Search

Most flavors used in e-liquids are generally recognized as safe for oral consumption, but their potential effects when inhaled are not well characterized. In vivo inhalation studies of flavor ingredients in e-liquids are scarce. A structure-based grouping approach was used to select 38 flavor group representatives (FGR) on the basis of known and in silico-predicted toxicological data. These FGRs were combined to create prototype e-liquid formulations and tested against cigarette smoke (CS) in a 5-week inhalation study. Female A/J mice were whole-body exposed for 6 h/day, 5 days/week, for 5 weeks to air, mainstream CS, or aerosols from (1) test formulations containing propylene glycol (PG), vegetable glycerol (VG), nicotine (N; 2% w/w), and flavor (F) mixtures at low (4.6% w/w), medium (9.3% w/w), or high (18.6% w/w) concentration or (2) base formulation (PG/VG/N). Male A/J mice were exposed to air, PG/VG/N, or PG/VG/N/F-high under the same exposure regimen. There were no significant mortality or in-life clinical findings in the treatment groups, with only transient weight loss during the early exposure adaptation period. While exposure to flavor aerosols did not cause notable lung inflammation, it caused only minimal adaptive changes in the larynx and nasal epithelia. In contrast, exposure to CS resulted in lung inflammation and moderate-to-severe changes in the epithelia of the nose, larynx, and trachea. In summary, the study evaluates an approach for assessing the inhalation toxicity potential of flavor mixtures, thereby informing the selection of flavor exposure concentrations (up to 18.6%) for a future chronic inhalation study., (© 2022 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

Trehalose is added in drug formulations to act as fillers or improve aerosolization performance. Its characteristics as a carrier molecule have been explored; however, the fate of trehalose in human airway tissues has not been thoroughly investigated. Here, we investigated the fate of nebulized trehalose using in vitro human air-liquid bronchial epithelial cultures. First, a tracing experiment was conducted using 13 C 12 -trehalose; we measured trehalose distribution in different culture compartments (apical surface liquid, epithelial culture, and basal side medium) at various time points following acute exposure to 13 C 12 -labeled trehalose. We found that 13 C 12 -trehalose was metabolized into 13 C 6 -glucose. The data was then used to model the kinetics of trehalose disappearance from the apical surface of bronchial cultures. Secondly, we evaluated the potential adverse effects of nebulized trehalose on the bronchial cultures after they were acutely exposed to nebulized trehalose up to a level just below its solubility limit (50 g/100 g water). We assessed the ciliary beating frequency and histological characteristics. We found that nebulized trehalose did not lead to marked alteration in ciliary beating frequency and morphology of the epithelial cultures. The in vitro testing approach used here may enable the early selection of excipients for future development of inhalation products., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cigarette smoking is the major cause of chronic obstructive pulmonary disease. Considerable attention has been paid to the reduced harm potential of nicotine-containing inhalable products such as electronic cigarettes (e-cigarettes). We investigated the effects of mainstream cigarette smoke (CS) and e-vapor aerosols (containing nicotine and flavor) generated by a capillary aerosol generator on emphysematous changes, lung function, and molecular alterations in the respiratory system of female Apoe -/- mice. Mice were exposed daily (3 h/day, 5 days/week) for 6 months to aerosols from three different e-vapor formulations-(1) carrier (propylene glycol and vegetable glycerol), (2) base (carrier and nicotine), or (3) test (base and flavor)-or to CS from 3R4F reference cigarettes. The CS and base/test aerosol concentrations were matched at 35 µg nicotine/L. CS exposure, but not e-vapor exposure, led to impairment of lung function (pressure-volume loop area, A and K parameters, quasi-static elastance and compliance) and caused marked lung inflammation and emphysematous changes, which were confirmed histopathologically and morphometrically. CS exposure caused lung transcriptome (activation of oxidative stress and inflammatory responses), lipidome, and proteome dysregulation and changes in DNA methylation; in contrast, these effects were substantially reduced in response to the e-vapor aerosol exposure. Compared with sham, aerosol exposure (carrier, base, and test) caused a slight impact on lung inflammation and epithelia irritation. Our results demonstrated that, in comparison with CS, e-vapor aerosols induced substantially lower biological and pathological changes in the respiratory tract associated with chronic inflammation and emphysema.

Background: Inflammatory bowel disease (IBD) is the collective term for chronic immune-mediated diseases of unknown, multifactorial etiology, arising from the interplay between genetic and environmental factors and including two main disease manifestations: ulcerative colitis (UC) and Crohn's disease. In the last few decades, naturally occurring alkaloids have gained interest because of their substantial anti-inflammatory effects in several animal models of disease. Studies on mouse models of IBD have demonstrated the anti-inflammatory action of the main tobacco alkaloid, nicotine. In addition, anatabine, a minor tobacco alkaloid also present in peppers, tomato, and eggplant presents anti-inflammatory properties in vivo and in vitro. In this study, we aimed to evaluate the anti-inflammatory properties of nicotine and anatabine in a dextran sulfate sodium (DSS) mouse model of UC., Results: Oral administration of anatabine, but not nicotine, reduced the clinical symptoms of DSS-induced colitis. The result of gene expression analysis suggested that anatabine had a restorative effect on global DSS-induced gene expression profiles, while nicotine only had limited effects. Accordingly, MAP findings revealed that anatabine reduced the colonic abundance of DSS-associated cytokines and increased IL-10 abundance., Conclusions: Our results support the amelioration of inflammatory effects by anatabine in the DSS mouse model of UC, and suggest that anatabine constitutes a promising therapeutic agent for IBD treatment., Competing Interests: Competing interestsAll authors are employees of Philip Morris International., (© The Author(s) 2020.)

Exposure to cigarette smoke (CS) causes detrimental health effects, increasing the risk of cardiovascular, pulmonary diseases and carcinogenesis in exposed individuals. The impact of CS on Inflammatory Bowel Disease (IBD) has been established by a number of epidemiological and clinical studies. In fact, CS is associated with a higher risk of developing Crohn's disease (CD) while inversely correlates with the development, disease risks, and relapse rate of ulcerative colitis (UC). To investigate the effect of CS exposure on experimental colitis, we performed a comprehensive and integrated comparative analysis of colon transcriptome and microbiome in mice exposed to dextran sodium sulfate (DSS) and CS. Colon transcriptome analysis revealed that CS downregulated specific pathways in a concentration-dependent manner, affecting both the inflammatory state and composition of the gut microbiome. Metagenomics analysis demonstrated that CS can modulate DSS-induced dysbiosis of specific bacterial genera, contributing to resolve the inflammation or accelerate recovery. The risks of smoking far outweigh any possible benefit, thus smoking cessation must always be encouraged because of its significant health benefits. However, the inverse association between active smoking and the development of UC cannot be ignored and the present study lays the foundation for investigating potential molecular mechanisms responsible for the attenuation of colitis by certain compounds of tobacco when decoupled from combustion.

Cigarette smoking is the leading cause of preventable lung cancer (LC). Reduction of harmful constituents by heating rather than combusting tobacco may have the potential to reduce the risk of LC. We evaluated functional and molecular changes in human bronchial epithelial BEAS-2B cells following a 12-week exposure to total particulate matter (TPM) from the aerosol of a candidate modified-risk tobacco product (cMRTP) in comparison with those following exposure to TPM from the 3R4F reference cigarette. Endpoints linked to lung carcinogenesis were assessed. Four-week 3R4F TPM exposure resulted in crisis and epithelial to mesenchymal transition (EMT) accompanied by decreased barrier function and disrupted cell-to-cell contacts. By week eight, cells regained E-cadherin expression, suggesting that EMT was reversible. Increased levels of inflammatory mediators were noted in cells treated to 3R4F TPM but not in cells treated to the same or a five-fold higher concentration of cMRTP TPM. A 20-fold higher concentration of cMRTP TPM increased oxidative stress and DNA damage and caused reversible EMT. Anchorage-independent growth was observed in cells treated to 3R4F or a high concentration of cMRTP TPM. 3R4F TPM-derived clones were invasive, while cMRTP TPM-derived clones were not. Long-term exposure to TPM from the cMRTP had a lower biological impact on BEAS-2B cells compared with that of exposure to TPM from 3R4F., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aims to develop a noninvasive atrial remodeling index (RI) to separate patients presenting paroxysmal atrial fibrillation (ParAF) from those with sustained persistent atrial fibrillation (PerAF), that is, AF episodes interrupted 7 days or more after the onset., Methods: Signal-averaged P-wave duration (SAPWd) and left atrial anteroposterior diameter (LADd) were measured in 33 ParAF patients, in 26 sustained PerAF patients, and in 18 control subjects. By using SAPWd and LADd, a dichotomous (0/1) RI was created. A logistic regression model on the probability of having a sustained PerAF vs a ParAF episode was estimated, including the RI, sex, age, and cardiac comorbidities as covariates., Results: Signal-averaged P-wave duration was significantly longer in sustained PerAF (153 ± 15 milliseconds) than in ParAF patients (142 ± 13 milliseconds, P < .001) and in both ParAF and sustained PerAF groups vs control group (123 ± 7 milliseconds, P < .001). Left atrial anteroposterior diameter was larger both in sustained PerAF (43 ± 6 mm) vs ParAF patients (38 ± 5 mm, P = .002) and in sustained PerAF group vs control group (38 ± 2 mm, P = .004), but no differences were observed between ParAF patients and controls (P = .6). A 12-fold increase (odds ratio, 11.8; 95% confidence interval, 2.2-63.5) in the odds of having a sustained PerAF vs a ParAF episode was observed in patients with RI equal to 1., Conclusions: P-wave duration and left atrium diameter enabled to define a noninvasive atrial RI to separate patients with ParAF from those with sustained PerAF. This could be a useful tool to select a suitable strategy for AF treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: To describe the duration and type, as classified by World Health Organization (WHO) criteria, of breastfeeding in Ligurian newborns up to 1 year of age, and to identify possible related factors., Methods: A prospective, observational study on a cohort of 757 women recruited in 10 hospitals in Northern Italy. Women were followed up by means of a questionnaire at discharge and by telephone interviews in the 4th, 12th, 24th and 48th weeks postpartum using the 'recall period' method., Results: At discharge, 97.3% of mothers had started breastfeeding; regional breastfeeding rates at the 4th, 12th, 24th and 48th weeks were respectively 84.4%, 71.2%, 54.4% and 26.3%. Socio-demographic factors did not significantly influence these percentages. Median duration of breastfeeding was 6.5 months. No statistically significant differences were observed in duration of breastfeeding between women who started exclusive breastfeeding (EBF) and those who did predominant breastfeeding (PBF), while the difference was statistically significant when comparing complementary breastfeeding (CBF) with EBF and with PBF., Conclusions: Our study is the first regional experience in the Liguria region and represents a starting point for the diffusion of the culture of breastfeeding. Our results are satisfactory with regards to the overall duration of breastfeeding until the first year of life (26.3%), while duration of EBF (9.5% at the 24th week) is still unsatisfactory according to WHO objectives that include EBF for all children up to the sixth month of life.