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1.
Angiogenesis ; 27(2): 229-243, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38345700

RESUMO

BACKGROUND: Electronic (e-) cigarettes are increasingly popular tobacco products on the US market. Traditional tobacco products are known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. However, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults. METHODS: Twenty-one regular users of e-cigarettes (ECU) and twenty-one demographically matched non-users (NU) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality, endothelium-dependent vasodilation (EDD), and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD). RESULTS: Our results suggest that regular users of e-cigarettes present with premature microvascular impairment when compared to non-users. Specifically, they exhibit lower hyperemic (p = 0.003), thermal (p = 0.010), and EDD (p = 0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than 3 years also present with systemic manifestations, as observed by significantly reduced macrovascular (p = 0.002) and microvascular (p ≤ 0.044) function. CONCLUSIONS: Our novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation when compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than 3 years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Humanos , Adulto Jovem , Vasodilatação/fisiologia , Endotélio Vascular
2.
Respirology ; 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39019777

RESUMO

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide that frequently presents with concomitant cardiovascular diseases. Despite the pathological distinction between individual COPD phenotypes such as emphysema and chronic bronchitis, there is a lack of knowledge about the impact of COPD phenotype on cardiovascular disease risk. Thus, this study aimed to utilize a nationally representative sample to investigate cardiovascular disease prevalence in patients with COPD with emphysema and chronic bronchitis phenotypes. METHODS: Data from 31,560 adults including 2504 individuals with COPD, collected as part of the National Health and Nutrition Examination Survey (1999-2018), were examined. RESULTS: A significantly increased cardiovascular disease risk, including coronary heart disease, heart failure, myocardial infarction and stroke, was identified in patients with COPD among all disease phenotypes. Particularly, compared to those without COPD, individuals with chronic bronchitis presented with 1.76 (95% CI: 1.41-2.20) times greater odds, individuals with emphysema with 2.31 (95% CI: 1.80-2.96) times greater odds, while those with a concurrent phenotype (combined chronic bronchitis and emphysema) exhibited 2.98 (95% CI: 2.11-4.21) times greater odds of reporting cardiovascular diseases. CONCLUSION: Our data confirms that patients with COPD present an elevated risk of developing cardiovascular disease among all phenotypes, with the most marked increase being in those with concurrent chronic bronchitis and emphysema phenotypes. These findings emphasize the need for awareness and appropriate cardiovascular screening in COPD.

3.
Fam Community Health ; 47(2): 176-190, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38372334

RESUMO

INTRODUCTION: The US Food and Drug Administration is poised to restrict the availability of menthol cigarettes and flavored cigars, products disproportionately used by Black/African American (B/AA) individuals. We examined B/AA youth and adult perceptions regarding factors contributing to tobacco use, as well as prevention/cessation resources. METHODS: In 2 mixed-methods studies in Richmond, Virginia, we conducted cross-sectional surveys among youth (n = 201) and adult (n = 212) individuals who were primarily B/AA and reported past 30-day cigar smoking or nontobacco use, followed by focus groups with a subset (youth: n = 30; adults: n = 24). Focus groups were analyzed using a thematic analysis framework, and descriptive survey data provided context to themes. RESULTS: Among focus group participants, 20% of youth and 75% of adults reported current cigar smoking. Six themes emerged across the groups: advertising/brands, sensory experiences, costs, social factors, youth-related factors, and dependence/cessation. Youth and adults perceived cigars as popular; cigar use was attributed to targeted advertising, flavors, affordability, and accessibility. While adults expressed concern regarding youth tobacco use, youth did not perceive tobacco prevention programs as helpful. Adults and youth reported limited access to community tobacco prevention/cessation programs. DISCUSSION: Expanded tobacco prevention and cessation resources for B/AA people who smoke could leverage federal regulatory actions to ban tobacco products targeted toward this group and decrease disparities in tobacco-related morbidity and mortality.


Assuntos
Negro ou Afro-Americano , Uso de Tabaco , Adulto , Humanos , Adolescente , Virginia , Estudos Transversais , Inquéritos e Questionários
4.
Inflamm Res ; 70(1): 7-10, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33079210

RESUMO

OBJECTIVE: The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS). METHODS: Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1. RESULTS: Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064). CONCLUSIONS: These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome.


Assuntos
COVID-19/patologia , Inflamassomos , Pulmão/patologia , Adulto , Idoso , Autopsia , Proteínas Adaptadoras de Sinalização CARD/análise , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/análise , Caspase 1/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/patologia , Feminino , Parada Cardíaca/etiologia , Humanos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/etiologia , Pneumonia Viral/patologia , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/patologia
5.
Respiration ; 98(3): 198-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31121583

RESUMO

BACKGROUND: Malignant pleural effusion (MPE) is commonly seen in patients with non-small cell lung cancer. However, the prevalence of MPE at presentation in small-cell lung cancer (SCLC) is not reported and the clinical impact of MPE at presentation on patients with SCLC remains largely unknown. OBJECTIVE: The objective of this study is to assess the occurrence rate of MPE and its prognostic implications at presentation in patients with SCLC. METHOD: We used the Surveillance Epidemiology and End Results (SEER) registry to extract data from patients with SCLC diagnosed between 2004 and 2014. The Kaplan-Meier method was used to estimate the overall survival and the Cox proportional hazard model was used to evaluate whether MPE was an independent risk for outcome. RESULTS: Among the 68,443 patients with SCLC, MPE was present in 7,639 (11.16%). The probability of MPE was higher in older patients with larger tumors and mediastinal lymph node involvement at presentation. Median overall survival (3 vs. 7 months), estimated 1-year survival (17 vs. 30%), and 2-year survival (6 vs. 14%) were significantly lower in patients with MPE than without MPE, respectively (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.41-1.50, p< 0.001). MPE was also an independent factor for worse survival in multivariate analysis (HR 1.36, 95% CI 1.32-1.41, p < 0.001). CONCLUSIONS: MPE is common at presentation (11%) in patients with SCLC and may be associated with decreased survival. Additional studies are required to assess the treatment-adjusted survival rate in the setting of MPE.


Assuntos
Neoplasias Pulmonares/diagnóstico , Derrame Pleural Maligno/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática , Masculino , Mediastino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Derrame Pleural Maligno/etiologia , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER , Carcinoma de Pequenas Células do Pulmão/complicações , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Taxa de Sobrevida , Carga Tumoral , Adulto Jovem
7.
Langmuir ; 34(32): 9387-9393, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-29542322

RESUMO

A model is proposed for characterizing exosome size distributions based on dynamic scaling of domain growth on the limiting membrane of multivesicular bodies in the established exosome biogenesis pathway. The scaling exponent in this model captures the asymmetry of exosome size distributions, which are notably right-skewed to larger vesicles, independent of the minimum detectable vesicle size. Analyses of exosome size distributions obtained by cryogenic transmission electron microscopy imaging and nanoparticle tracking show, respectively, that the scaling exponent is sensitive to the state of the cell source for exosomes in cell culture supernatants and can distinguish exosome size distributions in serum samples taken from cancer patients relative to those from healthy donors. Finally, we comment on mechanistic differences between our dynamic scaling model and random fragmentation models used to describe size distributions of synthetic vesicles.


Assuntos
Exossomos/metabolismo , Linhagem Celular Tumoral , Exossomos/química , Humanos , Modelos Biológicos , Tamanho da Partícula
8.
BMC Pulm Med ; 18(1): 42, 2018 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-29506519

RESUMO

BACKGROUND: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD. METHODS: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes. RESULTS: On a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D' = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D' = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3%-89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes. CONCLUSIONS: GM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis.


Assuntos
Brônquios/patologia , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Células Epiteliais/metabolismo , Proteínas Nucleares/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fatores de Transcrição/genética , Alelos , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/patologia , Locos de Características Quantitativas , Análise de Sequência de RNA
9.
Nanomedicine ; 13(2): 765-770, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27989853

RESUMO

We present a method that takes advantage of the fluorophore loading dependence of fluorescence nanoparticle tracking (fNTA) to determine the content of specific miRNA targets in extracellular vesicles (EVs) and their stoichiometry across the entire EV population. The method is based on an assay for detecting EV miRNA by hybridization to fluorescently labeled, miRNA-specific molecular beacons encapsulated in cationic lipoplex nanoparticles that fuse non-specifically with negatively charged EVs. To demonstrate the method, we carry out a stoichiometric analysis of miR-21 in EVs released from A549 lung cancer cells. We find approximately 2.3% of the A549 EVs have an average copy number of ~44 miR-21/A549 EV and contain at least a threshold number of 33 miR-21 copies/A549 EV required for fluorescence tracking. Potential applications of sizing, enumerating, and phenotyping EVs using this method include specifying dosages for therapeutic applications and identifying specific EV subpopulations in patient samples for diagnostic applications.


Assuntos
Fluorescência , MicroRNAs/farmacocinética , Nanopartículas , Vesículas Extracelulares , Corantes Fluorescentes , Humanos , Neoplasias Pulmonares , Fenótipo , Coloração e Rotulagem , Células Tumorais Cultivadas
11.
Proc Natl Acad Sci U S A ; 110(21): 8573-8, 2013 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-23650389

RESUMO

In the past decade, we have observed exciting advances in lung cancer therapy, including the development of targeted therapies. However, additional strategies for early detection and tumor-based therapy are still essential in improving patient outcomes. EGF receptor (EGFR) and MET (the receptor tyrosine kinase for hepatocyte growth factors) are cell-surface tyrosine kinase receptors that have been implicated in diverse cellular processes and as regulators of several microRNAs (miRNAs), thus contributing to tumor progression. Here, we demonstrate a biological link between EGFR, MET, and the miRNA cluster 23a ~ 27a ~ 24-2. We show that miR-27a regulates MET, EGFR, and Sprouty2 in lung cancer. In addition, we identify both direct and indirect mechanisms by which miR-27a can regulate both MET and EGFR. Thus, we propose a mechanism for MET and EGFR axis regulation that may lead to the development of therapeutics in lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/biossíntese , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-met/biossíntese , RNA Neoplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-met/genética , RNA Neoplásico/genética
12.
Proc Natl Acad Sci U S A ; 110(37): 15043-8, 2013 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-23980150

RESUMO

MicroRNAs (miRNAs) are small 19- to 24-nt noncoding RNAs that have the capacity to regulate fundamental biological processes essential for cancer initiation and progression. In cancer, miRNAs may function as oncogenes or tumor suppressors. Here, we conducted global profiling for miRNAs in a cohort of stage 1 nonsmall cell lung cancers (n = 81) and determined that miR-486 was the most down-regulated miRNA in tumors compared with adjacent uninvolved lung tissues, suggesting that miR-486 loss may be important in lung cancer development. We report that miR-486 directly targets components of insulin growth factor (IGF) signaling including insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1, or p85a) and functions as a potent tumor suppressor of lung cancer both in vitro and in vivo. Our findings support the role for miR-486 loss in lung cancer and suggest a potential biological link to p53.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Receptor IGF Tipo 1/metabolismo , Regiões 3' não Traduzidas , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Genes p53 , Humanos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Inibidores de Fosfoinositídeo-3 Quinase , RNA Interferente Pequeno/genética , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais
13.
J Biol Chem ; 289(38): 26406-26416, 2014 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-25092292

RESUMO

MicroRNAs (miRNAs) are regulatory RNAs frequently dysregulated in disease and following cellular stress. Investigators have described changes in miR-15b expression following exposure to several stress-inducing anticancer agents, including ionizing radiation (IR), etoposide, and hydrogen peroxide. However, the role for miR-15b as a mediator of cellular injury in organs such as the lung has yet to be explored. In this study, we examined miR-15b expression patterns as well as its potential role in DNA damage and repair in the setting of IR exposure. We showed that miR-15b is up-regulated in a dose- and time-dependent manner in human bronchial epithelial cells following IR. miR-15b expression was highest after 2 h of IR and decreased gradually. Survival rates following IR were also higher in miR-15b/16-2-overexpressing cells. Cell cycle arrest in G2/M phase and an increased DNA repair response were observed in IR-exposed miR-15b/16-2 stable cells. We observed an up-regulation of components of the ataxia telangiectasia mutated (ATM)/Chek1/p53 pathway in miR-15b/16-2-overexpressing cells after IR. Moreover, a pathway-based PCR expression array of genes demonstrated that miR-15b/16-2 overexpression significantly induced the expression of genes involved in ATM/ataxia telangiectasia and Rad-3-related (ATR) signaling, apoptosis, the cell cycle, and DNA repair pathways. Here we demonstrated a novel biological link between miR-15b and DNA damage and cellular protection in lung cells. We identified Wip1 (PPM1D) as a functional target for miR-15b and determined that miR-15b induction of the DNA damage response is partially dependent upon suppression of Wip1. Our study suggests that miR-15b/Wip1 could be a potential therapeutic target in radiation-induced lung disease.


Assuntos
Células Epiteliais/fisiologia , MicroRNAs/fisiologia , Processamento de Proteína Pós-Traducional , Proteína Supressora de Tumor p53/metabolismo , Regiões 3' não Traduzidas , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Quinase 1 do Ponto de Checagem , Dano ao DNA , Reparo do DNA , Células Epiteliais/efeitos da radiação , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Pulmão/patologia , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Proteína Fosfatase 2C , Interferência de RNA , Mucosa Respiratória/patologia
14.
Proc Natl Acad Sci U S A ; 109(31): E2110-6, 2012 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-22753494

RESUMO

MicroRNAs (miRNAs) are small noncoding RNAs, 19-24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread, thus representing a possible target for cancer treatment.


Assuntos
Glicoproteínas de Membrana/metabolismo , MicroRNAs/sangue , Neoplasias/sangue , RNA Neoplásico/sangue , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Animais , Células HEK293 , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , MicroRNAs/genética , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Comunicação Parácrina/genética , RNA Neoplásico/genética , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/genética
15.
Res Sq ; 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38260305

RESUMO

Introduction: Acute ischemic stroke with large vessel occlusion (LVO) continues to present a considerable challenge to global health, marked by substantial morbidity and mortality rates. Although definitive diagnostic markers exist in the form of neuroimaging, their expense, limited availability, and potential for diagnostic delay can often result in missed opportunities for life-saving interventions. Despite several past attempts, research efforts to date have been fraught with challenges likely due to multiple factors such as inclusion of diverse stroke types, variable onset intervals, differing pathobiologies, and a range of infarct sizes, all contributing to inconsistent circulating biomarker levels. In this context, microRNAs (miRNAs) have emerged as a promising biomarker, demonstrating potential as biomarkers across various diseases, including cancer, cardiovascular conditions, and neurological disorders. These circulating miRNAs embody a wide spectrum of pathophysiological processes, encompassing cell death, inflammation, angiogenesis, neuroprotection, brain plasticity, and blood-brain barrier integrity. This pilot study explores the utility of circulating exosome-enriched extracellular vesicle (EV) miRNAs as potential biomarkers for anterior circulation LVO (acLVO) stroke. Methods: In our longitudinal prospective cohort study, we collected data from acute large vessel occlusion (acLVO) stroke patients at four critical time intervals post-symptom onset: 0-6 hours, 6-12 hours, 12-24 hours, and 5-7 days. For comparative analysis, healthy individuals were included as control subjects. In this study, extracellular vesicles (EVs) were isolated from the plasma of participants, and the miRNAs within these EVs were profiled utilizing the NanoString nCounter system. Complementing this, a scoping review was conducted to examine the roles of specific miRNAs such as miR-140-5p, miR-210-3p, and miR-7-5p in acute ischemic stroke (AIS). This review involved a targeted PubMed search to assess their influence on crucial pathophysiological pathways in AIS, and their potential applications in diagnosis, treatment, and prognosis. The review also included an assessment of additional miRNAs linked to stroke. Results: Within the first 6 hours of symptom onset, three specific miRNAs (miR-7-5p, miR-140-5p, and miR-210-3p) exhibited significant differential expression compared to other time points and healthy controls. These miRNAs have previously been associated with neuroprotection, cellular stress responses, and tissue damage, suggesting their potential as early markers of acute ischemic stroke. Conclusion: This study highlights the potential of circulating miRNAs as blood-based biomarkers for hyperacute acLVO ischemic stroke. However, further validation in a larger, risk-matched cohort is required. Additionally, investigations are needed to assess the prognostic relevance of these miRNAs by linking their expression profiles with radiological and functional outcomes.

16.
Artigo em Inglês | MEDLINE | ID: mdl-38990977

RESUMO

BACKGROUND: Electronic nicotine delivery systems, often referred to as e-cigarettes, are popular tobacco products frequently advertised as safer alternatives to traditional cigarettes despite preliminary data suggesting a potential negative cardiovascular impact. Cardiorespiratory fitness is a critical cardiovascular health marker that is diminished in individuals who consume traditional tobacco products. Whether the use of e-cigarettes impacts cardiorespiratory fitness is currently unknown. Thus, the purpose of this study was to investigate the impact of regular e-cigarette use on cardiorespiratory fitness in young healthy adults. METHODS: Twenty-six users of e-cigarettes (ECU, 13 males, and 13 females; age: 24±3 yr; e-cigarette usage 4±2 yr.) and sixteen demographically matched non-users (NU, 6 males, and 10 females; age: 23±3 yr.) participated in this study. Cardiorespiratory fitness was measured by peak oxygen consumption (VO2peak) during a cardiopulmonary exercise test. Measurements of chronotropic response, hemodynamic, oxygen extraction and utilization were also evaluated. RESULTS: Our results suggest that regular users of e-cigarettes exhibited significantly lower peak oxygen consumption when compared to non-users, even when controlled by fat-free mass and lean body mass. Hemodynamic changes were not different between both groups during exercise, while lower chronotropic responses and skeletal muscle oxygen utilization were observed in users of e-cigarettes. CONCLUSIONS: Results from the present study demonstrate that young, apparently healthy, regular users of e-cigarettes exhibit significantly reduced cardiorespiratory fitness, lower chronotropic response, and impaired skeletal muscle oxygen utilization during exercise. Overall, our findings contribute to the growing body of evidence that supports adverse effects of regular e-cigarette use on cardiovascular health.

17.
iScience ; 27(2): 108858, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38303720

RESUMO

Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.

18.
FASEB J ; 26(8): 3351-64, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22593544

RESUMO

Mechanical ventilation generates biophysical forces, including high transmural pressures, which exacerbate lung inflammation. This study sought to determine whether microRNAs (miRNAs) respond to this mechanical force and play a role in regulating mechanically induced inflammation. Primary human small airway epithelial cells (HSAEpCs) were exposed to 12 h of oscillatory pressure and/or the proinflammatory cytokine TNF-α. Experiments were also conducted after manipulating miRNA expression and silencing the transcription factor NF-κB or toll-like receptor proteins IRAK1 and TRAF6. NF-κB activation, IL-6/IL-8/IL-1ß cytokine secretion, miRNA expression, and IRAK1/TRAF6 protein levels were monitored. A total of 12 h of oscillatory pressure and TNF-α resulted in a 5- to 7-fold increase in IL-6/IL-8 cytokine secretion, and oscillatory pressure also resulted in a time-dependent increase in IL-6/IL-8/IL-1ß cytokine secretion. Pressure and TNF-α also resulted in distinct patterns of miRNA expression, with miR-146a being the most deregulated miRNA. Manipulating miR-146a expression altered pressure-induced cytokine secretion. Silencing of IRAK1 or TRAF6, confirmed targets of miR-146a, resulted in a 3-fold decrease in pressure-induced cytokine secretion. Cotransfection experiments demonstrate that miR-146a's regulation of pressure-induced cytokine secretion depends on its targeting of both IRAK1 and TRAF6. MiR-146a is a mechanosensitive miRNA that is rapidly up-regulated by oscillatory pressure and plays an important role in regulating mechanically induced inflammation in lung epithelia.


Assuntos
Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Inflamação/etiologia , Pulmão/fisiopatologia , MicroRNAs/fisiologia , Células Cultivadas , Humanos , Quinases Associadas a Receptores de Interleucina-1/efeitos dos fármacos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Mecanotransdução Celular/efeitos dos fármacos , MicroRNAs/biossíntese , NF-kappa B/farmacologia , Pressão , Fator 6 Associado a Receptor de TNF/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
19.
Fac Rev ; 12: 22, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37675274

RESUMO

Lung cancer is the leading cause of malignancy-related death in the United States and the second most common cancer diagnosis worldwide. In the last two decades, lung cancer treatment has evolved to include advances in the development of mutation-based targeting, immunotherapy, radiation therapy, and minimally invasive surgical techniques. The discovery of lung cancer as a molecularly heterogeneous disease has driven investigation into the development of targeted therapies resulting in improved patient outcomes. Despite these advances, there remain opportunities, through further investigation of mechanisms of resistance, to develop novel therapeutics that better direct the personalization of lung cancer therapy. In this review, we highlight developments in the evolution of targeted therapies in non-small cell lung cancer, as well as future directions shaped by emerging patterns of resistance.

20.
Cancers (Basel) ; 15(12)2023 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-37370722

RESUMO

Sex disparities in the incidence and mortality of lung cancer have been observed since cancer statistics have been recorded. Social and economic differences contribute to sex disparities in lung cancer incidence and mortality, but evidence suggests that there are also underlying biological differences that contribute to the disparity. This review summarizes biological differences which could contribute to the sex disparity. Sex hormones and other biologically active molecules, tumor cell genetic differences, and differences in the immune system and its response to lung cancer are highlighted. How some of these differences contribute to disparities in the response to therapies, including cytotoxic, targeted, and immuno-therapies, is also discussed. We end the study with a discussion of our perceived future directions to identify the key biological differences which could contribute to sex disparities in lung cancer and how these differences could be therapeutically leveraged to personalize lung cancer treatment to the individual sexes.

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