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1.
Clin Transl Med ; 14(5): e1679, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38706045

RESUMEN

Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking-induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell-lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism-associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2-mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases.


Asunto(s)
Lipidómica , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Lipidómica/métodos , Fumar/efectos adversos , Fumar/metabolismo , Metabolismo de los Lípidos/genética , Masculino , Femenino , Metabolómica/métodos , Persona de Mediana Edad
2.
J Trace Elem Med Biol ; 84: 127440, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38522290

RESUMEN

BACKGROUND: Human lung tissue, as an interface with the environment, is susceptible to various environmental pollutants, including trace metals. However, quantitative data on trace metals in human lung tissues remain poorly described. METHODS: This study aimed to characterize the elemental composition of histologically healthy, unaffected parts of human lung tissues, associated with non-infective, non-infiltrative, and non-malignant diseases (n = 60) for essential (Cr, Mn, Fe, Co, Cu, Zn, and Se) and toxic trace elements (Sr, Ni, As, Cd, and Pb). Additionally, we investigated the influence of personal factors (sex, age, and smoking habits) on the examined trace element profiles, as well as between the trace elements correlations in the healthy human lungs. RESULTS: Among the analyzed trace elements, Fe was the most prevalent, while As was the least prevalent in healthy lung tissues. Stratifying by age revealed significantly higher Cr and Co (less Sr, Ni, and Pb) and lower Se levels in older individuals (above 65 years) compared to their younger counterparts. Sex-based differences were also notable, with Cu and Co 1.2- and 2.3-fold higher levels in females than in males. Exploring the impact of smoking habits revealed a striking 10-fold increase in Cd levels in the lung tissues of smokers compared to non-smokers. Correlation analyses showed significant positive associations between concentrations of certain toxic and essential trace elements in healthy lung tissues. CONCLUSIONS: This study could contribute to the establishment of baseline intervals for essential and toxic trace elements, valuable for toxicological and clinical assessment, in healthy, unaffected human lungs, and indicates the influence of sex, age, and smoking. However, further larger-scale studies are needed to make more stable conclusions.


Asunto(s)
Pulmón , Oligoelementos , Humanos , Oligoelementos/análisis , Masculino , Femenino , Pulmón/metabolismo , Pulmón/química , Persona de Mediana Edad , Anciano , Adulto , Fumar/metabolismo
3.
Inorg Chem ; 62(49): 20458-20466, 2023 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-38032229

RESUMEN

Nicotine and its major metabolite cotinine are widely used as markers of tobacco smoke abstinence as well as indicators of active smoking levels and the assessment of passive inhalation of tobacco smoke in nonsmokers. Therefore, using an easy-to-prepare sensing platform that can provide a rapid, highly sensitive response for the simultaneous detection of salivary nicotine levels and urinary cotinine levels is especially crucial for helping heavy cigarette smokers quit smoking and protecting public health. Hydrogen-bonded organic frameworks, as a novel class of porous crystalline materials, show immense potential for functional modification and optical sensing. Herein, a new HOF was prepared by a simple solvent evaporation method, and a dual-emitting material Eu(bpy)@HOF-215(1) was obtained by the postsynthetic modification of HOF by lanthanide luminescent complexes, which maintains favorable structural stability and introduces the characteristic emitting of Eu, allowing use as a ratiometric fluorescent sensor for salivary nicotine and urinary cotinine, with a limit of detection of nicotine of 0.045 µM in saliva and a limit of detection of cotinine of 0.591 µM in urine. Furthermore, luminescent inks based on HOF-215 have been fabricated based on the photoresponse variations of 1 to NIC and COT, which enables the multilevel encryption and decryption of information, in a dynamic and recyclable process. This work not only synthesizes a novel blue HOF but also provides a representative successful case of a dual-function platform for simultaneous application to ratiometric sensing and dynamic anticounterfeiting.


Asunto(s)
Nicotina , Contaminación por Humo de Tabaco , Nicotina/orina , Cotinina/orina , Contaminación por Humo de Tabaco/análisis , Agua , Fumar/metabolismo
4.
Am J Respir Crit Care Med ; 208(7): 780-790, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37531632

RESUMEN

Rationale: The small airway epithelium (beyond the sixth generation), the initiation site of smoking-induced airway disorders, is highly sensitive to the stress of smoking. Because of variations over time in smoking habits, the small airway epithelium transcriptome is dynamic, fluctuating not only among smokers but also within each smoker. Objectives: To perform accurate assessment of the smoking-related dysregulation of the human small airway epithelium despite the variation of smoking within the same individual and of the effects of smoking cessation on the dysregulated transcriptome. Methods: We conducted serial sampling of the same smokers and nonsmoker control subjects over time to identify persistent smoking dysregulation of the biology of the small airway epithelium over 1 year. We conducted serial sampling of smokers who quit smoking, before and after smoking cessation, to assess the effect of smoking cessation on the smoking-dysregulated genes. Measurements and Main Results: Repeated measures ANOVA of the small airway epithelium transcriptome sampled four times in the same individuals over 1 year enabled the identification of 475 persistent smoking-dysregulated genes. Most genes were normalized after 12 months of smoking cessation; however, 53 (11%) genes, including CYP1B1, PIR, ME1, and TRIM16, remained persistently abnormally expressed. Dysregulated pathways enriched with the nonreversible genes included xenobiotic metabolism signaling, bupropion degradation, and nicotine degradation. Conclusions: Analysis of repetitive sampling of the same individuals identified persistent smoking-induced dysregulation of the small airway epithelium transcriptome and the effect of smoking cessation. These results help identify targets for the development of therapies that can be applicable to smoking-related airway diseases.


Asunto(s)
Cese del Hábito de Fumar , Fumar , Humanos , Fumar/efectos adversos , Fumar/genética , Fumar/metabolismo , Fumar Tabaco , Transcriptoma , Epitelio/metabolismo , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
5.
Reprod Toxicol ; 119: 108409, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37209868

RESUMEN

Maternal smoking during pregnancy (MSDP) is a significant risk factor for the development of foetal, neonatal, and childhood morbidities. We hypothesized that infants exposed to MSDP have a distinct proteomic expression in their term placentas compared to infants without such an exposure. A total of 39 infants exposed (cord blood cotinine levels of >1 ng/mL) and 44 infants not exposed to MSDP were included in the study. Women with chronic disease, body mass index of > 30, or a history of uterine surgery were excluded. Total proteome abundance was analysed with quantitative mass spectrometry. For univariate analysis of differences in placental protein levels between groups, ANOVA with multiple testing corrections by the Benjamini-Hochberg method was used. For multivariate analysis, we used principal component analysis, partial least squares, lasso, random forest, and neural networks. The univariate analyses showed four differentially abundant proteins (PXDN, CYP1A1, GPR183, and KRT81) when heavy and moderate smoking groups were compared to non-smokers. With the help of machine learning, we found that an additional six proteins (SEPTIN3, CRAT, NAAA, CD248, CADM3, and ZNF648) were discriminants of MSDP. The placental abundance of these ten proteins together explained 74.1% of the variation in cord blood cotinine levels (p = 0.002). Infants exposed to MSDP showed differential abundance of proteins in term placentas. We report differential placental abundance of several proteins for the first time in the setting of MSDP. We believe that these findings supplement the current understanding of how MSDP affects the placental proteome.


Asunto(s)
Placenta , Proteoma , Recién Nacido , Humanos , Embarazo , Femenino , Niño , Placenta/metabolismo , Proteoma/metabolismo , Cotinina , Proteómica , Fumar/efectos adversos , Fumar/metabolismo , Antígenos de Neoplasias/metabolismo , Antígenos CD/metabolismo
6.
Int J Mol Sci ; 24(3)2023 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-36769181

RESUMEN

Lung cancer and chronic obstructive pulmonary disease (COPD) often co-occur, and individuals with COPD are at a higher risk of developing lung cancer. While the underlying mechanism for this risk is not well understood, its major contributing factors have been proposed to include genomic, immune, and microenvironment dysregulation. Here, we review the evidence and significant studies that explore the mechanisms underlying the heightened lung cancer risk in people with COPD. Genetic and epigenetic changes, as well as the aberrant expression of non-coding RNAs, predispose the lung epithelium to carcinogenesis by altering the expression of cancer- and immune-related genes. Oxidative stress generated by tobacco smoking plays a role in reducing genomic integrity, promoting epithelial-mesenchymal-transition, and generating a chronic inflammatory environment. This leads to abnormal immune responses that promote cancer development, though not all smokers develop lung cancer. Sex differences in the metabolism of tobacco smoke predispose females to developing COPD and accumulating damage from oxidative stress that poses a risk for the development of lung cancer. Dysregulation of the lung microenvironment and microbiome contributes to chronic inflammation, which is observed in COPD and known to facilitate cancer initiation in various tumor types. Further, there is a need to better characterize and identify the proportion of individuals with COPD who are at a high risk for developing lung cancer. We evaluate possible novel and individualized screening strategies, including biomarkers identified in genetic studies and exhaled breath condensate analysis. We also discuss the use of corticosteroids and statins as chemopreventive agents to prevent lung cancer. It is crucial that we optimize the current methods for the early detection and management of lung cancer and COPD in order to improve the health outcomes for a large affected population.


Asunto(s)
Neoplasias Pulmonares , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Femenino , Masculino , Fumar/efectos adversos , Fumar/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Pulmón/patología , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Comorbilidad , Microambiente Tumoral
7.
Sci Rep ; 13(1): 1870, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36725974

RESUMEN

The use of alternative tobacco products, particularly medwakh, has expanded among youth in the Middle East and around the world. The present study is conducted to investigate the biochemical and pathophysiological changes caused by medwakh smoking, and to examine the salivary metabolomics profile of medwakh smokers. Saliva samples were collected from 30 non-smokers and 30 medwakh smokers and subjected to metabolomic analysis by UHPLC-ESI-QTOF-MS. The CRP and Glutathione Peroxidase 1 activity levels in the study samples were quantified by ELISA and the total antioxidant capacity (TAC) by TAC assay kits. Statistical measurements and thorough validation of data obtained from untargeted metabolomics identified 37 uniquely and differentially abundant metabolites in saliva of medwakh smokers. The levels of phthalate, L-sorbose, cytosine, uridine, alpha-hydroxy hippurate, and L-nicotine were noticeably high in medwakh smokers. Likewise, 20 metabolic pathways were differentially altered in medwakh smokers. This study identified a distinctive saliva metabolomics profile in medwakh smokers associated with altered redox homeostasis, metabolic pathways, antioxidant system, and CRP levels. The impact of the altered metabolites in medwakh smokers and their diagnostic utility require further research in large cohorts.


Asunto(s)
Antioxidantes , Fumar , Humanos , Adolescente , Antioxidantes/metabolismo , Fumar/efectos adversos , Fumar/metabolismo , Fumar Tabaco , Metabolómica , Saliva/metabolismo , Oxidación-Reducción
8.
Drug Metab Dispos ; 50(12): 1454-1463, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36184079

RESUMEN

Two oxidation products of cotinine, 5-hydroxycotinine (5-HC) and cotinine N-oxide (CNO), were identified for the first time in vivo in the plasma of C57BL/6 mice after injection of nicotine (1 mg/kg) or exposure to an e-cigarette (e-cig) containing 2.4% nicotine. Liquid chromatography-mass spectrometry was used to separate 3-hydroxycotinine (3-HC), 5-HC, and CNO and to quantify each by the sensitive direct detection of their parent ion with m/z of 193.097. In nicotine-injected mice, 5-HC was as abundant as 3-HC 15 minutes postinjection, and CNO was readily detectable. In e-cig-exposed mice with plasma nicotine levels resembling that of human smokers, plasma 5-HC and CNO, as well as 3-HC, were readily quantifiable at the end of the 4-hour exposure time. In nicotine-injected mice, the combined concentration of 3-HC plus 5-HC plus CNO, all formed from cotinine by CYP2A5, was higher (P < 0.01) in females than in males, although the male-female difference in cotinine plasma level did not reach statistical significance. The result highlights the importance of considering these three oxidation products of cotinine in examining cotinine metabolism and disposition. Coumarin 7-hydroxylase activity, a specific marker of CYP2A5, measured in the hepatic microsomes of untreated mice showed that females have higher activity (P < 0.001) than males (N = 8 per sex). The abundance of plasma 5-hydroxycotinine in nicotine-treated mice raises intriguing questions about the site of its origin (hepatic or possibly kidney CYP2A5) and the routes of its disposition because urinary excretion of 5-HC has not been detected by liquid chromatography with tandem mass spectrometry in mice and is controversial in human smokers. SIGNIFICANCE STATEMENT: Nicotine is the active ingredient of tobacco, but its elimination route through its biomarker cotinine is not fully understood. By liquid chromatography-mass spectrometry, this study has identified and quantified for the first time 5-hydroxycotinine and cotinine N-oxide, which are oxidation products of cotinine, in the plasma of mice treated with nicotine or exposed to e-cigarettes. The results raise intriguing questions about nicotine disposition in vivo in this well established preclinical model of human smokers.


Asunto(s)
Cotinina , Sistemas Electrónicos de Liberación de Nicotina , Masculino , Femenino , Humanos , Ratones , Animales , Nicotina/metabolismo , Microsomas Hepáticos/metabolismo , Fumar/metabolismo , Ratones Endogámicos C57BL , Espectrometría de Masas en Tándem/métodos , Biomarcadores , Óxidos
9.
BMC Genomics ; 23(1): 663, 2022 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-36131240

RESUMEN

BACKGROUND: There is a need to match characteristics of tobacco users with cessation treatments and risks of tobacco attributable diseases such as lung cancer. The rate in which the body metabolizes nicotine has proven an important predictor of these outcomes. Nicotine metabolism is primarily catalyzed by the enzyme cytochrone P450 (CYP2A6) and CYP2A6 activity can be measured as the ratio of two nicotine metabolites: trans-3'-hydroxycotinine to cotinine (NMR). Measurements of these metabolites are only possible in current tobacco users and vary by biofluid source, timing of collection, and protocols; unfortunately, this has limited their use in clinical practice. The NMR depends highly on genetic variation near CYP2A6 on chromosome 19 as well as ancestry, environmental, and other genetic factors. Thus, we aimed to develop prediction models of nicotine metabolism using genotypes and basic individual characteristics (age, gender, height, and weight). RESULTS: We identified four multiethnic studies with nicotine metabolites and DNA samples. We constructed a 263 marker panel from filtering genome-wide association scans of the NMR in each study. We then applied seven machine learning techniques to train models of nicotine metabolism on the largest and most ancestrally diverse dataset (N=2239). The models were then validated using the other three studies (total N=1415). Using cross-validation, we found the correlations between the observed and predicted NMR ranged from 0.69 to 0.97 depending on the model. When predictions were averaged in an ensemble model, the correlation was 0.81. The ensemble model generalizes well in the validation studies across ancestries, despite differences in the measurements of NMR between studies, with correlations of: 0.52 for African ancestry, 0.61 for Asian ancestry, and 0.46 for European ancestry. The most influential predictors of NMR identified in more than two models were rs56113850, rs11878604, and 21 other genetic variants near CYP2A6 as well as age and ancestry. CONCLUSIONS: We have developed an ensemble of seven models for predicting the NMR across ancestries from genotypes and age, gender and BMI. These models were validated using three datasets and associate with nicotine dosages. The knowledge of how an individual metabolizes nicotine could be used to help select the optimal path to reducing or quitting tobacco use, as well as, evaluating risks of tobacco use.


Asunto(s)
Cotinina , Nicotina , Cotinina/metabolismo , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Nicotina/metabolismo , Fumar/genética , Fumar/metabolismo
10.
Biomed Khim ; 68(2): 134-143, 2022 Apr.
Artículo en Ruso | MEDLINE | ID: mdl-35485487

RESUMEN

To date, there are no drugs that can prevent progressive destruction of lung tissue and small airway fibrosis in patients with chronic obstructive pulmonary disease (COPD). Therefore, molecular mechanisms of this disease are being studied. The aim of this study was to determine the chemokine receptor expression pattern of B-lymphocytes from peripheral blood and airways of patients with COPD. Peripheral blood was collected from 51 smokers with COPD, 21 healthy smokers, and 20 healthy non-smokers. Seven smokers with COPD and 7 healthy smokers were recruited to undergo bronchoscopy with bronchoalveolar lavage (BAL). The expression of chemokine receptors CCR5, CCR6, CCR7, CXCR3, CXCR4, and CXCR5 on the surface of blood and BAL B-lymphocytes was determined by flow cytometry. It was found that the percentage of blood B-lymphocytes expressing chemokine receptors CCR5 and CXCR3 was higher in smokers with COPD compared with healthy smokers and healthy non-smokers. The percentage of CD27⁺ B-cells expressing CCR5 and CXCR3 receptors exceeded the proportion of CD27⁻ B-lymphocytes expressing these receptors in peripheral blood of patients with COPD and healthy controls. In smoking patients with COPD, the percentage of BAL B-cells expressing receptors CCR5 and CXCR3 was also increased compared with healthy smokers. There were no differences in the percentage of B-lymphocytes expressing receptors CXCR4, CXCR5, CCR6, and CCR7 in both peripheral blood and BAL between smokers with COPD and healthy smokers. A greater percentage of CD27⁻ B-lymphocytes than CD27⁺ B-cells expressed receptors CXCR4, CXCR5, CCR6, and CCR7 in the peripheral blood of smokers with COPD and healthy controls. The results of this study indicate a modification in the chemokine receptor profile of B-lymphocytes in COPD.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Linfocitos B/metabolismo , Humanos , Pulmón/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genética , Receptores CCR7/metabolismo , Fumar/efectos adversos , Fumar/metabolismo
11.
Cancer Med ; 11(15): 2896-2905, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35285182

RESUMEN

BACKGROUND: Smoking has shown interactions with bladder cancer (BC) genetic variants, especially N-acetyltransferase-2 (NAT2), a tobacco smoke metabolism gene, on BC risk. The interactions by disease aggressiveness are unknown. METHODS: We investigated the interaction between smoking and 18 single nucleotide polymorphisms (SNPs) for BC, individually and in a genetic risk score (GRS), on urothelial cancer (UC) risk including BC. We analysed data from 25,453 individuals with 520 incident UCs during follow-up, 339 non-aggressive (non-fatal, non-muscle invasive) and 163 aggressive (all other) UCs. Hazard ratios (HRs), absolute risks and additive and multiplicative interactions for two-by-two combinations of never/ever smoking with low/high genetic risk were calculated. RESULTS: Smoking and NAT2 rs1495741 interacted strongly, positively on aggressive UC on both the multiplicative (p = 0.004) and additive (p = 0.0002) scale, which was not observed for non-aggressive UC (pinteractions  ≥ 0.6). This manifested in a higher HR of aggressive UC by ever smoking for the slow acetylation NAT2 genotype (HR, 5.00 [95% confidence interval, 2.67-9.38]) than for intermediate/fast acetylation NAT2 (HR, 1.50 [0.83-2.71]), and in differences in absolute risks by smoking and NAT2 genotype. Smoking also interacted additively and positively with the GRS on any UC (p = 0.01) and non-aggressive UC (p = 0.02), but not on aggressive UC (p = 0.1). Gene-smoking interactions of lesser magnitude than for NAT2 were found for SNPs in APOBEC3A, SLC14A1 and MYNN. CONCLUSIONS: This study suggests that smoking increases UC risk more than expected when combined with certain genetic risks. Individuals with the slow acetylation NAT2 variant might particularly benefit from smoking intervention to prevent lethal UC; however, replication in larger studies is needed.


Asunto(s)
Arilamina N-Acetiltransferasa , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Acetiltransferasas/genética , Arilamina N-Acetiltransferasa/genética , Arilamina N-Acetiltransferasa/metabolismo , Carcinoma de Células Transicionales/genética , Estudios de Casos y Controles , Citidina Desaminasa , Genotipo , Humanos , Proteínas , Factores de Riesgo , Fumar/efectos adversos , Fumar/metabolismo , Neoplasias de la Vejiga Urinaria/genética
12.
Scand J Clin Lab Invest ; 82(2): 104-107, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35112632

RESUMEN

Chronic elevation of cardiac troponin I (cTnI) is associated with heart failure and cardiovascular death. Paradoxically, observational studies have indicated that current smokers have lower cTnI concentrations than non-smokers. We examined determinants of cTnI in smokers and the effect of smoking cessation on cTnI. Overweight or obese smokers received motivational support and varenicline to aid cessation and dietary advice to limit weight gain. Quitters were defined according to the Russell standard (≤5 cigarettes after the quit date) and validated with expired breath CO <10 ppm. Of the total 122 participants, 108 completed assessments at 12 weeks and 78 were classified as quitters versus 30 who continued smoking. cTnI was measured with a high-sensitivity assay with a limit of detection of 1.2 ng/L (Abbott Diagnostics), and concentrations (log-transformed) were compared between quitters and continuing smokers. cTnI concentrations were significantly higher in men than women and correlated with age, but not with number of cigarettes/day. Quitters had median baseline and 12-week levels of 1.4 ng/L (interquartile range [IQR] 1.2-2.5) and 1.4 ng/L (IQR 1.2-2.4), respectively, while nonquitters had baseline and 12-week levels of 1.5 ng/L (IQR 1.2-2.9) and 1.8 ng/L (IQR 1.3-3.4), respectively. The change in cTnI concentrations from baseline to 12 weeks did not differ between quitters and continuous smokers (p = .7). The results suggest that smoking cessation does not affect levels of cTnI, a marker of chronic subclinical myocardial injury, in contrast to prior observational data suggesting that tobacco smoking is associated with lower cTn concentrations.


Asunto(s)
Insuficiencia Cardíaca , Cese del Hábito de Fumar , Troponina I , Biomarcadores , Femenino , Insuficiencia Cardíaca/metabolismo , Humanos , Masculino , Estudios Observacionales como Asunto , Fumar/metabolismo , Troponina I/metabolismo
13.
Biomed Pharmacother ; 146: 112591, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35062064

RESUMEN

Genetic factors and tobacco smoke exposure can be associated with an increased risk of acute pancreatitis (AP). The pathogenesis of AP is associated with intensive oxidative stress. Glutathione peroxidase (GPx) is one of many enzymes involved in the neutralization of free radicals. This study aimed to investigate the impact of SNP rs1050450 in the GPX1 gene and rs713041 in the GPX4 gene on the activity of total GPx in a group of AP patients and healthy subjects. It was found that AP can contribute to decreased GPx activity (in plasma and erythrocyte lysate) accompanied by an increased glutathione reductase (GR) activity and decreased glutathione (GSH) concentration in two groups, non-smokers and smokers. A decreased GPx activity in erythrocyte lysate of AP patients compared to healthy subjects was associated with the occurrence of the CC genotype for SNP rs1050450. It was noted an increased GPx activity and decreased GR activity in erythrocytes of non-smoking AP patients with the TT genotype compared to subjects with the CC and TC genotype for SNP rs713041. However, in the group of smoking AP patients with this genotype, GR activity was elevated compared to non-smokers, which was accompanied by increased GSH concentration. These results can indicate that smoking in the course of AP can change the involvement of antioxidants in dependence on the genotype for the examined SNPs. The CC genotype for SNP rs1050450 and the TT genotype for rs713041 increases the risk of AP recurrence, which may be associated with increased MDA concentration.


Asunto(s)
Glutatión Peroxidasa/metabolismo , Pancreatitis/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Pancreatitis/sangre , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Fumar/efectos adversos , Fumar/metabolismo
14.
Life Sci ; 293: 120324, 2022 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-35032553

RESUMEN

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , Enzima Convertidora de Angiotensina 2/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Sistema Renina-Angiotensina/fisiología , Serina Endopeptidasas/metabolismo , Adulto , Factores de Edad , Anciano , Células Epiteliales Alveolares/química , Células Epiteliales Alveolares/efectos de los fármacos , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Enzima Convertidora de Angiotensina 2/análisis , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Femenino , Humanos , Pulmón/química , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Estudios Retrospectivos , Serina Endopeptidasas/análisis , Fumar/metabolismo , Fumar/patología
15.
Epigenomics ; 14(3): 153-162, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35021853

RESUMEN

Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.


Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.


Asunto(s)
COVID-19/genética , Dioxigenasas/genética , Epigénesis Genética , Histona Demetilasas/genética , Histonas/genética , Proteínas Nucleares/genética , Procesamiento Proteico-Postraduccional , Fumar/genética , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/diagnóstico , COVID-19/metabolismo , COVID-19/virología , Catepsina D/genética , Catepsina D/metabolismo , Catepsina L/genética , Catepsina L/metabolismo , Dioxigenasas/metabolismo , Histona Demetilasas/metabolismo , Histonas/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Metilación , Neuropilina-1/genética , Neuropilina-1/metabolismo , Neuropilina-2/genética , Neuropilina-2/metabolismo , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/metabolismo , Factores de Riesgo , SARS-CoV-2/genética , SARS-CoV-2/crecimiento & desarrollo , SARS-CoV-2/metabolismo , Fumar/metabolismo , Fumar/patología , Internalización del Virus
16.
Nat Commun ; 13(1): 208, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-35017538

RESUMEN

Cancer is often called a disease of aging. There are numerous ways in which cancer epidemiology and behaviour change with the age of the patient. The molecular bases for these relationships remain largely underexplored. To characterise them, we analyse age-associations in the nuclear and mitochondrial somatic mutational landscape of 20,033 tumours across 35 tumour-types. Age influences both the number of mutations in a tumour (0.077 mutations per megabase per year) and their evolutionary timing. Specific mutational signatures are associated with age, reflecting differences in exogenous and endogenous oncogenic processes such as a greater influence of tobacco use in the tumours of younger patients, but higher activity of DNA damage repair signatures in those of older patients. We find that known cancer driver genes such as CDKN2A and CREBBP are mutated in age-associated frequencies, and these alter the transcriptome and predict for clinical outcomes. These effects are most striking in brain cancers where alterations like SUFU loss and ATRX mutation are age-dependent prognostic biomarkers. Using three cancer datasets, we show that age shapes the somatic mutational landscape of cancer, with clinical implications.


Asunto(s)
Envejecimiento/genética , Proteína de Unión a CREB/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Reparación del ADN , ADN de Neoplasias/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Factores de Edad , Envejecimiento/metabolismo , Proteína de Unión a CREB/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Núcleo Celular/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , ADN de Neoplasias/metabolismo , Conjuntos de Datos como Asunto , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mitocondrias/metabolismo , Tasa de Mutación , Proteínas de Neoplasias/metabolismo , Neoplasias/clasificación , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Represoras/deficiencia , Proteínas Represoras/genética , Fumar/genética , Fumar/metabolismo , Transcriptoma , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo
17.
Mol Aspects Med ; 87: 101023, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-34521556

RESUMEN

Tobacco smoking is an important public health issue recognized by the world health organization as one of the most serious, preventable risk factors for developing a series of pregnancy pathologies. Maternal smoking is positively associated with intrauterine growth restriction (IUGR) and gestational diabetes (GDM), but negatively associated with preeclampsia (PE). In this review, we examine epidemiological, clinical and laboratory studies of smoking effects on immunoregulation during pregnancy, trophoblast function, and placental vasculature development and metabolism. We aim to identify effects of tobacco smoke components on specific placental compartments or cells, which may contribute to the understanding of the influences of maternal smoking on placenta function in normal and pathological pregnancies. Data corroborates that in any trimester, smoking is unsafe for pregnancy and that its detrimental effects outweigh questionable benefits. The effects of maternal smoking on the maternal immune regulation throughout pregnancy and the impact of different tobacco products on fetal growth have not yet been fully understood. Smoking cessation rather than treatment with replacement therapies is recommended for future mothers because also single components of tobacco and its smoke may have detrimental effects on placental function.


Asunto(s)
Placenta , Fumar , Femenino , Retardo del Crecimiento Fetal/epidemiología , Retardo del Crecimiento Fetal/etiología , Retardo del Crecimiento Fetal/metabolismo , Humanos , Placenta/metabolismo , Embarazo , Fumar/efectos adversos , Fumar/metabolismo , Fumar Tabaco , Uso de Tabaco , Trofoblastos/metabolismo
18.
Exp Biol Med (Maywood) ; 247(2): 77-86, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34775843

RESUMEN

Age-related macular degeneration is the leading cause of blindness in the elderly. The Y402H polymorphism in complement factor H promotes disease-like pathogenesis, and a Cfh+/- murine model can replicate this phenotype, but only after two years. We reasoned that by combining CFH deficiency with cigarette smoke exposure, we might be able to accelerate disease progression to facilitate preclinical research in this disease. Wild-type and Cfh+/- mice were exposed to nose-only cigarette smoke for three months. Retinal tissue morphology and visual function were evaluated by optical coherence tomography, fundus photography and autofluorescence, and electroretinogram. Retinal pigment epithelial cell phenotype and ultrastructure were evaluated by immunofluorescence staining and transmission electron microscopy. Cfh+/- smoking mice showed a dome-like protruding lesion at the ellipsoid zone (drusen-like deposition), many retinal hyper-autofluorescence spots, and a marked decrease in A- and B-wave amplitudes. Compared with non-smoking mice, wild-type and Cfh+/- smoking mice showed sub-retinal pigment epithelium complement protein 3 deposition, activation of microglia, metabolic waste accumulation, and impairment of tight junctions. Microglia cells migrated into the photoreceptor outer segment layer in Cfh+/- smoking mice showed increased activation. Our results suggest that exposing Cfh+/- mice to smoking leads to earlier onset of age-related macular degeneration than in other animal models, which may facilitate preclinical research into the pathophysiology and treatment of this disease.


Asunto(s)
Factor H de Complemento/deficiencia , Enfermedades por Deficiencia de Complemento Hereditario/metabolismo , Enfermedades Renales/metabolismo , Degeneración Macular/metabolismo , Fumar/metabolismo , Animales , Factor H de Complemento/genética , Factor H de Complemento/metabolismo , Modelos Animales de Enfermedad , Enfermedades por Deficiencia de Complemento Hereditario/genética , Enfermedades Renales/genética , Degeneración Macular/etiología , Degeneración Macular/genética , Ratones , Ratones Noqueados , Fumar/efectos adversos , Fumar/genética
19.
Ann N Y Acad Sci ; 1507(1): 108-120, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34480349

RESUMEN

This study aims to establish a biological age (BA) predictor and to investigate the roles of lifestyles on biological aging. The 14,848 participants with the available information of multisystem measurements from the Dongfeng-Tongji cohort were used to estimate BA. We developed a composite BA predictor showing a high correlation with chronological age (CA) (r = 0.82) by using an extreme gradient boosting (XGBoost) algorithm. The average frequency hearing threshold, forced expiratory volume in 1 second (FEV1 ), gender, systolic blood pressure, and homocysteine ranked as the top five important features for the BA predictor. Two aging indexes, recorded as the AgingAccel (the residual from regressing predicted age on CA) and aging rate (the ratio of predicted age to CA), showed positive associations with the risks of all-cause (HR (95% CI) = 1.12 (1.10-1.14) and 1.08 (1.07-1.10), respectively) and cause-specific (HRs ranged from 1.06 to ∼1.15) mortality. Each 1-point increase in healthy lifestyle score (including normal body mass index, never smoking, moderate alcohol drinking, physically active, and sleep 7-9 h/night) was associated with a 0.21-year decrease in the AgingAccel (95% CI: -0.27 to -0.15) and a 0.4% decrease in the aging rate (95% CI: -0.5% to -0.3%). This study developed a machine learning-based BA predictor in a prospective Chinese cohort. Adherence to healthy lifestyles showed associations with delayed biological aging, which highlights potential preventive interventions.


Asunto(s)
Envejecimiento/genética , Envejecimiento/metabolismo , Estilo de Vida Saludable/fisiología , Aprendizaje Automático/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/tendencias , China/epidemiología , Estudios de Cohortes , Ejercicio Físico/fisiología , Ejercicio Físico/tendencias , Femenino , Estudios de Seguimiento , Predicción , Humanos , Masculino , Persona de Mediana Edad , Análisis de Componente Principal/métodos , Estudios Prospectivos , Fumar/efectos adversos , Fumar/genética , Fumar/metabolismo , Fumar/tendencias
20.
Nature ; 600(7890): 713-719, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34880502

RESUMEN

Cigarette smoking constitutes a leading global cause of morbidity and preventable death1, and most active smokers report a desire or recent attempt to quit2. Smoking-cessation-induced weight gain (SCWG; 4.5 kg reported to be gained on average per 6-12 months, >10 kg year-1 in 13% of those who stopped smoking3) constitutes a major obstacle to smoking abstinence4, even under stable5,6 or restricted7 caloric intake. Here we use a mouse model to demonstrate that smoking and cessation induce a dysbiotic state that is driven by an intestinal influx of cigarette-smoke-related metabolites. Microbiome depletion induced by treatment with antibiotics prevents SCWG. Conversely, fecal microbiome transplantation from mice previously exposed to cigarette smoke into germ-free mice naive to smoke exposure induces excessive weight gain across diets and mouse strains. Metabolically, microbiome-induced SCWG involves a concerted host and microbiome shunting of dietary choline to dimethylglycine driving increased gut energy harvest, coupled with the depletion of a cross-regulated weight-lowering metabolite, N-acetylglycine, and possibly by the effects of other differentially abundant cigarette-smoke-related metabolites. Dimethylglycine and N-acetylglycine may also modulate weight and associated adipose-tissue immunity under non-smoking conditions. Preliminary observations in a small cross-sectional human cohort support these findings, which calls for larger human trials to establish the relevance of this mechanism in active smokers. Collectively, we uncover a microbiome-dependent orchestration of SCWG that may be exploitable to improve smoking-cessation success and to correct metabolic perturbations even in non-smoking settings.


Asunto(s)
Microbioma Gastrointestinal , Cese del Hábito de Fumar , Aumento de Peso , Animales , Estudios Transversales , Disbiosis/etiología , Disbiosis/metabolismo , Disbiosis/patología , Ratones , Modelos Animales , Fumar/metabolismo , Fumar/patología
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