RESUMEN
Intercellular cell adhesion molecule-1 (ICAM-1) is frequently overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the mechanism underlying the negative effects of neoplastic ICAM-1 remains obscure. Herein, we demonstrate that the survival of NSCLC cells but not normal human bronchial epithelial cells requires an anti-apoptosis signal triggered by fibrinogen γ chain (FGG)-ICAM-1 interaction. ICAM-1-FGG ligation preserves the tyrosine phosphorylation of ICAM-1 cytoplasmic domain and its association with SHP-2, and subsequently promotes Akt and ERK1/2 activation but suppresses JNK and p38 activation. Abolishing ICAM-1-FGG interaction induces NSCLC cell death by activating caspase-9/3 and significantly inhibits tumor development in a mouse xenograft model. Finally, we developed a monoclonal antibody against ICAM-1-FGG binding motif, which blocks ICAM-1âFGG interaction and effectively suppresses NSCLC cell survival in vitro and tumor growth in vivo. Thus, suppressing ICAM-1-FGG axis provides a potential strategy for NSCLC targeted therapy.
Asunto(s)
Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Fibrinógeno , Molécula 1 de Adhesión Intercelular , Neoplasias Pulmonares , Molécula 1 de Adhesión Intercelular/metabolismo , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Animales , Fibrinógeno/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ratones , Línea Celular Tumoral , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Fosforilación , Unión Proteica , Transducción de Señal , Ratones Endogámicos BALB CRESUMEN
The Mediterranean diet, featuring sourdough bread, shows promise in managing metabolic syndrome. This study explored the effects of two sourdough breads, with differing fermentation times but similar nutritional profiles, on inflammation, satiety, and gut microbiota composition in adults with metabolic syndrome. In a double-blind clinical trial, participants were randomized to consume either Elias Boulanger® long-fermentation (48 h) sourdough bread (EBLong) or Elias Boulanger® short-fermentation (2 h) sourdough bread (EBShort) over a two-month period. We assessed clinical parameters, inflammatory biomarkers, satiety-related hormones, and the richness and abundance of gut microbiota at baseline and follow-up. The participants included 31 individuals (mean age, 67, 51.6% female). EBShort was associated with reduced levels of soluble intercellular adhesion molecule (sICAM), and all participants, regardless of the intervention, exhibited a decrease in sICAM and diastolic pressure from baseline (p < 0.017). At follow-up, plasminogen activator inhibitor-1 (PAI-1) levels were lower in EBShort (-744 pg/mL; 95%CI: -282 to -1210 pg/mL) compared to EBLong. No differences in microbiota richness or abundance were observed. EBShort bread was effective in reducing some inflammation markers. The consumption of sourdough bread may offer potential benefits in reducing inflammation markers in individuals with metabolic syndrome; however, longer fermentation times did not show additional benefits.
Asunto(s)
Pan , Dieta Mediterránea , Fermentación , Microbioma Gastrointestinal , Síndrome Metabólico , Humanos , Síndrome Metabólico/dietoterapia , Síndrome Metabólico/microbiología , Síndrome Metabólico/terapia , Femenino , Masculino , Método Doble Ciego , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Factores de Tiempo , Molécula 1 de Adhesión Intercelular/sangre , InflamaciónRESUMEN
BACKGROUND: Type 1 diabetes mellitus (T1DM) is characterized by immune and metabolic dysregulation. Apo1/Fas is implicated in maintaining homeostasis of the immune system. Cytokeratin-18 (cCK-18) is a predictive marker of liver disorders in T2DM. Intercellular adhesion molecule-1 (ICAM-1) is considered to increase susceptibility to diabetes mellitus. All three markers are associated with endothelial function, apoptosis and diabetes-related complications. The possible role of Apo1/Fas, cCK-18 and ICAM-1 was investigated in children and adolescents with T1DM. METHOD: Forty-nine (49) children and adolescents with T1DM and 49 controls were included in the study. Somatometric measurements were obtained and the Body Mass Index (BMI) of the participants was calculated. Biochemical parameters were measured by standard laboratory methods and Apo1/Fas, cCK-18 and ICAM-1 were measured using appropriate ELISA kits. The statistical analysis was performed using the IBM SPSS Statistics 23 program. RESULTS: Apo1/Fas (p = 0.001), cCK-18 (p < 0.001) and ICAM-1 (p < 0.001) were higher in patients with T1DM compared to the controls. Apo1Fas was negatively correlated with glucose (p = 0.042), uric acid (p = 0.026), creatinine (p = 0.022), total cholesterol (p = 0.023) and LDL (p = 0.005) in the controls. In children and adolescents with T1DM, Apo1/Fas was positively correlated with total cholesterol (p = 0.013) and LDL (p = 0.003). ICAM-1 was negatively correlated with creatinine (p = 0.019) in the controls, whereas in patients with T1DM it was negatively correlated with HbA1c (p = 0.05). CONCLUSIONS: Apo1/Fas, cCK-18 and ICAM-1 may be useful as serological markers for immune and metabolic dysregulation in children and adolescents with T1DM. Also, Apo1/Fas may have a protective role against metabolic complications in healthy children.
Asunto(s)
Biomarcadores , Diabetes Mellitus Tipo 1 , Molécula 1 de Adhesión Intercelular , Humanos , Diabetes Mellitus Tipo 1/sangre , Molécula 1 de Adhesión Intercelular/sangre , Niño , Adolescente , Masculino , Femenino , Biomarcadores/sangre , Estudios de Casos y Controles , Queratina-18/sangre , Receptor fas/sangre , Apoptosis , Apolipoproteína A-I/sangreRESUMEN
OBJECTIVE: To review relevant literature regarding the role of metformin in angiogenesis among diabetic patients. METHODS: The systematic review and meta-analysis conducted from May to September 2022, and comprised search on Medline, ScienceDirect, ProQuest, Web of Science, EBSCOhost and Cochrane Library databases. The studies included were published in the English language and were human studies having angiogenesis endothelial markers as the outcomes of interest among patients of type 2 diabetes mellitus undergoing metformin therapy. Endothelial markers, including vascular endothelial growth factor, von-Willebrand-factor, plasminogen activator inhibitor-1, soluble vascular adhesion molecule- 1, intercellular adhesion molecule-1, soluble endothelialselectin, tissue plasminogen activator, urinary albumin excretion, platelet endothelial cell adhesion molecule-1 and thrombin-activatable fibrinolysis inhibitor, were assessed as angiogenesis outcomes. Data was statistically analysed using Review Manager 5.4. RESULTS: Of the 413 studies identified, 8(1.9%) were included; 5(62.5%) randomised control trials, 2(25.0%) cross-sectional, and 1(12.5%) cohort studies, with overall 1199 patients. Among the outcomes, von-Willebrandfactor (p=0.01), soluble vascular adhesion molecule-1 (p<0.00001), intercellular adhesion molecule-1 (p=0.0003), soluble endothelial-selectin (p=0.007), and tissue plasminogen activator (p<0.00001) showed significantly lower levels after metformin treatment using the random effect methods. CONCLUSIONS: Metformin was found to have an additional effect of endothelial function improvement.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Humanos , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Inhibidor 1 de Activador Plasminogénico/sangre , Inhibidor 1 de Activador Plasminogénico/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangre , Selectina E/sangre , Molécula 1 de Adhesión Celular Vascular/sangre , Activador de Tejido Plasminógeno , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/metabolismo , Factor de von Willebrand/metabolismo , AngiogénesisRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.
Asunto(s)
Antígeno CD47 , Carcinoma Ductal Pancreático , Transición Epitelial-Mesenquimal , Trampas Extracelulares , Neoplasias Hepáticas , Macrófagos , Necroptosis , Neoplasias Pancreáticas , Proteínas Quinasas , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/metabolismo , Animales , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/genética , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Línea Celular Tumoral , Antígeno CD47/metabolismo , Antígeno CD47/genética , Proteínas Quinasas/metabolismo , Trampas Extracelulares/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Masculino , Transducción de Señal , Femenino , Acrilamidas , SulfonamidasRESUMEN
The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation. The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy. Therefore, current study is aimed to evaluate the inflammatory and endothelial dysfunction markers with their correlation to biomarkers that can help for in-time diagnosis and efficient prognosis of developing diabetes-associated PAD. Enzyme-linked immunosorbent assay was used to evaluate the interlukin-6, interlukin-8, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) in PAD with diabetes group, diabetic group and healthy individual group while biomarkers were measured by kit method. It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16). The overall means for the parameters, IL-6, IL-8, ICAM, VCAM, urea, S/creatinine, CK-MB, AST, ALT, cholesterol, triglyceride, HDL, LDL, PT, aPTT, INR, HbA1C, and CRP within all groups were significantly (P < 0.05) different from each other. Therefore, it was concluded that the change in IL-6, IL-8, ICAM and VCAM can serve as an accurate diagnostic indicator and successful treatment.
Asunto(s)
Biomarcadores , Diabetes Mellitus Tipo 2 , Enfermedad Arterial Periférica , Molécula 1 de Adhesión Celular Vascular , Humanos , Biomarcadores/sangre , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/diagnóstico , Masculino , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/sangre , Persona de Mediana Edad , Molécula 1 de Adhesión Celular Vascular/sangre , Anciano , Inflamación/sangre , Interleucina-6/sangre , Molécula 1 de Adhesión Intercelular/sangre , Interleucina-8/sangre , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismo , Estudios de Casos y ControlesRESUMEN
Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7-9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p < 0.05). Immunohistochemical analysis revealed decreased intercellular adhesion molecule-1, 4-hydroxy-2-nonenal, caspase-3 and caspase-8 expression, while endothelial cell adhesion molecule-1 immunoreactivity was increased in the IR + DuraGraft grafts compared to the IR-group. DuraGraft mitigates endothelial dysfunction following IR injury in a rat bypass model. Its protective effect may be attributed, at least in part, to its ability to reduce the inflammatory response, oxidative stress, and apoptosis.
Asunto(s)
Endotelio Vascular , Ratas Endogámicas Lew , Daño por Reperfusión , Animales , Ratas , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Daño por Reperfusión/metabolismo , Masculino , Puente de Arteria Coronaria/métodos , Puente de Arteria Coronaria/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Modelos Animales de Enfermedad , Aldehídos/metabolismo , Aldehídos/farmacología , Caspasa 3/metabolismo , Vasodilatación/efectos de los fármacos , Apoptosis/efectos de los fármacos , Acetilcolina/farmacologíaRESUMEN
BACKGROUND: In this study, we aimed to identify the hub genes responsible for increased vascular endothelial cell permeability. METHODS: We applied the weighted Gene Expression Omnibus (GEO) database to mine dataset GSE178331 and ob-tained the most relevant high-throughput sequenced genes for an increased permeability of vascular endothelial cells due to inflammation. We constructed two weighted gene co-expression network analysis (WGCNA) networks, and the differential expression of high-throughput sequenced genes related to endothelial cell permeability were screened from the GEO database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the differential genes. Their degree values were obtained from the topological properties of protein-protein interaction (PPI) networks of differential genes, and the hub genes associated with an increased endothelial cell permeability were analyzed. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting techniques were used to detect the presence of these hub genes in TNF-α induced mRNA and the protein expression in endothelial cells. RESULTS: In total, 1,475 differential genes were mainly enriched in the cell adhesion and TNF-α signaling pathway. With TNF-α inducing an increase in the endothelial cell permeability and significantly increasing mRNA and protein expression levels, we identified three hub genes, namely PTGS2, ICAM1, and SNAI1. There was a significant difference in the high-dose TNF-α group and in the low-dose TNF-α group compared to the control group, in the endothelial cell permeability experiment (p = 0.008 vs. p = 0.02). Measurement of mRNA and protein levels of PTGS2, ICAM1, and SNAI1 by western blotting analysis showed that there was a significant impact on TNF-α and that there was a significant dose-dependent relationship (p < 0.05 vs. p < 0.01). CONCLUSIONS: The three hub genes identified through bioinformatics analyses in the present study may serve as biomarkers of increased vascular endothelial cell permeability. The findings offer valuable insights into the progress and mechanism of vascular endothelial cell permeability.
Asunto(s)
Biología Computacional , Células Endoteliales , Redes Reguladoras de Genes , Mapas de Interacción de Proteínas , Factor de Necrosis Tumoral alfa , Humanos , Biología Computacional/métodos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Células Endoteliales/metabolismo , Perfilación de la Expresión Génica/métodos , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Permeabilidad Capilar , Transducción de Señal , Bases de Datos Genéticas , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Ontología de GenesRESUMEN
Endothelial dysfunction plays a key role in the development of liver cirrhosis. Among the biomarkers of endothelial dysfunction, the soluble form of Vascular Adhesion Protein-1 (sVAP-1) is an unconventional and less known adhesion molecule endowed also with amine oxidase activity. The aim of this study was to explore and correlate the behavior of sVAP-1 with that of the soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) and with the severity of liver cirrhosis. A cross-sectional study was carried out by enrolling 28 controls, 59 cirrhotic patients without hepatocellular carcinoma, and 56 patients with hepatocellular carcinoma (HCC), mainly caused by alcohol abuse. The levels of adhesion molecules and of the pro-inflammatory cytokines (IL-6 and TNF-αα) were determined by immunoassay and the enzymatic activity of sVAP-1 by a fluorometric assay. In non-diabetic patients without HCC, a specific behavior of sVAP-1 was highlighted. Differently from sVCAM-1, sICAM-1, and cytokines, the sVAP-1 level was significantly increased only in the early stage of disease, and then, it decreased in the last stage (866 ± 390 ng/mL vs. 545 ± 316 ng/mL, in Child-Pugh class A vs. C, respectively, p < 0.05). Bivariate analysis correlates sVAP-1 to sVCAM-1, in the absence of HCC (Spearman's rho = 0.403, p < 0.01). Multiple linear regression analysis revealed that sVCAM-1 appears to be a predictor of sVAP-1 (ß coefficient = 0.374, p = 0.021). In conclusion, in non-diabetic and non-HCC cirrhotic patients, sVAP-1 may be a potential prognostic biomarker that, together with sVCAM-1 and pro-inflammatory cytokines, may provide information on the progression of sinusoidal liver endothelium damage.
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Amina Oxidasa (conteniendo Cobre) , Biomarcadores , Carcinoma Hepatocelular , Cirrosis Hepática , Molécula 1 de Adhesión Celular Vascular , Humanos , Masculino , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Molécula 1 de Adhesión Celular Vascular/sangre , Pronóstico , Carcinoma Hepatocelular/sangre , Anciano , Amina Oxidasa (conteniendo Cobre)/sangre , Neoplasias Hepáticas/sangre , Estudios Transversales , Molécula 1 de Adhesión Intercelular/sangre , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Adulto , Factor de Necrosis Tumoral alfa/sangre , Citocinas/sangre , Moléculas de Adhesión CelularRESUMEN
Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Leprdb/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Leprdb/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Leprdb/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Leprdb/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Leprdb/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.
Asunto(s)
Barrera Hematoencefálica , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Receptores de Leptina , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Ratones , Receptores de Leptina/metabolismo , Receptores de Leptina/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Fluoresceína/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Masculino , Diabetes Mellitus Experimental/metabolismo , Permeabilidad , Ratones Endogámicos C57BLRESUMEN
In systemic sclerosis (SSc), fibrosis of the myocardium along with ongoing autoimmune inflammation can alter the electric function of the cardiac myocytes, which may increase the risk for ventricular arrhythmias and sudden cardiac death. We analyzed the electrocardiographic (ECG) variables describing ventricular repolarization such as QT interval, QT dispersion (QTd), T wave peak-to-end interval (Tpe), and arrhythmogeneity index (AIX) of 26 patients with SSc and 36 healthy controls. Furthermore, echocardiographic and laboratory parameters were examined, with a focus on inflammatory proteins like C-reactive ptotein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and progranulin (PGRN). The CRP, sICAM-1, and sVCAM-1 levels were positively correlated with the length of the QT interval. Although the serum PGRN levels were not increased in the SSc group compared to the controls, in SSc patients, the PGRN levels were positively correlated with the QT interval and the AIX. According to our results, we conclude that there may be a potential association between autoimmune inflammation and the risk for ventricular arrhythmias in patients with SSc. We emphasize that the measurement of laboratory parameters of inflammatory activity including CRP, PGRN, sVCAM-1, and sICAM-1 could be helpful in the prediction of sudden cardiac death in patients with SSc.
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Arritmias Cardíacas , Molécula 1 de Adhesión Intercelular , Progranulinas , Esclerodermia Sistémica , Molécula 1 de Adhesión Celular Vascular , Humanos , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/complicaciones , Femenino , Masculino , Persona de Mediana Edad , Molécula 1 de Adhesión Celular Vascular/sangre , Molécula 1 de Adhesión Intercelular/sangre , Arritmias Cardíacas/etiología , Arritmias Cardíacas/sangre , Progranulinas/sangre , Electrocardiografía , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Anciano , Factores de Riesgo , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisisRESUMEN
Endothelial dysfunction is a critical feature of acute respiratory distress syndrome (ARDS) associated with higher disease severity and worse outcomes. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses and heterogeneity of human host responses. Use of microphysiological systems (MPS) to investigate lung endothelial function may shed light on underlying mechanisms and targeted treatments for ARDS. We assessed the response to plasma from critically ill sepsis patients in our lung endothelial MPS through measurement of endothelial permeability, expression of adhesion molecules, and inflammatory cytokine secretion. Sepsis plasma induced areas of endothelial cell (EC) contraction, loss of cellular coverage, and luminal defects. EC barrier function was significantly worse following incubation with sepsis plasma compared to healthy plasma. EC ICAM-1 expression, IL-6 and soluble ICAM-1 secretion increased significantly more after incubation with sepsis plasma compared with healthy plasma. Plasma from sepsis patients who developed ARDS further increased IL-6 and sICAM-1 compared to plasma from sepsis patients without ARDS and healthy plasma. Our results demonstrate the proof of concept that lung endothelial MPS can enable interrogation of specific mechanisms of endothelial dysfunction that promote ARDS in sepsis patients.
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Células Endoteliales , Pulmón , Síndrome de Dificultad Respiratoria , Sepsis , Humanos , Células Endoteliales/metabolismo , Molécula 1 de Adhesión Intercelular/sangre , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-6/sangre , Interleucina-6/metabolismo , Pulmón/fisiopatología , Pulmón/metabolismo , Sistemas Microfisiológicos , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/metabolismo , Sepsis/fisiopatología , Sepsis/complicaciones , Sepsis/metabolismoRESUMEN
Acute myeloid leukemia (AML) is a heterogenous disease characterized by the clonal expansion of myeloid progenitor cells. Despite recent advancements in the treatment of AML, relapse still remains a significant challenge, necessitating the development of innovative therapies to eliminate minimal residual disease. One promising approach to address these unmet clinical needs is natural killer (NK) cell immunotherapy. To implement such treatments effectively, it is vital to comprehend how AML cells escape the NK-cell surveillance. Signal transducer and activator of transcription 3 (STAT3), a component of the Janus kinase (JAK)-STAT signaling pathway, is well-known for its role in driving immune evasion in various cancer types. Nevertheless, the specific function of STAT3 in AML cell escape from NK cells has not been deeply investigated. In this study, we unravel a novel role of STAT3 in sensitizing AML cells to NK-cell surveillance. We demonstrate that STAT3-deficient AML cell lines are inefficiently eliminated by NK cells. Mechanistically, AML cells lacking STAT3 fail to form an immune synapse as efficiently as their wild-type counterparts due to significantly reduced surface expression of intercellular adhesion molecule 1 (ICAM-1). The impaired killing of STAT3-deficient cells can be rescued by ICAM-1 overexpression proving its central role in the observed phenotype. Importantly, analysis of our AML patient cohort revealed a positive correlation between ICAM1 and STAT3 expression suggesting a predominant role of STAT3 in ICAM-1 regulation in this disease. In line, high ICAM1 expression correlates with better survival of AML patients underscoring the translational relevance of our findings. Taken together, our data unveil a novel role of STAT3 in preventing AML cells from escaping NK-cell surveillance and highlight the STAT3/ICAM-1 axis as a potential biomarker for NK-cell therapies in AML.
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Molécula 1 de Adhesión Intercelular , Células Asesinas Naturales , Leucemia Mieloide Aguda , Factor de Transcripción STAT3 , Factor de Transcripción STAT3/metabolismo , Humanos , Leucemia Mieloide Aguda/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Vigilancia Inmunológica , Línea Celular Tumoral , Escape del Tumor , Transducción de Señal , Citotoxicidad InmunológicaRESUMEN
Vasogenic brain edema, a potentially life-threatening consequence following an acute ischemic stroke, is a major clinical problem. This research aims to explore the therapeutic benefits of nimodipine, a calcium channel blocker, in mitigating vasogenic cerebral edema and preserving blood-brain barrier (BBB) function in an ischemic stroke rat model. In this research, animals underwent the induction of ischemic stroke via a 60-min blockage of the middle cerebral artery and treated with a nonhypotensive dose of nimodipine (1 mg/kg/day) for a duration of five days. The wet/dry method was employed to identify cerebral edema, and the Evans blue dye extravasation technique was used to assess the permeability of the BBB. Furthermore, immunofluorescence staining was utilized to assess the protein expression levels of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). The study also examined mitochondrial function by evaluating mitochondrial swelling, succinate dehydrogenase (SDH) activity, the collapse of mitochondrial membrane potential (MMP), and the generation of reactive oxygen species (ROS). Post-stroke administration of nimodipine led to a significant decrease in cerebral edema and maintained the integrity of the BBB. The protective effects observed were associated with a reduction in cell apoptosis as well as decreased expression of MMP-9 and ICAM-1. Furthermore, nimodipine was observed to reduce mitochondrial swelling and ROS levels while simultaneously restoring MMP and SDH activity. These results suggest that nimodipine may reduce cerebral edema and BBB breakdown caused by ischemia/reperfusion. This effect is potentially mediated through the reduction of MMP-9 and ICAM-1 levels and the enhancement of mitochondrial function.
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Barrera Hematoencefálica , Edema Encefálico , Bloqueadores de los Canales de Calcio , Accidente Cerebrovascular Isquémico , Metaloproteinasa 9 de la Matriz , Nimodipina , Animales , Nimodipina/farmacología , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Edema Encefálico/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Masculino , Ratas , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas Sprague-Dawley , Molécula 1 de Adhesión Intercelular/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/complicaciones , Dilatación Mitocondrial/efectos de los fármacos , Succinato Deshidrogenasa/metabolismoRESUMEN
Objective: To investigate the role and underlying mechanisms of intercellular adhesion molecule-1 (ICAM-1) in the adhesion and migration of mesenchymal stem cells (MSCs) in patients with ankylosing spondylitis (AS). Methods: Bone marrow and ligament tissues were collected during surgery from patients with AS and thoracolumbar fractures (as controls, HC) treated from October 2021 to October 2022 at Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital. MSCs were isolated and cultured from the bone marrow using the Ficoll separation method. Cell morphology was observed under high-resolution microscopy, and differences in the cytoskeletal features between AS-and HC-MSCs were analyzed through immunofluorescence staining. The expression of ICAM-1 was quantified in both groups using real-time quantitative polymerase chain reaction (RT-qPCR) and flow cytometry. Transwell migration assays and wound healing experiments were conducted to evaluate the differences in migration rates between the two groups of MSCs. Results: The interspinous ligament and bone marrow was acquired in AS (2 males and 1 female; 33, 37, 32 years old, respectively) and no-AS patients (2 males and 1 female; 35, 32, 38 years old, respectively). AS-MSCs exhibited broader cell morphology compared to HC-MSCs under bright field and fluorescence microscopy. Immunofluorescence staining of the interspinous ligament showed higher expression of ICAM-1 (68.38±3.42 vs 48.31±2.43) and CD105 (37.97±2.16 vs 23.36±2.06) in AS patients (both P<0.001). Western blot and RT-qPCR analysis revealed significantly stronger protein expression and transcription levels of ICAM-1 in AS-MSCs when compared to those in HC-MSCs (both P<0.001). Flow cytometry confirmed greater mean fluorescence intensity of ICAM-1 in AS-MSCs than in that in HC-MSCs (924.30±54.99 vs 636.47±40.03, P=0.002). Regarding cell adhesion efficiency, it showed no significant difference between AS-MSCs and HC-MSCs in the early stage of adhesion (0.5 h: 1 496±213 vs 1 205±163, P=0.133), but they were all significantly higher in AS-MSCs in the later stage (1 h: 2 894±172 vs 1 908±155, P=0.002; 2 h: 4 540±286 vs 3 334±188, P=0.004; 3 h: 5 212±281 vs 4 208±303, P=0.014). Finally, cell migration experiments demonstrated a stronger migration capability of AS-MSCs compared to HC-MSCs (5 449±172 vs 4 016±155, P<0.001), and the inhibition efficiency of A-205804 on the migration rate of AS-MSCs was stronger than that on HC-MSCs (2 145±239 vs 3 539±316, P=0.004). Conclusions: The aberrant expression of ICAM-1 markedly influences the adhesion and migration dynamics of MSCs. Elevated ICAM-1 levels in MSCs derives from patients with AS significantly enhance their migratory capabilities.
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Adhesión Celular , Movimiento Celular , Molécula 1 de Adhesión Intercelular , Células Madre Mesenquimatosas , Espondilitis Anquilosante , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Espondilitis Anquilosante/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Adulto , Femenino , Masculino , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Estudios Retrospectivos , Células CultivadasRESUMEN
Introduction: The study hypothesizes that some patients with diabetic neovascular glaucoma (NVG) do not fully respond to transscleral (TSC) cyclophotocoagulation (CPC) due to significant inflammation and insufficient glucose control. Objective: The study aimed to determine the effect of baseline blood levels of intercellular adhesion molecule-1 (ICAM-1) and glycated haemoglobin (HbA1c) on the management of patients with diabetic NVG by TSC CPC. Methods: This open prospective study included 70 diabetic patients (75 eyes; aged Ðе 63.0 years) with painful NVG and 20 healthy individuals (aged Ðе 61.5 years) as an immunological control. All patients underwent TSC СPC with a diode laser. Baseline HbA1c levels and ICAM-1 expression in blood samples were determined. Follow-up was 12 months. Results: One month after TSC CPC, IOP decreased by 28% compared to baseline. The effectiveness of laser treatment after 12 months of follow-up was 63% with IOP decrease by 46%. In patients with NVG, the initial level of ICAM-1 was 2.5 times higher than in the control group. Patients who did not fully respond to the first TSC CPC (30 eyes) and required additional laser procedure, had high initial HbA1c (9.5%) and high expression values of the ICAM-1 (609.0 cells/µL). Conclusions: Repeated procedures of TSC CPC at high IOP in diabetic patients with NVG are associated with high initial values of expression of ICAM-1 in peripheral blood and high HbA1c. The strategy of management of patients with diabetic NVG should be aimed at intensive glucose control and local anti-inflammatory treatment. Abbreviations: PDR = proliferative diabetic retinopathy, DR = diabetic retinopathy, NVG = neovascular glaucoma, TSC CPC = transscleral cyclophotocoagulation, ICAM-1 = intercellular adhesion molecule-1, HbA1c = glycated haemoglobin, IOP = intraocular pressure.
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Glaucoma Neovascular , Hemoglobina Glucada , Molécula 1 de Adhesión Intercelular , Presión Intraocular , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Cuerpo Ciliar/cirugía , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/cirugía , Retinopatía Diabética/sangre , Estudios de Seguimiento , Glaucoma Neovascular/etiología , Glaucoma Neovascular/diagnóstico , Hemoglobina Glucada/metabolismo , Molécula 1 de Adhesión Intercelular/sangre , Coagulación con Láser/métodos , Estudios ProspectivosRESUMEN
High-grade gliomas (HGG) comprising WHO grades 3 and 4 have a poor overall survival (OS) that has not improved in the past decade. Herein, markers representing four components of the tumor microenvironment (TME) were identified to define their linked expression in TME and predict the prognosis in HGG, namely, interleukin6 (IL6, inflammation), inducible nitric oxide synthase(iNOS), heat shock protein-70 (HSP70, hypoxia), vascular endothelial growth receptor (VEGF), and endothelin1 (ET1) (angiogenesis) and matrix metalloprotease-14 (MMP14) and intercellular adhesion molecule1 (ICAM1, extracellular matrix). To establish a non-invasive panel of biomarkers for precise prognostication in HGG. Eighty-six therapy-naive HGG patients with 45 controls were analyzed for the defined panel. Systemic expression of extracellular/secretory biomarkers was screened dot-immune assay (DIA), quantified by ELISA, and validated by immunocytochemistry (ICC). Expression of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 was found to be positively associated with grade. Quantification of circulating levels of the markers by ELISA and ICC presented a similar result. The biomarkers were observed to negatively correlate with OS (p < 0.0001). Cox-regression analysis yielded all biomarkers as good prognostic indicators and independent of confounders. On applying combination statistics, the biomarker panel achieved higher sensitivity than single markers to define survival. The intra-association of all seven biomarkers was significant, hinting of a cross-talk between the TME components and a hypoxia driven systemic inflammation upregulating the expression of other components. This is a first ever experimental study of a marker panel that can distinguish between histopathological grades and also delineate differential survival using liquid biopsy, suggesting that markers of hypoxia can be a cornerstone for personalized therapy. The panel of biomarkers of iNOS, HSP70, IL-6, VEGF, ET1, MMP14, and ICAM1 holds promise for prognostication in HGG.
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Biomarcadores de Tumor , Neoplasias Encefálicas , Glioma , Proteínas HSP70 de Choque Térmico , Neovascularización Patológica , Óxido Nítrico Sintasa de Tipo II , Microambiente Tumoral , Humanos , Glioma/metabolismo , Glioma/patología , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP70 de Choque Térmico/sangre , Biomarcadores de Tumor/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Adulto , Neovascularización Patológica/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/sangre , Interleucina-6/metabolismo , Interleucina-6/sangre , Metaloproteinasa 14 de la Matriz/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangre , Endotelina-1/metabolismo , Endotelina-1/sangre , Anciano , Hipoxia Tumoral , Pronóstico , AngiogénesisAsunto(s)
Lesión Pulmonar Aguda , Inflamación , Molécula 1 de Adhesión Intercelular , Receptores Acoplados a Proteínas G , Transducción de Señal , Lesión Pulmonar Aguda/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Animales , Transducción de Señal/fisiología , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Inflamación/metabolismo , Ácido Láctico/metabolismo , Humanos , Ratones , MasculinoRESUMEN
AIMS: Diagnosis of idiopathic inflammatory myopathies (IIM) is based on morphological characteristics and the evaluation of disease-related proteins. However, although broadly applied, substantial bias is imposed by the respective methods, observers and individual staining approaches. We aimed to quantify the protein levels of major histocompatibility complex (MHC)-1, (MHC)-2 and intercellular adhesion molecule (ICAM)-1 using an automated morphometric method to mitigate bias. METHODS: Double immunofluorescence staining was performed on whole muscle sections to study differences in protein expression in myofibre and endomysial vessels. We analysed all IIM subtypes including dermatomyositis (DM), anti-synthetase syndrome (ASyS), inclusion body myositis (IBM), immune-mediated-necrotising myopathy (IMNM), dysferlinopathy (DYSF), SARS-CoV-2 infection and vaccination-associated myopathy. Biopsies with neurogenic atrophy (NA) and normal morphology served as controls. Bulk RNA-Sequencing (RNA-Seq) was performed on a subset of samples. RESULTS: Our study highlights the significance of MHC-1, MHC-2 and ICAM-1 in diagnosing IIM subtypes and reveals distinct immunological profiles. RNASeq confirmed the precision of our method and identified specific gene pathways in the disease subtypes. Notably, ASyS, DM and SARS-CoV-2-associated myopathy showed increased ICAM-1 expression in the endomysial capillaries, indicating ICAM-1-associated vascular activation in these conditions. In addition, ICAM-1 showed high discrimination between different subgroups with high sensitivity and specificity. CONCLUSIONS: Automated morphometric analysis provides precise quantitative data on immune-associated proteins that can be integrated into our pathophysiological understanding of IIM. Further, ICAM-1 holds diagnostic value for the detection of IIM pathology.
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Molécula 1 de Adhesión Intercelular , Músculo Esquelético , Miositis , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Miositis/patología , Miositis/diagnóstico , Miositis/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , COVID-19/patología , COVID-19/diagnóstico , Masculino , Femenino , Diagnóstico Diferencial , Antígenos de Histocompatibilidad Clase II/metabolismoRESUMEN
Increased immune-inflammatory activation has been repeatedly linked to etiopathogenesis and the progression of both major depressive disorder (MDD) and bipolar depression (BD). We explore the role of soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in diagnostic differentiation and disorder progression in patients with MDD and BD. Serum levels of sICAM-1 and sVCAM-1 were measured in 137 patients (MDD = 93 and BD = 44) and compared with 73 healthy controls. The severity of psychopathology was assessed using the Hamilton Depression Rating Scale and Clinical Global Impression Scale. After adjustment for multiple confounders, we noticed significant downregulation of sVCAM-1 and upregulation of sICAM-1 levels in both patient groups. Decreased sVCAM-1 levels were detected in patients with acute episodes of BD when compared to MDD. Immune mediators were related to indicators of progression in both mood disorders. They also followed different post-treatment normalization patterns in MDD and BD and in relation to the stage of each disorder. Adhesion molecules could potentially be useful in discriminating between patients with MDD and BD and determining the possible progression of the disorders. Future nosological methods should include time-dependent pathoplasticity and biological correlates, at least for affective disorders.