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Substance P (SP), encoded by the Tac1 gene, has been shown to promote leukocyte infiltration and organ impairment in mice with sepsis. Neurokinin-1 receptor (NK1R) is the major receptor that mediates the detrimental impact of SP on sepsis. This investigation studied whether SP affects the expression of adhesion molecules, including intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) on vascular endothelial cells in the liver and lungs, contributing to leukocyte infiltration in these tissues of mice with sepsis. Sepsis was induced by caecal ligation and puncture (CLP) surgery in mice. The actions of SP were inhibited by deleting the Tac1 gene, blocking NK1R, or combining these two methods. The activity of myeloperoxidase and the concentrations of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, were measured. The activity of myeloperoxidase and the concentration of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, increased in mice with CLP surgery-induced sepsis. Suppressing the biosynthesis of SP and its interactions with NK1R attenuated CLP surgery-induced alterations in the liver and lungs of mice. Our findings indicate that SP upregulates the expression of ICAM1 and VCAM1 on vascular endothelial cells in the liver and lungs, thereby increasing leukocyte infiltration in these tissues of mice with CLP surgery-induced sepsis by activating NK1R.
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Células Endoteliais , Molécula 1 de Adesão Intercelular , Fígado , Pulmão , Receptores da Neurocinina-1 , Sepse , Substância P , Molécula 1 de Adesão de Célula Vascular , Animais , Sepse/metabolismo , Sepse/patologia , Camundongos , Substância P/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Fígado/metabolismo , Fígado/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Molécula 1 de Adesão Intercelular/genética , Células Endoteliais/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-1/genética , Masculino , Leucócitos/metabolismo , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Modelos Animais de DoençasRESUMO
Substance P (SP), encoded by the TAC1/Tac1 gene, acts as a significant mediator in dysregulated systemic inflammatory response and associated organ injury in sepsis by activating the neurokinin-1 receptor (NK1R). This study investigated the impact of SP-NK1R signaling on ferroptosis in the liver and lungs of mice with sepsis. Sepsis was induced by caecal ligation puncture (CLP) surgery in mice. The SP-NK1R signaling was suppressed by Tac1 gene deletion, NK1R blockade, and a combination of these two approaches. The physiological conditions of mice were recorded. The profile of the SP-NK1R cascade, inflammatory response, ferroptosis, and tissue histology were investigated in the liver and lungs. Several manifestations of sepsis occurred in Tac1+/+ mice during the development of sepsis. Notably, hypothermia became significant four hours after the induction of sepsis. In the liver and lungs of mice subjected to CLP surgery, the concentrations of SP and NK1R were upregulated. Additionally, the concentrations of pro-inflammatory mediators, including cytokines (IL-1ß, IL-6, and TNF-α) and chemokines (MCP-1 and MIP-2), were increased. Moreover, ferroptosis was elevated, as evidenced by increased concentrations of iron and MDA and reduced concentrations of GSH, Nrf2, and Gpx4. Suppressing the SP-NK1R cascade significantly mitigated CLP-surgery-induced alterations in mice. Importantly, these three approaches used to suppress SP-NK1R signaling showed similar effects on protecting mice against sepsis. In conclusion, increased SP-mediated acute inflammatory response and injury in the liver and lungs in mice with CLP-surgery-induced sepsis was associated with elevated ferroptosis. The detrimental effect of SP on sepsis was predominantly mediated by NK1R. Therefore, the suppression of increased SP-NK1R signaling and ferroptosis may be a promising adjuvant therapeutic candidate for sepsis and associated acute liver and lung injury.
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INTRODUCTION: Methylmalonic acidemia (MMA) is a disorder of autosomal recessive inheritance, with an estimated prevalence of 1:50,000. First-tier clinical diagnostic tests often return many false positives [five false positive (FP): one true positive (TP)]. In this work, our goal was to refine a classification model that can minimize the number of false positives, currently an unmet need in the upstream diagnostics of MMA. METHODS: We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction. We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients, followed by additional ratio feature construction. Feature selection strategies (selection by filter, recursive feature elimination, and learned vector quantization) were used to determine the input set for evaluating the performance of 14 classification models to identify a candidate model set for an ensemble model development. RESULTS: Our work identified computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity. The best results [area under the receiver operating characteristic curve (AUROC) of 97%, sensitivity of 92%, and specificity of 95%] were obtained utilizing an ensemble of the algorithms random forest, C5.0, sparse linear discriminant analysis, and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor. The model achieved a good performance trade-off for a screening application with 6% false-positive rate (FPR) at 95% sensitivity, 35% FPR at 99% sensitivity, and 39% FPR at 100% sensitivity. CONCLUSIONS: The classification results and approach of this research can be utilized by clinicians globally, to improve the overall discovery of MMA in pediatric patients. The improved method, when adjusted to 100% precision, can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families.
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Purpose: To evaluate the degree of lung hyperinflation (LH) in patients with stable chronic obstructive pulmonary disease (COPD) by lung ultrasound score (LUS) and assess its value. Patients and Methods: We conducted a study of 149 patients with stable COPD and 100 healthy controls recruited by the Second Affiliated Hospital of Fujian Medical University. The pleural sliding displacement (PSD) was measured, the sliding of the pleura in different areas was observed, and LUS was calculated from both of them. The diaphragm excursion (DE), residual capacity (RV), total lung capacity (TLC), inspiratory capacity (IC) and functional residual capacity (FRC) were measured. We described the correlation between ultrasound indicators and pulmonary function indicators reflecting LH. Multiple linear regression analysis was used. The ROC curves of LUS and DE were drawn to evaluate their diagnostic efficacy, and De Long method was used for comparison. Results: (1) The LUS of patients with stable COPD were positively correlated with RV, TLC, RV/TLC and FRC and negatively correlated with IC and IC/TLC (r1=0.72, r2=0.41, r3=0.72, r4=0.70, r5=-0.56, r6=-0.65, P < 0.001). The correlation was stronger than that between DE at maximal deep inspiration and the corresponding pulmonary function indices (r1=-0.41, r2=-0.26, r3=-0.40, r4=-0.43, r5=0.30, r6=0.37, P < 0.001). (2) Multiple linear regression analysis showed that LUS were significantly correlated with IC/TLC and RV/TLC. (3) With IC/TLC<25% and RV/TLC>60% as the diagnostic criterion of severe LH, the areas under the ROC curves of LUS and DE at maximal deep inspiration for diagnosing severe LH were 0.914 and 0.385, 0.845 and 0.543, respectively (P < 0.001). Conclusion: The lung ultrasound score is an important parameter for evaluating LH. LUS is better than DE at maximal deep inspiration for diagnosing severe LH and is expected to become an effective auxiliary tool for evaluating LH.
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Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Pulmão/diagnóstico por imagem , Capacidade Pulmonar Total , Capacidade Inspiratória , Capacidade Residual FuncionalRESUMO
SUMMARY: The next-generation sequencing brought opportunities for the diagnosis of genetic disorders due to its high-throughput capabilities. However, the majority of existing methods were limited to only sequencing candidate variants, and the process of linking these variants to a diagnosis of genetic disorders still required medical professionals to consult databases. Therefore, we introduce diseaseGPS, an integrated platform for the diagnosis of genetic disorders that combines both phenotype and genotype data for analysis. It offers not only a user-friendly GUI web application for those without a programming background but also scripts that can be executed in batch mode for bioinformatics professionals. The genetic and phenotypic data are integrated using the ACMG-Bayes method and a novel phenotypic similarity method, to prioritize the results of genetic disorders. diseaseGPS was evaluated on 6085 cases from Deciphering Developmental Disorders project and 187 cases from Shanghai Children's hospital. The results demonstrated that diseaseGPS performed better than other commonly used methods. AVAILABILITY AND IMPLEMENTATION: diseaseGPS is available to freely accessed at https://diseasegps.sjtu.edu.cn with source code at https://github.com/BioHuangDY/diseaseGPS.
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Biologia Computacional , Criança , Humanos , Teorema de Bayes , China , Genótipo , FenótipoRESUMO
BACKGROUND: The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused by deficiencies in peroxisome function and are segmented into enzyme-and-transporter defects (defects in single peroxisomal proteins) and peroxisome biogenesis disorders (defects in the peroxin proteins, critical for normal peroxisome assembly and biogenesis). In this study, we employed multivariate supervised and non-supervised statistical methods and utilized mass spectrometry data of neurological patients, peroxisomal disorder patients (X-linked adrenoleukodystrophy and Zellweger syndrome), and healthy controls to analyze the role of common metabolites in peroxisomal disorders, to develop and refine a classification models of X-linked adrenoleukodystrophy and Zellweger syndrome, and to explore analytes with utility in rapid screening and diagnostics. RESULTS: T-SNE, PCA, and (sparse) PLS-DA, operated on mass spectrometry data of patients and healthy controls were utilized in this study. The performance of exploratory PLS-DA models was assessed to determine a suitable number of latent components and variables to retain for sparse PLS-DA models. Reduced-features (sparse) PLS-DA models achieved excellent classification performance of X-linked adrenoleukodystrophy and Zellweger syndrome patients. CONCLUSIONS: Our study demonstrated metabolic differences between healthy controls, neurological patients, and peroxisomal disorder (X-linked adrenoleukodystrophy and Zellweger syndrome) patients, refined classification models and showed the potential utility of hexacosanoylcarnitine (C26:0-carnitine) as a screening analyte for Chinese patients in the context of a multivariate discriminant model predictive of peroxisomal disorders.
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Adrenoleucodistrofia , Transtornos Peroxissômicos , Síndrome de Zellweger , Criança , Humanos , Adrenoleucodistrofia/diagnóstico , População do Leste Asiático , Análise Multivariada , Transtornos Peroxissômicos/diagnóstico , Transtornos Peroxissômicos/metabolismo , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/metabolismo , ChinaRESUMO
Tightly controlled inflammation is an indispensable mechanism in the maintenance of cellular and organismal homeostasis in living organisms. However, aberrant inflammation is detrimental and has been suggested as a key contributor to organ injury with different etiologies. Substance P (SP) is a neuropeptide with a robust effect on inflammation. The proinflammatory effects of SP are achieved by activating its functional receptors, namely the neurokinin 1 receptor (NK1R) receptor and mas-related G protein-coupled receptors X member 2 (MRGPRX2) and its murine homolog MRGPRB2. Upon activation, the receptors further signal to several cellular signaling pathways involved in the onset, development, and progression of inflammation. Therefore, excessive SP-NK1R or SP-MRGPRX2/B2 signals have been implicated in the pathogenesis of inflammation-associated organ injury. In this review, we summarize our current knowledge of SP and its receptors and the emerging roles of the SP-NK1R system and the SP-MRGPRX2/B2 system in inflammation and injury in multiple organs resulting from different pathologies. We also briefly discuss the prospect of developing a therapeutic strategy for inflammatory organ injury by disrupting the proinflammatory actions of SP via pharmacological intervention.
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Receptores da Neurocinina-1 , Substância P , Camundongos , Animais , Substância P/metabolismo , Receptores da Neurocinina-1/metabolismo , Inflamação/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismoRESUMO
Acute lung injury causes severe inflammation and oxidative stress in lung tissues. In this study, we analyzed the potential regulatory role of nuclear factor erythroid-2-related factor 2 (Nrf2) on NADPH oxidase 1 (NOX1) in tumor necrosis factor-α (TNF-α)-induced inflammation and oxidative stress in human type II alveolar epithelial cells. In this study, A549 cells were transfected with Nrf2 siRNA and overexpression vectors for 6 h before being induced by TNF-α for 24 h. TNF-α upregulated the expression of NOX1 and Nrf2 in A549 cells. Furthermore, overexpression of Nrf2 could reduce TNF-α-induced NF-κB mRNA and protein expression after transfection with the Nrf2 siRNA vector, and the levels of IL-6, IL-8, ROS, and malondialdehyde (MDA) in TNF-α-induced A549 cells increased, while the level of total antioxidation capability (T-AOC) decreased. On the other hand, the overexpression of Nrf2 decreased the levels of IL-6, IL-8, ROS, and MDA, while increasing T-AOC. The mRNA and protein levels of NOX1 were dramatically increased by TNF-α, while those changes were notably suppressed by Nrf2 overexpression. Further studies demonstrated that Nrf2 suppressed NOX1 transcription by binding to the -1199 to -1189 bp (ATTACACAGCA) region of the NOX1 promoter in TNF-α-stimulated A549 cells. Our study suggests that Nrf2 may bind to and regulate NOX1 expression to antagonize TNF-α-induced inflammatory reaction and oxidative stress in A549 cells.
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NADPH Oxidase 1 , Fator 2 Relacionado a NF-E2 , Fator de Necrose Tumoral alfa , Humanos , Células A549 , Inflamação/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , NADPH Oxidase 1/genética , NADPH Oxidase 1/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , RNA Mensageiro , RNA Interferente Pequeno/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Hydrogen sulfide (H2S) has been acknowledged as a novel gaseous mediator. The metabolism of H2S in mammals is tightly controlled and is mainly achieved by many physiological reactions catalyzed by a suite of enzymes. Although the precise actions of H2S in regulating programmed cell death, oxidative stress and inflammation are yet to be fully understood, it is becoming increasingly clear that H2S is extensively involved in these crucial processes. Since programmed cell death, oxidative stress and inflammation have been demonstrated as three important mechanisms participating in the pathogenesis of various pulmonary diseases, it can be inferred that aberrant H2S metabolism also functions as a critical contributor to pulmonary diseases, which has also been extensively investigated. In the meantime, substantial attention has been paid to developing therapeutic approaches targeting H2S for pulmonary diseases. In this review, we summarize the cutting-edge knowledge on the metabolism of H2S and the relevance of H2S to programmed cell death, oxidative stress and inflammation. We also provide an update on the crucial roles played by H2S in the pathogenesis of several pulmonary diseases. Finally, we discuss the perspective on targeting H2S metabolism in the treatment of pulmonary diseases.
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OBJECTIVE: To investigate the effectiveness, safety, adverse events (AEs), and outcomes of percutaneous radiologic gastrostomy (PRG) in patients with dysphagia caused by cerebral infarction. STUDY DESIGN: An interventional study. PLACE AND DURATION OF STUDY: Department of Interventional Oncology, Dahua Hospital, and the Department of Internal medicine, Changqiao Community Health Service Center, Shanghai, China, from January 2016 and December 2019. METHODOLOGY: This study included sixty patients with cerebral infarction-induced dysphagia aged between 49-79 years. All patients were equally and randomly divided into the observation group (PRG group) and the control group (NFT group). Early and long-term results of PRG and nasal feeding tube (NFT) treatment were assessed. RESULTS: No significant differences in serum albumin, prealbumin, haemoglobin, and circumference of triceps (p>0.05) were observed between the two groups before treatment. After treatment, both serum albumin, prealbumin, haemoglobin, and the circumference of the triceps increased in the PRG group compared with the NFT group (p<0.05), indicating better nutrition status. The adverse events (AEs) rate of the PRG group (3.33%, 1/30) was significantly lower than the NFT group (30%, 9/30, p=0.005). The comfort level of the PRG group (93.33%, 28/30) was significantly higher than the NFT group (53.33%, 16/30, p<0.001). CONCLUSION: Percutaneous radiologic gastrostomy can improve the nutritional status of patients with dysphagia caused by cerebral infarction. It can reduce the incidence of AE and improve the comfort level. KEY WORDS: Percutaneous Gastroscopy, Gastrostomy, Dysphagia, Nutrition status, Complications.
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Transtornos de Deglutição , Acidente Vascular Cerebral , Humanos , Pessoa de Meia-Idade , Idoso , Gastrostomia/efeitos adversos , Gastrostomia/métodos , Pré-Albumina , Transtornos de Deglutição/etiologia , Estudos Retrospectivos , China , Acidente Vascular Cerebral/complicações , Infarto CerebralRESUMO
BACKGROUND: Impaired respiratory function caused by respiratory muscle dysfunction is one of the common consequences of chronic obstructive pulmonary disease (COPD). In this study, two-dimensional shear wave elastography (2D-SWE) was used to measure diaphragm stiffness (DS) and intercostal muscle stiffness (IMS) in patients with COPD; in addition, the value of 2D-SWE in evaluating respiratory function was determined. METHODS: In total, 219 consecutive patients with COPD and 20 healthy adults were included. 2D-SWE was used to measure the DS and IMS, and lung function was also measured. The correlation between respiratory muscle stiffness and lung function and the differences in respiratory muscle stiffness in COPD patients with different severities were analysed. RESULTS: 2D-SWE measurements of the DS and IMS presented with high repeatability and consistency, with ICCs of 0.756 and 0.876, respectively, and average differences between physicians of 0.10 ± 1.61 and 0.07 ± 1.65, respectively. In patients with COPD, the DS and IMS increased with disease severity (F1 = 224.50, F2 = 84.63, P < 0.001). In patients with COPD, the correlation with the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC), predicted FEV1% value, residual volume (RV), total lung capacity (TLC), RV/TLC, functional residual capacity (FRC) and inspiratory capacity (IC) of DS (r1=-0.81, r2=-0.63, r3 = 0.65, r4 = 0.54, r5 = 0.60, r6 = 0.72 and r7=-0.41, respectively; P < 0.001) was stronger than that of IMS (r1=-0.76, r2=-0.57, r3 = 0.57, r4 = 0.47, r5 = 0.48, r6 = 0.60 and r7=-0.33, respectively; P < 0.001). CONCLUSION: 2D-SWE has potential for use in evaluating DS and IMS. A specific correlation was observed between respiratory muscle stiffness and lung function. With the worsening of the severity of COPD and the progression of lung function impairment, the DS and IMS gradually increased.
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Técnicas de Imagem por Elasticidade , Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Técnicas de Imagem por Elasticidade/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Sistema Respiratório , Testes de Função Respiratória , Músculos RespiratóriosRESUMO
Cigarette smoke is a complex aerosol containing a large number of compounds with a variety of toxicity and carcinogenicity. Long-term exposure to cigarette smoke significantly increases the risk of a variety of diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial-mesenchymal transition (EMT) is a unique biological process, that refers to epithelial cells losing their polarity and transforming into mobile mesenchymal cells, playing a crucial role in organ development, fibrosis, and cancer progression. Numerous recent studies have shown that EMT is an important pathophysiological process involved in airway fibrosis, airway remodeling, and malignant transformation of COPD. In this review, we summarized the effects of cigarette smoke on the development and progression of COPD and focus on the specific changes and underlying mechanisms of EMT in COPD induced by cigarette smoke. We spotlighted the signaling pathways involved in EMT induced by cigarette smoke and summarize the current research and treatment approaches for EMT in COPD, aiming to provide ideas for potential new treatment and research directions.
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Fumar Cigarros , Doença Pulmonar Obstrutiva Crônica , Remodelação das Vias Aéreas , Fumar Cigarros/efeitos adversos , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Doença Pulmonar Obstrutiva Crônica/metabolismo , NicotianaRESUMO
Sepsis, a potentially lethal condition resulting from failure to control the initial infection, is associated with a dysregulated host defense response to pathogens and their toxins. Sepsis remains a leading cause of morbidity, mortality and disability worldwide. The pathophysiology of sepsis is very complicated and is not yet fully understood. Worse still, the development of effective therapeutic agents is still an unmet need and a great challenge. Gases, including nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), are small-molecule biological mediators that are endogenously produced, mainly by enzyme-catalyzed reactions. Accumulating evidence suggests that these gaseous mediators are widely involved in the pathophysiology of sepsis. Many sepsis-associated alterations, such as the elimination of invasive pathogens, the resolution of disorganized inflammation and the preservation of the function of multiple organs and systems, are shaped by them. Increasing attention has been paid to developing therapeutic approaches targeting these molecules for sepsis/septic shock, taking advantage of the multiple actions played by NO, CO and H2S. Several preliminary studies have identified promising therapeutic strategies for gaseous-mediator-based treatments for sepsis. In this review article, we summarize the state-of-the-art knowledge on the pathophysiology of sepsis; the metabolism and physiological function of NO, CO and H2S; the crosstalk among these gaseous mediators; and their crucial effects on the development and progression of sepsis. In addition, we also briefly discuss the prospect of developing therapeutic interventions targeting these gaseous mediators for sepsis.
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Gasotransmissores , Sulfeto de Hidrogênio , Sepse , Monóxido de Carbono/metabolismo , Monóxido de Carbono/uso terapêutico , Gases , Gasotransmissores/metabolismo , Gasotransmissores/uso terapêutico , Humanos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/uso terapêutico , Óxido Nítrico/metabolismo , Sepse/tratamento farmacológicoRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a frequently encountered disease condition in clinical practice mainly caused by cigarette smoke (CS). The aim of this study was to investigate the protective roles of human adipose-derived stem cells-derived exosomes (ADSCs-Exo) in CS-induced lung inflammation and injury and explore the underlying mechanism by discovering the effects of ADSCs-Exo on alveolar macrophages (AMs) pyroptosis. METHODS: ADSCs were isolated from human adipose tissues harvested from three healthy donors, and then ADSCs-Exo were isolated. In vivo, 24 age-matched male C57BL/6 mice were exposed to CS for 4 weeks, followed by intratracheal administration of ADSCs-Exo or phosphate buffered saline. In vitro, MH-S cells, derived from mouse AMs, were stimulated by 2% CS extract (CSE) for 24 h, followed by the treatment of ADSCs-Exo or phosphate buffered saline. Pulmonary inflammation was analyzed by detecting pro-inflammatory cells and mediators in the bronchoalveolar lavage fluid. Lung histology was assessed by hematoxylin and eosin staining. Mucus production was determined by Alcian blue-periodic acid-Schiff staining. The profile of AMs pyroptosis was evaluated by detecting the levels of pyroptosis-indicated proteins. The inflammatory response in AMs and the phagocytic activity of AMs were also investigated. RESULTS: In mice exposed to CS, the levels of pro-inflammatory cells and mediators were significantly increased, mucus production was markedly increased and lung architecture was obviously disrupted. AMs pyroptosis was elevated and AMs phagocytosis was inhibited. However, the administration of ADSCs-Exo greatly reversed these alterations caused by CS exposure. Consistently, in MH-S cells with CSE-induced properties modelling those found in COPD, the cellular inflammatory response was elevated, the pyroptotic activity was upregulated while the phagocytosis was decreased. Nonetheless, these abnormalities were remarkably alleviated by the treatment of ADSCs-Exo. CONCLUSIONS: ADSCs-Exo effectively attenuate CS-induced airway mucus overproduction, lung inflammation and injury by inhibiting AMs pyroptosis. Therefore, hADSCs-Exo may be a promising cell-free therapeutic candidate for CS-induced lung inflammation and injury.
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Adipócitos/patologia , Fumar Cigarros/efeitos adversos , Exossomos/metabolismo , Macrófagos Alveolares/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Células-Tronco/patologia , Doadores de Tecidos , Adulto , Animais , Fumar Cigarros/metabolismo , Fumar Cigarros/patologia , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/metabolismo , Piroptose , Adulto JovemRESUMO
Background: Nocardia is a ubiquitous soil saprophyte transmitted through airborne or direct cutaneous inoculation routes. Although Nocardia is more common in immunocompromised patients, Nocardia may also arise in apparently immunocompetent patients. Case presentation: We report a rare case of Nocardia infection presenting as a large mediastinal mass in an immunocompetent ceramic worker. A 54-year-old man with no previous history of immune dysfunction, a ceramic worker by profession, was referred and admitted to our hospital because of a persistent fever for 19 days. Chest CT showed a large middle mediastinal mass. However, conventional anti-infective treatment was ineffective. Under the guidance of the Virtual bronchoscopic navigation (VBN) system, he underwent Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The purulent exudate obtained by EBUS-TBNA was further identified as Nocardia by weak acid-fast and metagenomic next-generation sequencing (mNGS). He was subsequently treated with intravenous imipenem/amikacin, switched to intravenous imipenem and oral trimethoprim/sulfamethoxazole, and the clinical symptoms were significantly improved. Conclusions: Even in immunocompetent patients, Nocardiosis cannot be excluded. For the public, especially soil contact workers, precautions should be taken to avoid Nocardia infection from occupational exposure. This rare case may provide a diagnosis and treatment reference for clinicians.
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BACKGROUND: Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial-mesenchymal transition (EMT) is an essential pathophysiological process in COPD and plays an important role in airway remodeling, fibrosis, and malignant transformation of COPD. Previous studies have indicated FERMT3 is downregulated and plays a tumor-suppressive role in lung cancer. However, the role of FERMT3 in COPD, including EMT, has not yet been investigated. METHODS: The present study aimed to explore the potential role of FERMT3 in COPD and its underlying molecular mechanisms. Three GEO datasets were utilized to analyse FERMT3 gene expression profiles in COPD. We then established EMT animal models and cell models through cigarette smoke (CS) or cigarette smoke extract (CSE) exposure to detect the expression of FERMT3 and EMT markers. RT-PCR, western blot, immunohistochemical, cell migration, and cell cycle were employed to investigate the potential regulatory effect of FERMT3 in CSE-induced EMT. RESULTS: Based on Gene Expression Omnibus (GEO) data set analysis, FERMT3 expression in bronchoalveolar lavage fluid was lower in COPD smokers than in non-smokers or smokers. Moreover, FERMT3 expression was significantly down-regulated in lung tissues of COPD GOLD 4 patients compared with the control group. Cigarette smoke exposure reduced the FERMT3 expression and induces EMT both in vivo and in vitro. The results showed that overexpression of FERMT3 could inhibit EMT induced by CSE in A549 cells. Furthermore, the CSE-induced cell migration and cell cycle progression were reversed by FERMT3 overexpression. Mechanistically, our study showed that overexpression of FERMT3 inhibited CSE-induced EMT through the Wnt/ß-catenin signaling. CONCLUSIONS: In summary, these data suggest FERMT3 regulates cigarette smoke-induced epithelial-mesenchymal transition through Wnt/ß-catenin signaling. These findings indicated that FERMT3 was correlated with the development of COPD and may serve as a potential target for both COPD and lung cancer.
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Remodelação das Vias Aéreas/fisiologia , Fumar Cigarros/efeitos adversos , Transição Epitelial-Mesenquimal/genética , Regulação da Expressão Gênica , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Doença Pulmonar Obstrutiva Crônica/genética , Via de Sinalização Wnt/genética , Animais , Ciclo Celular , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/biossíntese , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologiaRESUMO
Safety performance functions (SPFs) are indispensable analytical tools that usually play a crucial role in estimating crash frequencies, identifying hotspots, analyzing crash contributing factors, and assessing the effectiveness of safety countermeasures. Due to the limited availability of safety data, municipalities tended to adopt SPFs from Highway Safety Manual or other neighboring jurisdictions. Recently, boosting algorithms have been frequently exploited for data analysis and statistical regression modeling problems. This research, therefore, aims to examine the efficiency of boosting calibration techniques to transfer the SPF using the limited region data in an international context. To this end, AdaBoost.R2, an adaptive boosting algorithm, Two-stage TrAdaBoost.R2, an instance-based transfer learning algorithm, and Gradient Boosting algorithm were employed to investigate their efficiencies in acquiring knowledge from the available source domain data to predict crashes in the target domain. As a comparison, the calibration factor method was adopted to transfer the traditional negative binomial (NB) regression model. Two training dataset groups were developed to train the four calibration techniques. The first group was used to examine the adaptability of the employed calibration techniques to the limited target region data. While the second group was utilized to further investigate the influence of larger vital information on the performance of transferred models. This study was conducted between two U.S. states, Florida and New York, and two Chinese cities, Shanghai and Suzhou. According to the goodness-of-fit results, boosting calibration techniques showed better prediction accuracy than the calibrated NB-based model using the limited target region data. In addition, the amount and distribution of the training dataset were considered the two significant factors that influence the proficiency of the boosting calibration techniques.
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Acidentes de Trânsito , Planejamento Ambiental , Acidentes de Trânsito/prevenção & controle , China , Humanos , Modelos Estatísticos , SegurançaRESUMO
BACKGROUND: Kindlin Family Members have been reported to be aberrantly expressed in various human cancer types and involved in tumorigenesis, tumor progression, and chemoresistance. However, their roles in non-small cell lung cancer (NSCLC) remain poorly elucidated. METHODS: We analyzed the prognostic value and immune infiltration of Kindlins in NSCLC through Oncomine, GEPIA, UALCAN, CCLE, KaplanMeier plotter, cBioPortal, TIMER, GeneMANIA, STRING, and DAVID database. Additionally, the mRNA expression levels of Kindlins were verified in 30 paired NSCLC tissues and NSCLC cell lines by real-time PCR. RESULTS: The expression level of FERMT1 was remarkably increased in NSCLC tissues and NSCLC cell lines, while FERMT2 and FERMT3 were reduced. Kindlins expressions were associated with individual cancer stages and nodal metastasis. We also found that higher expression level of FERMT1 was obviously correlated with worse overall survival (OS) in patients with NSCLC, while higher FERMT2 was strongly associated with better overall survival (OS) and first progression (FP). Additionally, the expression of FERMT2 and FERMT3 were obviously correlated with the immune infiltration of diverse immune cells. Functional enrichment analysis has shown that Kindlins may be significantly correlated with intracellular signal transduction, ATP binding and the PI3K-Akt signaling pathway in NSCLC. CONCLUSIONS: The research provides a new perspective on the distinct roles of Kindlins in NSCLC and likely has important implications for future novel biomarkers and therapeutic targets in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não PequenasRESUMO
OBJECTIVE: Acute lung injury (ALI) is characterized by inflammation and oxidative stress. Nuclear factor-kappaB (NF-κB) mediates the expression of various inflammation-related genes, including the NADPH oxidase family. This study aimed to identify the potential regulatory role of NF-κB on NADPH oxidases in tumor necrosis factor-α (TNF-α)-induced oxidative stress in human alveolar epithelial cells. METHODS: A549 cells were treated with TNF-α for 24 h to establish ALI cell models. RT-PCR, western blot, assessment of oxidative stress, Alibaba 2.1 online analysis, electrophoretic mobility shift assays and luciferase reporter analysis were employed to identify the potential regulatory role of NF-κB on NADPH oxidases in TNF-α-induced oxidative stress in human alveolar epithelial cells. RESULTS: The expression of NF-κB/p65 was notably upregulated in TNF-α-stimulated A549 cells. NF-κB knockdown by siRNA significantly inhibited the TNF-α-induced oxidative stress. Moreover, NF-κB/p65 siRNA could inhibit the activation of NOX1, NOX2 and NOX4 mRNA and protein expression in TNF-α-stimulated A549 cells. The next study demonstrated that NF-κB activated the transcription of NOX1 by binding to the -261 to -252 bp (NOX1/κB2, TAAAAATCCC) region of NOX1 promoter in TNF-α-stimulated A549 cells. CONCLUSION: Our data demonstrated that NF-κB can aggravate TNF-α-induced ALI by regulating the oxidative stress response and the expression of NOX1, NOX2 and NOX4. Moreover, NF-κB could promote the NOX1 transcriptional activity via binding its promoter in TNF-α-stimulated A549 cells.