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BACKGROUND: This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM. METHODS: Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro. RESULTS: A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80-4.94) ng/mL and 1.64 (1.47-1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins. CONCLUSION: ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.
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Amitriptilina , Diferenciación Celular , Dermatomiositis , Ratones Noqueados , Esfingomielina Fosfodiesterasa , Linfocitos T Reguladores , Células Th17 , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/inmunología , Dermatomiositis/genética , Humanos , Animales , Diferenciación Celular/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Células Th17/efectos de los fármacos , Células Th17/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Amitriptilina/farmacología , Amitriptilina/uso terapéutico , Adulto , Ratones , Esfingomielina Fosfodiesterasa/genética , Esfingomielina Fosfodiesterasa/metabolismo , Ratones Endogámicos C57BLRESUMEN
Immune-mediated necrotizing myopathy (IMNM) is a rare and newly recognized autoimmune disease within the spectrum of idiopathic inflammatory myopathies. It is characterized by myositis-specific autoantibodies, elevated serum creatine kinase levels, inflammatory infiltrate, and weakness. IMNM can be classified into three subtypes based on the presence or absence of specific autoantibodies: anti-signal recognition particle myositis, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myositis, and seronegative IMNM. In recent years, IMNM has gained increasing attention and emerged as a research hotspot. Recent studies have suggested that the pathogenesis of IMNM is linked to aberrant activation of immune system, including immune responses mediated by antibodies, complement, and immune cells, particularly macrophages, as well as abnormal release of inflammatory factors. Non-immune mechanisms such as autophagy and endoplasmic reticulum stress also participate in this process. Additionally, genetic variations associated with IMNM have been identified, providing new insights into the genetic mechanisms of the disease. Progress has also been made in IMNM treatment research, including the use of immunosuppressants and the development of biologics. Despite the challenges in understanding the etiology and treatment of IMNM, the latest research findings offer important guidance and insights for delving deeper into the disease's pathogenic mechanisms and identifying new therapeutic strategies.
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Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of chronic autoimmune diseases characterized by muscle damage and extramuscular symptoms, including specific skin rash, arthritis, interstitial lung disease, and cardiac involvement. While the etiology and pathogenesis of IIM are not yet fully understood, emerging evidence suggests that neutrophils and neutrophil extracellular traps (NETs) have a role in the pathogenesis. Recent research has identified increased levels of circulating and tissue neutrophils as well as NETs in patients with IIM; these contribute to the activation of the type I and type II interferons pathway. During active IIM disease, myositis-specific antibodies are associated with the formation and incomplete degradation of NETs, leading to damage in the lungs, muscles, and blood vessels of patients. This review focuses on the pathogenic role and clinical significance of neutrophils and NETs in IIM, and it includes a discussion of potential targeted treatment strategies.
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Trampas Extracelulares , Miositis , Neutrófilos , Trampas Extracelulares/inmunología , Humanos , Neutrófilos/inmunología , Miositis/inmunología , Miositis/patología , Relevancia ClínicaRESUMEN
Billions of apoptotic cells are swiftly removed from the human body daily. This clearance process is regulated by efferocytosis, an active anti-inflammatory process during which phagocytes engulf and remove apoptotic cells. However, impaired clearance of apoptotic cells is associated with the development of various autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. In this review, we conducted a comprehensive search of relevant studies published from January 1, 2000, to the present, focusing on efferocytosis, autoimmune disease pathogenesis, regulatory mechanisms governing efferocytosis, and potential treatments targeting this process. Our review highlights the key molecules involved in different stages of efferocytosis-namely, the "find me," "eat me," and "engulf and digest" phases-while elucidating their relevance to autoimmune disease pathology. Furthermore, we explore the therapeutic potential of modulating efferocytosis to restore immune homeostasis and mitigate autoimmune responses. By providing theoretical underpinnings for the targeting of efferocytosis in the treatment of autoimmune diseases, this review contributes to the advancement of therapeutic strategies in this field.
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BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation, causing substantial disability and reducing life quality. While macrophages are widely appreciated as a master regulator in the inflammatory response of RA, the precise mechanisms underlying the regulation of proliferation and inflammation in RA-derived fibroblast-like synoviocytes (RA-FLS) remain elusive. Here, we provide extensive evidence to demonstrate that macrophage contributes to RA microenvironment remodeling by extracellular vesicles (sEVs) and downstream miR-100-5p/ mammalian target of rapamycin (mTOR) axis. RESULTS: We showed that bone marrow derived macrophage (BMDM) derived-sEVs (BMDM-sEVs) from collagen-induced arthritis (CIA) mice (cBMDM-sEVs) exhibited a notable increase in abundance compared with BMDM-sEVs from normal mice (nBMDM-sEVs). cBMDM-sEVs induced significant RA-FLS proliferation and potent inflammatory responses. Mechanistically, decreased levels of miR-100-5p were detected in cBMDM-sEVs compared with nBMDM-sEVs. miR-100-5p overexpression ameliorated RA-FLS proliferation and inflammation by targeting the mTOR pathway. Partial attenuation of the inflammatory effects induced by cBMDM-sEVs on RA-FLS was achieved through the introduction of an overexpression of miR-100-5p. CONCLUSIONS: Our work reveals the critical role of macrophages in exacerbating RA by facilitating the transfer of miR-100-5p-deficient sEVs to RA-FLS, and sheds light on novel disease mechanisms and provides potential therapeutic targets for RA interventions.
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Artritis Reumatoide , Macrófagos , MicroARNs , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Humanos , Masculino , Ratones , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Experimental/genética , Artritis Reumatoide/metabolismo , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Proliferación Celular , Vesículas Extracelulares/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos DBA , MicroARNs/genética , MicroARNs/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Sinoviocitos/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
This study aimed to analyze peripheral blood lymphocyte subsets in lupus nephritis (LN) patients and use machine learning (ML) methods to establish an effective algorithm for predicting co-infection in LN. This study included 111 non-infected LN patients, 72 infected LN patients, and 206 healthy controls (HCs). Patient information, infection characteristics, medication, and laboratory indexes were recorded. Eight ML methods were compared to establish a model through a training group and verify the results in a test group. We trained the ML models, including Logistic Regression, Decision Tree, K-Nearest Neighbors, Support Vector Machine, Multi-Layer Perceptron, Random Forest, Ada boost, Extreme Gradient Boosting (XGB), and further evaluated potential predictors of infection. Infected LN patients had significantly decreased levels of T, B, helper T, suppressor T, and natural killer cells compared to non-infected LN patients and HCs. The number of regulatory T cells (Tregs) in LN patients was significantly lower than in HCs, with infected patients having the lowest Tregs count. Among the ML algorithms, XGB demonstrated the highest accuracy and precision for predicting LN infections. The innate and adaptive immune systems are disrupted in LN patients, and monitoring lymphocyte subsets can help prevent and treat infections. The XGB algorithm was recommended for predicting co-infection in LN.
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Algoritmos , Coinfección , Nefritis Lúpica , Aprendizaje Automático , Humanos , Nefritis Lúpica/sangre , Nefritis Lúpica/inmunología , Femenino , Masculino , Adulto , Coinfección/inmunología , Persona de Mediana Edad , Subgrupos Linfocitarios/inmunología , Estudios de Casos y Controles , Máquina de Vectores de SoporteRESUMEN
BACKGROUND: The most promising biologics tumor necrosis factor α (TNFα) inhibitors are effective in treating rheumatoid arthritis (RA) in only 50-70 % of the cases; thus, new drugs targeting TNFα-mediated inflammation are required. METHODS: Firstly, the drugs that could inhibit FLS proliferation and TNFα induced inflammatory cytokine production were screened. Secondly, treatment effects of the identified drugs were screened in collagen-induced arthritis (CIA) mouse model. Thirdly, the inhibitory effect of the identified drug, agomelatine (AOM), on TNFα induced inflammatory cytokine production and NF-κB activity were confirmed. Fourthly, bioinformatics was applied to predict the binding target of AOM and the binding was confirmed, and the already known inhibitor of target was used to test the treatment effect for CIA mouse model. Finally, the effect of AOM on signaling pathway was tested and on TNFα induced inflammatory cytokine production was observed after inhibiting the target. RESULTS: AOM effectively inhibited TNFα-induced NF-κB activation, NF-κB p65 translocation, and inflammatory cytokines production in vitro and was therapeutic against CIA. The mechanistic study indicated inducible nitric oxide synthase (iNOS) as the binding target of AOM. 1400 W, a known inhibitor of iNOS, could effectively treat CIA by decreasing iNOS activity and the levels of inflammatory cytokines. The inhibitory effect of AOM on TNFα-induced inflammation was further elucidated by 1400 W, or NF-κB p65 inhibitor JSH-23, indicating that AOM is therapeutic against CIA via iNOS/ERK/p65 signaling pathway after binding with iNOS. CONCLUSIONS: AOM is therapeutic against CIA via inhibition of the iNOS/ERK/p65 signaling pathway after binding with iNOS.
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Acetamidas , Artritis Experimental , Reposicionamiento de Medicamentos , Iminas , Naftalenos , Óxido Nítrico Sintasa de Tipo II , Factor de Necrosis Tumoral alfa , Animales , Ratones , Acetamidas/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Ratones Endogámicos DBA , Naftalenos/uso terapéutico , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Background and Aims: Acetaminophen (APAP)-induced liver injury (AILI) has an increasing incidence worldwide. However, the mechanisms contributing to such liver injury are largely unknown and no targeted therapy is currently available. The study aimed to investigate the effect of BTF3L4 overexpression on apoptosis and inflammation regulation in vitro and in vivo. Methods: We performed a proteomic analysis of the AILI model and found basic transcription factor 3 like 4 (BTF3L4) was the only outlier transcription factor overexpressed in the AILI model in mice. BTF3L4 overexpression increased the degree of liver injury in the AILI model. Results: BTF3L4 exerts its pathogenic effect by inducing an inflammatory response and damaging mitochondrial function. Increased BTF3L4 expression increases the degree of apoptosis, reactive oxygen species generation, and oxidative stress, which induces cell death and liver injury. The damage of mitochondrial function by BTF3L4 triggers a cascade of events, including reactive oxygen species accumulation and oxidative stress. According to the available AILI data, BTF3L4 expression is positively associated with inflammation and may be a potential biomarker of AILI. Conclusions: Our results suggest that BTF3L4 is a pathogenic factor in AILI and may be a potential diagnostic maker for AILI.
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This study systematically analyzes the association between interleukin-18 (IL-18) gene polymorphisms and rheumatoid arthritis (RA) susceptibility. The electronic databases Ovid MEDLINE, Ovid Excerpta Medica Database, and Cochrane Library were searched to identify meta-analyses that included case-control studies reporting IL-18 gene polymorphisms and RA susceptibility. Data were reanalyzed using Review Manager Software 5.1, and Mantel-Haenszel random effects were applied for the five genetic models: allelic, recessive, dominant, homozygote, and heterozygote. The effect size of odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated. A total of seven meta-analyses with poor quality were included. The IL-18 polymorphisms -607 A/C, -137 C/G, -920 T/C, and -105 C/A have been reported. With weak evidence, IL-18 -607 A/C polymorphisms were associated with a reduced risk of RA susceptibility using the allele model (OR = 0.76, 95% CI: 0.61 - 0.93, p=0.01), dominant model (OR = 0.67, 95% CI: 0.50 - 0.90, p=0.008), homozygote model (OR = 0.57, 95% CI: 0.35 - 0.91, p=0.02), and heterozygote model (OR = 0.71, 95% CI: 0.54 - 0.93, p=0.01) in the overall population. IL-18 gene polymorphisms and RA susceptibility are affected by ethnicity: With weak evidence, IL-18 -137 C/G polymorphisms were related to reduce RA susceptibility in the Asian population (allele model: OR = 0.59, 95% CI: 0.40 - 0.88, p=0.01; dominant model: OR = 0.57, 95% CI: 0.37 - 0.89, p=0.01; heterozygote model: OR = 0.60, 95% CI: 0.38 - 0.94, p=0.03). IL-18 -607 A/C gene polymorphisms are a protective factor for RA susceptibility in the overall population, and IL-18 -137 C/G gene polymorphisms are a protective factor for RA susceptibility in the Asian population. Further studies are needed to confirm these results owing to the limitations of the included studies.
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Artritis Reumatoide , Interleucina-18 , Humanos , Artritis Reumatoide/genética , Etnicidad , Predisposición Genética a la Enfermedad , Interleucina-18/genética , Polimorfismo Genético , Polimorfismo de Nucleótido SimpleRESUMEN
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune condition marked by inflammation of the joints, degradation of the articular cartilage, and bone resorption. Recent studies found the absolute and relative decreases in circulating regulatory T cells (Tregs) in RA patients. Tregs are a unique type of cells exhibiting immunosuppressive functions, known for expressing the Foxp3 gene. They are instrumental in maintaining immunological tolerance and preventing autoimmunity. Increasing the absolute number and/or enhancing the function of Tregs are effective strategies for treating RA. This article reviews the studies on the mechanisms and targeted therapies related to Tregs in RA, with a view to provide better ideas for the treatment of RA.
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Artritis Reumatoide , Linfocitos T Reguladores , Humanos , Inflamación/metabolismo , Autoinmunidad , Tolerancia InmunológicaAsunto(s)
Artritis Reumatoide , Fibroblastos , Glucólisis , Lipopolisacáridos , Metotrexato , Sinoviocitos , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Metotrexato/farmacología , Sinoviocitos/efectos de los fármacos , Sinoviocitos/metabolismo , Sinoviocitos/patología , Glucólisis/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Lipopolisacáridos/farmacología , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Células CultivadasRESUMEN
OBJECTIVE: Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is a unique subtype of idiopathic inflammatory myopathy (IIM) that is associated with rapidly progressive interstitial lung disease (RPILD) and high mortality. This retrospective study aimed to identify predictors of mortality and discover novel easily detectable indicators. METHODS: We retrospectively reviewed 183 MDA5+ DM-ILD patients who were from West China Hospital of Sichuan University myositis cohort, the largest single-center cohort of southwest China, from January 2016 to October 2021. Clinical characteristics were reviewed, and risk factors for mortality were determined by univariate and multivariable Cox regression analyses. RESULTS: Of the 183 MDA5+ DM-ILD patients, 59 were presented with RP-ILD, and 53 died during the follow-up period. Compared with the survived patients, deceased patients had higher rates of dyspnea, higher concentrations of CRP, and LDH, but lower rates of heliotrope sign, lower quantity of lymphocyte and lower levels of serum uric acid (SUA). Notably, patients with hypouricemia (SUA <154 µmol/L) had higher concentrations of CRP and LDH, higher neutrophil counts, lower lymphocyte counts and higher mortality rate when compared with the non-hypouricemia group. Multivariate Cox regression analyses confirmed that hypouricemia, smoking, RPILD, high HRCT score, elevated LDH, and lymphopenia were independent risk factors for mortality in MDA5+ DM-ILD patients. Moreover, patients with hypouricemia had significantly lower survival rates than non-hypouricemia patients. CONCLUSION: Our study identified hypouricemia as a non-redundant promising prognostic factor for the mortality of MDA5+ DM-ILD patients, which may hopefully provide insight into the prevention and pathogenesis study.
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Dermatomiositis , Enfermedades Pulmonares Intersticiales , Humanos , Estudios Retrospectivos , Pronóstico , Enfermedades Pulmonares Intersticiales/diagnóstico , Ácido Úrico , Helicasa Inducida por Interferón IFIH1 , Autoanticuerpos , Progresión de la EnfermedadRESUMEN
BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterized by severe proximal weakness and muscle fiber necrosis, yet its pathogenesis remains unclear. So far, there are few bioinformatics studies on underlying pathogenic genes and infiltrating immune cell profiles of IMNM. Therefore, we aimed to characterize differentially expressed genes (DEGs) and infiltrating cells in IMNM muscle biopsy specimens, which may be useful for elucidating the pathogenesis of IMNM. METHODS: Three datasets (GSE39454, GSE48280 and GSE128470) of gene expression profiling related to IMNM were obtained from the Gene Expression Omnibus database. Data were normalized, and DEG analysis was performed using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using clusterProfiler. The CIBERSORT algorithm was performed to identify infiltrating cells. Machine learning algorithm and gene set enrichment analysis (GSEA) were performed to find distinctive gene signatures and the underlying signaling pathways of IMNM. RESULTS: DEG analysis identified upregulated and downregulated in IMNM muscle compared to the gene expression levels of other groups. GO and KEGG analysis showed that the pathogenesis of IMNM was notable for the under-representation of pathways that were important in dermatomyositis and inclusion body myositis. Three immune cells (M2 macrophages, resting dendritic cells and resting natural killer cells) with differential infiltration and five key genes (NDUFAF7, POLR2J, CD99, ARF5 and SKAP2) in patients with IMNM were identified through the CIBERSORT and machine learning algorithm. The GSEA results revealed that the key genes were remarkably enriched in diverse immunological and muscle metabolism-related pathways. CONCLUSIONS: We comprehensively explored immunological landscape of IMNM, which is indicative for the research of IMNM pathogenesis.
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Enfermedades Musculares , Miositis , Humanos , Transcriptoma , Miositis/genética , Miositis/patología , Enfermedades Musculares/genética , Perfilación de la Expresión Génica , Aprendizaje Automático , ARN Polimerasa II/genéticaRESUMEN
Neuropilin-2 (NRP2) is a multifunctional protein engaged in the regulation of angiogenesis, lymphangiogenesis, axon guidance, and tumor metastasis, but its function in colitis remains unclear. Here, we found that NRP2 was an inflammation-sensing protein rapidly and dramatically induced in myeloid cells, especially in macrophages, under inflammatory contexts. NRP2 deficiency in myeloid cells exacerbated dextran sulfate sodium salt-induced experimental colitis by promoting polarization of M1 macrophages and colon injury. Mechanistically, NRP2 could be induced via NF-κB activation by TNF-α in macrophages, but exerted an inhibitory effect on NF-κB signaling, forming a negative feedback loop with NF-κB to sense and alleviate inflammation. Deletion of NRP2 in macrophages broke this negative feedback circuit, leading to NF-κB overactivation, inflammatory exacerbation, and more severe colitis. Collectively, these findings reveal inflammation restriction as a role for NRP2 in macrophages under inflammation contexts and suggest that NRP2 in macrophages may relieve inflammation in inflammatory bowel disease. © 2023 The Pathological Society of Great Britain and Ireland.
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Colitis , FN-kappa B , Humanos , Animales , Ratones , FN-kappa B/metabolismo , Neuropilina-2/genética , Neuropilina-2/metabolismo , Colitis/patología , Inflamación/patología , Macrófagos/patología , Sulfato de Dextran/toxicidad , Sulfato de Dextran/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: Myocardial fibrosis occurs in the early subclinical stage of cardiac involvement in idiopathic inflammatory myopathies (IIMs). Soluble suppression of tumorigenicity 2 (sST2) is known to have an immunomodulatory impact during autoimmune disease development. The current study investigated the diagnostic value of sST2 for myocardial fibrosis during early stage of cardiac involvement in IIM. METHODS: A total of 44 IIM patients with normal heart function and 32 age- and gender-matched healthy controls (HCs) were enrolled. Serum sST2 levels were measured by ELISA and cardiac magnetic resonance (CMR) parameters for myocardial fibrosis [native T1, extracellular volume (ECV), late-gadolinium enhancement (LGE)] and oedema (T2 values) were analysed. RESULTS: IIM patients had significantly higher sST2 levels than HCs [67.5 ng/ml (s.d. 30.4)] vs 14.4 (5.5), P < 0.001] and levels correlated positively with diffuse myocardial fibrosis parameters, native T1 (r = 0.531, P = 0.000), ECV (r = 0.371, P = 0.013) and focal myocardial fibrosis index and LGE (r = 0.339, P = 0.024) by Spearman's correlation analysis. sST2 was an independent predictive factor for diffuse and focal myocardial fibrosis after adjustment for age, gender, BMI and ESR. Risk increased ≈15.4% for diffuse [odds ratio (OR) 1.154 (95% CI 1.021, 1.305), P = 0.022] and 3.8% for focal [OR 1.038 (95% CI 1.006, 1.072), P = 0.020] myocardial fibrosis per unit increase of sST2. Cut-off values for diagnosing diffuse and focal myocardial fibrosis were sST2 ≥51.3 ng/ml [area under the curve (AUC) = 0.942, sensitivity = 85.7%, specificity = 98.9%, P < 0.001] and 53.3 ng/ml (AUC = 0.753, sensitivity = 87.5%, specificity = 58.3%, P < 0.01), respectively. CONCLUSION: sST2 showed a marked elevation during the subclinical stage of cardiac involvement in IIM and has potential as a biomarker for predicting diffuse and focal myocardial fibrosis in IIM.
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Cardiomiopatías , Miositis , Humanos , Medios de Contraste , Gadolinio , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/etiología , FibrosisRESUMEN
INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by hyperplastic synovium, pannus formation, immune cell infiltration, and potential articular cartilage damage. Notably, fibroblast-like synoviocytes (FLS), especially rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), exhibit specific overexpression of glycolytic enzymes, resulting in heightened glycolysis. This elevated glycolysis serves to generate ATP and plays a pivotal role in immune regulation, angiogenesis, and adaptation to hypoxia. Key glycolytic enzymes, such as hexokinase 2 (HK2), phosphofructose-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2), significantly contribute to the pathogenic behavior of RAFLS. This increased glycolysis activity is regulated by various signaling pathways. MATERIALS AND METHODS: A comprehensive literature search was conducted to retrieve relevant studies published from January 1, 2010, to the present, focusing on RAFLS glycolysis, RA pathogenesis, glycolytic regulation pathways, and small-molecule drugs targeting glycolysis. CONCLUSION: This review provides a thorough exploration of the pathological and physiological characteristics of three crucial glycolytic enzymes in RA. It delves into their putative regulatory mechanisms, shedding light on their significance in RAFLS. Furthermore, the review offers an up-to-date overview of emerging small-molecule candidate drugs designed to target these glycolytic enzymes and the upstream signaling pathways that regulate them. By enhancing our understanding of the pathogenic mechanisms of RA and highlighting the pivotal role of glycolytic enzymes, this study contributes to the development of innovative anti-rheumatic therapies.
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Artritis Reumatoide , Sinoviocitos , Humanos , Sinoviocitos/metabolismo , Artritis Reumatoide/metabolismo , Membrana Sinovial/patología , Transducción de Señal , Fibroblastos/metabolismoRESUMEN
Importance: Randomized clinical trials (RCTs) testing innovative drugs must strive to use optimal control groups to reflect the best available treatments. A comprehensive evaluation of the quality of control groups in pivotal RCTs supporting systemic rheumatic disease (SRD) drug approvals by the Food and Drug Administration (FDA) is lacking. Objective: To examine the proportion of pivotal RCTs that used optimal control groups among RCTs supporting newly approved SRD drugs in the US over the past decade. Design, Setting, and Participants: In this study, individual RCTs supporting SRD new drug approvals by the FDA between January 2012 and October 2022 were analyzed for design, study duration, control group, and primary end point. The quality of control groups was determined by comparison with published guidelines before and during the trial. Main Outcomes and Measures: The primary measure was the proportion of RCTs using optimal control groups. Differences in response rate between investigating and control groups and the response rate of placebo control groups were also examined. Results: Between January 2012 and October 2022, the FDA approved 44 SRD drugs, involving 65 pivotal RCTs. Overall, 16 RCTs used optimal control groups. In 55 trials, no active groups were used, and more than 80% of these trials were suboptimal (47 trials [85.5%]). Among 56 trials for systemic arthritis, 49 trials used suboptimal control groups, mainly placebo or dose-response controls (47 trials), with a few active controls (2 trials). Studies of other SRDs frequently used placebo or dose-response controls but were considered optimal controls (8 trials). There was significant improvement in response rates of investigating compared with placebo groups, with relative risk mostly exceeding 1.50 (range, 0.90; 95% CI, 0.69-1.17 for anifrolumab to 11.00; 95% CI, 2.69-44.96 for mepolizumab). In all placebo-controlled trials, the median (IQR) response rate in placebo groups was 26.0% (19.2%-32.3%). Conclusions and Relevance: These findings suggest that the quality of control groups in RCTs leading to SRD drug approval needs improvement and that despite challenges in translating scientific theories to clinical scenarios, it is crucial to consistently prioritize efforts to promote appropriate control group selection to ensure the accurate assessment of innovative drug efficacy.
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Artritis , Enfermedades Reumáticas , Humanos , Grupos Control , Aprobación de Drogas , Enfermedades Reumáticas/tratamiento farmacológico , Estados Unidos , United States Food and Drug Administration , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Objective: YKL-40, also known as chitinase-3-like-1 (CHI3L1), is a human cartilage glycoprotein-39, with its N-terminus consisting of tyrosine (Y), lysine (K), and leucine (L), hence the name YKL-40. In this study, we explored whether YKL-40 could promote the expression of inflammatory factors in type â ¡ alveolar epithelial cells. Methods: A549 cells were cultured in vitro with interleukin (IL)-1ß (20 ng/mL), IL-6 (20 ng/mL), tumor necrosis factor-alpha (TNF-α) (20 ng/mL), and interferon-gamma (IFN-γ) (20 ng/mL). The expression of YKL-40 transcription was determined by RT-qPCR. A549 cells were cultured with IL-1ß at 5, 10, and 20 ng/mL and the expression of YKL-40 protein was determined by Western blot. A549 cells were cultured with recombinant YKL-40 protein at 0, 100, 500, and 1 000 ng/mL and the expression levels of IL-6 and IL-8 were measured by RT-qPCR. Three pairs of small interfering RNAs targeting YKL-40 (si- YKL-40-1/2/3) and the negative control (NC) were designed and used to transfect A549 cells, respectively, and the expression of YKL-40 was determined by RT-qPCR and Western blot. si- YKL-40-3 was screened out for subsequent experiments. In A549 cells, si- YKL-40-3 and si-NC were transfected and, then, IL-1ß (20 ng/mL) was added in for culturing. The expression of YKL-40, IL-6, and IL-8 was determined by RT-qPCR and the expression of multiple factors in the supernatant was measured with the QAH-INF-1 kit. Results: RT-qPCR results showed that IL-1ß could up-regulate YKL-40 protein transcription level compared with that of the control group and the difference was statistically significant ( P<0.01), but IL-6, TNF-α, and IFN-γ could not up-regulate YKL-40 protein transcription level. Western blot results showed that IL-1ß (20 ng/mL) could significantly promote the expression of YKL-40 and, compared with that of the control group, the differences showed by groups treated with different concentrations of IL-1ß were all statistical significant ( P<0.01). After adding human recombinant YKL-40 protein to A549 cells, the results showed that the expression of inflammatory factors IL-6 and IL-8 was significantly increased and the difference was statistically significant compared with that of the control group ( P<0.05). After the expression of YKL-40 was decreased by si- YKL-40-3 transfection, the expression of IL-6 ( P<0.05), IL-8 ( P<0.05), and other inflammatory factors was inhibited compared with that of the control group. Conclusion: YKL-40 can promote the expression and secretion of IL-6, IL-8, and other acute inflammatory factors in A549 cell line, a type â ¡ alveolar epithelial cell model, thus aggravating the inflammatory response. Targeted inhibition of YKL-40 expression may effectively inhibit inflammatory response.