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As a severe public health issue, depressive disorders (DD) has caused an increasingly burden of disease, especially in the older adults. To provide an overview and in-depth analysis of temporal trends in prevalence of DD in older adults at global, regional, and national levels over the last 30 years. Here, an age-period-cohort model was adopted to analyze age, period, and cohort effects. We showed that the global prevalence of DD in older adults was increasing. The net drift of the global prevalence of DD was showing an increasing trend in 78 countries, while local drift showing a declining trend in all age groups in high sociodemographic index (SDI) region. Additionally, period and cohort effects exhibited different patterns across regions. Over time, the declining trend was most significant in high SDI regions, while this trend was most significant in middle SDI region. Interestingly, those aged 60-64 years to 70-74 years was increasing globally, while age group aged 75-79 years to 95-99 years was on declining. In high, high-middle, and low SDI regions, individuals born early face higher risks than those born late, while the opposite results were observed in low-middle SDI region. Overall, our findings offer a insight global perspective for studying the temporal trends of DD prevalence, supplementing our evidence and understanding of DD epidemiology, and identifying gaps in DD prevention, management, and intervention plans in different aspects.
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Background: Macrophages constitute the main part of infiltrating immune cells in Malignant pleural mesothelioma (MPM) and abnormally high ratios of M2 macrophages are present in both pleural effusion and tissue samples of MPM patients. Whether MPM cells affect formation of M2 macrophages is poorly understood. In this study, we focused on identification of MPM-cells-derived soluble factors with M2-promoting effects. Methods: Media of malignant pleural mesothelioma cells were collected and soluble factors affecting macrophages were analyzed by mass spectrometry. TGF-ß receptor inhibitor SB431542 was used as the entry point to explore the downstream mechanism of action by qRT-PCR, WB and immunofluorescence. Results: The serum-free culture media collected from the human MPM cells Meso1 and Meso2 significantly enhanced expression of the M2 signature molecules including IL-10, TGF-ß and CD206 in the human macrophages THP-1, while the culture medium of the human MPM cells H2452 did not show such M2-promoting effects. Analysis of proteins by mass spectrometry and ELISA suggested that Leucine rich α2 glycoprotein 1(LRG1) was a potential candidate. LRG1 time- and dose-dependently increased expression of the M2 signature molecules, confirming its M2-promoting effects. Furthermore, LRG1's M2-promoting effects were reduced by the TGF-ß receptor inhibitor SB431542, and LRG1 increased phosphorylation of Smad2, indicating that M2-promoting effects of LRG1 were via the TGF-ß receptor/Smad2 signaling pathway. Conclusions: Our results provide a potential M2-promoting new member, LRG1, which contributes to the immune escape of MPM via the TGF-ß receptor/Smad2 signaling pathway.
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Macrófagos , Mesotelioma Maligno , Humanos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/tratamento farmacológico , Glicoproteínas/metabolismo , Glicoproteínas/farmacologia , Linhagem Celular Tumoral , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia , Fenótipo , Proteína Smad2/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Interleucina-10/metabolismo , Benzamidas , DioxóisRESUMO
Purpose: To explore the role of the mean apnea-hypopnea duration (MAD) and apnea-hypopnea duration per hour (HAD) in hypoxemia and evaluate whether they can effectively predict the occurrence of hypoxemia among adults with OSA. Patients and Methods: A total of 144 participants underwent basic information gathering and polysomnography (PSG). Logistic regression models were conducted to evaluate the best index in terms of hypoxemia. To construct the prediction model for hypoxemia, we randomly divided the participants into the training set (70%) and the validation set (30%). Results: The participants with hypoxemia tend to have higher levels of obesity, diabetes, AHI, MAD, and HAD compared with non-hypoxemia. The most relevant indicator of blood oxygen concentration is HAD (r = 0.73) among HAD, MAD, and apnea-hypopnea index (AHI). The fitness of HAD on hypoxemia showed the best. In the stage of establishing the prediction model, the area under the curve (AUC) values of both the training set and the validation set are 0.95. The increased HAD would elevate the risk of hypoxemia [odds ratio (OR): 1.30, 95% confidence interval (CI): 1.13-1.49]. Conclusion: The potential role of HAD in predicting hypoxemia underscores the significance of leveraging comprehensive measures of respiratory disturbances during sleep to enhance the clinical management and prognostication of individuals with sleep-related breathing disorders.
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BACKGROUND: Depressive symptoms (DS) have become a global public health problem. However, a risk prediction model for DS in the elderly population has not been established. The purpose of this study was to develop and validate a predictive nomogram to screen for DS in the elderly population. METHODS: A cross-sectional data of 3396 participants aged 60 and over were obtained from the China Health and Retirement Longitudinal Study 2018 (CHARLS). Participants were divided into the development and validation set. Predictive factors were selected through a single-factor analysis, and then a predictive model nomogram was established. The discrimination, calibration, and clinical validity were evaluated using the receiver operating characteristic (ROC) curves, Hosmer-Lemeshow tests, and decision curve analyses (DCA). RESULTS: A total of 2379 and 1017 participants were included in the development and validation set, respectively. The analysis found that gender, residence, dyslipidemia, self-rated health, and ADL disability were risk factors for DS in older adults, and were included in the final model. This nomogram showed an acceptable predictive performance as evaluated by the area under the ROC curve with values of 0.684 (95 % confidence interval (CI): 0.663-0.706) and 0.687 (95 % CI: 0.655-0.719) in the development and validation set, respectively. The calibration curve indicated that the model was accurate, and DCA demonstrated a good clinical application value. CONCLUSION: Five factors were selected to establish a nomogram for predicting DS in older adults. The nomogram has a good evaluation performance and can be used as a reliable tool to predict DS among older adults.
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Depressão , Nomogramas , Humanos , Masculino , Feminino , Idoso , China/epidemiologia , Depressão/diagnóstico , Depressão/epidemiologia , Pessoa de Meia-Idade , Estudos Transversais , Fatores de Risco , Estudos Longitudinais , Idoso de 80 Anos ou mais , Reprodutibilidade dos Testes , Curva ROCRESUMO
BACKGROUND: Aggression and violence by patient (and their relatives/friends) is widely acknowledged as a serious occupational hazard, with physicians being particularly susceptible to witnessing and experiencing such incidents within hospitals. Research has shown that the negative consequences of such aggression and violence are not only felt at the individual level, but also at the team and organizational levels. Understanding how to prevent and manage this behavior towards physicians in hospitals is urgent and not fully researched. While there are many potentially effective interventions, it is unclear which ones would be valuable and feasible for Chinese hospitals. Because patient aggression and violence may occur more frequently in Chinese hospitals than in other countries, this suggests that cultural differences play a role and that tailored interventions may be needed. METHOD: We conducted a Delphi study to reach a consensus on the importance and feasibility of hospital interventions to prevent and manage patient (and their relatives/friends) aggression and violence against physicians in Chinese hospitals. Seventeen experts in China were invited to complete online questionnaires over three rounds. RESULTS: After three rounds, consensus was achieved concerning 44 interventions, five other interventions were rejected, and no consensus was reached on another two. These interventions were clustered into eight categories: environment design, access and entrance, staffing and working practices, leadership and culture, training and education, support, during/after-the-event actions, and hospital policy. Each category is considered important in preventing and managing patient (and their relatives/friends) aggression and violence towards physicians in Chinese hospitals. This study also investigated the feasibility of the suggested interventions and found that 36 of the 44 interventions were considered not only relevant, but also feasible for implementation in Chinese hospitals. CONCLUSIONS: This study provides an overview of interventions that can be implemented in Chinese hospitals to prevent and manage patient (and their relatives/friends) aggression and violence before, during, and after a violent incident occurs.
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Agressão , Técnica Delphi , Estudos de Viabilidade , Médicos , Humanos , China , Médicos/psicologia , Masculino , Feminino , Hospitais , Violência no Trabalho/prevenção & controle , Adulto , Inquéritos e Questionários , Violência/prevenção & controle , Pessoa de Meia-Idade , LiderançaRESUMO
The pneumonia caused by novel coronavirus SARS-CoV-2 infection in early December 2019, which was later named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), rapidly spread across the world. China has made extraordinary efforts to this unprecedented pandemic, put its response and control at a very high level of infectious disease management (Category B but with measures for Category A), given top priority to the people and their lives, and balanced the pandemic control and socio-economic development. After more than three years' fighting against this disease, China downgraded the management of COVID-19 to Category B infectious disease on January 8, 2023 and the WHO declared the end of public health emergency on May 5, 2023. However, the ending of pandemic does not mean that the disease is no longer a health threat. Experiences against COVID-19 from China and the whole world should be learned to prepare well for the future public health emergencies. This article gives a systematic review of the trajectory of COVID-19 development in China, summarizes the critical policy arrangements and provides evidence for the adjustment during policy making process, so as to share experiences with international community and contribute to the global health for all humanity.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/terapia , China/epidemiologia , Saúde Pública , Controle de Doenças Transmissíveis/organização & administração , Controle de Doenças Transmissíveis/métodos , Política de Saúde , PandemiasRESUMO
Background: Airway remodeling is an essential pathological basis of respiratory diseases such as asthma and COPD, which is significantly related to pulmonary function and clinical symptoms. And pulmonary disease can be improved by regulating airway remodeling. This study aimed to establish a knowledge map of airway remodeling to clarify current research hotspots and future research trends. Methods: A comprehensive search was performed to analyze all relevant articles on airway remodeling using the Web of Science Core Collection Database from January 01, 2004 to June 03, 2023.2 reviewers screened the retrieved literature. Besides, the CiteSpace (6.2. R3) and VOSviewer (1.6.19) were utilized to visualize the research focus and trend regarding the effect of airway remodeling. Results: A total of 4077 articles about airway remodeling were retrieved. The United States is the country with the most published literature, underscoring the country's role in airway remodeling. In recent years, China has been the country with the fastest growth in the number of published literature, suggesting that China will play a more critical role in airway remodeling in the future. From the perspective of co-operation among countries, European co-operation was closer than Asian co-operation. The co-citation analysis showed that 98,313 citations were recorded in 3594 articles, and 25 clusters could be realized. In recent years, Burst detection shows that oxidative stress and epithelial-mesenchymal transition are hot words. Conclusions: Based on the bibliometric analysis of airway remodeling studies in the past 20 years, a multi-level knowledge structure map was drawn, it mainly includes countries, institutions, research fields, authors, journals, keywords and so on. The research directions represented by obstructive airway disease, PDGF-BB treatment of airway smooth muscle, allergen-induced airway remodeling, extracellular matrix, and non-coding RNA are the research hotspots in the field of airway remodeling. While the risk factors for airway remodeling, the application of new noninvasively assessing tools, biomarkers as well as The molecular mechanism represented by EMT and autophagy had been frontiers in recent years.
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Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36-/-) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36-/- mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment.
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Antígenos CD36 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ácidos Graxos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt , Antígenos CD36/genéticaRESUMO
BACKGROUND: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. METHODS: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. FINDINGS: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). INTERPRETATION: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). FUNDING: Dizal Pharmaceutical.
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Anemia , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Mutagênese Insercional , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , China , Receptores ErbB/genética , Éxons/genéticaRESUMO
Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.
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[This corrects the article DOI: 10.3389/fonc.2021.621992.].
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As an ideal anti-inflammatory target, cyclin-dependent kinase 8 (CDK8) has gradually attracted the attention of researchers. CDK8 inhibition up-regulates Interleukin-10 (IL-10) expression by enhancing the transcriptional activity of activator protein-1 (AP-1), and augmenting IL-10 abundance is a viable strategy for the treatment of inflammatory bowel disease (IBD). In this research, through structure-based drug design and dominant fragment hybridization, a series of poly-substituted pyridine derivatives were designed and synthesized as CDK8 inhibitors. Ultimately, compound CR16 was identified as the best one, which exhibited good inhibitory activity against CDK8 (IC50 = 74.4 nM). In vitro and in vivo studies indicated that CR16 could enhance the transcriptional activity of AP-1, augment the abundance of IL-10, and affect CDK8-related signaling pathways including TLR7/NF-κB/MAPK and IL-10-JAK1-STAT3 pathways. In addition, CR16 showed potent therapeutic effect in an animal model of IBD.
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Interleucina-10 , Inibidores de Proteínas Quinases , Animais , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Interleucina-10/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Transdução de Sinais , Fator de Transcrição AP-1RESUMO
Interstitial lung disease associated with rheumatoid arthritis (RA-ILD) can lead to interstitial fibrosis and even lung failure as a complication of rheumatoid arthritis (RA), and there is currently no effective treatment and related basic research. Studies have found that resveratrol (Res) can improve the progression of RA by regulating autophagy, and increasing evidence supports the connection between autophagy and common interstitial lung disease (ILD). We explored changes in autophagy levels in fibrotic lungs in RA-ILD and found that the level of autophagy is enhanced in the early stage but inhibited in the late stage. However, resveratrol treatment improved the level of autophagy and reversed the inhibition of autophagy, and attenuated fibrosis. We created corresponding cell models that exhibited the same phenotypic changes as animal models; under the effect of resveratrol, the level of fibrosis changed accordingly, and the fusion process of lysosomes and autophagosomes in autophagy was liberated from the inhibition state. Resveratrol effects were reversed by the addition of the late autophagy inhibitor chloroquine. These results suggest that resveratrol attenuates pulmonary fibrosis, increases autophagic flux, and modulates the autophagy-lysosome pathway, and particularly it may work by improving the formation of autophagic lysosomes, which may be an effective treatment for induced RA-ILD.
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Artrite Reumatoide , Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Animais , Resveratrol/farmacologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/complicações , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Fibrose , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/etiologia , AutofagiaRESUMO
Purpose: As a common respiratory disease, chronic obstructive pulmonary disease (COPD) has a high morbidity and mortality. Current clinical therapies are not ideal and do not improve lung function or long-term life quality. It is very important to find new potential pathogenic mechanisms, biomarkers, and targets with therapeutic value in COPD. Methods: Serum samples collected from acute exacerbation and stable COPD and healthy participants were analyzed using label-free liquid chromatography tandem mass spectrometry to identify the differentially expressed proteins (DEPs) between two groups. Bioinformatics analyses were performed to determine the biological processes associated with those DEPs. Key proteins were validated by enzyme linked immunosorbent assay (ELISA). Results: In total, 661 proteins were detected in serum from patients with COPD and healthy participants. Compared with healthy participants, patients with acute exacerbation of COPD had 45 DEPs, 13 were upregulated and 32 were downregulated; and patients with stable COPD had 79 DEPs, 18 were upregulated and 61 were downregulated. Gene Ontology functional annotation results indicated that the DEPs identified in patients with COPD were associated with the terms cellular anatomical entity, binding, and cellular process. Kyoto Encyclopedia of Genes and Genomes functional annotation analysis and the Clusters of Orthologous Genes database analysis indicated that the functions of these DEPs were primarily in signal transduction mechanisms and amino acid transport and metabolism. The ELISA results for three key proteins of IGFBP2, LRG1 and TAGLN were consistent with the LC-MS/MS results and the area under the receiver operating characteristic of the combined index was 0.893 (95% CI: 0.813, 0.974). Conclusion: Our findings suggested pathogenic mechanisms underlying COPD stages and indicated three key proteins that may warrant further study as potential biomarkers for early diagnosis or prognosis of COPD or as therapeutic targets.
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Proteômica , Doença Pulmonar Obstrutiva Crônica , Humanos , Proteômica/métodos , Biologia Computacional , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Cromatografia Líquida , Espectrometria de Massas em Tandem , Proteínas Sanguíneas , BiomarcadoresRESUMO
AIM: This study aimed to investigate the promoting effect of acid-sensing ion channel 1a (ASIC1a) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its mechanisms. METHODS: In this experiment, the ALI rat model was induced by intratracheal injection of LPS, and the ASIC1a specific blocker psalmotoxin-1 (PcTx-1) was injected into the tail vein before LPS administration once. Western blot, immunofluorescence, immunohistochemistry and real-time PCR methods were used to detect ASIC1a and apoptosis-related proteins expressions in lung tissue and RLE-6TN rat type II alveolar epithelial cells. Confocal Laser Scanning Microscopy was used to detect Ca2+ fluorescence intensity in RLE-6TN cells. RESULTS: PcTx-1 pretreatment not only inhibited the pathological changes of LPS-induced ALI in lung tissue, but also inhibited lung dysfunction. PcTx-1 also reduced the increased levels of the apoptosis-related proteins B-cell lymphoma-2-associated X (Bax) and cleaved cysteinyl aspartate specific proteinase 3 (Cleaved caspase-3) and increased the decreased level of B-cell lymphoma-2 (Bcl-2) in the lung tissue of the model group. LPS-induced changes in mitochondrial membrane potential and calcium influx in alveolar epithelial cells were also reversed by PcTx-1. CONCLUSION: ASIC1a induces an apoptotic response in ALI through mitochondrial apoptosis.
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Canais Iônicos Sensíveis a Ácido , Lesão Pulmonar Aguda , Animais , Ratos , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Ácido Aspártico , Proteína X Associada a bcl-2/metabolismo , Cálcio/metabolismo , Caspase 3/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Mieloblastina/metabolismoRESUMO
AIMS: Acute lung injury (ALI) is triggered by an acute inflammatory response. Lipopolysaccharide (LPS) is recognized as an important participant in the pathogenesis of sepsis, which may induce ALI. N-phenethyl-5-phenylpicolinamide (N5P) is a newly synthesized HIF-1α inhibitor. The purpose of the present study was to investigate the potential protective effects of N5P on LPS-induced ALI and the underlying mechanisms. MAIN METHODS: In vivo experiment, the ALI rat model was induced by intratracheal injection of LPS, and various concentrations of N5P were injected intraperitoneally before LPS administration. In vitro experiment, RAW264.7 macrophages were administrated LPS and N5P to detect inflammatory cytokine changes. HIF-1α overexpression plasmid (HIF1α-OE) and granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycolysis agonist, were used to examine the relationship between the HIF-1α/glycolysis/ASIC1a pathway. KEY FINDINGS: Pretreatment with N5P inhibited not only the histopathological changes that occurred in the lungs but also lung dysfunction in LPS-induced ALI. N5P also decreased the levels of lactic acid in lung tissue and arterial blood, and inflammatory factors IL-1ß and IL-6 levels in serum. LPS increased HIF-1α, glycolysis proteins GLUT1, HK2, ASIC1a, IL-1ß, IL-6, and these changes were reversed by N5P in primary alveolar macrophages and RAW264.7 macrophages. Overexpression of HIF-1α significantly increased glycolysis genes and ASIC1a as well as inflammatory cytokines. Excessive glycolysis levels weaken the ability of N5P to inhibit inflammation. SIGNIFICANCE: N5P may alleviate inflammation in ALI through the HIF-1α/glycolysis/ASIC1a signaling pathway. The present findings have provided pertinent information in the assessment of N5P as a potential, future therapeutic drug for ALI.
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Lesão Pulmonar Aguda , Lipopolissacarídeos , Humanos , Ratos , Animais , Lipopolissacarídeos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Transportador de Glucose Tipo 1/metabolismo , Interleucina-6/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Pulmão/metabolismo , Inflamação/patologia , Citocinas/metabolismo , Glicólise , Ácido Láctico/metabolismoRESUMO
Natural killer (NK) cells are regarded as the host's first line of defense against viral infection. Moreover, the involvement of NK cells in chronic obstructive pulmonary disease (COPD) has been documented. However, the specific mechanism and biological changes of NK cells in COPD development have not been determined. In this study, we extracted NK cells from the peripheral blood of 18 COPD patients who were recovering from an acute exacerbation and 45 healthy donors (HDs), then we labeled NK cells with different antibodies and analyzed with flow cytometry. The data showed that the frequencies of total NK cells in the peripheral blood of COPD patients were lower compared with HDs. Moreover, the inhibitory receptors on NK cells expressed higher levels and the expression of activating receptors were generally low. Importantly, both the expression levels of CD96 in NK cells and the frequencies of CD96+ NK cells were significantly upregulated in COPD patients. These findings suggest that surface receptor CD96 from NK cells may be a risk factor in the evolution of COPD.
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Células Matadoras Naturais , Doença Pulmonar Obstrutiva Crônica , Antígenos CD/metabolismo , Citometria de Fluxo , Humanos , Células Matadoras Naturais/metabolismoRESUMO
Natural killer (NK) cells typically function as frontline lymphocytes against cancer although little is known about their engagement in non-small cell lung cancer (NSCLC). This study compared the performance and activity of NK cells and their subsets in the peripheral blood of NSCLC sufferers and healthy participants. In total, 67 healthy controls (40 males; 59.7%) and 56 patients with NSCLC (35 males; 62.5%) were included (mean age, 66.6 years). Flow cytometry identified NK cells and their subpopulations in external blood, and the total number, proportion, activity, surface activating, and inhibitory receptor expression levels were determined. Results showed that NK cell surface receptors CD107a, IFN-γ, and TNF-α activity were markedly reduced in lung cancer patients compared to healthy controls. The number and ratio of NK cells within the lymphocyte population were decreased in patients. The concentration of the inhibitory receptors TIGIT, TIM-3, CD96, PD-1, and Siglec-7 were increased in patients, whereas the expression level of the activating receptor NKP30 was decreased. Moreover, the expression levels of IFN-γ, TIGIT, CD96, PD-1, and TIM-3 were correlated with the clinical phase of NSCLC. These findings suggest that surface receptors from NK cells are likely to be involved in the evolution of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Antígenos CD/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Células Matadoras Naturais , Neoplasias Pulmonares/metabolismo , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismoRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the world's leading causes of death and a major chronic disease, highly prevalent in the aging population exposed to tobacco smoke and airborne pollutants, which calls for early and useful biomolecular predictors. Roles of noncoding RNAs in COPD have been proposed, however, not many studies have systematically investigated the crosstalk among various transcripts in this context. The construction of RNA functional networks such as lncRNA-mRNA, and circRNA-miRNA-mRNA interaction networks could therefore facilitate our understanding of RNA interactions in COPD. Here, we identified the expression of RNA transcripts in RNA sequencing from COPD patients, and the potential RNA networks were further constructed. METHODS: All fresh peripheral blood samples of three patients with COPD and three non-COPD patients were collected and examined for mRNA, miRNA, lncRNA, and circRNA expression followed by qRT-PCR validation. We also examined mRNA expression to enrich relevant biological pathways. lncRNA-mRNA coexpression network and circRNA-miRNA-mRNA network in COPD were constructed. RESULTS: In this study, we have comprehensively identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs in peripheral blood of COPD patients with high-throughput RNA sequencing. 282 mRNAs, 146 lncRNAs, 85 miRNAs, and 81 circRNAs were differentially expressed. GSEA analysis showed that these differentially expressed RNAs correlate with several critical biological processes such as "ncRNA metabolic process", "ncRNA processing", "ribosome biogenesis", "rRNAs metabolic process", "tRNA metabolic process" and "tRNA processing", which might be participating in the progression of COPD. RT-qPCR with more clinical COPD samples was used for the validation of some differentially expressed RNAs, and the results were in high accordance with the RNA sequencing. Given the putative regulatory function of lncRNAs and circRNAs, we have constructed the co-expression network between lncRNA and mRNA. To demonstrate the potential interactions between circRNAs and miRNAs, we have also constructed a competing endogenous RNA (ceRNA) network of differential expression circRNA-miRNA-mRNA in COPD. CONCLUSIONS: In this study, we have identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs, providing a systematic view of the differentially expressed RNA in the context of COPD. We have also constructed the lncRNA-mRNA co-expression network, and for the first time constructed the circRNA-miRNA-mRNA in COPD. This study reveals the RNA involvement and potential regulatory roles in COPD, and further uncovers the interactions among those RNAs, which will assist the pathological investigations of COPD and shed light on therapeutic targets exploration for COPD.
Assuntos
MicroRNAs , Doença Pulmonar Obstrutiva Crônica , RNA Longo não Codificante , Idoso , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de TransferênciaRESUMO
BACKGROUND: Pentraxin 3 (PTX3), a soluble pattern recognition molecule, not only acts as a promising indicator reflecting the disease activity of rheumatoid arthritis (RA) patients but exerts essential pathogenic roles in the progression of RA and serves as a potential therapeutic target for RA patients. Our study intends to systematically evaluate the circulating PTX3 levels and their potential influencing factors in RA patients. METHODS: Articles regarding the circulating PTX3 levels of RA patients were identified in Pubmed, Embase, China National Knowledge Infrastructure (CNKI), and Cochrane databases. Standardized mean difference (SMD) and corresponding 95% confidence intervals (95% CI) were calculated and further illustrated by the forest plot. Egger's regression test and sensitivity analysis were conducted to assess the publication bias and stability of the results, respectively. RESULTS: Twenty articles with 21 individual studies were recruited in our meta-analysis. The overall results revealed that compared to healthy controls, RA patients had significantly higher circulating PTX3 levels (pooled SMD = 0.97, 95% CI: 0.48 to 1.45). Subgroup analyses further demonstrated that compared to healthy controls, RA patients of age ≤ 50 years, 2.6 < disease activity score in 28 joints (DAS28) ≤ 3.2, 3.2 < DAS28 ≤ 5.1, DAS28 > 5.1, C-reactive protein (CRP) levels > 10 mg/L, erythrocyte sedimentation rate (ESR) > 20 mm/h, and disease duration > 5 years had significantly higher circulating PTX3 levels, respectively; whereas RA patients of age > 50 years, DAS28 ≤ 2.6, CRP levels ≤ 10 mg/L, ESR ≤ 20 mm/h and disease duration ≤ 5 years had no significantly altered circulating PTX3 levels, respectively. Additionally, no matter whether the patients were of Caucasian ethnicity or not, circulating PTX3 levels were significantly increased in RA patients. CONCLUSION: Compared to healthy controls, circulating PTX3 levels are significantly increased in RA patients, which are influenced by age, disease activity, CRP levels, ESR, and disease duration.