RESUMEN
Osteopontin (OPN) is a bone-derived phosphoglycoprotein related to physiological and pathological mechanisms that nowadays has gained relevance due to its role in the immune system response to chronic degenerative diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). OPN is an extracellular matrix (ECM) glycoprotein that plays a critical role in bone remodeling. Therefore, it is an effector molecule that promotes joint and cartilage destruction observed in clinical studies, in vitro assays, and animal models of RA and OA. Since OPN undergoes multiple modifications, including posttranslational changes, proteolytic cleavage, and binding to a wide range of receptors, the mechanisms by which it produces its effects, in some cases, remain unclear. Although there is strong evidence that OPN contributes significantly to the immunopathology of RA and OA when considering it as a common denominator molecule, some experimental trial results argue for its protective role in rheumatic diseases. Elucidating in detail OPN involvement in bone and cartilage degeneration is of interest to the field of rheumatology. This review aims to provide evidence of the OPN's multifaceted role in promoting joint and cartilage destruction and propose it as a common denominator of AR and OA immunopathology.
Asunto(s)
Artritis Reumatoide , Osteoartritis , Osteopontina , Animales , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Osteoartritis/metabolismo , Osteoartritis/patología , Osteopontina/metabolismo , Membrana Sinovial/metabolismo , HumanosRESUMEN
Lameness is a common condition in dairy cattle caused by infectious or noninfectious agents. Joint lesions are the second most common cause of lameness and can be diagnosed in association with the presentation of digit injuries. Fibroblast-like synoviocyte (FLS) are predominant cells of synovia and play a key role in the pathophysiology of joint diseases, thus increasing the expression of proinflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is a potent proinflammatory cytokine involved in cyclooxygenase 2 (COX-2) and proinflammatory cytokine expression in FLS. Previously, TNF-α was demonstrated to increase hypoxia-inducible Factor 1 (HIF-1), a transcription factor that rewires cellular metabolism and increases the expression of interleukin (IL)-6 in bovine FLS (bFLS). Despite this, the proinflammatory effects of TNF-α in bFLS on metabolic reprogramming have been poorly studied. We hypothesized that TNF-α increases glycolysis and in this way controls the expression of IL-6, IL-8, and COX-2 in bFLS. Results first, gas chromatography/mass spectrometry (GC/MS)-based untargeted metabolomics revealed that bTNF-α altered the metabolism of bFLS, increasing glucose, isoleucine, leucine, methionine, valine, tyrosine, and lysine and decreasing malate, fumarate, α-ketoglutarate, stearate, palmitate, laurate, aspartate, and alanine. In addition, metabolic flux analysis using D-glucose-13C6 demonstrated an increase of pyruvate and a reduction in malate and citrate levels, suggesting a decreased flux toward the tricarboxylic acid cycle after bTNF-α stimulation. However, bTNF-α increased lactate dehydrogenase subunit A (LDHA), IL-6, IL-8, IL-1ß and COX-2 expression, which was dependent on glycolysis and the PI3K/Akt pathway. The use of FX11 and dichloroacetate (DCA), an inhibitor of LDHA and pyruvate dehydrogenase kinase (PDK) respectively, partially reduced the expression of IL-6. Our results suggest that bTNF-α induces metabolic reprogramming that favors glycolysis in bFLS and increases IL-6, IL-8, IL-1ß and COX-2/PGE2.
Asunto(s)
Artritis Reumatoide , Sinoviocitos , Bovinos , Animales , Sinoviocitos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Membrana Sinovial/patología , Dinoprostona/metabolismo , Interleucina-8/metabolismo , Malatos/metabolismo , Artritis Reumatoide/patología , Ciclooxigenasa 2/metabolismo , Cojera Animal , Fosfatidilinositol 3-Quinasas/metabolismo , Citocinas/metabolismo , Células Cultivadas , Fibroblastos/metabolismoRESUMEN
Chronic inflammatory diseases are triggered by causal stimuli that might occur long before the appearance of the symptoms. Increasing evidence suggests that these stimuli are necessary but not always sufficient to induce the diseases. The murine model of type II collagen emulsified in Freund's incomplete adjuvant (collagen-induced arthritis) to induce rheumatoid arthritis (RA) follows this pattern as some animals do not develop the chronically inflamed phenotype. Considering that in the immune-pineal axis (IPA) theory adrenal-pineal cross-talk adjusts early phases of inflammatory processes, we investigated whether differences in IPA activation could explain why some animals are resistant (RES) while others develop RA. We observed a similar increase in 6-sulfatoxymelatonin (aMT6s) excretion from day 3 to 13 in both RES and RA animals, followed by a significant decrease in RA animals. This pattern of aMT6s excretion positively correlated with plasma corticosterone (CORT) in RES animals. Additionally, RA animals presented a lower aMT6s/CORT ratio than saline-injected or RES animals. Plasmatic levels of tumour necrosis factor were similar in both groups, but interleukin (IL)-1ß and monocyte chemotactic protein 1 (MCP-1) levels were lower in RES compared to RA animals. IL-2 and IL-4 were decreased in RES animals compared to saline-injected animals. The aMT6s/CORT ratio inversely correlated with the paw thickness and the inflammatory score (levels of IL-1ß, MCP-1, IL-2 and IL-4 combined). Thus, adrenocortical-pineal positive interaction is an early defence mechanism for avoiding inflammatory chronification. KEY POINTS: Immune-pineal axis imbalance is observed in early-phase rheumatoid arthritis development. Only resistant animals present a positive association between adrenal and pineal hormones. The 6-sulfatoxymelatonin/corticosterone ratio is decreased in animals that develop rheumatoid arthritis. The inflammatory score combining the levels of nocturnal interleukin (IL)-1ß, monocyte chemotactic protein 1, IL-2 and IL-4 presents a very strong positive correlation with the size of inflammatory lesion. The 6-sulfatoxymelatonin/corticosterone ratio presents a strong negative correlation with the inflammatory score and paw oedema size.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Ratas , Ratones , Animales , Quimiocina CCL2 , Corticosterona , Interleucina-4/efectos adversos , Interleucina-2 , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Experimental/inducido químicamente , Artritis Experimental/patología , Citocinas/metabolismoRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and involvement of the synovial membrane, causing joint damage and deformities. No effective drug treatment is available, and physical exercise has been utilized to alleviate the inflammatory processes. This study aimed to investigate the effects of different exercise training protocols on Zymosan-induced RA inflammatory markers in the right knee of Wistar rats. The rodents were subjected to aerobic, resisted, and combined physical training protocols with variations in the total training volume (50% or 100% of resistance and aerobic training volume) for 8 weeks. All physical training protocols reduced cachexia and systemic inflammatory processes. The histological results showed an increase in the inflammatory influx to the synovial tissue of the right knee in all physical training protocols. The rats that underwent combined physical training with reduced volume had a lower inflammatory influx compared to the other experimental groups. A reduction in the mRNA expression of inflammatory genes and an increase in anti-inflammatory gene expression were also observed. The physical training protocol associated with volume reduction attenuated systemic and synovial inflammation of the right knee, reducing the impact of Zymosan-induced RA in rats.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Animales , Artritis Experimental/patología , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/patología , Artritis Reumatoide/terapia , Inflamación/inducido químicamente , Ratas , Ratas Wistar , Zimosan/efectos adversosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Herbs have been commonly used for the treatment of rheumatoid arthritis (RA). It has been verified that Erteng Tongbi Decoction has good therapeutic effects on RA, while, relatively few studies on the relationship between its components and anti-rheumatoid efficacy were carried out. AIM OF THE STUDY: To discuss the anti-RA effects of Erteng Tongbi Decoction on collagen-induced arthritis (CIA) in mice and the influence of T cell differentiation and cytokines balance. MATERIALS AND METHODS: Separate researches on the two traditional Chinese medicines of the Erteng Tongbi Decoction were conducted. First, a murine peritoneal macrophage model was established, and then the cytokines levels and macrophage maturity were measured to select the best extraction solvent. Furthermore, ethanol extracts were partitioned successively with four kinds of solvents, and the anti-inflammatory parts were selected by the same vitro model. Subsequently, mice were arbitrarily divided into control, CIA model, positive control, effective parts alone or in combination. After 20 days of oral administration, the weight, hind paw volume, rheumatism index value, and the pathological changes were checked to assess the obvious level of arthritis. Furthermore, the levels of IL-6, TNF-α, IL-10, and IL-17A in serum and the balance of Th17/Treg and Th1/Th2 cells in spleen and mesenteric lymph nodes (MLN) was detected. Finally, the major active constituents were identified. RESULTS: In vitro, the anti-inflammatory effects of ethanol extracts was much better than water extract. In addition, the effective parts of Celastrus orbiculatus Thunb. ethanol extract were petroleum ether parts and dichloromethane parts. The effective parts of Spatholobus suberectus Dunn. ethanol extracts was petroleum ether parts and ethyl acetate parts screened. In vivo, effective parts compatibility could inhibit the progression of inflammation by modulating T cell differentiation and cytokines balance. Constituent analysis revealed that effective parts contained sesquiterpenes alkaloids, phenolic acids, and flavanols. CONCLUSIONS: Erteng Tongbi Decoction could notably ameliorate CIA mice by modulating T cell differentiation and cytokines balance and support its application in folk medicine.
Asunto(s)
Antirreumáticos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Antirreumáticos/administración & dosificación , Antirreumáticos/aislamiento & purificación , Artritis Experimental/patología , Artritis Reumatoide/patología , Diferenciación Celular/efectos de los fármacos , Colágeno Tipo II , Citocinas/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Linfocitos T/citologíaRESUMEN
OBJECTIVES: To compare musculoskeletal changes on a physical examination (PE), ultrasound (US) and magnetic resonance imaging (MRI) of the hands and wrists of patients with Chikungunya fever (CF). METHODS: The sample consisted of 30 patients in the chronic phase of CF. The sites analyzed were the interphalangeal (IP), metacarpophalangeal (MCP) and wrist/mediocarpal (WMC) joints and periarticular soft tissue. The interval between the PE and imaging tests was 7 days, and the interval between US and MRI was 2 days. The kappa coefficient was calculated to estimate the agreement between the PE and US and MRI findings and between the US and MRI findings. RESULTS: Significant agreement was observed between PE and US in the diagnosis of synovitis. The only statistically significant agreement between US and MRI was the finding of flexor tenosynovitis; the agreement was moderate. CONCLUSIONS: US has great potential for use in diagnosing synovitis suspected based on a PE. The limited agreement observed between US and MRI, in turn, may suggest a complementary role of these methods.
Asunto(s)
Artritis Reumatoide , Fiebre Chikungunya , Sinovitis , Tenosinovitis , Artritis Reumatoide/patología , Fiebre Chikungunya/complicaciones , Fiebre Chikungunya/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Examen Físico , Sinovitis/diagnóstico por imagen , Tenosinovitis/diagnóstico por imagen , Muñeca , Articulación de la MuñecaRESUMEN
Abstract The aim of this study is the association between the scores of disease activity, functional capacity and quality of life among patients diagnosed with rheumatoid arthritis, under clinical treatment at the Regional University Hospital of Campos Gerais - Wallace Thadeu de Mello and Silva. The sample was composed by volunteer patients, who freely underwent 3 research questionnaires. With the results of the survey, the disease activity score was correlated to the functional capacity and the quality-of-life scores. A mean of 3.87 and 1.2 was observed for the disease activity and the functional capacity scores, respectively, yet not achieving a correlation between those two variables. A strong correlation between the disease activity and the "functional capacity", "general health status" and "mental health" domains was found. The lowest average observed corresponded to "physical limitation", from the quality-of-life questionnaire. There was no statistically significant correlation between disease activity and functional capacity, although disease activity seems to affect the mental health, general health status and functional capacity of patients.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Pacientes/clasificación , Artritis Reumatoide/patología , Calidad de Vida , Investigación/instrumentación , Encuestas y Cuestionarios/estadística & datos numéricos , Hospitales/clasificaciónRESUMEN
Abstract The Disease Activity Score 28 (DAS28) shows discrepancies when using erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) scores to assess rheumatoid arthritis (RA). This study aimed to verify the agreement between the DAS28-CRP and DAS28-ESR scores in patients with RA from the south of Brazil. A unicentric cross-sectional study was performed (n = 56). The diagnosis of the patients followed the American College of Rheumatology/ European League Against Rheumatism criteria, and their DAS28 were calculated. The DAS28- ESR score was higher than the DAS28-CRP (DAS28-ESR mean 4.8±1.6; DAS28-CRP mean 4.3±1.4) for 83.9% of the patients. The DAS28-CRP and DAS28-ESR scores showed a very strong correlation (Pearson's coefficient = 0.922; P<0.0001, 95% CI +0.87 to +0.95, statistical power 100%). Spearman's correlation coefficient (0.49; P=0.0001, 95% CI +0.25 to +0.67, statistical power 47.54%) showed a moderate correlation between the unique components of the DAS28 formulas. There was agreement between the tests in only 36 of the patients (64.29%). Among the discordant categories, DAS28-ESR overestimated the classification in 16 patients (28.5%). The Kappa coefficient between the categories was 0.465 (SE 0.084, 95% CI +0.301 to +0.630), showing a moderate degree of agreement between the instruments. Although the DAS28-ESR and DAS28-CRP were highly correlated, they differed significantly in terms of patient categorization and should not be used interchangeably
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Pacientes/clasificación , Artritis Reumatoide/patología , Brasil/etnología , Inducción de Remisión/métodos , Proteína C-Reactiva/efectos adversos , ClasificaciónRESUMEN
Abstract In the present research investigation, various concentrations of hydro-alcoholic extract of Saraca asoca (Roxb.) De Wilde (family: Caesalpinaceae) dried bark and carbopol polymer at different temperature ranges were optimized for the preparation of gel formulation. Natural penetration enhancers, v.i.z., eucalyptus oil and peppermint oil were incorporated separately in the extract based gel formulations to study the rate of drug permeation across egg membrane, using franz diffusion cell. In vitro anti-arthritis potential of the formulations was also studied using inhibition of albumin denaturation, antiproteinase activity and membrane stabilization method. As per the results of current study, it is established that S. asoca dried bark hydroalcoholic extract based gel prepared using peppermint oil as penetration enhancer exhibited good permeation rate of 8.48% at the end of 3 h. The percentage inhibition of proteins by antiproteinase method at concentration of 50 µg/ml was 50.01±1.00% which was close to 53.92±0.99% as shown by the standard drug, Diclofenac. Also, the percent protein inhibition determined using membrane stabilization method was found to be 49.70±1.00%, however, it was 63.32±0.94% for the standard drug, Diclofenac. Hence, it is concluded that peppermint oil may act as a good candidate for the preparation of potent anti-rheumatic gel preparations.
Asunto(s)
Aceites de Plantas/análisis , Preparaciones Farmacéuticas/análisis , Joanesia asoca/análisis , Mentha piperita/anatomía & histología , Solución Hidroalcohólica , Aceite de Eucalipto/análisis , Artritis Reumatoide/patología , Técnicas In Vitro/métodos , Extractos Vegetales/agonistasRESUMEN
Abstract Acrylamide is a neurotoxic compound. Moreover, anakinra is an interleukin-1 (IL-1) receptor antagonist used in rheumatoid arthritis treatment. This study investigated the effect of anakinra on acrylamide-related neuropathy and neuropathic pain. Acrylamide exposure caused a significant decrease in the pain threshold; an increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) levels; and a decrease in total glutathione (tGSH) values in the sciatic nerve. This indicates hyperalgesia presence, oxidative stress, and peripheral nerve tissue inflammation. Anakinra treatment significantly reduced the MDA, IL-1ß, and TNF-α levels, and increased the pain threshold and mean tGSH values. The analgesic effect of anakinra was 67.9% at the first hour, increasing to 74.9% and 76.7% at the second and third hours, respectively. The group receiving acrylamide exhibited histopathological changes (e.g., swollen and degenerated axons, hypertrophic and hyperplasic Schwann cells, and congested vessels). The use of anakinra significantly improved these morphological changes. Anakinra is concluded to reduce neuropathic pain and prevent neurotoxic effect of acrylamide on peripheral nerves due to its analgesic, antioxidant, and anti-inflammatory properties
Asunto(s)
Animales , Masculino , Ratas , Enfermedades del Sistema Nervioso Periférico/patología , Acrilamida/efectos adversos , Proteína Antagonista del Receptor de Interleucina 1/antagonistas & inhibidores , Inflamación/clasificación , Nervios Periféricos/anomalías , Artritis Reumatoide/patología , Factor de Necrosis Tumoral alfa/farmacología , Umbral del Dolor/clasificación , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND: Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. METHODS: Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. RESULTS: The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). CONCLUSION: High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.
Asunto(s)
Artritis Reumatoide/sangre , Remodelación Ósea/fisiología , Osteoporosis/sangre , Fracturas Osteoporóticas/diagnóstico , Osteoprotegerina/sangre , Ligando RANK/sangre , Artritis Reumatoide/complicaciones , Artritis Reumatoide/patología , Biomarcadores/sangre , Densidad Ósea , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis/etiología , Osteoporosis/patología , Fracturas Osteoporóticas/sangre , Fracturas Osteoporóticas/etiología , Posmenopausia/sangre , PronósticoRESUMEN
OBJECTIVES: This study was aimed at assessing the anti-arthritic effects of hesperidin on the inflammatory markers in serum/plasma, ectoenzymes activity in platelet, reactive oxygen species (ROS), apoptosis and cell cycle in bone marrow cells of a rat model of arthritis. METHODS: Fifty-six adult female Wistar rats (245-274 g) were grouped into eight of seven rats each: control rats given normal saline or 40 mg/kg of hesperidin or 80 mg/kg of hesperidin, 0.2 mg/kg of dexamethasone, arthritic rats given normal saline, or 40 mg/kg of hesperidin or 80 mg/kg of hesperidin, and 0.2 mg/kg of dexamethasone. Myeloperoxidase and nitrate plus nitrite levels were evaluated in the plasma and serum, respectively. The ecto-nucleoside triphosphate diphosphohydrolases, ecto-5'-nucleotidase and ecto-adenosine deaminase activities were assessed in platelets. Subsequently, the cells of the bone marrow were obtained, and the assays for ROS, apoptosis and cell cycle were evaluated using flow cytometry. KEY FINDINGS: The results showed that hesperidin mitigated inflammation, modulated adenosine nucleotides and nucleoside hydrolysing enzymes and levels, minimized ROS intracellularly, attenuated apoptotic process and activated cell cycle arrest in arthritic rat. CONCLUSION: This study suggests that hesperidin could be a natural and promising anti-inflammatory compound for the management of arthritis.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental , Puntos de Control del Ciclo Celular/efectos de los fármacos , Citrus/química , Hesperidina/farmacología , Hidrolasas/metabolismo , Inflamación , 5'-Nucleotidasa/metabolismo , Adenosina Desaminasa/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Apoptosis , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Femenino , Adyuvante de Freund , Hesperidina/uso terapéutico , Inflamación/metabolismo , Inflamación/prevención & control , Proteínas de la Membrana/metabolismo , Nucleósido-Trifosfatasa/metabolismo , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Pirofosfatasas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The complement receptor of the immunoglobulin superfamily (CRIg, encoded by the VSIG4 gene) is a macrophage receptor involved in the clearance of immune complexes and autologous cells. Our results suggest that the VSIG4 rs1044165T allele is a risk factor for severe functional status of rheumatoid arthritis in women, possibly by affecting VSIG4 gene expression.
Asunto(s)
Artritis Reumatoide/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Receptores de Complemento/genética , Adolescente , Adulto , Anciano , Alelos , Artritis Reumatoide/epidemiología , Artritis Reumatoide/patología , Brasil/epidemiología , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
Peripheral neuropathy in patients with rheumatoid arthritis is associated with a maladaptive autoimmune response that may cause chronic pain and disability. Nerve conduction studies are the routine method performed when rheumatologists presume its presence. However, this approach is invasive, may not reveal subtle malfunctions in the early stages of the disease, and does not expose abnormalities in structures surrounding the nerves and muscles, limiting the possibility of a timely diagnosis. This work aims to present a narrative review of new technologies for the clinical assessment of peripheral neuropathy in Rheumatoid Arthritis. Through a bibliographic search carried out in five repositories, from 1990 to 2020, we identified three technologies that could detect peripheral nerve lesions and perform quantitative evaluations: (1) magnetic resonance neurography, (2) functional magnetic resonance imaging, and (3) high-resolution ultrasonography of peripheral nerves. We found these tools can overcome the main constraints imposed by the previous electrophysiologic methods, enabling early diagnosis.
Asunto(s)
Artritis Reumatoide/complicaciones , Enfermedades del Sistema Nervioso Periférico/diagnóstico por imagen , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/patología , Humanos , Imagen por Resonancia Magnética/efectos adversos , Imagen por Resonancia Magnética/métodos , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/patología , Ultrasonografía/efectos adversos , Ultrasonografía/métodosRESUMEN
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show that microRNA-132 is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium. miRNA-132 thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown of miR-132 in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels of miR-132 than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.
Asunto(s)
Artritis Reumatoide/genética , MicroARNs/genética , Osteogénesis/fisiología , Adulto , Anciano , Animales , Artritis Experimental/patología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Fumar Cigarrillos/efectos adversos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Persona de Mediana Edad , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Receptores de Hidrocarburo de Aril/metabolismo , Humo , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction associated with increased pro-inflammatory mediators. In inflammatory microenvironments, exogenous ATP (eATP) is hydrolyzed to adenosine, which exerts immunosuppressive effects, by the consecutive action of the ectonucleotidases CD39 and CD73. Mature B cells constitutively express both ectonucleotidases, converting these cells to potential suppressors. Here, we assessed CD39 and CD73 expression on B cells from treated or untreated patients with RA. Neither the frequency of CD73+CD39+ and CD73-CD39+ B cell subsets nor the levels of CD73 and CD39 expression on B cells from untreated or treated RA patients showed significant changes in comparison to healthy controls (HC). CpG+IL-2-stimulated B cells from HC or untreated RA patients increased their CD39 expression, and suppressed CD4+ and CD8+ T cell proliferation and intracellular TNF-production. A CD39 inhibitor significantly restored proliferation and TNF-producing capacity in CD4+ T cells, but not in CD8+ T cells, from HC and untreated RA patients, indicating that B cells from untreated RA patients conserved CD39-mediated regulatory function. Good responder patients to therapy (R-RA) exhibited an increased CD39 but not CD73 expression on B cells after treatment, while most of the non-responder (NR) patients showed a reduction in ectoenzyme expression. The positive changes of CD39 expression on B cells exhibited a negative correlation with disease activity and rheumatoid factor levels. Our results suggest modulating the ectoenzymes/ADO pathway as a potential therapy target for improving the course of RA.
Asunto(s)
Apirasa/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Inmunomodulación , Adenosina/metabolismo , Apirasa/genética , Artritis Reumatoide/patología , Artritis Reumatoide/terapia , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Estudios de Casos y Controles , Citocinas/biosíntesis , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Expresión Génica , Humanos , Activación de Linfocitos , Recuento de Linfocitos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
The role of gut microbiota on immune regulation and the development of autoimmune diseases such as rheumatoid arthritis (RA) is an emerging research topic. Multiple studies have demonstrated alterations on gut microbiota composition and/or function (referred to as dysbiosis) both in early and established RA patients. Still, research delineating the molecular mechanisms by which gut microorganisms induce the loss of immune tolerance or contribute to disease progression is scarce. Available data indicate that gut microbiota alterations are involved in RA autoimmune response by several mechanisms including the post-translational modification of host proteins, molecular mimicry between bacterial and host epitopes, activation of immune system and polarization toward inflammatory phenotypes, as well as induction of intestinal permeability. Therefore, in this review we analyze recent clinical and molecular evidence linking gut microbiota with the etiopathogenesis of RA. The potential of the gut microbiota as a diagnostic or severity biomarker is discussed, as well as the opportunity areas for the development of complementary therapeutic strategies based on the modulation of gut microbiota in the rheumatic patient.
Asunto(s)
Artritis Reumatoide/patología , Disbiosis/complicaciones , Microbioma Gastrointestinal , Inflamación/complicaciones , Animales , Artritis Reumatoide/etiología , HumanosRESUMEN
Produtos liberados pela queima do cigarro convencional (CC) estão relacionados com a progressão clínica da artrite reumatoide (AR). Produtos fumígenos não combustíveis surgiram com a premissa de apresentarem menor toxicidade que o CC, dentre os quais está o tabaco aquecido (heat-not-burn tobacco; HNBT). Neste projeto investigamos os efeitos do HNBT sobre eventos envolvidos na AR, focando na sintomatologia, expressão de metalotioneínas (MTs), e na biologia de linfócitos T CD4+ primários e da linhagem Jurkat. Exposições in vivo ao ar, CC ou HNBT foram realizadas 2 vezes ao dia, 1 hora cada (12 CC ou 24 HNBT/hora), nos dias 14-21 da indução da artrite induzida por antígeno (AIA) em camundongos C57Bl/6. Foram realizadas análises dos parâmetros clínico da doenças, histopatologia e imunohistoquímica; quantificação de nicotina e cotinina séricas por cromatografia líquida acoplada a espectrometria de massas (MS). Os efeitos das exposições in vitro sobre linfócitos T foram mensurados por citometria de fluxo e ELISA. A concentração de metais emitidas pelo CC ou HNBT durante as exposições foram mensurados por MS com plasma acoplado. Camundongos expostos ao CC apresentaram intensa inflamação pulmonar, expressões acentuadas de MTs hepáticas e pulmonares e exacerbação dos parâmetros de AIA quando comparados ao grupo expostos ao HNBT. Animais expostos ao CC ou ao HNBT apresentaram redução na celularidade de órgãos linfoides. Somente a exposição in vitro ao CC causou estresse oxidativo e secreção de citocinas inflamatórias, ativação do receptor de hidrocarbonetos arila (AhR) e polarização de células Th17. Diferentemente, exposição ao CC ou ao HNBT provocaram redução da secreção de IL-2 e proliferação de células Jurkat. A exposição de células Jurkat à nicotina mimetizou os efeitos inibitórios da exposição ao HNBT sobre a secreção de IL-2 e proliferação de linfócitos T. O CC liberou maiores concentrações de metais nas câmaras de exposição. Associados, nossos resultados mostram que embora exposições ao HNBT não exacerbem parâmetros inflamatórios de AIA e nem em funções linfócitos T, ambos produtos prejudicam a celularidade de órgãos linfoides e a proliferação e secreção de IL-2 por linfócitos T
Products released by burning conventional cigarettes (CC) are related to the worsening of rheumatoid arthritis (RA). Non-combustible smoking products appeared with the premise of presenting less toxicity than the CC, among which is the heated tobacco (heat-not-burn tobacco; HNBT). Here, we investigate the effects of HNBT on events involved in RA, focusing on symptoms, expression of metallothioneins (MTs), and on the biology of primary CD4+ T lymphocytes and the Jurkat T cell lineage. In vivo exposures to air, CC or HNBT were performed twice a day, 1 hour each (12 CC or 24 HNBT / hour), on days 14-21 of the induction of antigen-induced arthritis (AIA) in C57Bl / 6 mice. Analyzes of the clinical parameters of the AIA, histopathology, and immunohistochemistry were performed; quantification of nicotine and cotinine by liquid chromatography coupled to mass spectrometry (MS). The in vitro effects of exposures on T lymphocytes were measured by flow cytometry and ELISA. The concentration of metals released by the CC or HNBT during the exposures was measured by MS with coupled plasma. Mice exposed to CC showed intense pulmonary inflammation, marked expressions of hepatic and pulmonary MTs, and exacerbation of AIA parameters when compared to the group exposed to HNBT. Animals exposed to CC or HNBT showed a reduction in the cellularity of lymphoid organs. Only in vitro exposure to CC caused oxidative stress and secretion of inflammatory cytokines, activation of the aryl hydrocarbon receptor (AhR), and polarization of Th17 cells. However, exposure to CC or HNBT led to reduced secretion of IL-2 and proliferation of Jurkat cells. The exposure of Jurkat T cells to nicotine mimicked the inhibitory effects of exposure to HNBT on IL-2 secretion and T lymphocyte proliferation. The CC released higher concentrations of metals in the exposure chambers. In association, our results show that although exposures to HNBT do not exacerbate inflammatory parameters of AIA or T lymphocyte functions, both products impair lymphoid organ cell function and the proliferation and secretion of IL-2 by T lymphocytes