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OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).
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Lupus Eritematoso Sistémico , Proteínas Recombinantes de Fusión , Adulto , Humanos , Método Doble Ciego , Glucocorticoides/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Diabetes increases the risk of hypertension morbidity, but whether this association is varied with glycemic control remains unknown. We aimed to examine the association of glycemic control with hypertension among individuals with diabetes. METHODS: Data was from the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2018. Participants were categorized as having adequate glycemic control (HbA1c < 7%) and inadequate glycemic uncontrol (HbA1c ≥ 7%) by combining blood glucose tests and physician's diagnoses in 2011. Incident hypertension was ascertained through self-reported physician diagnoses from 2011 to 2018. Cox proportional hazards regression models were used to examine the effect of glycemic control on hypertension. RESULTS: Among 436 participants with diabetes in this study, 102 met the glycemic control standard, and 334 were insufficient glycemic control. During 7 years of follow-up, 141 individuals developed hypertension. Compared with adequate glycemic control, the hazard ratio of inadequate glycemic control on hypertension was 1.54 (95% CI, 1.07-2.21) in the multivariate model. Additionally, the influence of glycemic control on hypertension varied based on educational attainment and the presence of depressive symptoms (P for interaction < 0.05). CONCLUSIONS: Insufficient glycemic control was associated with a higher risk of hypertension among individuals with diabetes. Notably, the effect of glycemic control on hypertension was more pronounced among those with lower educational attainment and those exhibiting depressive symptoms. These findings underscore the significance of vigilant glycemic monitoring, educational background considerations, and mental health assessments in managing diabetic individuals.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Control Glucémico , Hipertensión , Humanos , Glucemia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Hemoglobina Glucada , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Estudios Longitudinales , Estudios de Seguimiento , China/epidemiologíaRESUMEN
Ras homolog gene family member A (RhoA) plays a major role in the Wnt/planar cell polarity (PCP) pathway, which is significantly activated in patients with rheumatoid arthritis (RA). The function of RhoA in RA synovitis and bone erosion is still elusive. Here, we not only explored the impact of RhoA on the proliferation and invasion of RA fibroblast-like synoviocytes (FLSs) but also elucidated its effect on mouse osteoclast and a mouse model of collagen-induced arthritis (CIA). Results showed that RhoA was overexpressed in RA and CIA synovial tissues. Lentivirus-mediated silencing of RhoA increased apoptosis, attenuated invasion, and dramatically upregulated osteoprotegerin/receptor activator of nuclear factor-κB ligand (OPG/RANKL) ratio in RA-FLSs. Additionally, the silencing of RhoA inhibited mouse osteoclast differentiation in vitro and alleviated synovial hyperplasia and bone erosion in the CIA mouse model. These effects in RA-FLSs and osteoclasts were all regulated by RhoA/Rho-associated protein kinase 2 (ROCK2) and might interact with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.
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Artritis Experimental , Artritis Reumatoide , Sinoviocitos , Animales , Humanos , Ratones , Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Proliferación Celular , Células Cultivadas , Fibroblastos/metabolismo , Osteoclastos/metabolismo , Membrana Sinovial/metabolismo , Sinoviocitos/metabolismo , Vía de Señalización WntRESUMEN
OBJECTIVE: Our previous study revealed that synovial mesenchymal stem cell (SMSC)-derived exosomal microRNA-302c enhanced chondrogenesis by targeting a disintegrin and metalloproteinase 19 (ADAM19) in vitro. This study aimed to validate the potential of SMSC-derived exosomal microRNA-302c for the treatment of osteoarthritis in vivo. METHODS: After 4 weeks of destabilization of the medial meniscus surgery (DMM) to establish an osteoarthritis model, the rats received weekly articular cavity injection of SMSCs with or without GW4869 treatment (exosome inhibitor) or exosomes from SMSCs with or without microRNA-320c overexpression for another 4 weeks. RESULTS: SMSCs and SMSC-derived exosomes reduced the Osteoarthritis Research Society International (OARSI) score, improved cartilage damage repair, suppressed cartilage inflammation, suppressed extracellular matrix (ECM) degradation, and inhibited chondrocyte apoptosis in DMM rats. However, these effects were largely hampered in rats that were injected with GW4869-treated SMSCs. Moreover, exosomes from microRNA-320c-overexpressing SMSCs exerted a better effect than exosomes from negative control SMSCs on decreasing the OARSI score, enhancing cartilage damage repair, suppressing cartilage inflammation, and inhibiting ECM degradation and chondrocyte apoptosis. Mechanistically, exosomes from microRNA-320c-overexpressing SMSCs reduced the levels of ADAM19, as well as ß-catenin and MYC, which are two critical proteins in Wnt signalling. CONCLUSION: SMSC-derived exosomal microRNA-320c suppresses ECM degradation and chondrocyte apoptosis to facilitate cartilage damage repair in osteoarthritis rats by targeting ADAM19-dependent Wnt signalling.
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Células Madre Mesenquimatosas , MicroARNs , Osteoartritis , Ratas , Animales , MicroARNs/genética , Osteoartritis/terapia , Osteoartritis/metabolismo , Cartílago/metabolismo , Inflamación/metabolismoRESUMEN
OBJECTIVES: This study aimed to evaluate the therapeutic effect of iguratimod and its regulatory role on microRNA (miR-146a) and the downstream genes in treating rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis (CIA) rat model. METHODS: RA-FLS was isolated from knee synovial tissue of an active RA patient. In vitro, the effect of miR-146a mimic/inhibition on RA-FLS functions was investigated. Then the effect of Iguratimod on cell viability, proliferation, apoptosis, migration, invasion, inflammatory cytokines, miR-146a and its downstream gene/pathway in RA-FLS was evaluated. In vivo, the collagen induced arthritis (CIA) rat model was constructed, then the effects of iguratimod, miR-146a inhibition and their combination on treating CIA rat were assessed. RESULTS: Iguratimod treatment increased miR-146a while decreased cell proliferation, IRAK1 and TRAF6/JNK1 pathway in RA-FLS in a dose-dependent manner. Notably, iguratimod treatment repressed cell proliferation, migration, invasion, TNF-α, IL-1ß, IL-6, IL-17, IRAK1 and TRAF6/JNK1 pathway in RA-FLS, while miR-146a inhibition alleviated the abovementioned effects of Iguratimod on RA-FLS. The in vivo experiments disclosed that iguratimod reduced systemic arthritis score, and decreased TNF-α, IL-1ß, IL-6, IL-17, IRAK1 as well as TRAF6/JNK1 pathway, while enhanced apoptosis in synovial tissue of CIA rat model; and in miR-146a inhibition treated CIA rat model, the effect of iguratimod was diminished. CONCLUSIONS: Iguratimod ameliorates RA progression via regulating miR-146a mediated IRAK1 expression and TRAF6/JNK1 pathway.
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Artritis Reumatoide , MicroARNs , Sinoviocitos , Animales , Artritis Reumatoide/tratamiento farmacológico , Proliferación Celular , Células Cultivadas , Cromonas , Fibroblastos , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/genética , MicroARNs/genética , Ratas , Sulfonamidas , Membrana Sinovial , Factor 6 Asociado a Receptor de TNF/genéticaRESUMEN
Air pollution may trigger systemic lupus erythematosus (SLE). However, few studies have investigated the associations between air pollution and complications of SLE, such as lupus nephritis (LN). In this study, multicenter longitudinal data from 13 hospitals in China, including 8552 SLE patients with 24,762 visits, were used. Based on the generalized estimating equation (GEE) model, we assessed the associations of LN occurrence with short-term exposures to different air pollutants including particulate matter with an aerodynamic diameter < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). We identified 2672 LN patients, and about half of them were from east China. Our results based on the entire data set showed that PM2.5 and NO2 were risk factors for LN within one month after exposure, with odds ratio of 1.16 (95% confidence interval (CI), 1.08-1.19) at lag 18 day and 1.19 (95% CI, 1.12-1.26) at lag 16 day relative to an interquartile range (IQR) increase in PM2.5 and NO2, respectively. This positive association between LN and NO2 was also observed for south, west, and east China. In addition, we found that the short term exposure to CO and O3 was not generally associated with LN. Finally, the negative associations of LN with SO2 were found for the entire region and east China. Our results implied that SLE patients may gain the health benefits of air quality improvement in China. Our work also provided evidence that short-term variations in air pollution may trigger LN, and further studies are needed to confirm these findings and the potential pathogenic mechanisms should be explored.
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Contaminantes Atmosféricos , Contaminación del Aire , Lupus Eritematoso Sistémico , Nefritis Lúpica , Ozono , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , China/epidemiología , Exposición a Riesgos Ambientales/análisis , Humanos , Lupus Eritematoso Sistémico/epidemiología , Nefritis Lúpica/inducido químicamente , Nefritis Lúpica/epidemiología , Dióxido de Nitrógeno/análisis , Dióxido de Nitrógeno/toxicidad , Ozono/análisis , Material Particulado/análisis , Material Particulado/toxicidad , Dióxido de Azufre/análisisRESUMEN
JNK1 plays an important role in osteoclastogenesis in response to the osteoclastogenic cytokine receptor activator for nuclear factor-κB ligand (RANKL). JNK1 is widely accepted as an autophagy regulator under stress conditions. However, the role of JNK1-mediated autophagy in osteoclastogenesis remains largely unknown. In the current study, our data showed that JNK1 inhibition by a pharmacological inhibitor or RNA interference significantly reduced the autophagic response induced by RANKL in osteoclast precursors (OCPs) derived from bone marrow-derived macrophages. Overexpression of the key autophagy protein Beclin1 rescued autophagy deficiency and osteoclastogenesis in the presence of a JNK inhibitor (SP600125). In contrast, JNK activator (anisomycin)-induced autophagy was blocked by Beclin1 knockdown in OCPs. In addition, JNK1 inhibition increased apoptosis and blocked autophagy, whereas overexpression of Beclin1 reversed the enhanced apoptosis induced by JNK1 inhibition in OCPs. Furthermore, RANKL could induce the phosphorylation of Bcl-2, subsequently dissociating Beclin1 from the Bcl-2-Beclin1 complex, which could be blocked by JNK1 inhibition. Collectively, this study revealed that JNK1 regulated osteoclastogenesis by activating Bcl-2-Beclin1-autophagy signaling in addition to the classic c-Jun/activator protein 1 pathway, which provided the first evidence for the contribution of JNK1 signaling to OCP autophagy and the autophagic mechanism underlying JNK1-regulated osteoclastogenesis. An important osteoclastogenesis-regulating signaling pathway (JNK1-Bcl-2-Beclin1-autophagy activation) was identified, which provides novel potential targets for the clinical therapy of metabolic bone diseases.-Ke, D., Ji, L., Wang, Y., Fu, X., Chen, J., Wang, F., Zhao, D., Xue, Y., Lan, X., Hou, J. JNK1 regulates RANKL-induced osteoclastogenesis via activation of a novel Bcl-2-Beclin1-autophagy pathway.
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Autofagia , Diferenciación Celular , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Ligando RANK/metabolismo , Animales , Apoptosis , Beclina-1/metabolismo , Células Cultivadas , Ratones , Proteína Quinasa 8 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 8 Activada por Mitógenos/genética , Células Precursoras de Monocitos y Macrófagos/citología , Células Precursoras de Monocitos y Macrófagos/metabolismo , Osteoblastos/citología , Osteoclastos/citología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células RAW 264.7 , Transducción de SeñalRESUMEN
BACKGROUND: Genetic background affects serum urate concentration and gout risk, especially regarding these variants in the urate-transporter gene ABCG2. However, the role of epistasis between PKD2 and ABCG2 on the pathogenesis of gout is poorly understood. Here we assess this epistatic interaction in the progression from elevated serum urate to gout. RESULTS: We identified two epistatic interaction pairs (rs2728121: rs1481012 and rs2728121: rs2231137) were associated with urate levels in 4914 Chinese individuals (Pint = 0.018 and 0.004, respectively). Using subgroup analysis for gender and BMI, we found the degree of associations was varied by gender and BMI. The SNP pair rs2728121:rs1481012 influenced urate levels in females and overweight subjects (Pint = 0.006 and 0.022, respectively), but rs2728121:rs2231137 did in males, overweight and normal-weight subjects (Pint = 0.017, 0.047 and 0.013, respectively). Consistent results were also observed in associations between these epistatic interactions with hyperuricemia. Next, the SNP pair rs2728121:rs2231137 was identified to influence the development of gout from both hyperuricemia and healthy (Pint = 0.035 and 0.001, respectively), especially in males (Pint = 0.030 and 0.001, respectively). Furthermore, we demonstrated that interacting regions were enriched by regulatory elements. Finally, we observed a strong gene co-expression pattern between PKD2 and ABCG2 (r = 0.743, P = 5.83E-06). CONCLUSION: Our findings indicate epistasis between PKD2 and ABCG2 influence serum urate concentrations, hyperuricemia and gout risk, thus providing insight into the pathogenesis of gout.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Epistasis Genética , Predisposición Genética a la Enfermedad , Gota/genética , Hiperuricemia/genética , Proteínas de Neoplasias/genética , Canales Catiónicos TRPP/genética , Índice de Masa Corporal , Humanos , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , Fumar , Ácido Úrico/sangreRESUMEN
Synovial fibroblasts (SFs) of rheumatoid arthritis (RA) are phenotypically aggressive, typically progressing into arthritic cartilage degradation. Throughout our study, we made explorations into the effects of microRNA-135a (miR-135a) on the SFs involved in RA by mediating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway via regulation of phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2). The expression of PI3K was higher, the expression of PIK3R2 was lower, and AKT was phosphorylated in the RA synovial tissues, relative to the levels found in the normal synovial tissues. We predicted miR-135a to be a candidate miR targeting PIK3R2 using an online website, microRNA.org, which was verified with a dual-luciferase reporter gene assay. Subsequently, high miR-135a expression was observed in RA synovial tissues. To study the effect of the interaction between miR-135a and PIK3R2 in RA, the SFs isolated from RA samples were cultured and transfected with mimic, inhibitor, and small interfering RNA. The proliferation, invasion, and apoptosis of the SFs were detected after the transfection. The cells transfected with miR-135a inhibitor showed inhibited cell proliferation, migration, and invasion, while also displaying promoted cell apoptosis, G0/G1 cell ratio, and decreased S cell ratio, through upregulation of PIK3R2 and inactivation of the PI3K/AKT signaling pathway. These findings provided evidence that downregulation of miR-135a inhibits proliferation, migration, and invasion and promotes apoptosis of SFs in RA by upregulating the PIK3R2 coupled with inactivating the PI3K/AKT signaling pathway. The downregulation of miR-135a might be a potential target in the treatment of RA.
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Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Anciano , Apoptosis , Artritis Reumatoide/patología , Puntos de Control del Ciclo Celular/genética , Movimiento Celular , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Regulación hacia Arriba , Adulto JovenRESUMEN
The authors would like to add an article note stating that "The authors Jie Gao and Ruina Kong have equally contributed to the article".
RESUMEN
As an active form of vitamin D3, 1α,25-(OH)2D3 has a positive therapeutical effect on osteoporosis. However, 1α,25-(OH)2D3 can not only promote the osteoclastogenesis, but also inhibit the proliferation of osteoclast precursors (OCPs). Autophagy is regulated by 1α,25-(OH)2D3 and is considered to promote the osteoclastogenesis. Nevertheless, the role of 1α,25-(OH)2D3 in OCPs' autophagy remains unknown. Our study aims to explore whether the effect of 1α,25-(OH)2D3 on osteoclastogenesis is related to its regulation in autophagy. The results showed that 1α,25-(OH)2D3 exhibited a direct inhibitory effect on the autophagy activity and the proliferation of OCPs derived from bone marrow-derived macrophages (BMMs), which was reversed by the overexpression of autophagy-related gene. In presence of RANKL, the autophagy capacity of OCPs and the differentiation from OCPs into mature osteoclasts were significantly enhanced by 1α,25-(OH)2D3, while the suppression of autophagy with spautin-1 or 3-MA downregulated the osteoclastogenesis capacity. In summary, 1α,25-(OH)2D3 can directly suppress OCPs autophagy, which negatively regulates the proliferation of OCPs without RANKL. 1α,25-(OH)2D3 can indirectly upregulate the autophagy response of OCPs, thereby enhancing the osteoclasts formation in presence of RANKL. Therefore, our study found that 1α,25-(OH)2D3 had a dual effect on osteoclastogenesis by regulating autophagy, suggesting that some drugs targeting autophagy may act as an effective supplement of 1α,25-(OH)2D3 in treating osteoporosis.
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Autofagia/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Calcitriol/farmacología , Osteogénesis/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Ratones Endogámicos C57BL , Osteoclastos/citología , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Ligando RANK/metabolismoRESUMEN
BACKGROUND: The objectives of this study were to assess the maintenance of effect of duloxetine 60 mg once-daily (QD) in Chinese patients with chronic pain due to osteoarthritis (OA) of the knee or hip and to provide additional long-term safety data. METHODS: This was an open-label, extension phase of a randomized, double-blind, placebo-controlled clinical trial. Eligible patients were outpatients who met the American College of Rheumatology clinical and radiographic criteria for OA with a rating ≥4 on Brief Pain Inventory (BPI) 24-h average pain. After completing the 13-week placebo-controlled phase, patients originally assigned to placebo were titrated to duloxetine 60 mg QD (PLA_DLX), whereas patients originally assigned to duloxetine 60 mg QD remained on the same dose of duloxetine (DLX_DLX) for another 13 weeks. The maintenance effect of duloxetine 60 mg QD during the extension phase was evaluated by a 1-sided 97.5% confidence interval (CI) of the baseline-to-endpoint change in the extension phase for patients who took duloxetine and reported ≥30% reduction in BPI average pain at the end of placebo-controlled phase (placebo-controlled phase duloxetine responders). Other BPI severity and interference items, as well as safety and tolerability, were assessed. RESULTS: Of 342 patients entering the extension phase, 162 (97.6%) DLX_DLX-treated patients and 157 (89.2%) PLA_DLX-treated patients completed this phase. Most patients (76.0%) were female. Mean age was 60.6 years. Mean BPI average pain was 5.5 at baseline of the placebo-controlled phase. Among 113 placebo-controlled phase duloxetine responders, mean change in BPI average pain during the extension phase was - 0.59 (from 2.47 to 1.88); the upper bound of the 1-sided 97.5% CI was - 0.31 and less than the pre-specified non-inferiority margin of a 1.5-point increase (p < 0.001). Significant within-group improvements in all BPI items were observed for both PLA_DLX and DLX_DLX groups during the extension phase (all p < 0.01). No deaths or suicide-related events occurred. Seven (4.0%) PLA_DLX-treated patients and no DLX_DLX-treated patients discontinued due to an adverse event. CONCLUSION: The analgesic effect of duloxetine 60 mg QD among treatment responders was maintained for the entire duration of the extension phase. Duloxetine 60 mg QD was well tolerated during the extension phase. TRIAL REGISTRATION: ClinicalTrials.gov identification number NCT01931475 . Registered 29 August 2013.
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Analgésicos/administración & dosificación , Artralgia/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Clorhidrato de Duloxetina/administración & dosificación , Osteoartritis de la Cadera/tratamiento farmacológico , Osteoartritis de la Rodilla/tratamiento farmacológico , Anciano , Analgésicos/efectos adversos , Artralgia/diagnóstico , Artralgia/etiología , Dolor Crónico/diagnóstico , Dolor Crónico/etiología , Método Doble Ciego , Esquema de Medicación , Clorhidrato de Duloxetina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Cadera/complicaciones , Osteoartritis de la Rodilla/complicaciones , Dimensión del Dolor , Resultado del TratamientoRESUMEN
Both miR-126 and IL-23R affect rheumatoid arthritis (RA) procession. This study aimed to investigate the association of miR-126 and IL-23R and the possible modulation of miR-126 to RA pathogenesis. Serum, synovial tissue and synovial fluid were collected from patients with RA, and expression of miR-126, IL-23R, TNF-α and IFN-γ were detected. Fibroblast-like synoviocytes (FLS) was established using a collagen-induced arthritis mice model. The expression of miR-126 was manual intervened using pro-miR-126 and anti-miR-126 encoding lentivirus plasmids, or miR-126 agonists and corresponding negative controls. MiR-126 expression was inhibited in RA patients when compared with controls (P < 0.05). TNF-α and IFN-γ production and IL-23R expression were significantly upregulated in RA patients when compared to controls (P < 0.05). In pro-miR-126 treated FLS cells, the administration of pro-miR-126 plasmids upregulated miR-126, but inhibited IL-23R, TNF-α and IFN-γ expression or production. Moreover, the miR-126 agonist reversed the effects of the anti-miR-126 plasmid on FLS. These results revealed that miR-126 negative regulated the expression of IL-23R, TNF-α and IFN-γ. These results suggest the key impact of miR-126 on RA procession. Moreover, pro-miR-126 might be explored to be a potential therapy for RA.
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Artritis Reumatoide/metabolismo , Modelos Animales de Enfermedad , MicroARNs/metabolismo , Receptores de Interleucina/metabolismo , Sinoviocitos/metabolismo , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/patología , Células Cultivadas , Femenino , Silenciador del Gen , Humanos , Interferón gamma/genética , Interferón gamma/metabolismo , Masculino , Ratones , MicroARNs/agonistas , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Persona de Mediana Edad , Ratas , Ratas Endogámicas Lew , Receptores de Interleucina/genética , Líquido Sinovial/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
OBJECTIVE: The purpose of our study was to elucidate the impact of microRNA-126 (miR-126) targeting PIK3R2 gene on cell proliferation and apoptosis of rheumatoid arthritis synovial fibro-blasts (RASFs) by regulating PI3K/AKT signal pathway. METHODS: The synovial tissue samples of this study were from 55 RA patients undergoing joint replacement and 27 healthy people undergoing joint repair due to trauma. The target genes of miR-126 were collected by the TargetScan and PIK3R2 as the direct target gene of miR-126 was confirmed by dual-luciferase reporter assay system. Our experiment had five groups including the blank control, miR-126 mimic, miR-126 mimic control, miR-126 inhibitor and miR-126 inhibitor control groups. Additionally, real-time quantitative polymerase chain reaction (RT-qPCR), Western-Blot, cell counting kit (CCK-8) and flow cytometry were carried out in this study. RESULTS: Compared with healthy individuals, the RA patients had increased miR-126, but decreased PIK3R2 mRNA expressions in the synovial tissues. Pearson correlation analysis indicated that miR-126 expression was negatively correlated with PIK3R2 mRNA expression (all P<0.05). When compared with the blank group respectively, the miR-126 mimic group had raising cell proportions in S and G2/M phases with reduced rate of cell apoptosis, while the miR-126 inhibitor group had raising cell proportions in G0/G1 and G2/M phases with increased rate of cell apoptosis (all P<0.05). Besides, compared with the blank control group, the miR-126 mimic group had declined expression of PIK3R2 protein with ascended expression of PI3K and p-AKT (all P<0.05), while the miR-126 inhibitor group had increased expression of PIK3R2 protein with decreased expression of PI3K and p-AKT (all P<0.05). CONCLUSION: Our study demonstrated that down-regulation of miR-126 may indirectly inhibit PI3K/AKT signaling pathway to disrupt the imbalance between growth and death of RASFs by targeting PIK3R2, which may be clinically helpful to find therapeutic strategies directed toward miR-126 function for RA patients.
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Apoptosis/fisiología , Artritis Reumatoide/patología , Proliferación Celular/genética , Fibroblastos/metabolismo , MicroARNs/genética , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal , Adulto , Anciano , Apoptosis/genética , Artritis Reumatoide/genética , Regulación hacia Abajo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Adulto JovenRESUMEN
INTRODUCTION: Single-incision laparoscopic surgery (SILS) in gastric banding (SI-LAGB) has been reported to be a safe and technically feasible procedure among various operating methods. However, there is little evidence with regard to the question whether SI-LAGB has more advantages and should be recommended compared with conventional LAGB (CLAGB). Thus, this study was performed to assess the safety and efficacy of SI-LAGB. MATERIAL AND METHODS: A computerized search of the electronic databases PubMed and EMBASE was performed. Data regarding operative parameters, postoperative recovery parameters, follow-up time, percentage of excess weight loss, and postoperative complication were pooled and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. RESULTS: Ten comparative studies including 2,073 patients (1,038 patients who received SI-LAGB and 1,035 patients who received CLAGB) were included and analyzed. Compared with CLAGB, a similar weight loss could be obtained using SI-LAGB. The postoperative complications of SI-LAGB were within the acceptable range, but one study reported one perioperative death. SI-LAGB required a longer operative time. Other outcome variables, such as blood loss, days of hospitalization, pain score, and hospitalization costs, were not significantly different between the two groups. CONCLUSIONS: SI-LAGB might be a safe and effective alternative to C-LAGB when performed by experienced surgeons, but available data do not allow to give a definitive answer and randomized controlled trials are needed.
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Cirugía Bariátrica/métodos , Laparoscopía/métodos , Complicaciones Posoperatorias/epidemiología , Cirugía Bariátrica/efectos adversos , Hospitalización/estadística & datos numéricos , Humanos , Laparoscopía/efectos adversos , Tiempo de Internación , Tempo Operativo , Resultado del Tratamiento , Pérdida de PesoAsunto(s)
Apendicitis , Enfermedades Autoinmunes , Apendicitis/diagnóstico , Humanos , Inmunoglobulina GRESUMEN
To assess the clinical efficacy as well as safety profiles of Leining, a novel cytotoxic T-lymphocyte antigen-4 fusion protein, versus placebo in the treatment of Chinese active rheumatoid arthritis (RA) patients with an inadequate clinical response to methotrexate (MTX). In this 24-week, randomized, double-blind, placebo-controlled multicenter study, a total of 440 Chinese patients with active RA with an inadequate response to MTX were randomly assigned to receive Leining (10 mg/kg) or placebo. Clinical response was assessed using the American College of Rheumatology 20 % improvement criteria ACR20, ACR50, and ACR70, with ACR20 as the primary major endpoints. Disease activity scores in 28 joints with erythrocyte sedimentation rate assessment (DAS28-ESR) were used to evaluate disease activity. After 24 weeks of treatment, significantly more patients in Leining group achieved ACR20 response than those in placebo group (70.61 vs. 46.36 %; p < 0.001). Similarly, ACR50 and ACR70 responses of Leining group were significantly higher than those of placebo group (40.30 vs. 22.73 %; p < 0.001 and 16.67 vs. 7.27 %; p < 0.05, respectively). DAS28-ESR in Leining group was significantly reduced compared to that in placebo group, with greater clinically meaningful (>1.2 unit) improvement (54.85 vs. 29.09 %, p < 0.05). Both the rates of remission (DAS28-ESR < 2.6) and low disease activity (DAS28-ESR < 3.2) were greater in the Leining group than those in the placebo group (12.42 vs. 2.73 %; p < 0.05 and 15.45 vs. 2.73 %; p < 0.05 respectively). The overall incidence of adverse events was similar in both Leining and placebo groups. No neutralizing antibodies were detected. Leining demonstrated clinically meaningful efficacy compared with placebo in Chinese patients with active RA despite MTX therapy. Administration of Leining in combination with MTX for 24 weeks was well tolerated.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Antirreumáticos/efectos adversos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/etnología , Artritis Reumatoide/inmunología , Pueblo Asiatico , Sedimentación Sanguínea , China/epidemiología , Evaluación de la Discapacidad , Método Doble Ciego , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunosupresores/efectos adversos , Masculino , Metotrexato/efectos adversos , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/efectos adversos , Inducción de Remisión , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore the prevalence and characteristics of main organ involvement in adult patients with polymyositis (PM) or dermatomyositis (DM) and determine their specific relative factors. METHODS: Using unified questionnaire, we retrospectively collected the medical records of 1 387 confirmed adult PM/DM patients from 2007 to 2012 at 22 rheumatology centers in China. Statistical analyses were performed with chi-square or Fisher exact test and multivariate analyses with logistic regression. RESULTS: A total of 1 387 patients were collected with 460 (33.2%) PM and 927 (66.8%) DM. The female:male ratio was 2.4: 1. Their onset age was ( 47 ± 14) years. A total of 1 031 (74.3%) patients had organ involvement. The prevalence of pulmonary involvement, arthritis, gastrointestinal and cardiac involvement were 44.6%, 32.3%, 21.9% and 20.3% respectively. The multivariate analysis indicated that older onset age (P < 0.01) was positively associated with pulmonary involvement while myalgia (P < 0.05) was negatively associated. Fever (P < 0.05), weight loss (P < 0.05) and Raynaud's phenomenon (P < 0.01) were positively associated with arthritis while muscle weakness (P < 0.05) negatively associated. Weight loss (P < 0.05), Raynaud's phenomenon (P < 0.01) and muscle weakness (P < 0.05) were positively associated with gastrointestinal involvement. Weight loss (P < 0.05) and swollen limbs (P < 0.05) were positively associated with cardiac involvement. CONCLUSION: The prevalence of organ involvement is high in adult PM/DM patients. Our study may aid the diagnosis of organ damage in PM/DM patients.
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Dermatomiositis/patología , Polimiositis/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: To estimate the diagnostic accuracy of anti-alpha-fodrin antibodies for primary Sjögren's syndrome (pSS). METHODS: Sixty-four pSS subjects and 108 non-pSS patients were prospectively enrolled in this study. Serum anti-alpha-fodrin IgA and IgG were detected by ELISA in a blind fashion. The diagnostic accuracy of anti-alpha-fodrin antibodies was assessed by receiver operating characteristic (ROC) curve analysis. Logistic regression was used to investigate whether anti-alpha-fodrin antibodies could improve the accuracy of pSS diagnosis if used in addition to anti-SSA and anti-SSB. RESULTS: The areas under the ROC curves for anti-alpha-fodrin IgG and IgA were 0.69 (95% confidence interval (CI): 0.60-0.77) and 0.63 (95% CI: 0.54-0.72), respectively (P < 0.01 for both). The optimal diagnostic thresholds for anti-fodrin IgG and IgA were 11.75 U/ml and 9.75 U/ml, respectively, with a sensitivity of 0.59 and 0.55, and a specificity of 0.75 and 0.73, respectively. Anti-alpha-fodrin IgG and IgA antibodies were associated with pSS after adjustment for anti-SSA and anti-SSB. CONCLUSIONS: Anti-alpha-fodrin IgG and IgA antibodies are useful diagnostic markers which may improve the accuracy of pSS diagnosis.
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Autoanticuerpos/sangre , Proteínas Portadoras/inmunología , Proteínas de Microfilamentos/inmunología , Síndrome de Sjögren/diagnóstico , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Síndrome de Sjögren/sangre , Síndrome de Sjögren/inmunologíaRESUMEN
OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that is characterized by persistent morning stiffness, joint pain, and swelling. However, there is a lack of reliable diagnostic markers and therapeutic targets that are both effective and trustworthy. METHODS: In this study, gene expression profiles (GSE89408, GSE55235, GSE55457, and GSE77298) were obtained from the Gene Expression Omnibus database. Differentially expressed necroptosis-related genes were attained from intersection of necroptosis-related gene set, differentially expressed genes, and weighted gene co-expression network analysis. The LASSO, random forest, and SVM-RFE machine learning algorithms were utilized to further screen potential diagnostic genes for RA. Immune cell infiltration was analyzed using the CIBERSORT method. The expressions of diagnostic genes were validated through quantitative real-time PCR, western blotting, immunohistochemistry, and immunofluorescence staining in synovial tissues collected from three trauma controls and three RA patients. RESULTS: Five core necroptosis-related genes (FAS, CYBB, TNFSF10, EIF2AK2, and BIRC2) were identified as potential biomarkers for RA. Two different necroptosis patterns based on these five genes were confirmed to significantly correlated with immune cells (especially macrophages). In vitro experiments showed significantly higher mRNA and protein expression levels of CYBB and EIF2AK2 in RA patients compared to normal controls, consistent with the bioinformatics analysis results. CONCLUSION: Our study identified a novel necroptosis-related subtype and five diagnostic biomarkers of RA, revealed vital roles in the development and occurrence of RA, and offered potential targets for clinical diagnosis and immunotherapy.