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1.
Artigo em Inglês | MEDLINE | ID: mdl-33093772

RESUMO

Background: Forms of interstitial pneumonia secondary to exposure to an air-contaminant are varied and so far, insufficiently described. Objectives/Methods: We report here a case of a 57-year-old patient managed in our department for the exploration of MRC grade 2 dyspnoea and interstitial pneumonia. He mentioned multiple occupational and domestic exposures such as hens' excrements, asbestos and metal particles; he also had a previous history of smoking. Results: High-resolution computed tomography showed ground glass opacities predominating in posterior territories and surrounding cystic lesions or emphysematous destruction. The entire etiological assessment revealed only macrophagic alveolitis with giant multinucleated cells on the bronchoalveolar lavage. A surgical lung biopsy allowed us to refine the diagnosis with evidence of desquamative interstitial pneumonia and pulmonary granulomatosis. Finally, the analysis of the mineral particles in the biopsy revealed abnormally high rates of Zirconium and Aluminium. We were therefore able to conclude to a desquamative interstitial pneumonia associated with pulmonary granulomatosis linked to metal exposure (Aluminium and Zirconium). The clinical, functional and radiological evolution was favorable after a systemic corticosteroid treatment with progressive decay over one year. Conclusion: This presentation reports the first case to our knowledge of desquamative interstitial pneumonitis related to exposure to Zirconium and the third one in the context of Aluminium exposure. The detailed analysis of the mineral particles present on the surgical lung biopsy allows for the identification of the relevant particle to refine the etiological diagnosis, to guide the therapeutic management and to give access to recognition as an occupational disease. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 79-84).


Assuntos
Alumínio/efeitos adversos , Granuloma do Sistema Respiratório/induzido quimicamente , Exposição por Inalação/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Pulmão/efeitos dos fármacos , Zircônio/efeitos adversos , Corticosteroides/administração & dosagem , Alumínio/análise , Biópsia , Granuloma do Sistema Respiratório/diagnóstico , Granuloma do Sistema Respiratório/tratamento farmacológico , Granuloma do Sistema Respiratório/metabolismo , Humanos , Pulmão/química , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Zircônio/análise
2.
J Breath Res ; 14(4): 046012, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33021213

RESUMO

Breath analysis holds promise for non-invasive in vivo monitoring of disease related processes. However, physiological parameters may considerably affect profiles of exhaled volatile organic substances (VOCs). Volatile substances can be released via alveoli, bronchial mucosa or from the upper airways. The aim of this study was the systematic investigation of the influence of different sampling sites in the respiratory tract on VOC concentration profiles by means of a novel experimental setup. After ethical approval, breath samples were collected from 25 patients undergoing bronchoscopy for endobronchial ultrasound or bronchoscopic lung volume reduction from different sites in the airways. All patients had total intravenous anaesthesia under pressure-controlled ventilation. If necessary, respiratory parameters were adjusted to keep PETCO2 = 35-45 mm Hg. 30 ml gas were withdrawn at six sampling sites by means of gastight glass syringes: S1 = Room air, S2 = Inspiration, S3 = Endotracheal tube, S4 = Trachea, S5 = Right B6 segment, S6 = Left B6 segment (S4-S6 through the bronchoscope channel). 10 ml were used for VOC analysis, 20 ml for PCO2 determination. Samples were preconcentrated by solid-phase micro-extraction (SPME) and analysed by gas chromatography-mass spectrometry (GC-MS). PCO2 was determined in a conventional blood gas analyser. Statistically significant differences in substance concentrations for acetone, isoprene, 2-methyl-pentane and n-hexane could be observed between different sampling sites. Increasing substance concentrations were determined for acetone (15.3%), 2-methyl-pentane (11.4%) and n-hexane (19.3%) when passing from distal to proximal sampling sites. In contrast, isoprene concentrations decreased by 9.9% from proximal to more distal sampling sites. Blank bronchoscope measurements did not show any contaminations. Increased substance concentrations in the proximal respiratory tract may be explained through substance excretion from bronchial mucosa while decreased concentrations could result from absorption or reaction processes. Spatial mapping of VOC profiles can provide novel insights into substance specific exhalation kinetics and mechanisms.


Assuntos
Testes Respiratórios/métodos , Broncoscopia , Expiração , Manejo de Espécimes , Compostos Orgânicos Voláteis/análise , Dióxido de Carbono/química , Feminino , Humanos , Limite de Detecção , Pulmão/química , Masculino , Pessoa de Meia-Idade , Pressão Parcial
3.
Medicine (Baltimore) ; 99(31): e20076, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756072

RESUMO

C-terminal binding protein-2 (CtBP2) a transcriptional corepressor, has been reported to involve in tumorigenesis and progression and predict a poor prognosis in several human cancers. However, few studies on CtBP2 in lung cancer tissues have been performed. In the present study, we first explored the CtBP2 gene expression profile from the the cancer genome atlas (TCGA) datasets, then western blot analysis and immunohistochemistry were performed to investigate and verified whether lung adenocarcinoma (LUAD) tissues exhibit deregulated CtBP2 expression. We evaluated the correlations between CtBP2 expression and the clinicopathological characteristics, and Kaplan-Meier survival analyses were performed to estimate the effect of CtBP2 expression on prognosis of LUAD patients. The results revealed that CtBP2 expression was significantly upregulated in LUAD tissues compared with normal lung tissues. Furthermore, increasing CtBP2 expression in LUAD was significantly associated with tumor differentiation (P = .028), tumor node metastasis (TNM) stage (P = .042). CtBP2 expression was significantly correlated with LUAD patients' survival (P = .028). In conclusion, the present study revealed that CtBP2 protein is a novel prognostic marker for LUAD. A further large-scale study is needed to confirm the present results.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Oxirredutases do Álcool/análise , Proteínas Correpressoras/análise , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma de Pulmão/química , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/análise , Western Blotting , Feminino , Humanos , Pulmão/química , Neoplasias Pulmonares/química , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida
4.
Chemosphere ; 261: 127710, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32721691

RESUMO

Existing experimental data do not sufficiently explain which pathophysiologic processes are involved in different age of rats exposed to long-term particulate matter. This study explored the pulmonary and cardiovascular effects of long-term PM2.5 and PM10 exposure in juvenile, adult and senescent rats. Tail cuff plethysmography, whole-body plethysmographic system, myograph, enzyme-linked immunosorbent assay, and inductively coupled plasma-mass spectrometry were used to detect the blood pressure, lung function, endothelium-dependent relaxation, inflammatory cytokines and heavy metals, respectively. The exposure time was from November, 2017 to October, 2018, and the average concentrations of PM2.5 and PM10 were 78.7 and 128.2 µg/m3, respectively. Compared with the filtered air group, the body weight and survival rate in PM2.5 and PM10 exposure group were significantly decreased, and the survival rate of senescent exposed rats was only 30%. PM2.5 and PM10 exposure increased the blood pressure, elevated the levels of serum and bronchoalveolar lavage fluid inflammatory factors, and the senescent exposed rats showed an earlier rising trend in blood pressure and inflammatory factors than those of juvenile and adult exposed rats. Long-term PM2.5 and PM10 exposure could destroy intrapulmonary and small resistance arteries endothelial function, causing vasodilation disorders. PM2.5 and PM10 exposure caused particulate matter to accumulate in the lungs. Additionally, PM2.5 and PM10 exposure could also cause accumulation of cadmium (Cd) and lead in the liver, and chromium and Cd in the kidney. In conclusion, ambient PM2.5 and PM10 exposure induced particulate matter to accumulate in the body, caused severe pulmonary and vascular disorders, and demonstrated age-associated differences.


Assuntos
Pulmão/fisiopatologia , Material Particulado/toxicidade , Poluentes Atmosféricos/análise , Animais , Exposição Ambiental/análise , Humanos , Pulmão/química , Masculino , Material Particulado/análise , Ratos
5.
Biosens Bioelectron ; 165: 112435, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32729548

RESUMO

COVID-19 is the shocking viral pandemics of this year which affected the health, economy, communications, and all aspects of social activities all over the world. Early diagnosis of this viral disease is very important since it can prevent lots of mortalities and care consumption. The functional similarities between COVID-19 and COVID-2 in inducing acute respiratory syndrome lightened our mind to find a diagnostic mechanism based on early traces of mitochondrial ROS overproduction as lung cells' dysfunctions induced by the virus. We designed a simple electrochemical sensor to selectively detect the intensity of ROS in the sputum sample (with a volume of less than 500 µl). Comparing the results of the sensor with clinical diagnostics of more than 140 normal and involved cases resulted in a response calibration with accuracy and sensitivity both 97%. Testing the sensor in more than 4 hospitals shed promising lights in ROS based real-time tracing of COVID-19 from the sputum sample.


Assuntos
Betacoronavirus/isolamento & purificação , Técnicas Biossensoriais/métodos , Infecções por Coronavirus/diagnóstico , Técnicas Eletroquímicas/métodos , Pneumonia Viral/diagnóstico , Espécies Reativas de Oxigênio/análise , Escarro/virologia , Adulto , Idoso , Técnicas Biossensoriais/instrumentação , Infecções por Coronavirus/virologia , Diagnóstico Precoce , Técnicas Eletroquímicas/instrumentação , Desenho de Equipamento , Feminino , Humanos , Pulmão/química , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Sensibilidade e Especificidade , Escarro/química , Adulto Jovem
6.
Environ Pollut ; 263(Pt B): 114384, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32234644

RESUMO

The present investigation represents a new approach useful to evaluate the general population risk correlated with environmental exposure to air dispersed inorganic fibers. The used method is based on the evaluation of the respirable inorganic fibers both air dispersed in a big city and contained in lungs of the general population following their respiration. Moreover, these data allow to identify the sources of dispersion (anthropogenic or natural) in air of the inorganic fibers and therefore to apply strategies to improve air quality. To describe this approach, we investigated air samples from a big city in NW Italy and lung inorganic burden of people here lived. This paper reports the data of the airborne inorganic fibers detected in two sampling campaign (2014 and 2016), in 24 districts of Torino (Piemonte - NW Italy), and in some autoptic lungs of general population lived here. The airborne fibers (collected on mixed-cellulose esters membrane) were characterized by SEMEDS. The identified inorganic fiber species were assigned to 5 classes, one of these including 2 types of asbestos. These last are grouped as tremolite/actinolite asbestos. They are dispersed from natural sources (i.e. certain kinds of rocks outcropping in the city surrounding areas). In no-one of the 24 districts of Torino their concentration highlighted a situation of asbestos pollution in place. A correlation with inorganic fibers (collected on mixed-cellulose esters membrane and characterized by SEM-EDS) detected in lung tissue samples of 10 subjects lived in Torino all their life and without professional exposure to asbestos were attempted. The only types of fibers identified as asbestos are tremolite/actinolite asbestos, and they match those detected in air sampling. The number of fibers per 1 g of tissue dry weight is lower than the quantities reported as indicative of significant asbestos exposure. We observed interesting gender differences.


Assuntos
Poluição do Ar , Asbestos , Cidades , Humanos , Itália , Pulmão/química
7.
Nat Biotechnol ; 38(5): 629-637, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152598

RESUMO

Crosstalk between neighboring cells underlies many biological processes, including cell signaling, proliferation and differentiation. Current single-cell genomic technologies profile each cell separately after tissue dissociation, losing information on cell-cell interactions. In the present study, we present an approach for sequencing physically interacting cells (PIC-seq), which combines cell sorting of physically interacting cells (PICs) with single-cell RNA-sequencing. Using computational modeling, PIC-seq systematically maps in situ cellular interactions and characterizes their molecular crosstalk. We apply PIC-seq to interrogate diverse interactions including immune-epithelial PICs in neonatal murine lungs. Focusing on interactions between T cells and dendritic cells (DCs) in vitro and in vivo, we map T cell-DC interaction preferences, and discover regulatory T cells as a major T cell subtype interacting with DCs in mouse draining lymph nodes. Analysis of T cell-DC pairs reveals an interaction-specific program between pathogen-presenting migratory DCs and T cells. PIC-seq provides a direct and broadly applicable technology to characterize intercellular interaction-specific pathways at high resolution.


Assuntos
Células Dendríticas/citologia , Perfilação da Expressão Gênica/métodos , Análise de Célula Única/métodos , Linfócitos T/citologia , Algoritmos , Animais , Animais Recém-Nascidos , Comunicação Celular , Células Cultivadas , Biologia Computacional , Células Dendríticas/química , Feminino , Citometria de Fluxo , Pulmão/química , Pulmão/citologia , Camundongos , Análise de Sequência de RNA , Linfócitos T/química
9.
Environ Pollut ; 259: 113880, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32040986

RESUMO

Silver nanoparticles (AgNP) are commonly used in medical, cosmetics, clothing, and industrial applications for their antibacterial and catalytic properties. As AgNP become more prevalent, the doses to which humans are exposed may increase and pose health risks, particularly through incidental inhalation. This exposure was evaluated through in-vitro methods simulating lung fluids and lung epithelium, and through computational fluid dynamics (CFD) methods of AgNP transport. A high-dose scenario simulated a short-term inhalation of 10 µg AgNP/m3, based on an exposure limit recommended by the National Institute of Occupational Safety and Health for the case of a health-care worker who handles AgNP-infused wound dressings, and regularly wears AgNP-imbedded clothing. Bioaccessibility tests were followed by a Parallel Artificial Membrane Permeability Assay (PAMPA) and supported by CFD models of the lung alveoli, membrane, pores, and blood capillaries. Results indicate that such exposure produces an average and maximum AgNP flux of approximately 4.7 × 10-21 and 6.5 × 10-19 mol m-2·s-1 through lung tissue, respectively, yielding a blood-silver accumulation of 0.46-64 mg per year, which may exceed the lowest adverse effect level of 25 mg for an adult male. Results from in-silico simulations were consistent with values estimated in vitro (within an order of magnitude), which suggest that CFD models may be used effectively to predict silver exposure from inhaled AgNP. Although the average short-term exposure concentrations are 3 orders of magnitude smaller than the reported threshold for mammalian cytotoxicity effects (observed at 5000 ppb), cumulative effects resulting from constant exposure to AgNP may pose risks to human health in the long-term, with predicted bioaccumulation reaching potential toxic effects after only five months of exposure, based on maximum flux.


Assuntos
Pulmão , Nanopartículas Metálicas , Prata , Adulto , Antibacterianos , Simulação por Computador , Exposição Ambiental , Humanos , Hidrodinâmica , Técnicas In Vitro , Pulmão/química , Pulmão/metabolismo , Masculino , Prata/metabolismo
10.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012911

RESUMO

Naringenin, a flavonoid compound which exists abundantly in Citrus fruits, is proven to possess excellent antitussive and expectorant effects. However, the clinical applications of naringenin are restricted by its poor solubility and low local concentration by oral administration. The aim of the present study is to prepare a naringenin-hydroxypropyl-ß-cyclodextrin (naringenin-HPßCD) inclusion as an inhalation solution for pulmonary delivery. The naringenin-HPßCD inclusion was characterized by phase solubility study, XRD, differential scanning calorimetry (DSC), proton nuclear magnetic resonance (1HNMR), and two-dimensional rotating frame Overhauser effect spectroscopy (2D ROESY). The in vitro permeability of the inclusion was evaluated on Calu-3 cells and the pharmacokinetic profile of pulmonary delivery was investigated in Sprague-Dawley (SD) rats. Based on the linear model of phase solubility study, the relationship between naringenin and HPßCD was identified as AL type with a 1:1 stoichiometry. XRD, DSC, and NMR studies indicated that the entire naringenin molecule is encapsulated into the cavity of HPßCD. HPßCD could increase the concentration of naringenin in the epithelium-lining fluid (ELF) of Calu-3 cells and act as a sustained release system for naringenin. The pharmacokinetic profile of naringenin-HPßCD inclusion showed rapid response and higher local concentration by pulmonary delivery. In conclusion, pulmonary delivery of naringenin-HPßCD inclusion is a promising formulation strategy, which could provide a new possibility for the clinical application of naringenin.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Flavanonas/administração & dosagem , Pulmão/química , Administração Oral , Animais , Varredura Diferencial de Calorimetria , Linhagem Celular , Feminino , Flavanonas/química , Flavanonas/farmacocinética , Humanos , Masculino , Nebulizadores e Vaporizadores , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Solubilidade , Difração de Raios X
11.
Kobe J Med Sci ; 65(3): E100-E109, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-32029695

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis due to limited clinical treatment options. IPF is characterized by the augmented deposition of extracellular matrix driven by myofibroblasts, and the epithelial-mesenchymal transition (EMT) has been known to play an essential role in the mechanism of pulmonary fibrosis. Previous genome-wide association study identified Fam13a as one of genes that showed genetic link with IPF and chronic obstructive pulmonary disease. Here, we analyzed the role of Fam13a in the pathogenesis of pulmonary fibrosis using Fam13a-deficient mice. We found that Fam13a was down-regulated in mouse lungs of bleomycin-induced pulmonary fibrosis model. Of note, genetic deletion of Fam13a exacerbated the lung fibrosis induced by bleomycin in association with enhanced EMT in mice. Moreover, silencing of Fam13a accelerated EMT induced by TGF-ß and TNF-α in alveolar epithelial cells, accompanied by increased active ß-catenin and its nuclear accumulation. Our data revealed a crucial role of Fam13a in the development of pulmonary fibrosis potentially through inhibiting EMT, and thus Fam13a has a therapeutic potential in the treatment of IPF.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Proteínas Ativadoras de GTPase/deficiência , Proteínas Ativadoras de GTPase/fisiologia , Fibrose Pulmonar Idiopática/genética , Células A549 , Animais , Bleomicina/farmacologia , Núcleo Celular/química , Modelos Animais de Doenças , Regulação para Baixo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/fisiologia , Proteínas Ativadoras de GTPase/antagonistas & inibidores , Proteínas Ativadoras de GTPase/genética , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/química , Pulmão/patologia , Pulmão/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miofibroblastos/química , Miofibroblastos/patologia , Transfecção , Fator de Crescimento Transformador beta/farmacologia , beta Catenina/análise
12.
Molecules ; 25(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046011

RESUMO

Understanding interactions between inhaled nanoparticles and lung surfactants (LS) present at the air-water interface in the lung, is critical to assessing the toxicity of these nanoparticles. Specifically, in this work, we assess the impact of engineered carbon nanoparticles (ECN) on the ability of healthy LS to undergo reversible collapse, which is essential for proper functioning of LS. Using a Langmuir trough, multiple compression-expansion cycles are performed to assess changes in the surface pressure vs. area isotherms with time and continuous cyclic compression-expansion. Further, theoretical analysis of the isotherms is used to calculate the ability of these lipid systems to retain material during monolayer collapse, due to interactions with ECNs. These results are complemented with fluorescence images of alterations in collapse mechanisms in these monolayer films. Four different model phospholipid systems, that mimic the major compositions of LS, are used in this study. Together, our results show that the ECN does not impact the mechanism of collapse. However, the ability to retain material at the interface during monolayer collapse, as well as re-incorporation of material after a compression-expansion cycle is altered to varying extent by ECNs and depends on the composition of the lipid mixtures.


Assuntos
Carbono/química , Pulmão/química , Modelos Teóricos , Nanodiamantes/química , Surfactantes Pulmonares/química , Água/química , Ar , Fosfolipídeos/química , Propriedades de Superfície
13.
Ecotoxicol Environ Saf ; 191: 110211, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31978763

RESUMO

This study aimed to verify possible alterations involving histological and oxidative stress parameters in the lungs of wild bats in the Carboniferous Basin of Santa Catarina (CBSC) state, Southern Brazil, as a means to evaluate the impact of coal dust on the health of wildlife. Specimens of frugivorous bat species Artibeus lituratus and Sturnira lilium were collected from an area free of coal dust contamination and from coal mining areas. Chemical composition, histological parameters, synthesis of oxidants and antioxidant enzymes, and oxidative damage in the lungs of bats were analyzed. Levels of Na, Cl, Cu, and Br were higher in both species collected in the CBSC than in the controls. Levels of K and Rb were higher in A. lituratus, and levels of Si, Ca, and Fe were higher in S. lilium collected in the carboniferous basin. Both bat species inhabiting the CBSC areas exhibited an increase in the degree of pulmonary emphysema compared to their counterparts collected from control areas. Sturnira lilium showed increased reactive oxygen species (ROS) and 2',7'-dichlorofluorescein (DCF) levels, while A. lituratus showed a significant decrease in nitrite levels in the CBSC samples. Superoxide dismutase (SOD) activity did not change significantly; however, the activity of catalase (CAT) and levels of glutathione (GSH) decreased in the A. lituratus group from CBSC compared to those in the controls. There were no differences in NAD(P)H quinone dehydrogenase 1 protein (NQO1) abundance or nitrotyrosine expression among the different groups of bats. Total thiol levels showed a significant reduction in A. lituratus from CBSC, while the amount of malondialdehyde (MDA) was higher in both A. lituratus and S. lilium groups from coal mining areas. Our results suggested that bats, especially A. lituratus, living in the CBSC could be used as sentinel species for harmful effects of coal dust on the lungs.


Assuntos
Quirópteros , Minas de Carvão , Carvão Mineral/toxicidade , Pulmão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Brasil , Catalase/metabolismo , Quirópteros/anatomia & histologia , Quirópteros/metabolismo , Poeira , Glutationa/metabolismo , Pulmão/anatomia & histologia , Pulmão/química , Pulmão/metabolismo , Malondialdeído/metabolismo , Metais/análise , Modelos Biológicos , Enfisema Pulmonar/veterinária , Espécies Reativas de Oxigênio/metabolismo
14.
J Agric Food Chem ; 68(6): 1563-1570, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927998

RESUMO

Ethanamizuril(N-{4-[4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenoxy]-phenyl}-acetamide, EZL) is a new anticoccidiosis compound and belongs to the class of triazines. In this study, the metabolism, distribution, and excretion of EZL were evaluated in chickens after administration of EZL at a single dosage. According to the relevant drug biotransformation rules, the exact molecular mass detection, the fragmentation characteristics, and the retention times, a total of five metabolites were identified in vivo in chickens, including two phase I metabolites and three phase II conjugated metabolites. The major metabolic pathways of EZL in chickens were deacetylation, hydroxylation, and glucuronidation. Regarding 14C-tissue residues after administration, kidney was considered to be the target tissue, as 14C-tissue residues could be detected at 240 h postdose. DeacetylEZL (M3) was the main metabolite, accounting for 68.65% and 25.62% of 14C in kidney at 6 and 24 h, respectively. In heart, muscle, skin+fat, and lung tissues, EZL was the main radioactive substance accounting for 94.88%, 97.32%, 96.23%, and 91.3% of 14C, respectively. In the liver, EZL and M3 were 20.76% and 54.65% of 14C, respectively. In chicken tissues the ratio of M5 was too low to be quantitated and it was mainly detected in chicken fecal and bile samples. In chicken excreta, EZL, M3, and glucuronidation of EZL (M5) accounted for 7.02%, 12.33%, and 10.32% of the dose, respectively and were eliminated primarily. This study presents the first detection of EZL metabolites, which is helpful for further understanding of the metabolic mechanism and in vivo intermediate processes of EZL. The results of this study will be good bases for better understanding EZL's anticoccidiosis mechanism and will serve as a helpful reference for assessing the risks to animals and humans.


Assuntos
Coccidiostáticos/farmacocinética , Triazinas/farmacocinética , Animais , Biotransformação , Galinhas , Coccidiostáticos/administração & dosagem , Coccidiostáticos/metabolismo , Hidroxilação , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Pulmão/química , Pulmão/metabolismo , Músculos/química , Músculos/metabolismo , Triazinas/administração & dosagem , Triazinas/metabolismo
15.
Ecotoxicol Environ Saf ; 190: 110116, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911387

RESUMO

Exposure to outdoor concentrations of fine particulate matter (PM2.5) is a leading global health concern. Waste incineration emission has been recognized as a potential major contributor of ambient PM2.5. Respiratory inflammation is a central feature induced by PM2.5 exposure by inhalation. However, the molecular mechanisms are not fully understood. Dual-specificity phosphatase 1 (Dusp1) plays an instrumental role in the regulation of airway inflammation. In this study, fly ash particles (20 mg/kg BW) collected from a municipal waste incinerator in China were given to BALB/c wild-type (WT) and Dusp1-/- mice by intranasal administration daily for three consecutive days. While these particles induced mild inflammation in both genotypes, a significantly higher level of serum interleukin-6 (665 pg/ml) was measured in Dusp1-/- mice challenged with fly ash particles than in their WT counterparts. Genome-wide transcriptome profiling of pulmonary coding genes in response to the exposure were performed in both genotypes by RNA sequencing. We identified 487 differentially-expressed genes (DEGs) in fly ash-challenged Dusp1-/- mice versus their WT counterparts with a log2fold-change >1.5 and p < 0.05. Functional enrichment and molecular pathway mapping of the DEGs specific to Dusp1-/- mice exposed to the particles revealed that the top 10 perturbed molecular pathways were associated with the immune response. Our study demonstrates the anti-inflammatory role of Dusp1 in protecting the lung against insults by fly ash particles, suggesting that Dusp1 might be a therapeutic target for the treatment of PM2.5-induced respiratory diseases.


Assuntos
Fosfatase 1 de Especificidade Dupla/metabolismo , Material Particulado/toxicidade , Animais , Carbono/análise , China , Cinza de Carvão/análise , Perfilação da Expressão Gênica , Incineração , Pulmão/química , Camundongos , Camundongos Endogâmicos BALB C , Material Particulado/análise , Transcriptoma
16.
Ecotoxicol Environ Saf ; 190: 110132, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31918253

RESUMO

Exposure to combustion-derived nanoparticles is recognized as a major health hazard, but the molecular responses are still insufficiently described. The transcription factor erythroid 2-related factor 2 (Nrf2, also known as NFE2L2) is a master regulator of the pulmonary defense system against insults by particulate matter. However, its downstream molecular processes are not fully characterized. In the current study, BALB/c wild-type (WT) and Nrf2-/- mice were exposed by intranasal administration to fly ash particles (F3-S; 20 mg/kg BW), which were collected from a municipal waste incinerator in China, for three consecutive days. Using a comparative transcriptomics approach, the pulmonary global gene expression profiles to F3-S exposure were characterized for both genotypes. The preponderance of the differentially-expressed genes (DEGs) in WT mice induced by the fly ash particles, was related to inflammation. Functional enrichment and molecular pathway mapping of the DEGs specific to Nrf2-/- mice exposed to the particles revealed that all of the top 10 perturbed molecular pathways were associated with the inflammatory response. Our study identified a transcriptional signature related to the initial pulmonary injury in mouse upon fly ash exposure, and suggests an anti-inflammatory role of Nrf2 in protecting the lung against such exposure.


Assuntos
Fator 2 Relacionado a NF-E2/metabolismo , Material Particulado/toxicidade , Animais , Carbono , China , Cinza de Carvão/análise , Perfilação da Expressão Gênica , Incineração , Pulmão/química , Camundongos , Camundongos Endogâmicos BALB C , Transcriptoma
17.
Anal Bioanal Chem ; 412(7): 1521-1534, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31993728

RESUMO

Pseudomonas aeruginosa is an opportunistic pathogen that produces numerous exoproducts during infection that help it evade the host immune system and procure nutrients from the host environment. Among these products are a family of secreted 2-alkyl-4(1H)-quinolone metabolites (AQs), which exhibit a range of biological activities. Here, we describe the validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method for quantifying multiple AQ congeners in complex biological matrices. The assay was validated for selectivity, sensitivity, linearity, accuracy, precision, carryover, dilution integrity, recovery, matrix effects, and various aspects of stability (freeze-thaw, bench-top, long-term storage, and autosampler/post-preparative). Using authentic standards for 6 distinct AQ congeners, we report accurate quantitation within a linear range between 25 and 1000 nmol/L for all of the validated AQ standards. This method was successfully applied to quantify AQ concentrations in P. aeruginosa cell culture and in the lungs of mice infected with P. aeruginosa. Further, we confirmed the presence of unsaturated forms of several AQ congeners in cell culture. Graphical abstract.


Assuntos
Cromatografia Líquida/métodos , Pulmão/química , Pseudomonas aeruginosa/metabolismo , Quinolonas/análise , Espectrometria de Massas em Tandem/métodos , Animais , Feminino , Masculino , Camundongos , Pseudomonas aeruginosa/efeitos dos fármacos , Quinolonas/farmacologia , Reprodutibilidade dos Testes
18.
Nat Biotechnol ; 38(3): 303-308, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31959954

RESUMO

Monitoring drug-target interactions with methods such as the cellular thermal-shift assay (CETSA) is well established for simple cell systems but remains challenging in vivo. Here we introduce tissue thermal proteome profiling (tissue-TPP), which measures binding of small-molecule drugs to proteins in tissue samples from drug-treated animals by detecting changes in protein thermal stability using quantitative mass spectrometry. We report organ-specific, proteome-wide thermal stability maps and derive target profiles of the non-covalent histone deacetylase inhibitor panobinostat in rat liver, lung, kidney and spleen and of the B-Raf inhibitor vemurafenib in mouse testis. In addition, we devised blood-CETSA and blood-TPP and applied it to measure target and off-target engagement of panobinostat and the BET family inhibitor JQ1 directly in whole blood. Blood-TPP analysis of panobinostat confirmed its binding to known targets and also revealed thermal stabilization of the zinc-finger transcription factor ZNF512. These methods will help to elucidate the mechanisms of drug action in vivo.


Assuntos
Sangue/metabolismo , Proteoma/química , Proteoma/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Azepinas/administração & dosagem , Azepinas/farmacologia , Células Hep G2 , Humanos , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Pulmão/química , Pulmão/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Especificidade de Órgãos , Panobinostat/administração & dosagem , Panobinostat/farmacologia , Estabilidade Proteica , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia , Baço/química , Baço/metabolismo , Testículo/química , Testículo/metabolismo , Termodinâmica , Triazóis/administração & dosagem , Triazóis/farmacologia , Vemurafenib/administração & dosagem , Vemurafenib/farmacologia
19.
Arch Environ Occup Health ; 75(2): 75-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30741110

RESUMO

The objective of this study was to determine the concentration of aluminum in the autopsied lungs of eight hardrock miners. These miners had inhaled McIntyre Powder (a mixture of aluminum and aluminum oxide) as a prophylaxis against silicosis. The study involved chemical analysis of lungs, where each whole lung was divided horizontally into three sections and analyzed by atomic absorption spectrophotometer equipped with a graphite furnace. The grand mean level of aluminum was found to be 476.4 µg/g of dry tissue, which is similar in the range reported for occupationally exposed groups. The effect of smoking was also examined and found to be unrelated. This study provides an estimate of retained aluminum in the lungs of Ontario hardrock miners as a result of occupational exposure to hardrock mining environment and inhalation of McIntyre Powder.


Assuntos
Alumínio/análise , Pulmão/química , Mineradores , Exposição Ocupacional/efeitos adversos , Silicose/etiologia , Humanos , Ontário
20.
Am J Clin Pathol ; 153(2): 258-265, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31603186

RESUMO

OBJECTIVES: To evaluate the effects of decalcifying agents on programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC). METHODS: Fragments of 10 placentas (high PD-L1 expressor) and 10 lungs (lower PD-L1 expressor) were formalin-fixed and subjected to four decalcifying solutions (EDTA, formic acid/MasterCal IM Plus [FA/MC], 12% HCl, and Decal STAT/23% HCl) for 1, 2, 6, or 24 hours. H&E staining and PD-L1 using IHC 22C3 pharmDx were performed, and PD-L1 staining was assessed. RESULTS: Minimal to no change in staining intensity or proportion of stained cells was seen with EDTA or FA/MC at all decalcifying durations. Both HCl-based decalcifiers demonstrated a progressive decrease in percentage of positive cells and staining intensity with longer decalcifying duration, particularly with Decal STAT. CONCLUSIONS: EDTA and FA/MC have little effect on PD-L1 expression. 12% HCl causes a progressive decline in staining. Decal STAT dramatically reduced staining with all treatment durations, especially at 24 hours.


Assuntos
Antígeno B7-H1/análise , Quelantes de Cálcio/farmacologia , Ácido Edético/farmacologia , Ácido Clorídrico/farmacologia , Feminino , Formiatos/farmacologia , Humanos , Imuno-Histoquímica , Pulmão/química , Placenta/química , Gravidez , Estudos Prospectivos
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