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1.
Lung ; 200(5): 619-631, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36107242

RESUMEN

PURPOSE: It has been shown that activation of autophagy promotes the development of pulmonary arterial hypertension (PAH). Meanwhile, forkhead box M1 (FOXM1) has been found to induce autophagy in several types of cancer. However, it is still unclear whether FOXM1 mediates autophagy activation in PAH, and detailed mechanisms responsible for these processes are indefinite. METHOD: PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) to rats. The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), percentage of medial wall thickness (%MT), α-smooth muscle actin (α-SMA) staining, and Ki67 staining were performed to evaluate the development of PAH. The protein levels of FOXM1, phospho-focal adhesion kinase (p-FAK), FAK, and LC3B were determined by immunoblotting or immunohistochemistry. RESULTS: FOXM1 protein level and FAK activity were significantly increased in MCT-induced PAH rats, this was accompanied with the activation of autophagy. Pharmacological inhibition of FOXM1 or FAK suppressed MCT-induced autophagy activation, decreased RVSP, RVHI and %MT in MCT-induced PAH rats, and inhibited the proliferation of pulmonary arterial smooth muscle cells and pulmonary vessel muscularization in MCT-induced PAH rats. CONCLUSION: FOXM1 promotes the development of PAH by inducing FAK phosphorylation and subsequent activation of autophagy in MCT-treated rats.


Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Actinas/metabolismo , Animales , Autofagia , Modelos Animales de Enfermedad , Hipertensión Pulmonar Primaria Familiar , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/metabolismo , Antígeno Ki-67/metabolismo , Monocrotalina/metabolismo , Monocrotalina/toxicidad , Fosforilación , Hipertensión Arterial Pulmonar/inducido químicamente , Arteria Pulmonar , Ratas , Ratas Sprague-Dawley
2.
J Cell Physiol ; 236(6): 4694-4708, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33283886

RESUMEN

The aims of the present study were to examine the molecular mechanisms underlying sphingosine-1-phosphate (S1P)-induced rat pulmonary artery smooth muscle cells (PASMCs) proliferation/migration and to determine the effect of yes-associated protein (YAP) activation on S1P-induced PASMCs proliferation/migration and its potential mechanisms. S1P induced YAP dephosphorylation and nuclear translocation, upregulated microRNA-130a/b (miR-130a/b) expression, reduced bone morphogenetic protein receptor 2 (BMPR2), and inhibitor of DNA binding 1(Id1) expression, and promoted PASMCs proliferation and migration. Pretreatment of cells with Rho-associated protein kinase (ROCK) inhibitor Y27632 suppressed S1P-induced YAP activation, miR-130a/b upregulation, BMPR2/Id1 downregulation, and PASMCs proliferation/migration. Knockdown of YAP using small interfering RNA also suppressed S1P-induced alterations of miR-130a/b, BMPR2, Id1, and PASMCs behavior. In addition, luciferase reporter assay indicated that miR-130a/b directly regulated BMPR2 expression in PASMCs. Inhibition of miR-130a/b functions by anti-miRNA oligonucleotides attenuated S1P-induced BMPR2/Id1 downregulation and the proliferation and migration of PASMCs. Taken together, our study indicates that S1P induces activation of YAP through ROCK signaling and subsequently increases miR-130a/b expression, which, in turn, downregulates BMPR2 and Id1 leading to PASMCs proliferation and migration.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisofosfolípidos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Esfingosina/análogos & derivados , Transporte Activo de Núcleo Celular , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Células Cultivadas , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Fosforilación , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Ratas Sprague-Dawley , Transducción de Señal , Esfingosina/farmacología , Proteínas Señalizadoras YAP , Quinasas Asociadas a rho/metabolismo
3.
Mol Cell Biochem ; 476(8): 3037-3049, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33797701

RESUMEN

Galectin-3(Gal-3) is an effective regulator in the pathological process of pulmonary arterial hypertension (PAH). However, the detailed mechanisms underlying Gal-3 contribution to PAH are not yet entirely clear. The aim of the present study was to explore these issues. Proliferation of rat pulmonary arterial smooth muscle cells (PASMCs) was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Small interfering RNA (siRNA) was applied to silence the expression of yes-associated protein (YAP) and Forkhead box M1 (FOXM1). The protein expression and phosphorylation were measured by immunoblotting. The subcellular location of YAP was determined using immunoblotting and immunofluorescence. Gal-3-stimulated PASMCs proliferation in a time- and dose-dependent manner, this was accompanied with, YAP upregulation, dephosphorylation, and nucleus translocation. Gal-3 further increased FOXM1 and cyclinD1 expression via YAP activation. Interfering YAP/FOXM1 axis suppressed Gal-3-induced PASMCs proliferation. Activation of AMPK also inhibited Gal-3-triggered cells proliferation by targeting YAP/FOXM1/cyclinD1 pathway. Gal-3 induced PASMCs proliferation by regulating YAP/FOXM1/cyclinD1 signaling cascade, and activation of AMPK targeted on this axis and suppressed Gal-3-stimulated PASMCs proliferation. Our study provides novel therapeutic targets for prevention and treatment of PAH.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proliferación Celular , Galectina 3/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Miocitos del Músculo Liso/citología , Proteínas Serina-Treonina Quinasas/metabolismo , Arteria Pulmonar/citología , Proteínas Quinasas Activadas por AMP/genética , Animales , Apoptosis , Movimiento Celular , Galectina 3/genética , Regulación de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Miocitos del Músculo Liso/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Arteria Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Señalizadoras YAP
4.
BMC Pulm Med ; 20(1): 182, 2020 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-32586317

RESUMEN

BACKGROUND: In recent years, many studies have discovered that cystatin C (Cys C) may play an important role in respiratory diseases, especially in chronic obstructive pulmonary disease (COPD). However, the findings of these studies were inconsistent. This systematic review and meta-analysis aimed to assess the relationship between serum Cys C and COPD. METHODS: We conducted a systematic literature search in PubMed, Embase, Web of Science, Wanfang databases, and the China National Knowledge Infrastructure. The standardized mean difference (SMD), Fisher's Z-value and 95% confidence interval (CI) were calculated to investigate the effect sizes. Subgroup analyses were performed on disease status, ethnicity, assay method, and study design. Sensitivity was performed, and publication bias was assessed. RESULTS: A total of 15 studies, including 4079 COPD patients and 5949 controls, were included in this meta-analysis. The results showed that serum Cys C levels in patients with COPD were significantly higher than those in controls (SMD = 0.99, 95% CI =0.62-1.37, P < 0.001), especially in AECOPD (SMD = 1.59, 95% CI =1.05-2.13, P < 0.001), and there were statistically different among AECOPD and SCOPD (SMD = 0.35, 95% CI =0.10-0.59, P = 0.005). The serum Cys C levels were negatively correlated with FEV1%pre (Z = - 0.45, 95%CI = -0.58--0.32, P = 0.011) and FEV1/FVC (Z = - 0.32, 95%CI = -0.50--0.14, P = 0.006). The serum Cys C levels were independent of ethnicity, assay method, and study design. CONCLUSION: Serum Cys C levels were associated with COPD and COPD exacerbation, and they were inversely correlated with FEV1%pre and FEV1/FVC.


Asunto(s)
Cistatina C/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/patología , Biomarcadores/sangre , Progresión de la Enfermedad , Humanos
5.
Biochem Biophys Res Commun ; 516(3): 921-927, 2019 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-31277946

RESUMEN

The upregulation of osteopontin(OPN) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells(PASMCs), and activation of PPARγ has been shown to suppress OPN expression in THP-1 cells. However, the molecular mechanisms underlying the upregulation of OPN expression and PPARγ agonist modulation of OPN expression in PASMCs remain largely unclear. Here we found that S1P stimulated PASMCs proliferation and up-regulated OPN expression in rat PASMCs, which was accompanied with the activation of phospholipase C(PLC), calcineurin and translocation of NFATc3 to nucleus. Further study showed that inhibition of PLC by U73122, suppression of calcineurin activity by cyclosporine A(CsA) or knockdown of NFATc3 using small interfering RNA suppressed S1P-induced OPN up-regulation. Activation of PPARγ by pioglitazone suppressed S1P-induced activation of calcineurin/NFATc3 signaling pathway and followed OPN up-regulation. Taken together, our study indicates that S1P stimulates OPN expression by activation of PLC/calcineurin/NFATc3 signaling pathway, and activation of PPARγ suppresses calcineurin/NFATc3-mediated OPN expression in PASMCs.


Asunto(s)
Calcineurina/genética , Lisofosfolípidos/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Factores de Transcripción NFATC/genética , Osteopontina/genética , Transducción de Señal/efectos de los fármacos , Esfingosina/análogos & derivados , Animales , Calcineurina/metabolismo , Calcio/metabolismo , Cationes Bivalentes , Proliferación Celular/efectos de los fármacos , Ciclosporina/farmacología , Estrenos/farmacología , Femenino , Regulación de la Expresión Génica , Transporte Iónico , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Factores de Transcripción NFATC/antagonistas & inhibidores , Factores de Transcripción NFATC/metabolismo , Osteopontina/metabolismo , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , PPAR gamma/metabolismo , Pioglitazona/farmacología , Cultivo Primario de Células , Arteria Pulmonar/citología , Arteria Pulmonar/metabolismo , Pirrolidinonas/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Esfingosina/farmacología , Fosfolipasas de Tipo C/antagonistas & inhibidores , Fosfolipasas de Tipo C/genética , Fosfolipasas de Tipo C/metabolismo
6.
Exp Cell Res ; 371(2): 379-388, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30180991

RESUMEN

Up-regulation of mammalian COP9 signalosome subunit 6 (CSN6) and consequent reduction of SCF ubiquitin ligase substrate receptor ß-transduction repeat-containing protein (ß-TrCP) have been shown to be associated with cancer cells proliferation. However, it is unclear whether CSN6 and ß-TrCP are also involved in PDGF-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study aims to address this issue and further explore its potential mechanisms. Our results indicated that PDGF phosphorylated Akt, stimulated PASMCs proliferation; while inhibition of PDGF receptor (PDGFR) by imatinib prevented these effects. PDGF further up-regulated CSN6 protein expression, this was accompanied with ß-TrCP reduction and increase of Cdc25A. Inhibition of PDGFR/PI3K/Akt signaling pathway reversed PDGF-induced such changes and cell proliferation. Prior transfection of CSN6 siRNA blocked PDGF-induced ß-TrCP down-regulation, Cdc25A up-regulation and cell proliferation. Furthermore, pre-treatment of cells with MG-132 also abolished PDGF-induced ß-TrCP reduction, Cdc25A elevation and cell proliferation. In addition, pre-depletion of Cdc25A by siRNA transfection suppressed PDGF-induced PASMCs proliferation. Taken together, our study indicates that up-regulation of CSN6 by PDGFR/PI3K/Akt signaling pathway decreases ß-TrCP by increasing its ubiquitinated degradation, and thereby increases the expression of Cdc25A, which promotes PDGF-induced PASMCs proliferation.


Asunto(s)
Complejo del Señalosoma COP9/genética , Miocitos del Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Factor de Crecimiento Derivado de Plaquetas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Complejo del Señalosoma COP9/antagonistas & inhibidores , Complejo del Señalosoma COP9/metabolismo , Proliferación Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Regulación de la Expresión Génica , Mesilato de Imatinib/farmacología , Leupeptinas/farmacología , Masculino , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Factor de Crecimiento Derivado de Plaquetas/farmacología , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/metabolismo , Arteria Pulmonar/citología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal , Proteínas con Repetición de beta-Transducina/genética , Proteínas con Repetición de beta-Transducina/metabolismo , Fosfatasas cdc25/genética , Fosfatasas cdc25/metabolismo
7.
J Cell Physiol ; 234(1): 669-681, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-30132829

RESUMEN

The aims of the current study were to examine the signaling mechanisms for transforming growth factor-ß1 (TGF-ß1)-induced rat airway smooth muscle cell (ASMC) proliferation and to determine the effect of activation of peroxisome proliferation-activated receptor-γ (PPAR-γ) on TGF-ß1-induced rat ASMC proliferation and its underlying mechanisms. TGF-ß1 upregulated microRNA 21 (miR-21) expression by activating Smad2/3, and this in turn downregulated forkhead box O1 (FOXO1) mRNA expression. In addition, TGF-ß1-Smad-miR-21 signaling also downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and thus de-repressed the PI3K-Akt pathway. Depletion of PTEN reduced the nuclear FOXO1 protein level without affecting its mRNA level. Inhibition of the PI3K-Akt pathway or proteasome function reversed PTEN knockdown-induced nuclear FOXO1 protein reduction. Our study further showed that loss of FOXO1 increased cyclin D1 expression, leading to rat ASMC proliferation. Preincubation of rat ASMCs with pioglitazone, a PPAR-γ activator, blocked TGF-ß1-induced activation of Smad2/3 and its downstream targets changes of miR-21, PTEN, Akt, FOXO1, and cyclin D1, resulting in the inhibition of rat ASMC proliferation. Our study suggests that the activation of PPAR-γ inhibits rat ASMC proliferation by suppressing Smad-miR-21 signaling and therefore has a potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.


Asunto(s)
Bronquios/citología , MicroARNs/genética , PPAR gamma/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Bronquios/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclina D1/genética , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Proteínas del Tejido Nervioso , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasas/genética , Pioglitazona/farmacología , Cultivo Primario de Células , Complejo de la Endopetidasa Proteasomal/genética , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Transducción de Señal , Proteína Smad2/genética
8.
Am J Physiol Lung Cell Mol Physiol ; 315(4): L609-L621, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-29999407

RESUMEN

Sphingosine-1-phosphate (S1P), a bioactive lipid, has been shown to be elevated in the airways of individuals with asthma and modulates the airway smooth muscle cell (ASMC) functions, yet its underlying molecular mechanisms are not completely understood. The aim of the present study is to address this issue. S1P induced yes-associated protein (YAP) dephosphorylation and nuclear localization via the S1PR2/3/Rho-associated protein kinase (ROCK) pathway, and this in turn increased forkhead box M1 (FOXM1) and cyclin D1 expression leading to ASMC proliferation, migration, and contraction. Pretreatment of cells with S1PR2 antagonist JTE013, S1PR3 antagonist CAY10444, or ROCK inhibitor Y27632 blocked S1P-induced alterations of YAP, FOXM1, cyclin D1, and ASMC proliferation, migration, and contraction. In addition, prior silencing of YAP or FOXM1 with siRNA reversed the effect of S1P on ASMC functions. Taken together, our study indicates that S1P stimulates ASMC proliferation, migration, and contraction by binding to S1PR2/3 and modulating ROCK/YAP/FOXM1 axis and suggests that targeting this pathway might have potential value in the management of asthma.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Lisofosfolípidos/farmacología , Miocitos del Músculo Liso/patología , Transducción de Señal/efectos de los fármacos , Esfingosina/análogos & derivados , Animales , Proteínas Reguladoras de la Apoptosis/genética , Células Cultivadas , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/metabolismo , Esfingosina/farmacología , Receptores de Esfingosina-1-Fosfato , Proteínas Señalizadoras YAP , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo
9.
Med Sci Monit ; 23: 4612-4618, 2017 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-28947730

RESUMEN

BACKGROUND Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) aggravates the overall severity in COPD patients, resulting in severe morbidity and mortality. However, there are no objective biomarkers currently available to predict the development of AECOPD. Several studies have indicated that galectin-3 (Gal-3) is involved in diseases characterized by excessive inflammatory response and fibrosis. The objective of this study was to examine the dynamic changes of Gal-3 in acute exacerbation and convalescence phases of COPD. MATERIAL AND METHODS Serum levels of Gal-3, high sensitivity C-reactive protein (hsCRP), and prohormone of brain natriuretic peptide (pro-BNP) were determined using multiplex enzyme-linked immunosorbent assay kits. Serum levels of Gal-3 in 44 patients with COPD were further analyzed and correlated with the parameters of lung function and the biomarkers of systemic inflammation. RESULTS The mean level of serum Gal-3 was significantly higher in acute exacerbation of COPD compared with the level in COPD convalescence phase (32.10±9.83 versus 29.02±8.68 ng/mL, p<0.01). Serum levels of Gal-3 positively correlated with hsCRP (r=0.354, p=0.018 for total patients) and pro-BNP (r=0.319, p=0.035 for total patients) in AECOPD. In addition, the level of Gal-3 was the highest in the current smoker group, and the lowest in the never-smoker group in either the acute exacerbation phase (33.91±3.55 versus 29.12±11.73 ng/mL, p=0.036) or the convalescence phase (30.94±3.40 versus 27.76±9.68 ng/mL, p=0.045) of COPD. CONCLUSIONS Our results indicated that serum Gal-3 is increased in AECOPD patients, which is also positively associated with systemic inflammation and smoking in patients with COPD, suggesting that Gal-3 might be a valuable biomarker for AECOPD.


Asunto(s)
Progresión de la Enfermedad , Galectina 3/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/patología , Anciano , Proteínas Sanguíneas , Proteína C-Reactiva/metabolismo , Femenino , Galectinas , Humanos , Masculino , Péptido Natriurético Encefálico/sangre , Fumar/efectos adversos
10.
BMC Pulm Med ; 17(1): 193, 2017 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-29233108

RESUMEN

BACKGROUND: Previous studies have indicated that chitinase 3-like 1 (CHI3L1) gene rs4950928 polymorphism and acidic mammalian chitinase (AMCase or CHIA) gene rs10494132 polymorphism are associated with the risk of asthma. However, the results are inconsistent because of small sample size and varied ethnicity and age in studies. Therefore, a systematic meta-analysis was important to clarify the effect of CHI3L1 rs4950928 polymorphism and CHIA rs10494132 variant on asthma risk. METHODS: An electronic literature search was conducted to identify all the eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and sensitivity analysis as well as publication bias were assessed to investigate the associations. All statistical analyses were performed using STATA 12.0. RESULTS: Eight published articles with 10 case-control studies were included, 5 studies were of CHI3L1 rs4950928 polymorphism and another 5 studies involved CHIA rs10494132 polymorphism. Overall, no significant association was found between CHI3L1 polymorphism and asthma susceptibility. After stratified according to ethnicity, CHI3L1 rs4950928 variant was associated with decreased asthma risk in Caucasians (GG + GC vs. CC: OR = 0.621, 95% CI = 0.484-0.797, P = 0.000; GC vs. CC: OR = 0.612, 95% CI = 0.470-0.796, P = 0.000; G vs. C: OR = 0.696, 95% CI = 0.567-0.856, P = 0.001). When stratified population by age, there was no association in children under all genetic models. As for CHIA rs10494132 polymorphism, no evidence of association between CHIA rs10494132 polymorphism and asthma risk was identified. Furthermore, subgroup analysis by ethnicity revealed a positive correlation between CHIA rs10494132 polymorphism and asthma risk among Asians (TT vs. TC + CC: OR = 1.476, 95% CI = 1.071-2.032, P = 0.017; T vs. C: OR = 1.326, 95% CI = 1.024-1.717, P = 0.032). Additionally, in the subgroup analysis conducted according to age, CHIA rs10494132 variant was also found to be associated with the increased risk of asthma in children (TT vs. TC + CC: OR = 1.472, 95% CI = 1.067-2.030, P = 0.019; T vs. C: OR = 1.320, 95% CI = 1.016-1.713, P = 0.037). CONCLUSIONS: The G allele of CHI3L1 rs4950928 might be a protective factor against the development of asthma. However, the rs10494132 polymorphism of CHIA might be a risk factor for asthma.


Asunto(s)
Asma , Proteína 1 Similar a Quitinasa-3/genética , Quitinasas/genética , Asma/genética , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Factores Protectores
11.
Inflamm Res ; 64(11): 875-83, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26289094

RESUMEN

OBJECTIVE: The Val66Met polymorphisms in brain-derived neurotrophic factor (BDNF) gene have been reported to be associated with asthma risk, while the results are inconclusive. Considering a single study may lack the power to provide reliable conclusion, we performed a meta-analysis to investigate the association between the Val66Met polymorphisms and asthma susceptibility. METHODS: A comprehensive literature search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases was conducted before February 12, 2015. The pooled odds ratio (OR) with 95 % confidence intervals (CIs) were calculated. RESULTS: Six eligible studies with a total of 3501 subjects were finally included in this meta-analysis. Overall, a significantly increased risk was detected in the Val66Met G allele (G vs. A: OR 1.33, 95 % CI 1.19-1.49, P = 5.61E-07; GG vs. GA + AA: OR 1.48, 95 % CI 1.20-1.83, P = 3.14E-04; GG vs. GA: OR 1.48, 95 % CI 1.17-1.89, P = 0.001; GG vs. AA: OR 1.62, 95 % CI 1.20-2.19, P = 0.002). Moreover, stratification by ethnicity indicated marked association between the Val66Met G allele and asthma risk in Caucasians (G vs. A: OR 1.29, 95 % CI 1.12-1.49, P = 0.001; GG + GA vs. AA: OR 1.59, 95 % CI 1.03-2.46, P = 0.039; GG vs. GA + AA: OR 1.32, 95 % CI 1.11-1.57, P = 0.001; GG vs. GA: OR 1.28, 95 % CI 1.07-1.53, P = 0.007; GG vs. AA: OR 1.72, 95 % CI 1.11-2.68, P = 0.015). CONCLUSION: Our present meta-analysis suggests that the Val66Met polymorphisms in BDNF gene are potentially associated with asthma risk in Caucasians. Further well-designed case-control studies with larger sample size and more ethnic groups are needed to confirm these conclusions.


Asunto(s)
Asma/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo Genético
12.
Exp Lung Res ; 41(8): 435-43, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26317171

RESUMEN

It has been shown that activation of Notch3 signaling is involved in the development of pulmonary arterial hypertension (PAH) by stimulating pulmonary arteries remodeling, while the molecular mechanisms underlying this are still largely unknown. The aims of this study are to address these issues. Monocrotaline dramatically increased right ventricle systolic pressure to 39.0 ± 2.6 mmHg and right ventricle hypertrophy index to 53.4 ± 5.3% (P < 0.05 versus control) in rats, these were accompanied with significantly increased proliferation and reduced apoptosis of pulmonary vascular cells as well as pulmonary arteries remodeling. Treatment of PAH model with specific Notch inhibitor DAPT significantly reduced right ventricle systolic pressure to 26.6 ± 1.3 mmHg and right ventricle hypertrophy index to 33.5 ± 2.6% (P < 0.05 versus PAH), suppressed proliferation and enhanced apoptosis of pulmonary vascular cells as well as inhibited pulmonary arteries remodeling. Our results further indicated that level of Notch3 protein and NICD3 were increased in MCT-induced model of PAH, this was accompanied with elevation of Skp2 and Hes1 protein level and reduction of P27Kip1. Administration of rats with DAPT-prevented MCT induced these changes. Our results suggest that Notch3 signaling activation stimulated pulmonary vascular cells proliferation by Skp2-and Hes1-mediated P27Kip1 reduction, and Notch3 might be a new target to treat PAH.


Asunto(s)
Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Monocrotalina/farmacología , Arteria Pulmonar/metabolismo , Receptores Notch/antagonistas & inhibidores , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Hipertrofia Ventricular Derecha/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Arteria Pulmonar/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor Notch3 , Transducción de Señal/efectos de los fármacos
13.
J Invest Dermatol ; 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38580105

RESUMEN

IL-6 signaling plays a crucial role in the survival and metastasis of skin cancer. NEDD4L acts as a suppressor of IL-6 signaling by targeting GP130 degradation. However, the effects of the NEDD4L-regulated IL-6/GP130 signaling pathway on skin cancer remain unclear. In this study, protein expression levels of NEDD4L and GP130 were measured in tumor tissues from patients with cutaneous squamous cell carcinoma. Skin tumors were induced in wild-type and Nedd4l-knockout mice, and activation of the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway was detected. The results indicated a negative correlation between the protein expression levels of NEDD4L and GP130 in cutaneous squamous cell carcinoma tissues from patients. Nedd4l deficiency significantly promoted 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin tumorigenesis and benign-to-malignant conversion by activating the IL-6/GP130/signal transducer and activator of transcription 3 signaling pathway, which was abrogated by supplementation with the GP130 inhibitor SC144. Furthermore, our findings suggested that NEDD4L can interact with GP130 and promote its ubiquitination in skin tumors. In conclusion, our results indicate that NEDD4L could act as a tumor suppressor in skin cancer, and inhibition of GP130 could be a potential therapeutic method for treating this disease.

14.
Pulm Circ ; 11(4): 20458940211046131, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34552711

RESUMEN

Pulmonary arterial hypertension is a devastating pulmonary vascular disease, in which the pathogenesis is complicated and unclear. Pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathological feature of pulmonary arterial hypertension. It has been shown that ubiquitin-specific protease 7 (USP7) is involved in cancer cell proliferation via deubiquitinating and stabilizing E3 ubiquitin ligase mouse double minute 2 (MDM2). However, the effect of USP7 and MDM2 on platelet-derived growth factor (PDGF)-induced PASMCs proliferation is uncertain. This study aims to explore this issue. Our results indicated that PDGF up-regulated USP7 protein expression and stimulated PASMCs proliferation; this was accompanied with the increase of MDM2, forkhead box O4 (FoxO4) reduction and elevation of CyclinD1. While prior transfection of USP7 siRNA blocked PDGF-induced MDM2 up-regulation, FoxO4 down-regulation, increase of CyclinD1 and cell proliferation. Pre-depletion of MDM2 by siRNA transfection reversed PDGF-induced reduction of FoxO4, up-regulation of CyclinD1 and PASMCs proliferation. Furthermore, pre-treatment of cells with proteasome inhibitor MG-132 also abolished PDGF-induced FoxO4 reduction, CyclinD1 elevation and cell proliferation. Our study suggests that USP7 up-regulates MDM2, which facilitates FoxO4 ubiquitinated degradation, and subsequently increases the expression of CyclinD1 to mediate PDGF-induced PASMCs proliferation.

15.
Am J Manag Care ; 27(2): e36-e41, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33577159

RESUMEN

OBJECTIVES: This study aimed to evaluate factors affecting adherence to inhaled therapy in patients with asthma to further identify the determinants most closely associated with adherence to inhaled therapy for asthma, especially inhaled glucocorticosteroids (ICS). STUDY DESIGN: A 2-stage study was conducted. In stage 1, we performed nonassumptive deep-dive qualitative scoping to investigate the determinants of poor adherence in patients with asthma, and in stage 2 we developed a new questionnaire for cross-sectional surveys to obtain more accurate information about critical issues related to asthma management. METHODS: Patients with asthma who were 18 years and older in the outpatient clinic of The First Affiliated Hospital of Xi'an Jiaotong University from November 2016 to January 2018 were investigated. RESULTS: In the 350 patients with asthma recruited, 32% of patients showed good adherence, whereas 68% of patients displayed poor adherence to inhaled therapy due to various reasons. Further analysis indicated that inadequate understanding of asthma treatment and control, poor self-management, financial burden, adverse reactions, and the fear of potential adverse reactions were significant independent risk factors for poor ICS inhalation adherence in patients with asthma. CONCLUSIONS: Our research shows that many patients with asthma in western China have poor disease control and poor inhalation therapy adherence. We hope this research can alert clinicians and help them identify patients who may be experiencing uncontrolled asthma due to poor adherence to inhaled therapy, and we suggest that clinicians help those patients obtain appropriate information about asthma control and self-management.


Asunto(s)
Corticoesteroides , Asma , Administración por Inhalación , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Estudios Transversales , Humanos , Cumplimiento de la Medicación
16.
Front Cell Infect Microbiol ; 11: 541092, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33777827

RESUMEN

Background: Metagenomic next-generation sequencing (mNGS) is a powerful method for pathogen detection. In this study, we assessed the value of mNGS for bronchoalveolar lavage (BAL) samples in the diagnosis of pulmonary infections. Methods: From February 2018 to April 2019, BAL samples were collected from 235 patients with suspected pulmonary infections. mNGS and microbial culture were performed to evaluate the effectiveness of mNGS in pulmonary infection diagnosis. Results: We employed mNGS to evaluate the alpha diversity, results suggesting that patients with confirmed pathogens had a lower microbial diversity index compared to that of patients with uncertain pathogens. For the patients admitted to the respiratory intensive care unit (RICU) or on a ventilator, they experienced a lower diversity index than that of the patients in the general ward or not on a ventilator. In addition, mNGS of BAL had a diagnostic sensitivity of 88.89% and a specificity of 14.86% in pulmonary infection, with 21.16% positive predictive value (PPV) and 83.87% negative predictive value (NPV). When rare pathogens were excluded, the sensitivity of mNGS decreased to 73.33%, and the specificity increased to 41.71%. For patients in the simple pulmonary infection group and the immunocompromised group, the main infection types were bacterial infection (58.33%) and mixed-infection (43.18%). Furthermore, mNGS had an advantage over culture in describing polymicrobial ecosystem, demonstrating the microbial distribution and the dominant strains of the respiratory tract in patients with different underlying diseases. Conclusions: The study indicated that mNGS of BAL samples could provide more accurate diagnostic information in pulmonary infections and demonstrate the changes of respiratory microbiome in different underlying diseases. This method might play an important role in the clinical use of antimicrobial agents in the future.


Asunto(s)
Ecosistema , Metagenómica , Lavado Broncoalveolar , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Sensibilidad y Especificidad
17.
Life Sci ; 242: 117159, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31837334

RESUMEN

AIMS: It has been shown that up-regulation of E3 ubiquitin ligase seven-in-absentia-homolog 2 (Siah2) and activation of Hippo signaling pathway effector yes-associated protein (YAP) are involved in the development of pulmonary arterial hypertension (PAH). However, it is still unclear whether Siah2 activates YAP in monocrotaline (MCT)-induced PAH rat models. MAIN METHODS: Intraperitoneal injection of MCT was used to induce PAH rat models. The right ventricular systolic pressure (RVSP), right ventricle hypertrophy index (RVHI), percentage of medial wall thickness (%MT), α-SMA, Ki-67 and TUNEL staining were performed to evaluate the development of PAH. Protein levels of Siah2, Lats1/2, YAP phosphorylation and total YAP, and the subcellular localization of YAP were examined using immunoblotting. Proteasome activity was measured by an assay kit. KEY FINDINGS: The protein level of Siah2 was significantly increased in MCT-induced PAH rats, this was accompanied with the proteasome-dependent degradation of Lats1/2 and subsequent up-regulation and dephosphorylation of YAP and its nuclear localization. Administration of PAH rats with Siah2 inhibitor Vitamin K3 or proteasome inhibitor MG-132 dramatically suppressed MCT-induced down-regulation of Lats1/2 and activation of YAP, finally reduced RVSP, RVHI, %MT, pulmonary arterial muscularization, pulmonary arterial smooth muscle cells (PASMCs) proliferation and enhanced PASMCs apoptosis in PAH rats. SIGNIFICANCE: Siah2 contributes to the development of MCT-induced PAH by destabilizing Lats1/2 and subsequently stimulating YAP activation. Inhibition of Siah2 or proteasome alleviates pulmonary arterial remodeling through inactivation of YAP, indicating Siah2 ubiquitin ligase as a novel target might have potential value in the management of PAH.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Monocrotalina/farmacología , Proteínas Nucleares/fisiología , Hipertensión Arterial Pulmonar/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Remodelación Vascular/efectos de los fármacos , Animales , Proteínas Reguladoras de la Apoptosis/fisiología , Immunoblotting , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiología , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Remodelación Vascular/fisiología , Proteínas Señalizadoras YAP
18.
Eur J Pharmacol ; 884: 173302, 2020 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-32659302

RESUMEN

It has been shown that sphingosine-1-phosphate (S1P) is elevated in patients with pulmonary arterial hypertension (PAH) and promotes the proliferation of pulmonary artery smooth muscle cells (PASMCs). Meanwhile, S1P has been found to induce the activation of autophagy in several types of human diseases including cancers. However, it is still unclear whether activation of autophagy mediates S1P-induced PASMCs proliferation, and detailed mechanisms responsible for these processes are indefinite. The aims of this study are to address these issues. S1P dose- and time-dependently reduced the expression of E-cadherin/CDH1 and stimulated PASMCs proliferation; this was accompanied with the elevation of TNF receptor-associated factor 2 (TRAF2), up-regulation and ubiquitination of BECN1 and the activation of autophagy. Prior silencing TRAF2 or BECN1 using siRNA or pre-incubation of cells with autophagy inhibitor chloroquine phosphate (CQ) suppressed S1P-induced autophagy activation and subsequent CDH1 degradation and further PASMCs proliferation. Taken together, our study indicates that S1P promotes the activation of autophagy by accelerating TRAF2-mediated BECN1 up-regulation and ubiquitination, which in turn results in CDH1 reduction and contributes to PASMCs proliferation.


Asunto(s)
Autofagia/efectos de los fármacos , Cadherinas/metabolismo , Proliferación Celular/efectos de los fármacos , Lisofosfolípidos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Esfingosina/análogos & derivados , Animales , Beclina-1/genética , Beclina-1/metabolismo , Cadherinas/genética , Células Cultivadas , Regulación hacia Abajo , Masculino , Músculo Liso Vascular/metabolismo , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Ratas Sprague-Dawley , Transducción de Señal , Esfingosina/farmacología , Factor 2 Asociado a Receptor de TNF/genética , Factor 2 Asociado a Receptor de TNF/metabolismo , Ubiquitinación
19.
Eur J Pharmacol ; 867: 172823, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31770525

RESUMEN

Leukotriene B4 (LTB4) has been found to contribute to pulmonary arterial smooth muscle cells (PASMCs) proliferation and pulmonary arterial remodeling therefore the development of pulmonary arterial hypertension (PAH). Yet, the underlying molecular mechanisms remain poorly understood. The present study aims to address this issue. Our results demonstrate that LTB4 dose- and time-dependently induced proliferation of primary cultured rat PASMCs, this was accompanied with the activation of phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, and consequent inactivation of glycogen synthase kinase-3ß (GSK-3ß), up-regulation of ß-catenin and induction of cyclin D1 expression. The presence of PI3K inhibitor (LY294002) or MEK inhibitor (U0126) or prior silencing of ß-catenin with siRNA suppressed LTB4-induced cyclin D1 up-regulation and PASMCs proliferation. In addition, inactivation or lack of GSK-3ß up-regulated ß-catenin and cyclin D1 in PASMCs. Taken together, our study indicates that activation of PI3K/Akt and ERK1/2 pathways mediates LTB4-induced PASMCs proliferation by modulating GSK-3ß/ß-catenin/cyclin D1 axis and suggests that targeting this pathway might have potential value in alleviating vascular remodeling and benefit PAH.


Asunto(s)
Hipertensión Pulmonar/inmunología , Leucotrieno B4/inmunología , Miocitos del Músculo Liso/patología , Arteria Pulmonar/patología , Remodelación Vascular/inmunología , Animales , Butadienos/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cromonas/farmacología , Ciclina D1/inmunología , Ciclina D1/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Hipertensión Pulmonar/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Morfolinas/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/inmunología , Nitrilos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/inmunología , Cultivo Primario de Células , Arteria Pulmonar/inmunología , Arteria Pulmonar/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Remodelación Vascular/efectos de los fármacos , beta Catenina/genética , beta Catenina/metabolismo
20.
Artif Cells Nanomed Biotechnol ; 47(1): 3315-3321, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31385542

RESUMEN

Objective: The long intergenic non-coding RNA 01296 (LINC01296) has been reported to be overexpressed in multiple tumours. However, the role of LINC01296 in clinicopathologic and prognostic value in cancers remains completely unknown. The aim of the present meta-analysis was to comprehensively elucidate the correlation between LINC01296 with clinicopathological features and survival outcomes in tumours. Methods: Electronic databases of PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Database were used to search relevant studies. The role of LINC01296 in cancers was evaluated by pooled hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (CIs). Results: In total, nine studies compromising 720 participants were enrolled in this analysis. The pooled results showed increased LINC01296 expression could predict unfavourable overall survival (OS) (HR = 1.89, 95%CI = 1.47-2.43, p < .001). Additionally, elevated LINC01296 expression was correlated with clinical stage (OR = 2.95, 95%CI = 2.13-4.08, p < .001), lymph node metastasis (OR = 2.76, 95%CI = 2.00-3.81, p < .001), tumour size (OR = 2.80, 95%CI = 1.77-4.41, p < .001), and tumour differentiation (OR = 2.11, 95%CI = 1.36-3.27, p < .001) in patients with cancers. Conclusion: The results of this meta-analysis indicated LINC01296 was a novel biomarker for prognosis and clinicopathological parameters in cancers.


Asunto(s)
Neoplasias/diagnóstico , Neoplasias/genética , ARN Largo no Codificante/genética , Humanos , Neoplasias/patología , Pronóstico , Análisis de Supervivencia
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