RESUMEN
Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr-/-.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy.
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Biomarcadores , Cirrosis Hepática , Semaforinas , Humanos , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/patología , Biomarcadores/sangre , Animales , Masculino , Ratones , Femenino , Semaforinas/sangre , Semaforinas/genética , Semaforinas/metabolismo , Persona de Mediana Edad , Hígado Graso/sangre , Hígado Graso/diagnóstico , Hígado Graso/patología , Hígado/patología , Hígado/metabolismo , Modelos Animales de Enfermedad , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transcriptoma , Ratones Noqueados , Adulto , Ratones Endogámicos C57BL , Proteínas de Unión a Factor de Crecimiento Similar a la InsulinaRESUMEN
BACKGROUND: Kawasaki disease (KD) is a pediatric systemic vasculitis characterized by endothelial cell dysfunction. Semaphorin 7A (Sema7A) has been reported to regulate endothelial phenotypes associated with cardiovascular diseases, while its role in KD remains unknown. This study aims to investigate the effect of Sema7A on endothelial permeability and inflammatory response in KD conditions. METHODS: Blood samples were collected from 68 KD patients and 25 healthy children (HC). The levels of Sema7A and A Disintegrin and Metalloprotease 17 (ADAM17) in serum were measured by enzyme-linked immunosorbent assay (ELISA), and Sema7A expression in blood cells was analyzed by flow cytometry. Ex vivo monocytes were used for Sema7A shedding assays. In vitro human coronary artery endothelial cells (HCAECs) were cultured in KD sera and stimulated with Sema7A, and TNF-α, IL-1ß, IL-6, and IL-18 of HCAECs were measured by ELISA and qRT-PCR. HCAECs monolayer permeability was measured by FITC-dextran. RESULTS: The serum level of Sema7A was significantly higher in KD patients than in HC and correlated with disease severity. Monocytes were identified as one of the source of elevated serum Sema7A, which implicates a process of ADAM17-dependent shedding. Sera from KD patients induced upregulation of plexin C1 and integrin ß1 in HCAECs compared to sera from HC. Sema7A mediated the proinflammatory cytokine production of HCAECs in an integrin ß1-dependent manner, while both plexin C1 and integrin ß1 contributed to Sema7A-induced HCAEC hyperpermeability. CONCLUSIONS: Sema7A is involved in the progression of KD vasculitis by promoting endothelial permeability and inflammation through a plexin C1 and integrin ß1-dependent pathway. Sema7A may serve as a potential biomarker and therapeutic target in the prognosis and treatment of KD.
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Antígenos CD , Integrina beta1 , Síndrome Mucocutáneo Linfonodular , Receptores de Superficie Celular , Semaforinas , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteína ADAM17/metabolismo , Antígenos CD/metabolismo , Permeabilidad Capilar , Estudios de Casos y Controles , Células Cultivadas , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Proteínas Ligadas a GPI , Inflamación/metabolismo , Integrina beta1/metabolismo , Monocitos/metabolismo , Síndrome Mucocutáneo Linfonodular/metabolismo , Síndrome Mucocutáneo Linfonodular/sangre , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/sangre , Semaforinas/metabolismo , Semaforinas/sangreAsunto(s)
Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico por imagen , Mamografía/métodos , Semaforinas/sangre , Ultrasonografía Mamaria/métodos , Adulto , Anciano , Biomarcadores/sangre , Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Femenino , Humanos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Semaforinas/genética , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: Semaphorin4D (Sema4D), a novel integral membrane glycoprotein, plays a role in atherosclerosis, angiogenesis and chronic inflammation. Elevated levels of sema4D were presented in myocardial infarction, heart failure and atrial fibrillation. Aim of the study was to investigate the relation between sema4D and recurrence after catheter ablation (CA) in paroxysmal AF. METHODS: The present study included 161 paroxysmal AF patients (PAF) (101 patients undergone CA) and 60 healthy subjects. Serum levels of sema4D were measured and study participants were followed-up for 3 months and 1 year since CA in terms of recurrence respectively. RESULTS: Sema4D levels were significantly elevated in the recurrent group compared to the non-recurrent PAF patients (p < 0.001). Sema4D was importantly positively correlated with both left atrial volume index (r = 0.51, p < 0.013) and high sensitive C-reactive protein (r = 0.38), p < 0.011). In multivariate analysis, sema4D [odds ratio (OR) = 1.23, 95% CI 1.11-1.42; p < 0.001] and left atrial diameter (OR = 1.13, 95% CI 1.02-1.23; p = 0.012) were found to be significant independent risk parameters for recurrence. CONCLUSIONS: Sema4D is a novel biomarker that may help to identify individuals with recurrence after CA procedure in long term period in PAF.
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Antígenos CD/sangre , Fibrilación Atrial/cirugía , Ablación por Catéter , Semaforinas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/sangre , Fibrilación Atrial/diagnóstico , Biomarcadores/sangre , Estudios de Casos y Controles , Ablación por Catéter/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recurrencia , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Adulto JovenRESUMEN
Semaphorin 4D (Sema4D) is a glycoprotein that is expressed by several tumors and immune cells. It can function as a membrane bound protein or as a cleaved soluble protein (sSema4D). We sought to investigate the translational potential of plasma sSema4D as an immune marker in plasma of patients with head and neck squamous cell carcinoma (HNSCC). Paired peripheral blood and tumor tissue samples of 104 patients with HNSCC were collected at the same time point to allow for real time analysis. Scoring of the histological inflammatory subtype (HIS) was carried out using Sema4D immunohistochemistry on the tumor tissue. sSema4D was detected in plasma using direct ELISA assay. Defining elevated sSema4D as values above the 95th percentile in healthy controls, our data showed that sSema4D levels in plasma were elevated in 25.0% (95% CI, 16.7-34.9%) of the patients with HNSCC and showed significant association with HIS immune excluded (HIS-IE) (p = 0.007), Sema4D+ve tumor cells (TCs) (p = 0.018) and PD-L1+ve immune cells (ICs) (p = 0.038). A multi-variable logistic regression analysis showed that HIS was significantly (P = 0.004) associated with elevated sSema4D, an association not explained by available patient-level factors. Using the IO-360 nanoString platform, differential gene expression (DGE) analysis of 10 HNSCC tumor tissues showed that patients with high sSema4D in plasma (HsS4D) clustered as IFN-γ negative tumor immune signature and were mostly HIS-IE. The IC type in the HsS4D paired tumor tissue was predominantly myeloid, while the lymphoid compartment was higher in the low sSema4D (LsS4D). The Wnt signaling pathway was upregulated in the HsS4D group. Further analysis using the IO-360, 770 gene set, showed significant non-inflamed profile of the HsS4D tumors compared to the LsS4D. In conclusion, our data reveals an association between sSema4D and the histological inflammatory subtype.
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Antígenos CD , Neoplasias de Cabeza y Cuello , Proteínas de Neoplasias , Semaforinas , Carcinoma de Células Escamosas de Cabeza y Cuello , Vía de Señalización Wnt/inmunología , Anciano , Antígenos CD/sangre , Antígenos CD/inmunología , Femenino , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/inmunología , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/inmunología , Semaforinas/sangre , Semaforinas/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunologíaRESUMEN
OBJECTIVE: Semaphorin 5A (SEMA 5A) is a neuroprotein that regulates the formation of excitatory synapses between neurons, important in autoimmunity, inflammatory processes and behaviors. This study aimed to investigate the SEMA 5A levels in patients with obsessive-compulsive disorder (OCD) diagnosed for the first time and evaluate the relationship of disease and disease severity with the blood SEMA 5A level and hemogram. METHODS: More than 41,465 patients who applied to the psychiatry clinic from January 2018 to December 2020 were evaluated according to the DSM-5 criteria; 57 patients diagnosed with OCD for the first time, who met the inclusion criteria, were included in the study. Disease severity was investigated administering the Yale Brown Obsessive Compulsion Scale. The peripheral blood SEMA 5A level and hemogram were measured and evaluated in relation to platelet (PLT) activity, neutrophil-lymphocyte ratio (NLR), PLT-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), C-reactive protein (CRP), and compared with control group of 26 people. RESULTS: The comparison of the groups revealed a significant difference in SEMA 5A and CRP level, neutrophil count and percentage, lymphocyte count, PLT activity. A significant correlation was found between disease and SEMA 5A level, NLR, PLR, and PLT parameters in diagnosis of OCD. As the severity of OCD increased, the SEMA 5A level and PLT count decreased, while the PDW and MLR values increased. CONCLUSION: In patients with OCD, a relationship was found between plasma SEMA 5A, PLT activity, NLR, PLR, and MLR activity levels with disease and the disease severity.
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Trastorno Obsesivo Compulsivo , Semaforinas , Humanos , Linfocitos , Neutrófilos , Trastorno Obsesivo Compulsivo/diagnóstico , Semaforinas/sangre , Índice de Severidad de la EnfermedadRESUMEN
Semaphorin 4D (Sema4D) is highly expressed in a variety of tumors and is associated with high invasion, poor prognosis and poor therapeutic response. However, the expression and role of Sema4D in leukemia remains unclear. The present study investigated the expression of Sema4D in pediatric leukemia and its effects in leukemia cells. The results demonstrated that Sema4D protein was highly expressed in peripheral blood mononuclear cells of patients with pediatric leukemia, and high levels of soluble Sema4D were also observed in the plasma of these patients. Sema4D knockdown induced cell cycle arrest in G0/G1 phase, inhibited proliferation and promoted apoptosis in BALL1 cells, while Sema4D overexpression exhibited the opposite effect. In Jurkat cells, Sema4D knockdown inhibited proliferation and promoted apoptosis, while Sema4D overexpression decreased the abundance of the cells in the G0/G1 phase of the cell cycle and promoted proliferation. Sema4D overexpression also increased the migratory capacity of Jurkat cells and the invasive capacity of BALL1 cells. The phosphorylation level of PI3K was decreased in both Sema4D knockeddown Jurkat and BALL1 cells, and the phosphorylation level of ERK was decreased in Sema4D knockeddown BALL1 cells. The phosphorylation levels of PI3K, ERK and AKT were elevated in patients with pediatric leukemia, and were correlated to the increased Sema4D expression. Sema4D overexpression was associated with a shorter overall survival in patients with acute myeloid leukemia. Overall, the results of the present study indicated that Sema4D serves an important role in leukemia development by activating PI3K/AKT and ERK signaling, and it may be used as a potential target for the diagnosis and treatment of leukemia.
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Antígenos CD/sangre , Leucemia Mieloide Aguda/metabolismo , Sistema de Señalización de MAP Quinasas , Fosfatidilinositol 3-Quinasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Semaforinas/sangre , Adolescente , Antígenos CD/biosíntesis , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular/fisiología , Niño , Preescolar , Femenino , Humanos , Lactante , Células Jurkat , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Leucocitos Mononucleares/metabolismo , Masculino , Fosforilación , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Semaforinas/biosíntesisRESUMEN
Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors-plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1ß, IL-6, and IL-8. The disintegrin and metalloproteinase domain 17- (AMAM17-) mediated Sema4D shedding from neutrophils contributed to the elevation of sSema4D in the serum of KD patients. Furthermore, we found that Sema4D induced IL-1ß production of HCAECs via plexin B2, whereas it promoted IL-6 and IL-8 production via plexin B1. Moreover, the expression of both plexin B1 and plexin B2 was upregulated in HCAECs treated with KD sera, and silencing of the two plexin receptors suppressed the overexpression of IL-1ß, IL-6, and IL-8 in KD serum-treated HCAECs. Thus, our findings indicated that sSema4D released from neutrophils participates in the pathogenesis of KD-CALs by promoting inflammatory cytokine production of ECs via both plexin B1 and plexin B2, and Sema4D may be a novel predictor for KD-CALs and a candidate therapeutic target for anti-inflammatory strategies of KD.
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Antígenos CD/sangre , Citocinas/metabolismo , Células Endoteliales/metabolismo , Síndrome Mucocutáneo Linfonodular/sangre , Neutrófilos/metabolismo , Semaforinas/sangre , Proteína ADAM17/sangre , Estudios de Casos y Controles , Preescolar , Vasos Coronarios/metabolismo , Femenino , Humanos , Lactante , Inflamación , Interleucina-1/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Proteínas del Tejido Nervioso/sangre , Receptores de Superficie Celular/sangreRESUMEN
Objectives: Semaphorin 4D (Sema4D) is constitutively expressed on T cells and osteoclasts, and regulates T cell proliferation and bone remodeling. In addition, several studies have shown that Sema4D is involved in the pathogenesis of autoimmunity. We undertook this study to investigate the mechanism by which Sema4D affects the pathogenic progress of ankylosing spondylitis (AS). Methods: Soluble Sema4D (sSema4D) levels in serum were analyzed by enzyme-linked immunosorbent assay. The cell surface levels and transcripts of Sema4D were evaluated in CD4 + and CD19 + cells from the AS patients and healthy individuals. The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from CD4 + T cells were analyzed by flow cytometric analysis. The aryl hydrocarbon receptor (AhR) agonistic effect of Sema4D was detected by analyzing the activation of downstream signaling pathways and target genes using Luciferase and EROD assay. Results: Levels of sSema4D were elevated in both serum from AS patients, and clinical features markers were correlated with serum sSema4D levels. Sema4D facilitated CD4 + T cells proliferation and Th17 cells differentiation and inhibited Treg cells differentiation by enhancing RORγt expression and reducing Foxp3 expression, with increasing expression and secretion of IL-17 and IL-22. It induced the expression and activity of AhR target gene CYP1A1 and XRE reporter activity via interaction with CD72. Conclusion: These findings indicate that Sema4D as a potent activator of T cells in the immune response contributes to the inflammation of AS by inducing imbalance in Th17 and Treg cell populations in an AhR-dependent manner, suggesting it is a crucial participant in AS pathogenesis.
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Antígenos CD/sangre , Recuento de Linfocito CD4 , Receptores de Hidrocarburo de Aril/agonistas , Semaforinas/sangre , Espondilitis Anquilosante/inmunología , Linfocitos T Reguladores , Células Th17 , Adulto , Antígenos CD/farmacología , Diferenciación Celular , Citocromo P-450 CYP1A1/biosíntesis , Citocromo P-450 CYP1A1/genética , Femenino , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica , Humanos , Interleucina-17/biosíntesis , Interleucina-17/genética , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/biosíntesis , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Interleucina-17/biosíntesis , Receptores de Interleucina-17/genética , Semaforinas/farmacología , Espondilitis Anquilosante/sangre , Adulto JovenRESUMEN
Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Naïve Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome.
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Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Efrinas/sangre , Aprendizaje Automático , Monocitos/metabolismo , Netrina-1/sangre , Semaforinas/sangre , Adulto , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/genética , Estudios de Casos y Controles , Estudios de Cohortes , Efrinas/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Netrina-1/genética , Semaforinas/genética , TranscriptomaRESUMEN
OBJECTIVE: Recently, members of the semaphorin family have received major attention in various medical fields, especially autoimmunity. In this study, we selected semaphorin-3A (Sema3A), semaphorin-7A (Sema7A), and their receptors to determine the possible relationship between these molecules and multiple sclerosis (MS). METHOD: We measured the gene expression of Sema3A, Sema7A, neuropilin-1 (NP-1), plexin-C1, and ß1 integrin in the blood samples of relapsing-remitting multiple sclerosis (RRMS) patients, treated with high-dose interferon-ß1a (IFN-ß1a), low-dose IFN-ß1a, IFN-ß1b, and glatiramer acetate (GA) via quantitative real-time polymerase chain reaction (qRT-PCR) assay, and then, compared the results of treatment-naive patients with the healthy controls. RESULTS: The gene expression of Sema3A (P = 0.02), NP-1 (P < 0.001), and plexin-C1 (P < 0.01) significantly decreased in the treatment-naive group, compared to the healthy controls. Sema3A significantly increased in all treated patients, compared to the treatment-naive patients (P < 0.001). However, expression of NP-1 (P < 0.001), plexin-C1 (P < 0.001), and ß1 integrin (P < 0.05) only increased in patients receiving high-dose IFN-ß1a, IFN-ß1b, and GA. Expression of Sema7A increased in only two groups of patients treated with IFN-ß1b (P < 0.001) and GA (P = 0.018), without any significant decrease in the treatment-naive group, compared to the healthy controls (P > 0.05). CONCLUSION: Our findings confirm that the presence of Sema3A, Sema7A, and their receptors can play critical roles in the treatment of MS patients. Therefore, they can be potential target molecules for MS treatment in the future.
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Antígenos CD/genética , Expresión Génica , Integrina beta1/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Neuropilina-1/genética , Semaforina-3A/genética , Semaforinas/genética , Adulto , Antígenos CD/sangre , Femenino , Proteínas Ligadas a GPI/sangre , Proteínas Ligadas a GPI/genética , Acetato de Glatiramer/uso terapéutico , Humanos , Integrina beta1/sangre , Interferón beta/uso terapéutico , Masculino , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Neuropilina-1/sangre , Semaforina-3A/sangre , Semaforinas/sangreRESUMEN
This study investigated the endurance exercise-induced changes in lesser known adipokines (visfatin, chemerin, apelin, semaphorin 3 C) related to obesity and metabolism, and their correlations with the changes in the parameters of obesity and glucose homeostasis. Forty metabolically healthy obese young males were randomly assigned to control group (C, n = 12) or exercise group (Ex, n = 28). The subjects in Ex participated in a 8-week supervised endurance exercise training program, comprised of four sessions of treadmill running at 65-70% of VO2max per week. Serum levels of visfatin, chemerin, apelin, and semaphorin 3 C were significantly decreased in Ex. At baseline, apelin and semaphorin 3 C appeared to be correlated with obesity measures, including body mass index, % total fat and trunk fat, and waist circumference. Exercise-induced changes in these obesity measures significantly correlated with the changes in chemerin and semaphorin 3 C. Basal chemerin, apelin and semaphorin 3 C correlated with glucose homeostasis parameters, including fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance and ß-cell function, and quantitative insulin-sensitivity check index to different extents. Furthermore, the changes in apelin and semaphorin 3 C well predicted the improvements in glycemic parameters. We suggest that semaphorin 3 C is a novel adipokine involved in pathophysiology of obesity and metabolism, and that it is a biomarker representing an exercise-induced improvement in metabolically healthy obese young males.
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Glucemia/metabolismo , Metabolismo Energético/fisiología , Ejercicio Físico/fisiología , Obesidad Metabólica Benigna/sangre , Semaforinas/sangre , Circunferencia de la Cintura/fisiología , Adulto , Apelina/sangre , Índice de Masa Corporal , Quimiocinas/sangre , Humanos , Masculino , Nicotinamida Fosforribosiltransferasa/sangre , Adulto JovenRESUMEN
Objective: To explore the correlation between Semaphorin 4D (Sema4D) and rheumatoid arthritis (RA) clinical manifestations, laboratory indexes, bone destruction and rheumatoid arthritis related interstitial lung disease(RA-ILD), and to analyze its significance in evaluating the severity of patients with rheumatoid arthritis. Methods: A total of 108 RA patients and 50 healthy controls from September 2018 to October 2019 were collected from the Department of Rheumatology and Immunology, Peking University People's Hospital and Beijing Haidian Hospital. According to the DAS 28 score, RA patients were divided into active disease group (DAS28>2.6) and stable disease group (DAS28 ≤ 2.6). Fifty healthy controls. The levels of Sema4D in serum were detected by enzyme-linked immunoassay method (ELISA), and their correlation with clinical manifestations of RA, laboratory indicators, degree of bone damage and RA-ILD were analyzed. Results: The level of serum Sema4D in RA active group was significantly higher than that in stable group and healthy control group (P<0.05). The concentration serum Sema4D was positively correlated with C-reactive protein(CRP) (r=0.28, P<0.05), rheumatoid factor(RF) (r=0.25, P<0.05) and the 28-joint disease activity score (DAS28) (r=0.45, P<0.01). The concentration serum Sema4D was positively correlated with ß-Crosslaps(r=0.20, P<0.05) and Sharp-van der Heijde score (SHS)(r=0.13, P<0.05). The concentration serum Sema4D was positively correlated with Vascular endothelial growth factor (VEGF)(r=0.25, P<0.05) and Warrick score of chest CT in RA patients(r=0.27, P<0.05). The anti-cyclic citrullinated peptid(CCP) antibody, DAS28, VEGF and the incidence of RA-ILD were significantly higher than that in Sema4D negative group (P<0.05). Conclusions: Serum Sema4D level in RA patients is closely related to the disease activity, bone destruction and RA-ILD. Serum Sema4D can be used as an indicator of disease monitoring and prognosis evaluation in RA patients.
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Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Semaforinas/sangre , Biomarcadores , Humanos , Péptidos Cíclicos , Factor Reumatoide , Factor A de Crecimiento Endotelial VascularRESUMEN
CD100 is an immune semaphorin constitutively expressed on T-cells. Matrix metalloproteinase (MMP) is an important mediator of membrane-bound CD100 (mCD100) cleavage to generate soluble CD100 (sCD100), which has immunoregulatory activity in immune cell responses. The aim of the study was to investigate the level and role of sCD100 and mCD100 in modulating CD8+ T-cell function in non-small cell lung cancer (NSCLC). sCD100 and MMP-14 levels in the serum and bronchoalveolar lavage fluid (BALF), and mCD100 expression on peripheral and lung-resident CD8+ T-cells were analysed in NSCLC patients. The ability to induce sCD100 and the effect of MMP-14 on mCD100 shedding for the regulation of non-cytolytic and cytolytic functions of CD8+ T-cells were also analysed in direct and indirect contact co-culture systems. NSCLC patients had lower serum sCD100 and higher mCD100 levels on CD8+ T-cells compared with healthy controls. BALF from the tumour site also had decreased sCD100 and increased mCD100 on CD8+ T-cells compared with the non-tumour site. Recombinant CD100 stimulation enhanced non-cytolytic and cytolytic functions of CD8+ T-cells from NSCLC patients, whereas blockade of CD100 receptor CD72 attenuated CD8+ T-cell activity. NSCLC patients had lower MMP-14 in the serum and in BALF from the tumour site. Recombinant MMP-14 mediated mCD100 shedding from CD8+ T-cell membrane, and led to promotion of CD8+ T-cell response in NSCLC patients. Overall, decreased MMP-14 resulted in insufficient CD100 shedding, leading to suppression of peripheral and lung-resident CD8+ T-cell activity in NSCLC.
Asunto(s)
Antígenos CD/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/inmunología , Metaloproteinasa 14 de la Matriz/metabolismo , Semaforinas/metabolismo , Adulto , Anciano , Antígenos CD/sangre , Líquido del Lavado Bronquioalveolar/química , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Membrana Celular/metabolismo , Técnicas de Cocultivo , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Activación de Linfocitos , Masculino , Metaloproteinasa 14 de la Matriz/sangre , Persona de Mediana Edad , Cultivo Primario de Células , Proteínas Recombinantes/metabolismo , Semaforinas/sangre , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Escape del Tumor , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS. METHODS: We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-ß (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study. RESULTS: Sema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-γ levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-ß unresponsiveness than those with low Sema4A levels. CONCLUSIONS: Sema4A is involved not only in the Th cell priming but also in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in RRMS patients with high serum Sema4A levels.
Asunto(s)
Inflamación/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Semaforinas/inmunología , Células Th17/inmunología , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Semaforinas/sangreRESUMEN
A growing body of data suggests that semaphorins are involved in both normal and pathological immune responses, as well as autoimmune pathologies. To investigate the plasma semaphorin 3A (Sema3A) and semaphorin 7A (Sema7A) levels in systemic lupus erythematosus (SLE) patients and their correlation with clinical manifestations and laboratory indexes, a two-step method was applied. First, 80 SLE patients and 80 healthy controls were recruited for comparing serum Sema3A and Sema7A concentrations. Second, 40 rheumatoid arthritis (RA) patients and 40 sjögren's syndrome (SS) patients were then included as disease controls. Plasma Sema3A and Sema7A concentrations were detected by ELISA. There were significant differences in Sema3A and Sema7A among four groups. When compared to healthy controls, both Sema3A and Sema7A levels were decreased in SLE and increased in RA; increased Sema3A level and decreased Sema7A level were found in SS. There were significant differences in Sema3A concentration between SLE and RA, SLE and SS. Moreover, there were significant differences in Sema7A level between SLE and RA, SS and RA. However, no significant differences in Sema3A between SS and RA and no significant differences in Sema7A between SS and SLE were observed. Both plasma Sema3A and Sema7A levels were correlated with anti-SSA and IgM. Area under curve (AUC) of the receiver operating characteristic (ROC) curve for Sema3A and Sema7A were 0.535 (0.455-0.613) and 0.671 (0.594-0.742), respectively. Aberrant Sema3A and Sema7A expression and their clinical associations in SLE suggest their important role in this disease.
Asunto(s)
Antígenos CD/sangre , Lupus Eritematoso Sistémico/sangre , Semaforina-3A/sangre , Semaforinas/sangre , Adulto , Femenino , Proteínas Ligadas a GPI/sangre , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The aim of this study was to detect the expression of long noncoding RNA small nucleolar RNA host gene 18 (SNHG18) andsemaphorin 5A (SEMA5A) genes in multiple myeloma (MM) patients and to explore the correlation of the expression of these genes with the clinical characteristics and prognosis of MM patients. METHODS: Forty-seven newly diagnosed MM, 18 complete remission MM, 13 refractory/relapse MM, and 22 iron deficiency anemia (serving as control) samples were extracted at the Department of Hematology, Second Aï¬liated Hospital of Xian Jiaotong University between January 2015 and December 2016. The clinical features of the MM patients are summarized. Real-time quantitative PCR was performed to analyze the relative expression levels of the SNHG18 and SEMA5Agenes. The clinical characteristics and overall survival (OS) of the MM patients were statistically analyzed while measuring different levels of SNHG18 and SEMA5Agene expression. At the same time, the correlation between the expression of SNHG18 and SEMA5A was also analyzed. RESULTS: The analysis confirmed that SNHG18 and its possible target gene SEMA5A were both highly expressed in newly diagnosed MM patients. After analyzing the clinical signiï¬cance of SNHG18 and SEMA5A in MM patients, we found that the expression of SNHG18 and SEMA5A was related to the Durie-Salmon (DS), International Staging System (ISS), and Revised International Staging System (R-ISS) classification systems, and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART; p < 0.05). Moreover, we observed a significant difference in OS between the SNHG18/SEMA5A high expression group and the low expression group. We found a positive correlation between SNHG18 and SEMA5A expression (r = 0.709, p < 0.01). Surprisingly, the expected median OS times of both the SNHG18 and SEMA5Ahigh expression groups were significantly decreased, which was in contrast to those of both the SNHG18 and SEMA5Alow expression groups and the single-gene high expression group (p < 0.05). CONCLUSION: High expression of both SNHG18 and SEMA5A is associated with poor prognosis in patients with MM.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/sangre , Proteínas de Neoplasias/sangre , ARN Largo no Codificante/sangre , ARN Neoplásico/sangre , Semaforinas/sangre , Adulto , Anciano , Anemia Ferropénica/sangre , Anemia Ferropénica/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Pronóstico , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Recurrencia , Inducción de Remisión , Semaforinas/biosíntesis , Semaforinas/genéticaRESUMEN
Obesity is a worldwide health problem. Semaphorins are involved in axonal guidance; however, the role of secretory semaphorin 3G (SEMA3G) in regulating adipocyte differentiation remains unclear. Microarray analysis showed that the SEMA3G gene was upregulated in an in vitro model of adipogenesis. In this study, SEMA3G was highly expressed in the white adipose tissue and liver. Analysis of 3T3-L1 cell and primary mouse preadipocyte differentiation showed that SEMA3G mRNA and protein levels were increased during the middle stage of cell development. In vitro experiments also showed that adipocyte differentiation was promoted by SEMA3G; however, SEMA3G inhibition using a recombinant lentiviral vector expressing a specific shRNA showed the opposite results. Mice were fed a chow or high-fat diet (HFD); knockdown of SEMA3G was found to inhibit weight gain, reduce fat mass in the tissues, prevent lipogenesis in the liver tissue, reduce insulin resistance and ameliorate glucose tolerance in HFD mice. Additionally, the effect of SEMA3G on HFD-induced obesity was activated through PI3K/Akt/GSK3ß signaling in the adipose tissue and the AMPK/SREBP-1c pathway in the liver. Moreover, the plasma concentrations of SEMA3G and leptin were measured in 20 obese and 20 non-obese human subjects. Both proteins were increased in obese subjects, who also exhibited a lower level of adiponectin and presented with insulin resistance. In summary, we demonstrated that SEMA3G is an adipokine essential for adipogenesis, lipogenesis, and insulin resistance and is associated with obesity. SEMA3G inhibition may, therefore, be useful for treating diet-induced obesity and its complications.
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Dieta Alta en Grasa/efectos adversos , Técnicas de Silenciamiento del Gen , Obesidad/genética , Semaforinas/sangre , Semaforinas/genética , Células 3T3-L1 , Adipocitos/fisiología , Adipogénesis/genética , Adulto , Animales , Diferenciación Celular/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Resistencia a la Insulina/genética , Leptina/sangre , Lipogénesis/genética , Masculino , Ratones , Obesidad/sangre , Obesidad/etiología , Aumento de Peso/genéticaRESUMEN
BACKGROUND & AIMS: CD100 is constitutively expressed on T cells and can be cleaved from the cell surface by matrix metalloproteases (MMPs) to become soluble CD100 (sCD100). Both membrane-bound CD100 (mCD100) and sCD100 have important immune regulatory functions that promote immune cell activation and responses. This study investigated the expression and role of mCD100 and sCD100 in regulating antiviral immune responses during HBV infection. METHODS: mCD100 expression on T cells, sCD100 levels in the serum, and MMP expression in the liver and serum were analysed in patients with chronic HBV (CHB) and in HBV-replicating mice. The ability of sCD100 to mediate antigen-presenting cell maturation, HBV-specific T cell activation, and HBV clearance were analysed in HBV-replicating mice and patients with CHB. RESULTS: Patients with CHB had higher mCD100 expression on T cells and lower serum sCD100 levels compared with healthy controls. Therapeutic sCD100 treatment resulted in the activation of DCs and liver sinusoidal endothelial cells, enhanced HBV-specific CD8 T cell responses, and accelerated HBV clearance, whereas blockade of its receptor CD72 attenuated the intrahepatic anti-HBV CD8 T cell response. Together with MMP9, MMP2 mediated mCD100 shedding from the T cell surface. Patients with CHB had significantly lower serum MMP2 levels, which positively correlated with serum sCD100 levels, compared with healthy controls. Inhibition of MMP2/9 activity resulted in an attenuated anti-HBV T cell response and delayed HBV clearance in mice. CONCLUSIONS: MMP2/9-mediated sCD100 release has an important role in regulating intrahepatic anti-HBV CD8 T cell responses, thus mediating subsequent viral clearance during HBV infection. LAY SUMMARY: Chronic hepatitis B virus (HBV) infection is a major public health problem worldwide. The clearance of HBV relies largely on an effective T cell immune response, which usually becomes dysregulated in chronic HBV infection. Our study provides a new mechanism to elucidate HBV persistence and a new target for developing immunotherapy strategies in patients chronically infected with HBV.
Asunto(s)
Antígenos CD , Linfocitos T CD8-positivos/inmunología , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica , Inmunidad Celular/inmunología , Hígado , Metaloproteinasa 2 de la Matriz/inmunología , Metaloproteinasa 9 de la Matriz/inmunología , Semaforinas , Animales , Antígenos CD/sangre , Antígenos CD/inmunología , Perfilación de la Expresión Génica , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Hígado/inmunología , Hígado/virología , Activación de Linfocitos/inmunología , Ratones , Semaforinas/sangre , Semaforinas/inmunologíaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is one of the most lethal cancers mainly due to the high rate of metastasis. Here, we find that the expression level of CD100 in HNSCC is positively correlated with the T category, pathological grade and lymph node metastasis of the tumor. The level of soluble CD100 (sCD100) is highly increased in serum of HNSCC patients, and sCD100 markedly induces the epithelial-mesenchymal transition (EMT) of HNSCC through its receptor, Plexin-B1 (PlxnB1), and promotes the metastasis in a xenograft mouse model. Furthermore, sCD100 promotes the stabilization of Snail through the regulation of the Vav1-Rac1/RhoA-p21-activated kinase pathway for the induction of EMT. Anti-CD100 antibody abolishes the CD100-induced EMT and prevents the metastasis of HNSCC, and anti-CD100 antibody also increases the drug sensitivity of HNSCC. Taken together, our study shows for the first time that CD100 induces the EMT of HNSCC and promotes the metastasis, and CD100 would be a candidate as a novel prognostic biomarker and a potential therapeutic target for HNSCC.