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2.
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
3.
Clin Immunol ; 230: 108813, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34333094

RESUMO

Cigarette smoking has been implicated in the pathogenesis of seropositive rheumatoid arthritis (RA), as well as RA-associated lung disease. Fibrotic interstitial lung disease as well as emphysema occur in RA and cause substantial morbidity. We used arthritis-susceptible HLA-DQ8 transgenic mice to generate RA-associated lung disease. Mice were exposed to cigarette smoke (CS) prior to induction of arthritis, and subsequently injected with a low dose of bleomycin intra-tracheally to induce lung injury. Exposure of arthritic mice to both CS and bleomycin led to a significant reduction in lung compliance consistent with development of diffuse lung disease. Morphologic evaluation of the lung demonstrated areas of emphysematous change and co-existent fibrosis, consistent with a combined pattern of fibrosis and emphysema. These changes were accompanied by inflammatory cell infiltration and upregulation of fibrosis-associated genes. This humanized mouse model can serve as a valuable research tool to understand the pathogenesis of RA associated lung disease.


Assuntos
Artrite Reumatoide/complicações , Doenças Pulmonares Intersticiais/etiologia , Animais , Artrite Reumatoide/etiologia , Bleomicina/toxicidade , Fumar Cigarros/efeitos adversos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Pulmão/metabolismo , Pulmão/patologia , Complacência Pulmonar/efeitos dos fármacos , Doenças Pulmonares Intersticiais/patologia , Masculino , Camundongos , Camundongos Transgênicos , Enfisema Pulmonar/etiologia , Fibrose Pulmonar/etiologia
4.
Front Immunol ; 12: 655477, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220809

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Membrana Sinovial/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Artrite Reumatoide/patologia , Biomarcadores , Comunicação Celular/imunologia , Suscetibilidade a Doenças , Humanos , Imunomodulação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Nutrients ; 13(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209676

RESUMO

Alcohol consumption may be associated with the risk of rheumatoid arthritis (RA), but potential sex-related differences in this association have not been explored. Thus, we utilized 87,118 participants in the Kailuan Study, a prospective cohort initiated in 2006 to study the risk factors of cardiovascular disease in a Chinese population. We included those that did not have RA at baseline (2006), and performed cox proportional hazard modeling to calculate the hazard ratio (HR) and 95% confidence interval (95% CI) of RA according to the levels of alcohol consumption (never or past, light or moderate (<1 serving/day for women, <2 servings/day for men), and heavy (>1 serving/day for women, >2 servings/day for men), adjusting for age, sex, body mass index, and smoking. Diagnoses of RA were confirmed via medical record review by rheumatologists. From 2006 to 2018, we identified 87 incident RA cases. After adjusting for potential confounders, the HR of RA was 1.26 (95% CI: 0.62, 2.56) for participants with light or moderate alcohol consumption and 1.98 (95% CI: 0.93, 4.22) for participants with heavy alcohol consumption) versus non-drinkers. The HR of each 10 g increase in alcohol consumption was 1.11 (95% CI: 0.98, 1.26) (p-trend = 0.09). A significant association between alcohol consumption and RA risk was observed in women, but not in men (p for interaction = 0.06). Among women, each 10 g increase in alcohol consumption was significantly associated with a high risk of RA (HR: 1.56; 95% CI: 1.06, 2.29). In contrast, each 10 g increase in alcohol consumption was not significantly associated with the risk of RA in men (HR: 1.10; 95% CI: 0.97, 1.25). Excluding past drinkers generated similar results. In this prospective Chinese cohort, increasing alcohol consumption was associated with an elevated risk of RA among women, but not in men. These findings highlight the importance of incorporating analysis of sex differences into future studies of alcohol consumption and RA risk.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Artrite Reumatoide/epidemiologia , Fatores Sexuais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/efeitos adversos , Artrite Reumatoide/etiologia , Índice de Massa Corporal , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
6.
Clin Immunol ; 230: 108793, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34242749

RESUMO

Rheumatoid arthritis (RA) is characterized by systemic synovitis leading to joint destruction in which imbalances in pro-inflammatory and anti-inflammatory cytokines promote the induction of autoimmunity. Some pro-inflammatory cytokines can trigger the signaling pathways which responsible for immune-mediated inflammation in RA, and the activated signaling pathways produce pro-inflammatory cytokines, resulting in aggravation of RA. Hence, understanding of the signaling pathways and their inhibitors might be advantageous in the development of therapeutic targets and new drugs for RA. In the current review, we summarize the signaling pathways involved in the pathogenesis of RA as well as the potential role of specific inhibitors in its management. We hope this paper may serve a reference for future studies on signaling pathways implicated in the pathogenesis of RA and benefit the treatment of RA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Transdução de Sinais/imunologia , Artrite Reumatoide/etiologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Inibidores de Janus Quinases/farmacologia , Janus Quinases/imunologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Modelos Imunológicos , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299122

RESUMO

Immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis), are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis-associated neoplasia. Only 40-60% of patients respond to currently used standard-of-care immunotherapies. In addition to this limited long-term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is considered as "the great hope" for improving the treatment of IMIDs. This review sheds light on the progressive development and the numerous approaches from basic science that gradually lead to the transfer from "bench to bedside" and the implementation into general patient care procedures.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doenças do Sistema Imunitário/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Genômica , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Metabolômica , Transcriptoma
8.
BMJ Open ; 11(7): e043416, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226211

RESUMO

OBJECTIVE: This study aimed to explore the association between famine exposure in early life and the odds of rheumatoid arthritis (RA) in adulthood. DESIGN: A population-based retrospective cohort study. SETTING: China. PARTICIPANTS: A total of 111 706 participants (1775 with RA) born from 1956 to 1964 were selected from the baseline survey of a large cohort in China. PRIMARY AND SECONDARY OUTCOME MEASURES: Four famine exposure groups were generated based on dates of birth, namely prenatal-exposed, infant-exposed, preschool-exposed and non-exposed groups. Logistic regressions were used to explore the association between famine exposure and self-reported RA in adulthood, adjusting for sex, region, monthly income, highest education, alcohol consumption, tobacco use, body mass index (BMI) and metabolic equivalent tasks. Analyses were also performed with stratification for sex (female or male), residing region (urban or rural), famine severity (severe or non-severe) and BMI (≥24 or <24). RESULTS: The study included 1775 (1.59%) RA cases and 109 931 (98.41%) non-RA controls. Among them, 22 413 (20.06%) were prenatal-exposed, 14 899 (13.34%) were infant-exposed and 34 356 (30.76%) were preschool-exposed. Prenatal exposure to famine was not associated with onset of RA in adulthood. Infant-exposed group and preschool-exposed group had significantly elevated odds of getting RA compared with non-exposed group (infant-exposed: OR=1.44, 95% CI 1.24 to 1.67; preschool-exposed: OR=1.38, 95% CI 1.22 to 1.57, p<0.001), and the relationship was stronger among women, urban residents and participants with BMI ≥24. Similar results were additionally observed when an age-balanced control group was used. CONCLUSIONS: Exposure to the Great Chinese Famine in early life after birth especially in infancy may be associated with a higher risk of RA in adulthood. Strengthening early-life nutrition could be an implication to prevent future RA.


Assuntos
Artrite Reumatoide , Efeitos Tardios da Exposição Pré-Natal , Adulto , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/etiologia , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Fome Epidêmica , Feminino , Humanos , Lactente , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Prevalência , Estudos Retrospectivos
9.
Front Immunol ; 12: 655614, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079544

RESUMO

Objectives: Rheumatoid arthritis (RA) is a disabling disease with a high incidence that is regularly accompanied by cardiovascular complications. Several studies have suggested that renin-angiotensin-aldosterone system (RAAS) is closely associated with RA. The aim of this study was to investigate the mechanisms underlying Angiotensin-(1-7) [Ang-(1-7)] and its Mas receptor agonist (AVE0991) on joint inflammation and cardiac complications in a collagen-induced arthritis (CIA) model. Methods: Collagen type II was injected into DBA/1 mice to construct an arthritis model. CIA mice were treated with Ang-(1-7) (2.0 mg/kg intraperitoneally) and AVE0991 (3.0 mg/kg intraperitoneally). The serum levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 ß, IL-6, and C-reactive protein (CRP)] were determined by ELISA. The mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways in joint tissues and the transforming growth factor (TGF)-ß/Smad pathway and levels of α-Smooth muscle action (SMA) and ß-myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-ß/Smad pathway, α-SMA, and ß-MHC RNA in cardiac tissues were analyzed by real time-PCR. The levels of receptor activator of nuclear factor kappa ligand (RANKL) and promoting matrix metalloproteinase (MMP)-3 expression in the ankle joints were detected by immunohistochemistry and real time-PCR. Results: Ang-(1-7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-κB signaling pathways in ankle joint tissues, reduced RANKL and MMP3 expression, and ameliorated local joint inflammation and bone destruction compared with the control group. In addition, Ang-(1-7) and AVE0991 attenuated the TGF-ß/Smad signaling pathway, reduced the levels of α-SMA and ß-MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice. Conclusions: Ang-(1-7) alleviated joint damage caused by inflammation likely through the attenuation of NF-κB and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-ß/Smad pathway. Moreover, Ang-(1-7) was likely mediated through the Mas receptor. This study provides theoretical evidence for exploring novel clinical therapeutic approaches for RA and its cardiac complications.


Assuntos
Angiotensina I/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/etiologia , Fragmentos de Peptídeos/efeitos adversos , Cardiopatia Reumática/etiologia , Animais , Artrite Experimental , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Biomarcadores , Biópsia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fibrose , Imuno-Histoquímica , Masculino , Camundongos , Cardiopatia Reumática/diagnóstico , Transdução de Sinais , Avaliação de Sintomas
10.
Front Immunol ; 12: 609644, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34017324

RESUMO

Bacterial therapeutics are the emergent alternatives in treating autoimmune diseases such as Rheumatoid Arthritis [RA]. P. histicola MCI 001 is one such therapeutic bacterium that has been proven to treat autoimmune diseases such as RA and multiple sclerosis [MS] in animal models. The present study characterized P. histicola MCI 001 isolated from a human duodenal biopsy, and evaluated its impact on the gut microbial and metabolic profile in a longitudinal study using the collagen-induced arthritis model in HLA-DQ8.AEo transgenic mice. P. histicola MCI 001 though closely related to the type strain of P. histicola, DSM 19854, differed in utilizing glycerol. In culture, P. histicola MCI 001 produced vitamins such as biotin and folate, and was involved in digesting complex carbohydrates and production of acetate. Colonization study showed that duodenum was the predominant niche for the gavaged MCI 001. A longitudinal follow-up of gut microbial profile in arthritic mice treated with MCI 001 suggested that dysbiosis caused due to arthritis was partially restored to the profile of naïve mice after treatment. A taxon-level analysis suggested an expansion of intestinal genus Allobaculum in MCI001 treated arthritic mice. Eubiosis achieved post treatment with P. histicola MCI 001 was also reflected in the increased production of short-chain fatty acids [SCFAs]. Present study suggests that the treatment with P. histicola MCI 001 leads to an expansion of Allobaculum by increasing the availability of simple carbohydrates and acetate. Restoration of microbial profile and metabolites like butyrate induce immune and gut homeostasis.


Assuntos
Terapia Biológica/métodos , Butiratos/metabolismo , Prevotella/fisiologia , Simbiose , Adaptação Fisiológica , Animais , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/terapia , Ácidos e Sais Biliares/farmacologia , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Suco Gástrico , Microbioma Gastrointestinal , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Transgênicos , Prevotella/classificação , Prevotella/efeitos dos fármacos , Prevotella/genética
11.
Front Immunol ; 12: 652771, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868292

RESUMO

Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Autoimunidade , Suscetibilidade a Doenças/imunologia , Metabolismo Energético , Animais , Artrite Reumatoide/patologia , Doenças Autoimunes/patologia , Glutamina/metabolismo , Glicólise , Humanos , Imunomodulação , Metabolismo dos Lipídeos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Fatores de Risco , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
Front Immunol ; 12: 654623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815416

RESUMO

Background: Rheumatoid arthritis (RA) is a prototypical autoantibody-driven autoimmune disease in which T-B interactions play a critical role. Recent comprehensive analysis suggests that PD-1+CD8+ T cells as well as two distinct IL-21-producing PD-1+CD4+ T cell subsets, follicular helper T (Tfh) and peripheral helper T (Tph) cells, are involved in the pathogenesis of RA. Herein, we aimed to clarify a generation mechanism of IL-21-producing CD8+ T cells in humans, and to characterize this novel subset in patients with RA. Methods: CD8+ T cells in the peripheral blood (PB) and synovial fluid (SF) of healthy control (HC) and patients with RA were subject to the analysis of IL-21 mRNA and protein. We evaluated the surface marker, cytokine and transcription profiles of IL-21-producing CD8+ T cells in HCPB, RAPB and RASF. Results: IL-21-producing CD8+ T cells were enriched in the CD45RA-(memory) PD-1+, especially PD-1hi subpopulation, and IL-12 and IL-21 synergistically induced IL-21 production by naïve CD8+ T cells. Memory PD-1hiCD8+ T cells in HCPB facilitated plasmablast differentiation and IgG production in an IL-21-dependent manner. In addition, PD-1hiCD8+ T cells in RASF and RAPB produced large amounts of IL-21 and were characterized by high levels of CD28, ICOS, CD69, HLA-DR, and CCR2 but not CXCR5. Furthermore, PD-1hiCD8+ T cells expressed high levels of transcripts of MAF and PRDM1, a feature observed in Tph cells. Conclusions: Identification of IL-21-producing PD-1hiCD8+ T cells expands our knowledge of T cell subsets with B helper functions in RA. Selective targeting of these subsets could pave an avenue for the development of novel treatment strategies for this disease.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Interleucinas/biossíntese , Receptor de Morte Celular Programada 1/metabolismo , Artrite Reumatoide/patologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Comunicação Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
13.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918929

RESUMO

Hypoxia inducible factor (HIF)-1α has been implicated in the pathogenesis of rheumatoid arthritis (RA). HIF-1α, which is expressed in hypoxia, is reversely suppressed in sustained hypoxia. Here, we investigated the inhibitory effect of hypoxia on arthritis by controlling HIF-1α. Rheumatoid fibroblast-like synoviocyte MH7A cells were cultured in a hypoxic incubator for up to 72 h to evaluate the expression of HIF-1. Furthermore, collagen-induced arthritis (CIA) model rats were maintained under 12% hypoxia in a hypoxic chamber for 28 days to evaluate the effect on arthritis. In MH7A cells, HIF-1α protein level increased at 3 h, peaked at 6 h, and subsequently decreased in a time-dependent manner. The transcription of pro-inflammatory cytokines increased at 1 h; however, they decreased after 3 h (p < 0.05). Deferoxamine-mediated activation of HIF-1α abolished the inhibitory effect of sustained hypoxia on pro-inflammatory cytokines. In the rat CIA model, the onset of joint swelling was delayed and arthritis was suppressed in the hypoxia group compared with the normoxia group (p < 0.05). Histologically, joint destruction was suppressed primarily in the cartilage. Thus, sustained hypoxia may represent a new safe, and potent therapeutic approach for high-risk patients with RA by suppressing HIF-1α expression.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Animais , Artrite Reumatoide/patologia , Biomarcadores , Hipóxia Celular , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Suscetibilidade a Doenças , Fibroblastos/metabolismo , Expressão Gênica , Hipóxia/genética , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Mediadores da Inflamação/metabolismo , Ratos , Sinoviócitos/metabolismo , Sinoviócitos/patologia
14.
Front Immunol ; 12: 619392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841401

RESUMO

Objectives: Mounting evidence has demonstrated that microRNAs (miRNAs) participate in rheumatoid arthritis (RA). The role of highly conserved miR-15/107 family in RA has not been clarified yet, and hence investigated in this study. Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of miRNAs and genes. Cell counting kit 8 (CCK-8) and FACS were used to detect proliferation and apoptosis. Protein expression was detected by using Western blotting. mRNA deep sequencing and cytokine antibody array were used to analyze differentially expressed genes, signaling pathways and cytokines. Results: The expression of miR-15a, miR-103, miR-497, and miR-646 was found decreased, while miR-424 increased in RA patients. MiR-424 and miR-497 were further investigated and the results showed that they could regulate the expression of multiple genes in rheumatoid arthritis synovial fibroblast (RASF) and affect signaling pathways. At the protein level, miR-497 mimic altered all the selected inflammation-related genes while miR-424 inhibitor only affected part of genes. MiR-497 mimic, rather than miR-424 inhibitor, had significant effects on proliferation and apoptosis of RASF. DICER1 was found to positively regulate the expression of miR-424 and miR-497, while DICER1 was also negatively regulated by miR-424. The increase of miR-424 could reduce miR-497 expression, thus forming a loop, which facilitated explaining the dysregulated miR-424 and miR-497 in RA. Conclusion: The miR-424 and miR-497 of miR-15/107 family affect cell proliferation and apoptosis in RA, and the proposed miR-424-DICER1-miR-497 feedback loop provides a novel insight into regulating miRNA expression and a candidate target for controlling RA.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Membrana Sinovial/metabolismo , Apoptose/genética , Artrite Reumatoide/patologia , Biomarcadores , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , Matriz Extracelular , Humanos , Transdução de Sinais , Membrana Sinovial/patologia
16.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671090

RESUMO

In the last decades, the comprehension of the pathophysiology of bone metabolism and its interconnections with multiple homeostatic processes has been consistently expanded. The branch of osteoimmunology specifically investigating the link between bone and immune system has been developed. Among molecular mediators potentially relevant in this field, vitamin D has been recently pointed out, and abnormalities of the vitamin D axis have been described in both in vitro and in vivo models of inflammatory bowel diseases (IBD) and arthritis. Furthermore, vitamin D deficiency has been reported in patients affected by IBD and chronic inflammatory arthritis, thus suggesting the intriguing possibility of impacting the disease activity by the administration vitamin D supplements. In the present review, the complex interwoven link between vitamin D signaling, gut barrier integrity, microbiota composition, and the immune system was examined. Potential clinical application exploiting vitamin D pathway in the context of IBD and arthritis is presented and critically discussed. A more detailed comprehension of the vitamin D effects and interactions at molecular level would allow one to achieve a novel therapeutic approach in gastro-rheumatologic inflammatory diseases through the design of specific trials and the optimization of treatment protocols.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Gastroenteropatias/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Deficiência de Vitamina D/complicações , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem , Animais , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Gastroenteropatias/etiologia , Gastroenteropatias/patologia , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/patologia , Deficiência de Vitamina D/imunologia
17.
Nutrients ; 13(3)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652915

RESUMO

Modern high-throughput 'omics' science tools (including genomics, transcriptomics, proteomics, metabolomics and microbiomics) are currently being applied to nutritional sciences to unravel the fundamental processes of health effects ascribed to particular nutrients in humans and to contribute to more precise nutritional advice. Diet and food components are key environmental factors that interact with the genome, transcriptome, proteome, metabolome and the microbiota, and this life-long interplay defines health and diseases state of the individual. Rheumatoid arthritis (RA) is a chronic autoimmune disease featured by a systemic immune-inflammatory response, in genetically susceptible individuals exposed to environmental triggers, including diet. In recent years increasing evidences suggested that nutritional factors and gut microbiome have a central role in RA risk and progression. The aim of this review is to summarize the main and most recent applications of 'omics' technologies in human nutrition and in RA research, examining the possible influences of some nutrients and nutritional patterns on RA pathogenesis, following a nutrigenomics approach. The opportunities and challenges of novel 'omics technologies' in the exploration of new avenues in RA and nutritional research to prevent and manage RA will be also discussed.


Assuntos
Artrite Reumatoide/etiologia , Biologia Computacional/tendências , Nutrigenômica/tendências , Perfilação da Expressão Gênica/tendências , Genômica/tendências , Humanos , Metabolômica/tendências , Microbiota , Proteômica/tendências
18.
Front Immunol ; 12: 605616, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664742

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.


Assuntos
Artrite Reumatoide/etiologia , Diterpenos/farmacologia , Fator de Transcrição E2F1/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Proteína Supressora de Tumor p53/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Proliferação de Células/efeitos dos fármacos , Suscetibilidade a Doenças , Diterpenos/uso terapêutico , Fator de Transcrição E2F1/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Modelos Biológicos , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteína Supressora de Tumor p53/metabolismo
19.
Nutrients ; 13(2)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562353

RESUMO

BACKGROUND: To date, few studies have compared the dietary quality of US adults with diabetes mellitus (DM), osteoarthritis (OA), and rheumatoid arthritis (RA) by age groups. METHODS: This study used cross-sectional data from adult participants from National Health and Nutrition Examination Survey 2011-2016 to identify dietary quality measured by Healthy Eating Index (HEI)-2015 total and component scores and self-reported disease status for DM, OA, and RA. Associations between the disease status and HEI-2015 total/component scores among younger adults aged 20-59 years (n = 7988) and older adults aged 60 years and older (n = 3780) were examined using logistic regression models. These accounted for the complex survey design and were adjusted for self-reported disease status, sex, race/ethnicity, education levels, income status, weight status, physical activity levels, and smoking status. RESULTS: Among younger adults, 7% had DM, 7% had OA, and 3% had RA. Among older adults, 20% had DM, 32% had OA, and 6% had RA. Moderate added sugar intake was associated with diabetes in all adults. Excess sodium intake was associated with DM among younger adults. Inadequate seafood and plant protein intake was associated with RA among younger adults, while a poor overall dietary pattern was associated with RA among older adults. CONCLUSIONS: The dietary quality of US adults varied by self-reported DM, OA, and RA status, and each varied by age group.


Assuntos
Artrite Reumatoide , Diabetes Mellitus , Dieta Saudável , Ingestão de Alimentos/fisiologia , Política Nutricional , Inquéritos Nutricionais , Osteoartrite , Autorrelato , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/etiologia , Estudos Transversais , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenômenos Fisiológicos da Nutrição , Osteoartrite/epidemiologia , Osteoartrite/etiologia , Proteínas de Vegetais Comestíveis , Alimentos Marinhos , Sódio na Dieta/administração & dosagem , Sódio na Dieta/efeitos adversos , Estados Unidos/epidemiologia , Adulto Jovem
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