RESUMEN

BACKGROUND: Electronic nicotine-delivery systems - also called e-cigarettes - are used by some tobacco smokers to assist with quitting. Evidence regarding the efficacy and safety of these systems is needed. METHODS: In this open-label, controlled trial, we randomly assigned adults who were smoking at least five tobacco cigarettes per day and who wanted to set a quit date to an intervention group, which received free e-cigarettes and e-liquids, standard-of-care smoking-cessation counseling, and optional (not free) nicotine-replacement therapy, or to a control group, which received standard counseling and a voucher, which they could use for any purpose, including nicotine-replacement therapy. The primary outcome was biochemically validated, continuous abstinence from smoking at 6 months. Secondary outcomes included participant-reported abstinence from tobacco and from any nicotine (including smoking, e-cigarettes, and nicotine-replacement therapy) at 6 months, respiratory symptoms, and serious adverse events. RESULTS: A total of 1246 participants underwent randomization; 622 participants were assigned to the intervention group, and 624 to the control group. The percentage of participants with validated continuous abstinence from tobacco smoking was 28.9% in the intervention group and 16.3% in the control group (relative risk, 1.77; 95% confidence interval, 1.43 to 2.20). The percentage of participants who abstained from smoking in the 7 days before the 6-month visit was 59.6% in the intervention group and 38.5% in the control group, but the percentage who abstained from any nicotine use was 20.1% in the intervention group and 33.7% in the control group. Serious adverse events occurred in 25 participants (4.0%) in the intervention group and in 31 (5.0%) in the control group; adverse events occurred in 272 participants (43.7%) and 229 participants (36.7%), respectively. CONCLUSIONS: The addition of e-cigarettes to standard smoking-cessation counseling resulted in greater abstinence from tobacco use among smokers than smoking-cessation counseling alone. (Funded by the Swiss National Science Foundation and others; ESTxENDS ClinicalTrials.gov number, NCT03589989.).

Asunto(s)

Sistemas Electrónicos de Liberación de Nicotina , Cese del Hábito de Fumar , Adulto , Humanos , Nicotina/administración & dosificación , Nicotina/efectos adversos , Cese del Hábito de Fumar/métodos , Dispositivos para Dejar de Fumar Tabaco/efectos adversos

RESUMEN

Oxidative stress can contribute to the development of diseases, and may originate from exposures to toxicants commonly found in air pollution and cigarette smoke such as polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs). Yet, associations between these exposures and oxidative stress biomarkers are poorly characterized. We report here novel associations between 14 exposure biomarkers of PAHs and VOCs, and two oxidative stress biomarkers; 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-isoprostaglandin F2α (8-isoprostane) in urine obtained from smokers participating in an ongoing clinical study (ESTxENDS, NCT03589989). We also assessed associations between six biomarkers of tobacco smoke exposure (metabolites of nicotine and tobacco-specific nitrosamines (TSNAs)) and both oxidative stress biomarkers. We then quantified the relative importance of each family of the 20 exposure biomarkers on oxidative stress. Participating smokers (153 men and 117 women, median age 44 years) had on average smoked 25 [2-62] years and smoked about 17 [5-40] cigarettes per day at the time of the study. Multiple linear regression results showed an association between 8-oxodG concentrations and the following metabolites in decreasing relative importance: PAHs (beta coefficient ß = 0.105, p-value <0.001, partial R2 = 0.15) > VOCs (ß = 0.028, p < 0.001, partial R2 = 0.09) > nicotine (ß = 0.226, p < 0.001, partial R2 = 0.08); and between 8-isoprostane concentrations and metabolites of PAHs (ß = 0.117, p < 0.001, partial R2 = 0.14) > VOCs (ß = 0.040, p < 0.001, partial R2 = 0.14) > TSNAs (ß = 0.202, p = 0.003, partial R2 = 0.09) > nicotine (ß = 0.266, p < 0.001, partial R2 = 0.08). Behavioral factors known to contribute to oxidative stress, including sleep quality, physical activity, and alcohol consumption, did not play a significant role. Exposures to PAHs and VOCs among smokers were significantly associated with oxidative stress.

Asunto(s)

Nitrosaminas , Hidrocarburos Policíclicos Aromáticos , Contaminación por Humo de Tabaco , Compuestos Orgánicos Volátiles , Adulto , Femenino , Humanos , Masculino , 8-Hidroxi-2'-Desoxicoguanosina , Biomarcadores/orina , Nicotina/análisis , Nitrosaminas/orina , Estrés Oxidativo , Hidrocarburos Policíclicos Aromáticos/análisis , Fumadores , Contaminación por Humo de Tabaco/análisis , Compuestos Orgánicos Volátiles/análisis

RESUMEN

Mitochondrial membrane potential (ΔΨm) is a universal selective indicator of mitochondrial function and is known to play a central role in many human pathologies, such as diabetes mellitus, cancer and Alzheimer's and Parkinson's diseases. Here, we report the design, synthesis and several applications of mitochondria-activatable luciferin (MAL), a bioluminescent probe sensitive to ΔΨm, and partially to plasma membrane potential (ΔΨp), for non-invasive, longitudinal monitoring of ΔΨm in vitro and in vivo. We applied this new technology to evaluate the aging-related change of ΔΨm in mice and showed that nicotinamide riboside (NR) reverts aging-related mitochondrial depolarization, revealing another important aspect of the mechanism of action of this potent biomolecule. In addition, we demonstrated application of the MAL probe for studies of brown adipose tissue (BAT) activation and non-invasive in vivo assessment of ΔΨm in animal cancer models, opening exciting opportunities for understanding the underlying mechanisms and for discovery of effective treatments for many human pathologies.

Asunto(s)

Envejecimiento/genética , Diagnóstico por Imagen/métodos , Luciferina de Luciérnaga/química , Colorantes Fluorescentes/química , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Potencial de la Membrana Mitocondrial/genética , Adipocitos/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/diagnóstico por imagen , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Animales , Carbonil Cianuro p-Trifluorometoxifenil Hidrazona/farmacología , Dioxoles/farmacología , Femenino , Luciferina de Luciérnaga/metabolismo , Colorantes Fluorescentes/metabolismo , Luciferasas/genética , Luciferasas/metabolismo , Mediciones Luminiscentes , Neoplasias Mamarias Experimentales/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Nigericina/farmacología , Compuestos de Piridinio

RESUMEN

Human biomonitoring of oxidative stress relies on urinary effect biomarkers such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and 8-iso-prostaglandin F2α (8-isoprostane); however, their levels reported for similar populations are inconsistent in the scientific literature. One of the reasons is the multitude of analytical methods with varying degrees of selectivity used to quantify these biomarkers. Single-analyte methods are often used, requiring multiple injections that increase both time and cost. We developed a rapid ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to quantify both urinary biomarkers simultaneously. A reversed-phase column using a gradient consisting of 0.1% acetic acid in water and 0.1% acetic acid in methanol/acetonitrile (70:30) was used for separation. The MS detection was by positive (8-oxodG) and negative (8-isoprostane) ion-mode by multiple reaction monitoring. Very low limit of detection (<20 pg/mL), excellent linearity (R2 > 0.999), accuracy (near 100%), and precision (CV < 10%) both for intra-day and inter-day experiments were achieved, as well as high recovery rates (>91%). Matrix effects were observed but were compensated by using internal standards. Our newly developed method is applicable for biomonitoring studies as well as large epidemiological studies investigating the effect of oxidative damage, as it requires only minimal clean up using solid phase extraction.

RESUMEN

Sulfur Mustard (SM) is a blistering agent used as a chemical weapon. Glutathione (GSH) is involved in the ß-lyase degradation pathway of SM and recently, bioadducts between SM and GSH were observed in vitro. While these bioadducts have never been isolated from in vivo tests or real poisoning with SM, they could be of interest as potential future biomarkers for the retrospective validation of exposure. We herein report the synthesis of different observed and new potential GSH-SM bioadducts as reference materials for analytical investigation. Two distinct approaches were investigated: a building-block pathway and the direct reaction with GSH. The availability of these references will aid future studies and may lead to the discovery of new GSH-SM biomarkers.