCl2-catalyzed construction of the 4-allyl substituted 3-aryl isocoumarin ring starting from the appropriate 2-alkynyl benzamide derivative. Several compounds showed good inhibition of PDE4B in vitro and the SAR indicated superiority of aminosulfonamide moiety over aminocarboxamide in terms of PDE4B inhibition. Two compounds 3q and 3u with PDE4B IC50 = 0.43 ± 0.11 and 0.54 ± 0.19 µM and ≥ 2-fold selectivity over PDE4D emerged as initial hits. The participation of aminosulfonamide moiety in PDE4B inhibition and the reason for selectivity though moderate shown by 3q and 3u was revealed by the in silico docking studies. In view of potential usefulness of moderately selective PDE4B inhibitors the compound 3u (that showed PDE4 selectivity over other PDEs) was further evaluated in adjuvant induced arthritic rats. At an intraperitoneal dose of 30 mg/kg the compound showed a significant reduction in paw swelling (in a dose dependent manner), inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels and increase in body weight. Moreover, besides its TNF-α inhibition and no significant toxicity in an MTT assay the compound did not show any adverse effects in a thorough toxicity studies e.g. teratogenicity, hepatotoxicity, cardiotoxicity and apoptosis in zebrafish. Thus, the isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Isocumarinas/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/toxicidade , Artrite Experimental/patologia , Catálise , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Feminino , Isocumarinas/síntese química , Isocumarinas/metabolismo , Isocumarinas/toxicidade , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Paládio/química , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/metabolismo , Inibidores da Fosfodiesterase 4/toxicidade , Ligação Proteica , Células RAW 264.7 , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Sulfonamidas/toxicidade , Peixe-Zebra
19.
Drug Des Devel Ther ; 15: 1981-1992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007158

RESUMO

Background: Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model is not clear. Materials and Methods: Following the oral administration of FTY720 (2 mg/kg) was treated into CIA mice per day for 35 days, intravital microscopy and immunofluorescence assays were performed to examine immune cell recruitment in the affected joints. Human MH7A synoviocytes were stimulated with tumour necrosis factor (TNF)-α and incubated with FTY720. Interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression were evaluated using RT-PCR and enzyme-linked immunosorbent assay, respectively. Signal transduction pathway protein expression was measured by Western blotting. Nuclear translocation of nuclear factor (NF)-κB was also analyzed by fluorescence microscopy. Results: In vivo experiments showed that FTY720 inhibited the recruitment of CD4+ lymphocytes in the affected joints of CIA mice. FTY720 reduced the secretion of IL-1ß, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. FTY720 also inhibited TNF-α-induced phosphorylation of NF-κBp65 and IκBα, as well as NF-κBp65 nuclear translocation, in a dose- and time-dependent manner. Interestingly, FTY720 blocked PI3K/Akt, the upstream targets of the NF-κB pathway. Conclusion: Our findings demonstrated that oral administration of FTY720 exerted beneficial effects in CIA mice by inhibiting CD4+ T lymphocyte recruitment to the affected joints. Our data also indicated that FTY720 inhibited TNF-α-induced inflammation by suppressing the AKT/PI3K/NF-κB pathway in MH7A cells.


Assuntos
Artrite Experimental/prevenção & controle , Linfócitos T CD4-Positivos/imunologia , Cloridrato de Fingolimode/farmacologia , Imunossupressores/farmacologia , Animais , Artrite Experimental/patologia , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/administração & dosagem , Humanos , Imunossupressores/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/administração & dosagem
20.
Chem Biol Interact ; 341: 109451, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-33798506

RESUMO

The pathogenesis of rheumatoid arthritis (RA) is characterized by synoviocyte hyperplasia and proinflammatory cytokine secretion, as well as the destruction of cartilage and bone. Glaucocalyxin A (GLA) is an alkaloid derived from a Chinese medicinal plant that exhibits anti-inflammatory, anti-tumor and neuroprotective properties. We investigated the effects of GLA on RA-fibroblast-like synoviocytes (FLS cells), and collagen-induced arthritis (CIA), and further explored the underlying mechanisms. GLA inhibited TNF-a-induced RA-FLS proliferation, increased apoptotic ratios and upregulated levels of caspase-3, cleaved PARP, and Bax. GLA also inhibited the expression of IL-10, IL-1ß, and IL-6 in vitro. Levels of p-STAT3 were downregulated in a dose-dependent manner. Over-expression of STAT3 partly neutralized the GLA-mediated elevation of caspase-3 and cleaved PARP levels as well as the downregulation of IL-10, IL-1B and IL-6 expression levels. This suggests that GLA inactivated the STAT3 pathway. Furthermore, the production of inflammatory cytokines in RA-FLS and a CIA rat model were inhibited effectively by GLA. Taken together, our data suggest that GLA is a potential long-term therapeutic agent for patients with RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Diterpenos do Tipo Caurano/farmacologia , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos Endogâmicos DBA , Ratos Wistar , Fator de Transcrição STAT3/genética , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Células Th17/efeitos dos fármacos , Células Th17/fisiologia , Fator de Necrose Tumoral alfa/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...