RÉSUMÉ
OBJECTIVE: The study compared the impact of unfractionated heparin (UFH) administered via two routes (infusion and subcutaneous injection) on heparin-binding protein (HBP) and plasminogen activator inhibitor-1 (PAI-1) levels in critically ill sepsis patients. PATIENTS AND METHODS: Forty critically ill sepsis patients were randomly assigned to receive either a low-dose intravenous infusion of UFH (500 units/hour) or subcutaneous UFH (5,000 units/8 hours) for seven days. HBP and PAI-1 were measured at baseline and on days one, two, and seven. RESULTS: Intravenous administration of UFH showed a significant reduction in percentage change of HBP compared to subcutaneous administration on days one [(-35% vs. -13%, p = 0.03*) (*indicates a significant result *p < 0.05, relative to the subcutaneous group)] and seven (-62% vs. -39%, p = 0.02*). Also, the percentage change of PAI-1 was significantly reduced in the infusion group compared to the subcutaneous group on days one (-28% vs. -3%, p = 0.008*), two (-42% vs. -3%, p = 0.001*), and seven (-62% vs. 27%, p = 0.001*), respectively. Furthermore, a significant improvement in the 14-day survival was observed in the infusion group compared to the subcutaneous group (p = 0.008*). CONCLUSIONS: Intravenous infusion was the route of choice for UFH administration in critically ill septic patients, with a promising effect on HBP, PAI-1, and survival.
Sujet(s)
Maladie grave , Héparine , Inhibiteur-1 d'activateur du plasminogène , Sepsie , Humains , Héparine/administration et posologie , Perfusions veineuses , Sepsie/traitement médicamenteux , Injections sous-cutanées , Mâle , Femelle , Adulte d'âge moyen , Inhibiteur-1 d'activateur du plasminogène/administration et posologie , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Protéines du sang/métabolisme , Sujet âgé , Peptides antimicrobiens cationiques/administration et posologie , Anticoagulants/administration et posologieRÉSUMÉ
The serine protease inhibitor clade E member 1 (SERPINE1) is a key modulator of the plasminogen/plasminase system and has been demonstrated to promote tumor progression and metastasis in various tumours. However, although much literature has explored the cancer-promoting mechanism of SERPINE1, the pan-cancer analyses of its predictive value and immune response remain unexplored. The differential expression, and survival analysis of SERPINE1 expression in multiple cancers were analysed using The Cancer Genome Atlas and Genotype-Tissue Expression database. Kaplan-Meier (K-M) plotter and survival data analysis were used to analyze the prognostic value of SERPINE1 expression, including overall survival (OS), disease-specific survival, disease-free interval and progression-free interval and investigated the relationship of SERPINE1 expression with microsatellite instability. We further analysed the correlation between the expression of SERPINE1 and immune infiltration. The Kyoto Encyclopaedia of Genes and Genomes pathway was used for enrichment analysis, and the Gene Set Enrichment Analysis (GSEA) database was used to perform pathway analysis. Finally, in vitro experiments demonstrated that knockdown or overexpression of SERPINE1 could alter the proliferation and migration of gastric cancer (GC) cells. The results indicated that SERPINE1 expression levels different significantly between cancer and normal tissues, meanwhile, it was highly expressed in various cancers. By analysing online data, it has been observed that the gene SERPINE1 exhibits heightened expression levels across a variety of human cancers, significantly impacting patient survival rates. Notably, the presence of SERPINE1 was strongly associated with decrease OS and disease-free survival in individuals diagnosed with GC. Furthermore, an observed link indicates that higher levels of SERPINE expression are associated with increased infiltration of immune cells in GC. Finally, in vitro experiments showed that knockdown or overexpression of SERPINE1 inhibited the growth, and migration, of GC cells. SERPINE1expression potentially represents a novel prognostic biomarker due to its significant association with immune cell infiltration in GC. This study shows that SERPINE1 is an oncogene that participates in regulating the immune infiltration and affecting the prognosis of patients in multiple cancers, especially in GC. These findings underscore the importance of further investigating the role of SERPINE1 in cancer progression and offer a promising direction for the development of new therapeutic strategies.
Sujet(s)
Prolifération cellulaire , Régulation de l'expression des gènes tumoraux , Inhibiteur-1 d'activateur du plasminogène , Tumeurs de l'estomac , Humains , Inhibiteur-1 d'activateur du plasminogène/génétique , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Tumeurs de l'estomac/génétique , Tumeurs de l'estomac/immunologie , Tumeurs de l'estomac/anatomopathologie , Tumeurs de l'estomac/métabolisme , Pronostic , Prolifération cellulaire/génétique , Lignée cellulaire tumorale , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Mouvement cellulaire/génétique , Estimation de Kaplan-Meier , Instabilité des microsatellitesRÉSUMÉ
The level of cytokine expression was measured in human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells exposed to 500 ng/ml alkylating mutagen mitomycin C (MMC) and 5 µM atorvastatin. It was found that treatment of MMC-exposed HCAEC with atorvastatin decreased secretion of macrophage migration inhibitory factor (MIF), IL-8, and IL8 gene expression, but increased the expression of SERPINE1 gene encoding the PAI-1 protein. In atorvastatin-treated HITAEC, the concentration of MIF protein and the expression of the IL8 and SERPINE1 genes were reduced. We can conclude that atorvastatin prevents proinflammatory activation of endothelial cells cultured under conditions of genotoxic load. However, the molecular mechanisms of this effect require further research.
Sujet(s)
Atorvastatine , Vaisseaux coronaires , Cellules endothéliales , Interleukine-8 , Mitomycine , Inhibiteur-1 d'activateur du plasminogène , Humains , Atorvastatine/pharmacologie , Cellules endothéliales/effets des médicaments et des substances chimiques , Cellules endothéliales/métabolisme , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Inhibiteur-1 d'activateur du plasminogène/génétique , Mitomycine/pharmacologie , Interleukine-8/métabolisme , Interleukine-8/génétique , Vaisseaux coronaires/effets des médicaments et des substances chimiques , Vaisseaux coronaires/cytologie , Anti-inflammatoires/pharmacologie , Cellules cultivées , Facteurs inhibiteurs de la migration des macrophages/génétique , Facteurs inhibiteurs de la migration des macrophages/métabolismeRÉSUMÉ
The aim of the present study was to determine whether adipokines monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) can affect the functions of ovarian cells in cats. The addition of either MCP-1 or PAI-1 increased viability; promoted the accumulation of proliferation markers and progesterone and estradiol release; and decreased the accumulation of apoptosis markers in cultured feline granulosa cells. The present observations suggest that MCP-1 or PAI-1 can be physiological stimulators of ovarian granulosa cell functions.
Sujet(s)
Chimiokine CCL2 , Cellules de la granulosa , Inhibiteur-1 d'activateur du plasminogène , Animaux , Chats , Femelle , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Cellules de la granulosa/métabolisme , Cellules de la granulosa/physiologie , Cellules de la granulosa/effets des médicaments et des substances chimiques , Chimiokine CCL2/métabolisme , Cellules cultivées , Prolifération cellulaire/physiologie , Oestradiol/métabolisme , Oestradiol/pharmacologie , Progestérone/métabolisme , Progestérone/pharmacologie , Apoptose , Survie cellulaireRÉSUMÉ
BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.
Sujet(s)
Chirurgie bariatrique , Obésité , Inhibiteur-1 d'activateur du plasminogène , Proprotéine convertase 9 , Humains , Inhibiteur-1 d'activateur du plasminogène/sang , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Proprotéine convertase 9/sang , Proprotéine convertase 9/métabolisme , Mâle , Femelle , Adulte , Adulte d'âge moyen , Obésité/chirurgie , Obésité/métabolisme , Obésité/sang , Études longitudinales , Insulinorésistance , Diabète de type 2/métabolisme , Diabète de type 2/chirurgie , Triglycéride/sang , Triglycéride/métabolismeRÉSUMÉ
BACKGROUND/AIM: How tumors regulate the genes of the coagulome is crucial for cancer-associated thrombosis and the occurrence of venous thromboembolic complications in patients with cancer. We have previously reported potent yet complex effects of glucocorticoids (GC) on the expression of three genes that play a key role in the regulation of thrombin/plasmin activation (F3, PLAU, and SERPINE1). This study aimed to extend the investigation of GC effects to the whole tumor coagulome and assess the resulting impact on the ability of cancer cells to activate thrombin and plasmin. MATERIALS AND METHODS: Cancer RNA expression data were retrieved from various sources. Additionally, oral squamous cell carcinoma (OSCC) cells exposed to GC in vitro were analyzed using QPCR, enzymatic assays measuring thrombin and urokinase-type Plasminogen Activator (uPA) activity, and D-dimer concentrations. RESULTS: Our findings highlight the potent and specific stimulatory effect of GC on SERPINE1 expression across different types of cancer. Consistently, GC were found to inhibit uPA proteolytic activity and reduce the concentrations of D-dimers in OSCC in vitro. CONCLUSION: Fibrinolysis inhibition is a key consequence of cancer cell exposure to GC, possibly leading to the stabilization of the fibrin clot in cancer.
Sujet(s)
Fibrinolyse , Glucocorticoïdes , Inhibiteur-1 d'activateur du plasminogène , Humains , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Inhibiteur-1 d'activateur du plasminogène/génétique , Fibrinolyse/effets des médicaments et des substances chimiques , Glucocorticoïdes/pharmacologie , Lignée cellulaire tumorale , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Activateur du plasminogène de type urokinase/métabolisme , Activateur du plasminogène de type urokinase/génétique , Thrombine/métabolisme , Thrombine/pharmacologie , Produits de dégradation de la fibrine et du fibrinogène/métabolisme , Activation de la transcription/effets des médicaments et des substances chimiques , Tumeurs de la bouche/génétique , Tumeurs de la bouche/métabolisme , Tumeurs de la bouche/anatomopathologie , Tumeurs de la bouche/traitement médicamenteux , Tumeurs/génétique , Tumeurs/traitement médicamenteux , Tumeurs/métabolisme , Tumeurs/anatomopathologie , Coagulation sanguine/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Kawasaki disease (KD) is the most common cause of acquired heart disease in childhood. Coronary artery lesions (CALs) are serious complications of KD that can result in stenosis and thrombosis, but the specific underlying pathogenic mechanisms have not been elucidated. Therefore, exploring biomarkers to help predict early CALs is urgently needed for clinical treatment. METHODS: Patients were recruited from three independent cohorts. In the discovery cohort, Data-Independent Acquisition Mass Spectrometry (DIA-MS) was performed to screen plasma proteins from healthy controls (HCs), KD patients prior to intravenous immunoglobulin (IVIG) treatment, and KD patients post-IVIG treatment. KD patients were further divided into KD patients without CALs (nCAL) and with CALs (CALs) groups. Bioinformatic analysis was carried out for the differentially expressed proteins (DEPs) and hub proteins. Candidate proteins were quantified by enzyme-linked immunosorbent assay (ELISA) in the validation cohort 1 and 2. Furthermore, candida albicans cell wall extract (CAWS)-induced KD vasculitis mice and cell models were established to investigate the expression of biomarkers identified in the aforementioned clinical cohort. RESULTS: According to the quantitative proteomics analysis, SERPINE1 was significantly increased in KD patients with CALs. Receiver operating characteristic curves (ROC) revealed that plasma SERPINE1 exhibited greater ability in predicting CALs (AUC = 0.824, P < 0.0001). After IVIG treatment, the concentrations of SERPINE1 in the nCALs group significantly decreased. However, the concentration of SERPINE1 remained persistently elevated in the CALs group. Moreover, the expression of SERPINE1 was significantly upregulated in the heart tissue of KD mice, KD plasma, or tumor necrosis factor-α (TNF-α)-stimulated human coronary artery endothelial cells (HCAECs). CONCLUSIONS: Overall, our results suggest that the plasma concentration of SERPINE1 might serve as a new potential predictive biomarker for CALs in KD patients.
Sujet(s)
Marqueurs biologiques , Maladie de Kawasaki , Inhibiteur-1 d'activateur du plasminogène , Protéomique , Humains , Maladie de Kawasaki/sang , Animaux , Marqueurs biologiques/sang , Inhibiteur-1 d'activateur du plasminogène/sang , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Mâle , Femelle , Souris , Enfant d'âge préscolaire , Maladie des artères coronaires/sang , Enfant , Immunoglobulines par voie veineuse/usage thérapeutique , Nourrisson , Modèles animaux de maladie humaine , Souris de lignée C57BL , Vaisseaux coronaires/anatomopathologieRÉSUMÉ
Antisense long non-coding RNAs (lncRNAs) played a crucial role in the precise regulation of essential biological processes and were abundantly present in animals. Many of these antisense lncRNAs have been identified as key roles in adipose tissue accumulation in livestock, underscoring their vital role in the regulation of animal physiology. Nonetheless, the functional roles of these antisense lncRNAs in regulating adipogenesis and the specific molecular mechanisms these processes were still unclear, which was a significant gap in current scientific research. In this study, we identified and characterized SERPINE1AS2, a novel natural antisense lncRNA, was highly expressed in the fat tissues of adult cattle and calves. Its expression gradually increased during the differentiation of intramuscular adipocytes. Through functional studies, we observed that knockdown of SERPINE1AS2 inhibited the proliferation and adipogenesis of intramuscular adipocytes, while overexpression of SERPINE1AS2 produced the opposite effect. RNA sequencing (RNA-seq) analysis following SERPINE1AS2 knockdown revealed that differential expression genes (DEGs) were significantly enriched in key signaling pathways, notably the MAPK, Wnt, and mTOR signaling pathways. Furthermore, SERPINE1AS2 interacted with Plasminogen Activator Inhibitor-1 (PAI1), forming RNA dimers through complementary base pairing and consequently influencing PAI1 expression. Interestingly, studies on PAI1 suggested that reduced expression facilitated adipogenesis and the downregulation of PAI1 alleviated the inhibitory effect of reduced SERPINE1AS2 on adipogenesis. In summary, this study suggested that SERPINE1AS2 played a crucial role in the adipogenesis of bovine intramuscular adipocytes by modulating the expression of PAI1. SERPINE1AS2 also regulated adipogenesis by engaging in the MAPK, Wnt, and mTOR signaling pathways. Our results suggested that SERPINE1AS2 had a complex regulatory mechanism on adipogenesis in intramuscular adipocytes.
Sujet(s)
Adipocytes , Adipogenèse , Inhibiteur-1 d'activateur du plasminogène , ARN long non codant , Adipogenèse/génétique , Animaux , Inhibiteur-1 d'activateur du plasminogène/génétique , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Bovins , ARN long non codant/génétique , ARN long non codant/métabolisme , Adipocytes/métabolisme , Adipocytes/cytologie , Régulation de l'expression des gènes , Différenciation cellulaire/génétique , Prolifération cellulaire/génétique , Transduction du signal , Tissu adipeux/métabolisme , Tissu adipeux/cytologieRÉSUMÉ
The paracrine actions of adipokine plasminogen activator inhibitor-1 (PAI-1) are implicated in obesity-associated tumorigenesis. Here, we show that PAI-1 mediates extracellular matrix (ECM) signaling via epigenetic repression of DKK1 in endometrial epithelial cells (EECs). While the loss of DKK1 is known to increase ß-catenin accumulation for WNT signaling activation, this epigenetic repression causes ß-catenin release from transmembrane integrins. Furthermore, PAI-1 elicits the disengagement of TIMP2 and SPARC from integrin-ß1 on the cell surface, lifting an integrin-ß1-ECM signaling constraint. The heightened interaction of integrin-ß1 with type 1 collagen (COL1) remodels extracellular fibrillar structures in the ECM. Consequently, the enhanced nanomechanical stiffness of this microenvironment is conducive to EEC motility and neoplastic transformation. The formation of extensively branched COL1 fibrils is also observed in endometrial tumors of patients with obesity. The findings highlight PAI-1 as a contributor to enhanced integrin-COL1 engagement and extensive ECM remodeling during obesity-associated neoplastic development.
Sujet(s)
Matrice extracellulaire , Antigènes CD29 , Obésité , Inhibiteur-1 d'activateur du plasminogène , bêta-Caténine , Humains , Obésité/métabolisme , Obésité/anatomopathologie , Femelle , Inhibiteur-1 d'activateur du plasminogène/métabolisme , bêta-Caténine/métabolisme , Antigènes CD29/métabolisme , Matrice extracellulaire/métabolisme , Tumeurs de l'endomètre/métabolisme , Tumeurs de l'endomètre/anatomopathologie , Inhibiteur tissulaire de métalloprotéinase-2/métabolisme , Animaux , Ostéonectine/métabolisme , Ostéonectine/génétique , Collagène/métabolisme , Endomètre/métabolisme , Endomètre/anatomopathologie , Collagène de type I/métabolisme , Membrane cellulaire/métabolisme , Cellules épithéliales/métabolisme , Cellules épithéliales/anatomopathologie , Protéines et peptides de signalisation intercellulaireRÉSUMÉ
PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive condition often requiring lung transplantation. Accelerated senescence of type II alveolar epithelial cells (AECII) plays a crucial role in pulmonary fibrosis progression through the secretion of the senescence-associated secretory phenotype (SASP). Low-dose carbon monoxide (CO) possesses anti-inflammatory, anti-oxidative, and anti-aging properties. This study aims to explore the preventive effects of CO-releasing molecule 2 (CORM2) in a bleomycin-induced pulmonary fibrosis model. METHODS: We established an pulmonary fibrosis model in C57BL/6J mice and evaluated the impact of CORM2 on fibrosis pathology using Masson's trichrome staining, fluorescence staining, and pulmonary function tests. Fibrogenic marker expression and SASP secretion in tissues and AECII cells were analyzed using qRT-PCR, Western blot, and ELISA assays both in vivo and in vitro. Additionally, we investigated DNA damage and cellular senescence through immunofluorescence and SA-ß-gal staining. RESULTS: CORM2 showed a preventive effect on bleomycin-induced lung fibrosis by improving pulmonary function and reducing the expression of fibrosis-related genes, such as TGF-ß, α-SMA, Collagen I/III. CORM2 decreased the DNA damage response by inhibiting γ-H2AX, p53, and p21. We identified PAI-1 as a new target gene that was downregulated by CORM2, and which was associated with cellular senescence and fibrosis. CORM2 effectively inhibited cellular senescence and delayed EMT occurrence in AECII cells. CONCLUSION: Our study highlights the potential of CORM2 in preventing DNA damage-induced cellular senescence in bleomycin-induced pulmonary fibrosis through modulation of the p53/PAI-1 signaling pathway. These findings underscore the promising prospects of CORM2 in targeting cellular senescence and the p53/PAI-1 pathway as a potential preventive strategy for IPF.
Sujet(s)
Bléomycine , Monoxyde de carbone , Vieillissement de la cellule , Inhibiteur-1 d'activateur du plasminogène , Transduction du signal , Protéine p53 suppresseur de tumeur , Animaux , Mâle , Souris , Bléomycine/toxicité , Monoxyde de carbone/pharmacologie , Monoxyde de carbone/métabolisme , Vieillissement de la cellule/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Altération de l'ADN/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Composés organométalliques/pharmacologie , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/métabolisme , Fibrose pulmonaire/anatomopathologie , Fibrose pulmonaire/traitement médicamenteux , Fibrose pulmonaire/prévention et contrôle , Transduction du signal/effets des médicaments et des substances chimiques , Protéine p53 suppresseur de tumeur/métabolismeRÉSUMÉ
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.
Sujet(s)
Diabète de type 2 , Hypoglycémiants , Metformine , Humains , Metformine/usage thérapeutique , Diabète de type 2/traitement médicamenteux , Hypoglycémiants/usage thérapeutique , Inhibiteur-1 d'activateur du plasminogène/sang , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Facteur de croissance endothéliale vasculaire de type A/métabolisme , Facteur de croissance endothéliale vasculaire de type A/sang , Sélectine E/sang , Molécule-1 d'adhérence des cellules vasculaires/sang , Activateur tissulaire du plasminogène , Molécule-1 d'adhérence intercellulaire/sang , Molécule-1 d'adhérence intercellulaire/métabolisme , Facteur de von Willebrand/métabolisme ,RÉSUMÉ
Background: Chronic rhinosinusitis (CRS) is an inflammatory disease affecting more than 10% of the global adult population. It is classified into Th1, Th2, and Th17 endotypes and eosinophilic and non-eosinophilic types. Th2-based inflammation and eosinophilic CRS (ECRS) are associated with tissue remodeling and fibrinolytic system impairment. Objective: To elucidate the role of eosinophils in inducing fibrin deposition in CRS nasal polyp tissues and explore potential regulatory mechanisms. Methods: We analyzed the expression of genes related to the serpin family and fibrinolytic system using Gene Expression Omnibus and Next-generation sequencing data. Differentially expression genes (DEGs) analysis was used to compare control and nasal polyp tissues, followed by KEGG and Gene ontology (GO) analysis. We measured the expression and correlation of plasminogen activator-1 (PAI-1), tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and urokinase plasminogen activator surface receptor (u-PAR) in CRS tissues, and evaluated the effect of eosinophils on the fibrinolytic system using a cytokine array and co-culture. Results: Nasal polyp tissues showed upregulated PAI-1, u-PA, and u-PAR expression and downregulated t-PA expression. Fibrinolytic system-related genes positively correlated with Th2 cytokines, except for t-PA. Eosinophil-derived Chitinase-3-like protein 1 (CHI3L1) increased PAI-1 expression and decreased t-PA levels in fibroblasts and epithelial cells. The inhibition of CHI3L1 suppresses these alterations. Conclusion: CHI3L1 contributes to fibrin deposition by impairing the fibrinolytic system during nasal polyp formation. The regulation of CHI3L1 expression may inhibit fibrin deposition and edema in ECRS, presenting a potential treatment for this condition.
Sujet(s)
Protéine-1 similaire à la chitinase-3 , Granulocytes éosinophiles , Fibrinolyse , Polypes du nez , Inhibiteur-1 d'activateur du plasminogène , Rhinite , Sinusite , Humains , Polypes du nez/métabolisme , Polypes du nez/immunologie , Sinusite/métabolisme , Sinusite/immunologie , Rhinite/métabolisme , Rhinite/immunologie , Maladie chronique , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Inhibiteur-1 d'activateur du plasminogène/génétique , Protéine-1 similaire à la chitinase-3/métabolisme , Protéine-1 similaire à la chitinase-3/génétique , Adulte , Femelle , Mâle , Adulte d'âge moyen , Granulocytes éosinophiles/immunologie , Granulocytes éosinophiles/métabolisme , Récepteurs à l'activateur du plasminogène de type urokinase/génétique , Récepteurs à l'activateur du plasminogène de type urokinase/métabolisme , Activateur du plasminogène de type urokinase/génétique , Activateur du plasminogène de type urokinase/métabolisme , Activateur tissulaire du plasminogène/métabolisme , Activateur tissulaire du plasminogène/génétique , Cytokines/métabolisme ,Sujet(s)
COVID-19 , Inhibiteur-1 d'activateur du plasminogène , Thrombose , Humains , COVID-19/complications , COVID-19/épidémiologie , Complications du diabète , Diabète/épidémiologie , Inhibiteur-1 d'activateur du plasminogène/sang , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Facteurs de risque , Thrombose/étiologie , Thrombose/épidémiologieRÉSUMÉ
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) are the primary physiological inhibitors of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but their roles in PAH are unsettled. Here, we report that: 1) PAI-1, but not PAI-2, is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared with controls; 2) PAI-1-/- mice spontaneously develop pulmonary vascular remodeling associated with upregulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and 3) pharmacological inhibition of uPA in human PAH PASMCs suppresses proproliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation, and induces apoptosis in vitro, and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that downregulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent upregulation of mTOR and transforming growth factor-ß (TGF-ß) signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH.NEW & NOTEWORTHY This study identifies a novel role for the deficiency of plasminogen activator inhibitor (PAI)-1 and resultant unrestricted uPA activity in PASMC remodeling and PH in vitro and in vivo, provides novel mechanistic link from PAI-1 loss through uPA-induced Akt/mTOR and TGFß-Smad3 upregulation to pulmonary vascular remodeling in PH, and suggests that inhibition of uPA to rebalance the uPA-PAI-1 tandem might provide a novel approach to complement current therapies used to mitigate this pulmonary vascular disease.
Sujet(s)
Hypertension pulmonaire , Muscles lisses vasculaires , Inhibiteur-1 d'activateur du plasminogène , Remodelage vasculaire , Animaux , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Inhibiteur-1 d'activateur du plasminogène/génétique , Humains , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Souris , Hypertension pulmonaire/métabolisme , Hypertension pulmonaire/anatomopathologie , Artère pulmonaire/métabolisme , Artère pulmonaire/anatomopathologie , Transduction du signal , Mâle , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/anatomopathologie , Prolifération cellulaire , Souris knockout , Complexe-1 cible mécanistique de la rapamycine/métabolisme , Souris de lignée C57BL , Apoptose , Activateur du plasminogène de type urokinase/métabolisme , Activateur du plasminogène de type urokinase/génétique , Hypertrophie ventriculaire droite/métabolisme , Hypertrophie ventriculaire droite/anatomopathologie , Hypertrophie ventriculaire droite/physiopathologie , Cellules endothéliales/métabolisme , Cellules endothéliales/anatomopathologie , Inhibiteur-2 d'activateur du plasminogène/métabolisme , Inhibiteur-2 d'activateur du plasminogène/génétiqueRÉSUMÉ
Upon injury to the CNS, astrocytes undergo morphological and functional changes commonly referred to as astrocyte reactivity. Notably, these reactive processes include altered expression of factors that control immune processes and neuronal survival, as well as increased expression of the CXCL12 receptor, CXCR7/ACKR3. We now asked whether these events are related in that the astrocytic CXCL12 system modulates immune responses and/or neuronal survival. Short-term exposure of astrocytes cultured from the postnatal rat cortex to CXCL12 prominently increased the expression of serpine1/PAI1 on the mRNA level, but showed either no or only minor effects on the expression of additional reactive genes, selected from previous array studies. CXCL12-induced increases in PAI1 protein levels were only detectable in the additional presence of chemokines/cytokines, suggesting that translation of serpine1 mRNA depends on the cooperation of various factors. As expected, expression of most of the selected genes increased after acute or chronic activation of astrocytes with either LPS or a combination of IL-1ß and TNFα. CXCL12 partially attenuated expression of some of the LPS and IL-1ß/TNFα-induced genes under acute conditions, in particular those encoding CXCL9, CXCL10, CXCL11, and CCL5. Taken together, these findings argue for the involvement of the astrocyte CXCL12 system in the control of the immune response of the injured CNS, where it may control distinct steps.
Sujet(s)
Astrocytes , Chimiokine CXCL12 , Inhibiteur-1 d'activateur du plasminogène , Animaux , Rats , Astrocytes/métabolisme , Astrocytes/effets des médicaments et des substances chimiques , Cellules cultivées , Cortex cérébral/métabolisme , Cortex cérébral/cytologie , Chimiokine CXCL12/génétique , Chimiokine CXCL12/métabolisme , Interleukine-1 bêta/métabolisme , Interleukine-1 bêta/génétique , Lipopolysaccharides/pharmacologie , Inhibiteur-1 d'activateur du plasminogène/génétique , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Rat Wistar , Facteur de nécrose tumorale alpha/métabolisme , Facteur de nécrose tumorale alpha/génétiqueRÉSUMÉ
It has been reported that immune factors are associated with the occurrence of polycystic ovary syndrome (PCOS). Interleukin-1 (IL-1) is a member of the interleukin family that widely participates in the regulation of the inflammatory response in the immune system. In addition, it has been reported that aberrant IL-1 accumulation in serum is associated with the occurrence of PCOS. However, little is known about how IL-1 participates in the pathogenesis of PCOS. In the present study, we demonstrated that the immune microenvironment was altered in follicular fluid from PCOS patients and that the expression levels of two IL-1 cytokines, IL-1α and IL-1ß were increased. Transcriptome analysis revealed that IL-1α and IL-1ß treatment induced primary human granulosa-lutein (hGL) cell inflammatory response and increased the expression of serpin family E member 1 (SERPINE1). Mechanistically, we demonstrated that IL-1α and IL-1ß upregulated SERPINE1 expression through IL-1R1-mediated activation of downstream P50 and P52 signaling pathways in human granulosa cells. Our study highlighted the role of immune state changes in the occurrence of PCOS and provided new insight into the treatment of patients with IL-1-induced ovarian function disorders.
Sujet(s)
Cellules de la granulosa , Interleukine-1 , Cellules lutéales , Inhibiteur-1 d'activateur du plasminogène , Syndrome des ovaires polykystiques , Transduction du signal , Humains , Femelle , Inhibiteur-1 d'activateur du plasminogène/génétique , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Cellules lutéales/métabolisme , Cellules lutéales/effets des médicaments et des substances chimiques , Syndrome des ovaires polykystiques/métabolisme , Syndrome des ovaires polykystiques/génétique , Interleukine-1/métabolisme , Interleukine-1/génétique , Cellules de la granulosa/métabolisme , Cellules de la granulosa/effets des médicaments et des substances chimiques , Interleukine-1 bêta/métabolisme , Adulte , Liquide folliculaire/métabolisme , Interleukine-1 alpha/métabolisme , Interleukine-1 alpha/génétique , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Récepteur à l'interleukine-1 de type I/génétique , Récepteur à l'interleukine-1 de type I/métabolisme , Cellules cultivéesRÉSUMÉ
The most prevalent glycoprotein on the influenza virus envelope is called hemagglutinin (HA), yet little is known about its involvement in the pathophysiology and etiology of severe influenza pneumonia. Here, after stimulating human bronchial epithelial cells (16-HBE) and mice with HA of H1N1 for 12 h, we investigated the proliferation, migration, inflammatory cytokines expression, and apoptosis in 16-HBE and the pathological damage in mouse lung tissue. The expression of inflammatory cytokines plasminogen activator inhibitor 1(PAI-1), urokinase-type (uPA) and tissue-type (tPA) plasminogen activators, and apoptosis were all enhanced by HA, which also prevented the proliferation and migration of bronchial epithelial cells. HA enhanced up-regulated PAI-1, uPA, and tPA protein expression within mouse lung tissue and caused lung injury. In conclusion, HA alone, but not the whole H1N1 virus, induces lung tissue injury by inhibiting cell proliferation and migration, while promoting the expression of inflammatory cytokines and apoptosis.
Sujet(s)
Apoptose , Prolifération cellulaire , Glycoprotéine hémagglutinine du virus influenza , Sous-type H1N1 du virus de la grippe A , Animaux , Humains , Souris , Glycoprotéine hémagglutinine du virus influenza/métabolisme , Glycoprotéine hémagglutinine du virus influenza/génétique , Mouvement cellulaire , Cytokines/métabolisme , Cellules épithéliales/métabolisme , Cellules épithéliales/virologie , Poumon/métabolisme , Poumon/virologie , Poumon/anatomopathologie , Lignée cellulaire , Pneumopathie virale/virologie , Pneumopathie virale/métabolisme , Pneumopathie virale/anatomopathologie , Grippe humaine/métabolisme , Grippe humaine/virologie , Activateur du plasminogène de type urokinase/génétique , Activateur du plasminogène de type urokinase/métabolisme , Infections à Orthomyxoviridae/métabolisme , Infections à Orthomyxoviridae/virologie , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Inhibiteur-1 d'activateur du plasminogène/génétique , Pneumopathie infectieuse/métabolisme , Pneumopathie infectieuse/virologieRÉSUMÉ
Background: Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy. Methods: The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors. Results: PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression. Conclusions: PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.
Sujet(s)
Antigène CD274 , Inhibiteur-1 d'activateur du plasminogène , Échappement de la tumeur à la surveillance immunitaire , Animaux , Femelle , Humains , Souris , Antigène CD274/métabolisme , Antigène CD274/génétique , Lignée cellulaire tumorale , Régulation de l'expression des gènes tumoraux , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Échappement immunitaire , Souris de lignée C57BL , Tumeurs/immunologie , Tumeurs/métabolisme , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Inhibiteur-1 d'activateur du plasminogène/génétique , Transduction du signal , Microenvironnement tumoral/immunologieRÉSUMÉ
Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Crizotinib , Résistance aux médicaments antinéoplasiques , Tumeurs du poumon , Inhibiteur-1 d'activateur du plasminogène , Protéines proto-oncogènes c-met , Humains , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/génétique , Carcinome pulmonaire non à petites cellules/métabolisme , Carcinome pulmonaire non à petites cellules/anatomopathologie , Lignée cellulaire tumorale , Crizotinib/pharmacologie , Crizotinib/usage thérapeutique , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Inhibiteur-1 d'activateur du plasminogène/métabolisme , Inhibiteur-1 d'activateur du plasminogène/génétique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Protéines proto-oncogènes c-met/métabolisme , Protéines proto-oncogènes c-met/génétique , Protéines proto-oncogènes c-met/antagonistes et inhibiteursRÉSUMÉ
Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at determining the risk factors involved recognizes a group of "traditional" risk factors, but also more recent studies identified over 100 "novel" ones which may have a role in the disease. Among the latter is the thrombophilia profile of a patient, a pathology well-established for its involvement in venous thromboembolism, but with less studied implications in arterial thrombosis. This paper reviews the literature, explaining the pathophysiology of the thrombophilia causes associated most with coronary thrombosis events. Results of several studies on the subject, including a meta-analysis with over 60,000 subjects, determined the significant involvement of factor V Leiden, prothrombin G20210A mutation, plasminogen activator inhibitor-1 and antiphospholipid syndrome in the development of coronary artery disease. The mechanisms involved are currently at different stages of research, with some already established and used as therapeutic targets.