Search

Background: Chronic obstructive pulmonary disease (COPD) characterized by the airway and lung inflammation, is a leading cause of morbidity and mortality worldwide, especially among smokers over 40 years of age and individuals exposed to biomass smoke. Although the detailed mechanisms of this disease remain elusive, there is feasible evidence that protein posttranslational modifications (PTMs) may play a role in its pathoetiology. We thus conducted studies to dissect the effect of cigarette smoke extracts (CSE) on the change of SUMOylated substrates in human bronchial epithelial cells (HBEs)., Methods: Samples were collected in HBEs with or without 24 h of CSE insult and then subjected to Western-blot and LC-MS/MS analysis. Subsequently, bioinformatic tools were used to analyze the data. The effect of SUMOylation on cytochrome P450 1A1 (CYP1A1) was evaluated by flow cytometry., Results: It was noted that CSE stimulated HBEs to undergo a SUMOylation turnover as evidenced by the changes of SUMOylated substrates and SUMOylation levels for a particular substrate. The SUMOylated proteins are relevant to the regulation of biological processes, molecular function and cellular components. Particularly, CSE stimulated a significant increase of SUMOylated CYP1A1, a critical enzyme involved in the induction of oxidative stress., Conclusions: Our data provide a protein SUMOylation profile for better understanding of the mechanisms underlying COPD and support that smoking induces oxidative stress in HBEs, which may predispose to the development of COPD in clinical settings.

It is widely known that cigarette smoke damages host defenses and increases susceptibility to bacterial infections. Pseudomonas aeruginosa , a Gram-negative bacterium that commonly colonizes the airways of smokers and patients with chronic lung disease, can cause pneumonia and sepsis and can trigger exacerbations of lung diseases. Pseudomonas aeruginosa colonizing airways is consistently exposed to inhaled cigarette smoke. Here, we investigated whether cigarette smoke alters the ability of this clinically significant microbe to bypass host defenses and cause invasive disease. We found that cigarette smoke extract (CSE) exposure enhances resistance to human neutrophil killing, but this increase in pathogenicity was not due to resistance to neutrophil extracellular traps. Instead, Pseudomonas aeruginosa exposed to CSE (CSE-PSA) had increased resistance to oxidative stress, which correlated with increased expression of tpx , a gene essential for defense against oxidative stress. In addition, exposure to CSE induced enhanced biofilm formation and resistance to the antibiotic levofloxacin. Finally, CSE-PSA had increased virulence in a model of pneumonia, with 0% of mice infected with CSE-PSA alive at day 6, while 28% of controls survived. Altogether, these data show that cigarette smoke alters the phenotype of P. aeruginosa , increasing virulence and making it less susceptible to killing by neutrophils and more capable of causing invasive disease. These findings provide further explanation of the refractory nature of respiratory illnesses in smokers and highlight cigarette smoking as a potential driver of virulence in this important airway pathogen., (Copyright © 2020 American Society for Microbiology.)

Objectives: There are more than 300 million smokers in China. This study aimed to evaluate the rate of smoking cessation, smoking relapse and related factors in middle-aged and older smokers in China., Methods: We performed a secondary analysis of data from China Health and Retirement Longitudinal Study (CHARLS) that recruited a nationally representative sample of adults aged 45 and older. Participants were 3708 smokers in 2011 who completed two waves of follow-up interviews in 2013 and 2015. Self-reported quit and relapse rates at follow-ups were estimated. Multiple logistic regressions were conducted to identify factors associated with smoking cessation and relapse., Results: The overall quit rate was 8.5% (95% CI 7.7% - 9.5%) at the 2-year follow-up in 2013, and 16.6% (95% CI 15.5% - 17.9%) at the 4-year follow up. Smoking cessation in 2013 was associated with not living in the northeast region (p = 0.003), fewer cigarettes smoked daily (p <0.001), and longer time to the first cigarette in the morning (p<0.001). Smoking cessation in 2015 was associated with older age (p = 0.049), smoking initiation at age ≥20 years (p<0.001), longer time to the first cigarette in the morning (p<0.001), and self-perceived poor health (p<0.001). Of the 317 participants who stopped smoking in 2013, 13.3% (95% CI 9.9% - 17.5%) relapsed by 2015. Smoking relapse was associated with younger age (p = 0.025), shorter time to the first cigarette in the morning (p = 0.003), and self-perception of not poor health (p = 0.018)., Conclusion: The overall quit rate was 8.5% at the 2-year follow up, and 16.6% at the 4-year follow up in the middle-aged and older smokers, but 13% of quitters returned to smoking in two years. Successful smoking cessation was associated with older age, lower nicotine dependence, and self-perceived poor health., Competing Interests: The authors have declared that no competing interests exist.

Introduction: With 250 published cases worldwide, diffuse esophageal intramural pseudo-diverticulosis (DEIPD) is a poorly understood disease. The aim of this study was to determine the prevalence of DEIPD in our own population, identify risk factors and clinical symptoms, and characterize its typical endoscopic signs., Methods: Retrospective search in our center's endoscopic and clinical database. Reviewing of all cases by re-examining stored endoscopic photographs. Reviewing of all cases regarding age, sex, risk factors, comorbidities, histology, and clinical symptoms., Results: In a population of 150.000 we found 21 cases of DEIPD. Mean age was 56 ± 10 years. 86% were males, 76% had alcohol abuse, 57% had nicotine abuse, 38% had arteriosclerosis, 33% had COPD, 29% had malignancies, 24% had liver cirrhosis, 19% had impaired kidney function, and 15% had diabetes. Dysphagia was present in 62% and food bolus impaction (single or repeated) in 48%. Endoscopically, 95% of patients had multiple (> 4), small (0.25-2.5 mm) pseudodiverticle openings in the esophageal wall. In 62%, openings were aligned longitudinally. 86% showed edematous swelling of mucosa ("frosted glass look"), 76% showed a fine-grained pattern of small (10-100 µm) red dots ("faux uni pattern"), and 76% had a rigid, narrow lumen with multiple rings ("trachealization")., Conclusion: With a prevalence of approximately 5 to 50/100.000, DEIPD may be more frequent than previously estimated. It preferably affects middle-aged male alcoholics. Key symptoms are chronic dysphagia and food impaction. Typical endoscopic findings are multiple, small, longitudinally aligned pseudodiverticle openings, frosted glass look, faux uni pattern, and trachealization of the esophagus.

Objective: This study aims to further quantify evidence of the association between exposure to indoor air pollution (IAP), tobacco smoke etc., on the one hand and the risk of contracting tuberculosis (TB) on the other., Study Design: This was a systematic review and meta-analysis of articles published between June 2014 and February 2020 in PubMed, Web of Science, among others., Methods: We only included studies that controlled for confounders, screened both the exposed and unexposed study participants, and passive smoking studies that limited the study population to non-smokers. Quality of studies was assessed using the Newcastle-Ottawa scale. The analysis was conducted using STATA, and pooled effect sizes were calculated using the random-effects model, and heterogeneity was tested for using the Cochran Q test and I 2 statistic., Results: A total of 26 articles were included in the final analysis. There was an increased risk of contracting TB among people exposed to IAP (risk ratio [RR] = 1.68, 95% confidence interval [CI] 1.108-2.542). We also observed a two-fold increase in the risk of contracting TB from exposure to secondhand tobacco smoke (RR = 2.15, 95%CI 1.419-3.242). Tobacco smoking doubled the risk of contracting TB (RR = 2.67, 95%CI 2.017-3.527). Furthermore, studies that used microbiological tests showed a higher RR compared to those that used other TB diagnostic methods., Conclusion: Exposure to IAP and secondhand tobacco smoke increases the risk of contracting TB. Various disease prevention campaigns should include IAP awareness and encourage a shift to cleaner sources of energy., (Copyright © 2020 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Prenatal smoke exposure is a risk factor for impaired lung development in children. Recent studies have indicated that amphiregulin (AREG), which is a ligand of the epidermal growth factor receptor (EGFR), has a regulatory role in airway epithelial cell differentiation. In this study, we investigated the effect of prenatal smoke exposure on lung epithelial cell differentiation and linked this with AREG-EGFR signaling in 1-day-old mouse offspring. Bronchial and alveolar epithelial cell differentiations were assessed by immunohistochemistry. Areg , epidermal growth factor ( Egf ), and mRNA expressions of specific markers for bronchial and alveolar epithelial cells were assessed by RT-qPCR. The results in neonatal lungs were validated in an AREG-treated three-dimensional mouse lung organoid model. We found that prenatal smoke exposure reduced the number of ciliated cells and the expression of the cilia-related transcription factor Foxj1, whereas it resulted in higher expression of mucus-related transcription factors Spdef and Foxm1 in the lung. Moreover, prenatally smoke-exposed offspring had higher numbers of alveolar epithelial type II cells (AECII) and lower expression of the AECI-related Pdpn and Gramd2 markers. This was accompanied by higher expression of Areg and lower expression of Egf in prenatally smoke-exposed offspring. In bronchial organoids, AREG treatment resulted in fewer ciliated cells and more basal cells when compared with non-treated bronchiolar organoids. In alveolar organoids, AREG treatment led to more AECII cells than non-treated AECII cells. Taken together, the observed impaired bronchial and alveolar cell development in prenatally smoke-exposed neonatal offspring may be induced by increased AREG-EGFR signaling.

Many human cancers are caused by environmental and lifestyle factors. Biomarkers of exposure and risk developed by our team have provided critical data on internal exposure to toxic and genotoxic chemicals and their connection to cancer in humans. This review highlights our research using biomarkers to identify key factors influencing cancer risk as well as their application to assess the effectiveness of exposure intervention and chemoprevention protocols. The use of these biomarkers to understand individual susceptibility to the harmful effects of tobacco products is a powerful example of the value of this type of research and has provided key data confirming the link between tobacco smoke exposure and cancer risk. Furthermore, this information has led to policy changes that have reduced tobacco use and consequently, the tobacco-related cancer burden. Recent technological advances in mass spectrometry led to the ability to detect DNA damage in human tissues as well as the development of adductomic approaches. These new methods allowed for the detection of DNA adducts in tissues from patients with cancer, providing key evidence that exposure to carcinogens leads to DNA damage in the target tissue. These advances will provide valuable insights into the etiologic causes of cancer that are not tobacco-related. See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention.", (©2020 American Association for Cancer Research.)

Objectives: The finalized 'Deeming Rule' extended the Food and Drug Administration (FDA) authority to regulate e-cigarettes, cigars, and other newly deemed tobacco products. We seek to assess the neighborhood characteristics associated with retail violations of sales to minors (RVSM) by tobacco product., Study Design: We collected national inspection data on tobacco retailers during August 8, 2016, and May 31, 2018, from the FDA compliance check database., Methods: A web scraping tool was applied to text mine the FDA decision letters and extract information on the tobacco product involved in RVSM. Separate logistic regression models with random effects were performed to examine the association between zip code-level neighborhood characteristics and RVSM by tobacco product., Results: Of 268,317 minor-involved compliance inspections, 35,403 (13.2%) were identified as RVSM. Among 23,352 warning letters included in the final analysis, e-cigarettes, cigars, cigarettes, and smokeless tobacco accounted for 20.0% (n = 4673), 40.4% (9439), 35.6% (8303), and 4.0% (937) of RVSM, respectively. Flavored tobacco products were abundant among underage sales. For e-cigarettes, RVSM were more likely to occur in zip codes with a larger proportion of youth population aged 10-17 years (adjusted odds ratio [AOR] = 1.17 [1.02-1.34]). A larger proportion of African Americans was associated with a higher risk of RVSM for cigars (AOR = 1.09 [1.07-1.11]) but a lower risk of RVSM for e-cigarettes (AOR = 0.90 [0.87-0.93])., Conclusions: Retail violations of underage sales for cigars and e-cigarettes are prevalent and neighborhood characteristics associated with violations differ by tobacco product. Continued inspections with tailored strategies to reduce RVSM of all tobacco products are needed., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Chronic cigarette smoking primes immense decline in lung functions and retardation of motor functions with increase in age. This raise the question of whether age status overwhelm the susceptibility to smoking induced lung inflammatory diseases and neuro-motor dysfunctions., Methods: To study the hypothesis 11-12 month old aged wistar rats ( n  = 6) were administered cigarette smoke extract (CSE) through intraperitoneal route (0.5 ml/rat) twice a week for 2 months. Respiratory lung functions were measured through whole body plethysmography. Lung histopathological evaluation and neuronal degeneration were observed by using H&E, picrosirius red and nissl staining respectively. Motor function tests were done through panel of neuro-behavioral tests and protein expressions were performed in lung and brain tissue homogenates through western blotting., Results: Sub-chronic CSE exposure worsened the lung functions including decreased tidal volume ( p  < 0.05), peak inspiratory flow ( p  < 0.05) and enhanced pause ( p  < 0.05). Grossly, solid neoplastic lesions were visible on the supra-lateral surface of the lungs of the CSE treated animals. Histopathological examination revealed immune cell infiltration, dominated with macrophages and alveolar type II cells stained positive for PCNA. Increased expression of BAX, PCNA, Wnt-3a, p-β-catenin ( p  < 0.05) was seen in the lungs of CSE treated aged animals. Elevated expression of inflammatory markers including NF-ϏB, TNF-α, TNF-R1, p-AKT was found in CSE treated lung tissues. Moreover, our result showed increased MCP-1, VEGF and IL-6 levels in BALF and plasma ( p  < 0.01) which might lead to neo-vascularization and excessive cell proliferation in lungs of CSE induced rats. Sub-chronic cigarette smoke exposure retarded the motor activity with suppression of D1 and D2 receptor expression in brain tissues. Brain tissue revealed the abundance of hyperchromatic and pyknotic nuclei suggesting neuronal degeneration., Conclusion: So in conclusion, chronic cigarette smoking in old age creates susceptibility to fast onset of lung inflammatory diseases and neuro-motor retardation than their nonsmoker counterparts.

Cigarette smoking is a major risk factor for pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and cancer. Cigarette smoke is reported to contain over 4,000 chemical compounds. Therefore, it needs to study the effects of cigarette smoke extract (CSE) administration on intracellular calcium concentration. In this study, we investigated how CSE influences intracellular calcium concentration in human lung adenocarcinoma A549 cells. The CSE concentrations used (0.4, 2, 3%) did not influence cell viability. However, at these CSE concentrations, calcium influx transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential vanilloid 6 (TRPV6) proteins significantly increased, whereas calcium efflux sodium-calcium exchanger (NCX1) and plasma membrane Ca 2+ ATPase (PMCA1) proteins significantly decreased from those of the control cells. The 3% CSE treatment produced an intracellular calcium concentration higher than that of the control treatment through methods of co-transfection of pGP-CMV-GCaMP6f/CMV-R-GECO1.2 and Rhod-4 Assay. CSE induced concentration-dependent increments in hypoxia-inducible factor (HIF)-1α and HIF-2α protein levels. Moreover, phosphorylation of ERK and Akt was induced by CSE treatment. Also, mitochondrial marker B-cell lymphoma 2 (Bcl-2) protein level decreased and Bcl-2-associated X (Bax) protein level increased following CSE treatment. Also, endoplasmic reticulum (ER) stress markers BiP, CHOP, p-SAPK, and p-eIF2α levels were increased by CSE treatment. These results suggest that CSE may increase the concentration of intracellular calcium, thus increasing mitochondrial and ER stress.

Introduction: First study of social inequalities in tobacco-attributable mortality (TAM) in Spain considering the joint influence of sex, age, and education (intersectional perspective)., Methods: Data on all deaths due to cancer, cardiometabolic and respiratory diseases among people aged ≥35 years in 2016 were obtained from the Spanish Statistical Office. TAM was calculated based on sex-, age- and education-specific smoking prevalence, and on sex-, age- and disease-specific relative risks of death for former and current smokers vs lifetime non-smokers. As inequality measures, the relative index of inequality (RII) and the slope index of inequality (SII) were calculated using Poisson regression. The RII is interpreted as the relative risk of mortality between the lowest and the highest educational level, and the SII as the absolute difference in mortality., Results: The crude TAM rate was 55 and 334 per 100,000 in women and men, respectively. Half of these deaths occurred among people with the lowest educational level (27% of the population). The RII for total mortality was 0.39 (95%CI: 0.35-0.42) in women and 1.61 (95%CI: 1.55-1.67) in men. The SII was -41 and 111 deaths per 100,000, respectively. Less-educated women aged <55 years and men (all ages) showed an increased mortality risk; nonetheless, less educated women aged ≥55 had a reduced risk., Conclusions: TAM is inversely associated with educational level in men and younger women, and directly associated with education in older women. This could be explained by different smoking patterns. Appropriate tobacco control policies should aim to reduce social inequalities in TAM., Competing Interests: The authors have declared that no competing interests exist.

Objective: Precise phenotypic characterization of prenatal tobacco exposure (PTE)-related disruptive behavior (DB) that integrates nuanced measures of both exposures and outcomes is optimal for elucidating underlying mechanisms. Using this approach, our goals were to identify dimensions of DB most sensitive to PTE prior to school entry and assess contextual variation in these dimensions., Methods: A community obstetric sample of N = 369 women (79.2% lifetime smokers; 70.2% pregnancy smokers) from two Midwestern cities were assessed for PTE using cotinine-calibrated interview-based reports at 16, 28, and 40 weeks of gestation. A subset of n = 244 who completed observational assessments with their 5-year-old children in a subsequent preschool follow-up study constitute the analytic sample. Using two developmentally-meaningful dimensions previously associated with emergent clinical risk for DB-irritability and noncompliance-we assessed children with 2 parent-report scales: the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB) and the Early Childhood Inventory (ECI). We also assessed children by direct observation across 3 interactional contexts with the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS). We used generalized linear models to examine between-child variability across behavioral dimensions, and mixed effects models to examine directly observed within-child variability by interactional context., Results: Increasing PTE predicted increasing impairment in preschoolers' modulation of negative affect (irritability), but not negative behavior (noncompliance) across reported (MAP-DB) and observed (DB-DOS) dimensional measures. Moreover, children's PTE-related irritability was more pronounced when observed with parents than with the examiner. The ECI did not detect PTE-related irritability nor noncompliance., Conclusions: Nuanced, dimension- and context-specific characterization of PTE-related DB described can optimize early identification of at-risk children., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells., (Copyright © 2020 by The American Association of Immunologists, Inc.)

In this viewpoint we briefly review the evidence for smoke-free car legislation. We find that this legislation has been consistently associated with reduced secondhand exposure in cars with children/youth in all nine jurisdictions studied. Despite this, there are various aspects of this intervention that warrant further study-especially determining its impact on reducing tobacco-related ethnic inequalities. So we argue that the New Zealand Ministry of Health should invest in a thorough evaluation of this important upcoming public health intervention. This could both help the country in further refining the design of the law (if necessary) and would also be a valuable contribution to advancing the knowledge base for international tobacco control., Competing Interests: Nil.

Materials and Methods: The planktonic and biofilm-forming cultures were prepared in Middlebrook 7H9 and Sauton broth media, respectively, using Mtb strain, H37Rv. The effects of CSC at concentrations of 0.05-3.12 mg/L on growth, biofilm formation and structure were evaluated using microplate Alamar Blue assay, spectrophotometric procedure and scanning electron microscopy (SEM), respectively. Involvement of reactive oxygen species in CSC-mediated biofilm formation was investigated by including catalase in biofilm-forming cultures., Results: CSC did not affect the growth of planktonic bacteria, but rather led to a statistically significant increase in biofilm formation at concentrations of 0.4-3.12 mg/L, as well as in the viability of biofilm-forming bacteria at CSC concentrations of 0.2-1.56 mg/L. SEM confirmed an agglomerated biofilm matrix and irregular bacterial morphology in CSC-treated biofilms. Inclusion of catalase caused significant attenuation of CSC-mediated augmentation of biofilm formation by Mtb , implying involvement of oxidative stress. These findings demonstrate that exposure of Mtb to CSC resulted in increased biofilm formation that appeared to be mediated, at least in part, by oxidative stress, while no effect on planktonic cultures was observed., Conclusion: Smoking-related augmentation of biofilm formation by Mtb may contribute to persistence of the pathogen, predisposing to disease reactivation and counteracting the efficacy of antimicrobial chemotherapy., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Moloko C. Cholo et al.)

Background: The term 'commercial determinants of health' (CDOH) is increasingly focussing attention upon the role of tobacco, alcohol and food and beverage companies and others-as important drivers of non-communicable diseases (NCDs). However, the CDOH do not seem to be clearly represented in the most common social determinants of health (SDOH) frameworks. We review a wide range of existing frameworks of the determinants of health to determine whether and how commercial determinants are incorporated into current SDOH thinking., Methods: We searched for papers and non-academic reports published in English since 2000 describing influences on population health outcomes. We included documents with a formal conceptual framework or diagram, showing the integration of the different determinants., Results: Forty-eight framework documents were identified. Only one explicitly included the CDOH in a conceptual diagram. Ten papers discussed the commercial determinants in some form in the text only and fourteen described negative impacts of commercial determinants in the text. Twelve discussed positive roles for the private sector in producing harmful commodities. Overall, descriptions of commercial determinants are frequently understated, not made explicit, or simply missing. The role of commercial actors as vectors of NCDs is largely absent or invisible in many of the most influential conceptual diagrams., Conclusions: Our current public health models may risk framing public health problems and solutions in ways that obscure the role that the private sector, in particular large transnational companies, play in shaping the broader environment and individual behaviours, and thus population health outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Public Health Association.)

Genetic predispositions and environmental exposures are regarded as the main predictors of respiratory disease development. Although the impact of dietary essential nutrient deficiencies on cardiovascular disease, obesity, and type II diabetes has been widely studied, it remains poorly explored in chronic respiratory diseases. Dietary choline and methionine deficiencies are common in the population, and their impact on pulmonary homeostasis is currently unknown. Mice were fed choline- and/or methionine-deficient diets while being exposed to room-air or cigarette smoke for up to 4 wk. Lung functions were assessed using the FlexiVent. Pulmonary transcriptional activity was assessed using gene expression microarrays and quantitative PCR. Immune cells, cytokines, and phosphatidylcholine were quantified in the bronchoalveolar lavage. In this study, we found that short-term dietary choline and/or methionine deficiencies significantly affect lung function in mice in a reversible manner. It also reduced transcriptional levels of collagens and elastin as well as pulmonary surfactant phosphatidylcholine levels. We also found that dietary choline and/or methionine deficiencies markedly interfered with the pulmonary response to cigarette smoke exposure, modulating lung function and dampening inflammation. These findings clearly show that dietary choline and/or methionine deficiencies can have dramatic pathophysiological effects on the lungs and can also affect the pathobiology of cigarette smoke-induced pulmonary alterations. Expanding our knowledge in the field of "nutri-respiratory research" may reveal a crucial role for essential nutrients in pulmonary health and disease, which may prove to be as relevant as genetic predispositions and environmental exposures.

About 14.2% of women in the general Indian population and 4.8% in Delhi use tobacco but its use among women with Major Mental Illness (MMI) in developing countries has not been adequately studied. We assessed tobacco use in women with MMI in a tertiary care psychiatry outpatient department through a cross-sectional, observational study, with sample size of at least n= 77 each for schizophrenia-SZ, bipolar disorder-BD and Recurrent Depressive Disorder-RDD. Fagerstrom Test for Nicotine Dependence (FTND) both for smoke and smokeless tobacco were applied along with a subset of questions from Global Adult Tobacco Survey 2016. After diagnosis and referral by the treating psychiatrist and written informed consent, in our total sample of 321 women participants, lifetime use of tobacco was reported by 14.64%. Of all those who had ever used tobacco, 12.14% used it currently as well. As for diagnosis, those with BD (16.25%) used tobacco most frequently followed by SZ (14.18%) and RDD (6%). The FTND score was higher for schizophrenia indicating greater dependence. Tobacco use among women with MMI was thrice as common as women in general population of Delhi State, with smoke and smokeless tobacco use being equally prevalent, a grave cause for concern and intervention., Competing Interests: Declaration of Competing Interests The authors declare NO conflict of interest. The content of this manuscript is solely the responsibility of the authors. This paper is an expanded version of BK's presentation at the Annual National Conference of the Indian Psychiatric Society 2019 where it was shortlisted for the Bhagwat Award., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Although Australia is a world leader in tobacco control, smoking remains the behavioural risk factor making the largest contribution to death and disease. Smoking rates remain high in Aboriginal and Torres Strait Islander people and in people with mental health problems. Priority groups for cessation include women who are pregnant and people with cardiovascular disease., Objective: This article, based on the recently published second edition of Supporting smoking cessation: A guide for health professionals, provides an update on current evidence-based practice to support quitting. A brief, time-efficient intervention approach (Ask, Advise, Help) is proposed. New approaches to the use of pharmacotherapy are covered, as is the controversial role of nicotine-containing e-cigarettes and advice for groups with high smoking prevalence and those with special needs., Discussion: A combination of behavioural support along with pharmacotherapy to treat nicotine dependence maximises the chances of successful long-term cessation. Combination nicotine replacement therapy (patch and short-acting oral form) or varenicline are the most effective forms of pharmacotherapy.

Smoking as a major risk factor for morbidity affects numerous regulatory systems of the human body including DNA methylation. Most of the previous studies with genome-wide methylation data are based on conventional association analysis and earliest threshold-based gene set analysis that lacks sensitivity to be able to reveal all the relevant effects of smoking. The aim of the present study was to investigate the impact of active smoking on DNA methylation at three biological levels: 5'-C-phosphate-G-3' (CpG) sites, genes and functionally related genes (gene sets). Gene set analysis was done with mGSZ, a modern threshold-free method previously developed by us that utilizes all the genes in the experiment and their differential methylation scores. Application of such method in DNA methylation study is novel. Epigenome-wide methylation levels were profiled from Young Finns Study (YFS) participants' whole blood from 2011 follow-up using Illumina Infinium HumanMethylation450 BeadChips. We identified three novel smoking related CpG sites and replicated 57 of the previously identified ones. We found that smoking is associated with hypomethylation in shore (genomic regions 0-2 kilobases from CpG island). We identified smoking related methylation changes in 13 gene sets with false discovery rate (FDR) ≤ 0.05, among which is olfactory receptor activity, the flagship novel finding of the present study. Overall, we extended the current knowledge by identifying: (i) three novel smoking related CpG sites, (ii) similar effects as aging on average methylation in shore, and (iii) a novel finding that olfactory receptor activity pathway responds to tobacco smoke and toxin exposure through epigenetic mechanisms., (© 2020 The Author(s).)

Cigarette smoke exposure (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD). Macrophages have an important role in COPD because they release pro-inflammatory and anti-inflammatory cytokines. The present study's we investigate the functional changes in macrophages and monocytes exposed to cigarette smoke extract (CSE). Herein, using human monocyte-derived macrophages (MDMs) from healthy donors and we found that CSE was not associated with significant changes in the production of pro inflammatory cytokines by MDMs. In contrast, exposure to CSE suppressed the production of IL-6 and Gro-a/CXCL1 by LPS-stimulated-MDMs, but had an additive effect on the release of IL-8/CXCL8 and MCP1/CCL2. However, CSE exposure was associated with greater production, TARC/CCL-17 and CCL22/MDC. Moreover, MDMs displayed a lower uptake capacity after CSE exposure. We identify, for what is to our knowledge the first time that monocytes from patients with COPD produced less IL-8/CXCL8 and Gro-α/CXCL1 after LPS stimulation and produced higher levels of TARC/CCL17 and MDC/CCL-22 after IL-4 stimulation. Our present results highlighted a skewed immune response, with an imbalance in M1 vs. M2 cytokine production. In conclusion, exposure to CS has contrasting, multifaceted effects on macrophages and monocytes. Our data may provide a better understanding of the mechanisms underlying COPD.

Human research of nicotine and tobacco effects demonstrates that non-pharmacological factors may systematically affect responses to administered substances and inert placebos. Failure to measure or manipulate these factors may compromise study reliability and validity. This is especially relevant for double-blind placebo-controlled research of nicotine, tobacco, and related substances. In this article, we review laboratory-based human research of the impact of non-pharmacological factors on responses to tobacco and nicotine administration. Results suggest that varying beliefs about drug content and effects, perceptions about drug use opportunities, and intentions to cease drug use systematically alter subjective, behavioral, and physiological responses to nicotine, tobacco, and placebo administration. These non-pharmacological factors should be considered when designing and interpreting the findings of human research of nicotine and tobacco effects, particularly when a double-blind placebo-controlled design is used. The clinical implications of these findings are discussed, and we propose methodological strategies to enhance the reliability and validity of future research., Implications: Growing research demonstrates that non-pharmacological factors systematically alter responses to acute nicotine, tobacco, and placebo administration. Indeed, varying beliefs about nicotine and/or tobacco administration and effects, differing perceptions about nicotine and/or tobacco use opportunities, and inconsistent motivation to quit smoking have been found to exert important influences on subjective, physiological, and behavioral responses. These variables are infrequently measured or manipulated in nicotine and tobacco research, which compromises the validity of study findings. Incorporating methodological strategies to better account for these non-pharmacological factors has the potential to improve the quality of addiction research and treatment., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In 2018, there were more than 371 million cigarette smokers and 12. 6 million electronic cigarette users, with 340.2 million non-smokers exposed to secondhand smoke (SHS) in China, which resulted in heavy tobacco-attributable disease burden. According to the definition by the Global Burden of Disease Study 2017 (GBD 2017), tobacco is a level 2 risk factor that consists of three sublevel risk factors, namely, smoking, SHS, and chewing tobacco. In this study, we aimed to evaluate the trends in deaths and disability-adjusted life years (DALYs) attributable to tobacco, smoking, SHS, and chewing tobacco by sex in China from 1990 to 2017 and to explore the leading causes of tobacco-attributable deaths and DALYs using data from the GBD 2017. From 1990 to 2017, the tobacco-attributable death rates per 100,000 people decreased from 75.65 [95% uncertainty interval (95% UI) = 56.23-97.74] to 70.90 (95% UI = 59.67-83.72) in females and increased from 198.83 (95% UI = 181.39-217.47) to 292.39 (95% UI = 271.28-313.76) in males. From 1990 to 2017, the tobacco-attributable DALY rates decreased from 2209.11 (95% UI = 1678.63-2791.91) to 1489.05 (95% UI = 1237.65-1752.57) in females and increased from 5650.42 (95% UI = 5070.06-6264.39) to 6994.02 (95% UI = 6489.84-7558.41) in males. In 2017, the tobacco-attributable deaths in China were concentrated on chronic obstructive pulmonary disease, ischemic heart disease, lung cancer, and stroke. The focus of tobacco control for females was SHS in 1990, whereas smoking and SHS were equally important for tobacco control in females in 2017. Increasing tobacco taxes and prices may be the most effective and feasible measure to reduce tobacco-attributable disease burdens., (Copyright © 2020 Wen, Xie, Wang, Wu and Yu.)

The presence of flavors is one of the commonly cited reasons for use of e-cigarettes by youth; however, the potential harms from inhaling these chemicals and byproducts have not been extensively studied. One mechanism of interest is DNA adduct formation, which may lead to carcinogenesis. We identified two chemical classes of flavors found in tobacco products and byproducts, alkenylbenzenes and aldehydes, documented to form DNA adducts. Using in silico toxicology approaches, we identified structural analogs to these chemicals without DNA adduct information. We conducted a structural similarity analysis and also generated in silico model predictions of these chemicals for genotoxicity, mutagenicity, carcinogenicity, and skin sensitization. The empirical and in silico data were compared, and we identified strengths and limitations of these models. Good concordance (80-100%) was observed between DNA adduct formation and models predicting mammalian mutagenicity (mouse lymphoma sassy L5178Y) and skin sensitization for both chemical classes. On the other hand, different prediction profiles were observed for the two chemical classes for the modeled endpoints, unscheduled DNA synthesis and bacterial mutagenicity. These results are likely due to the different mode of action between the two chemical classes, as aldehydes are direct acting agents, while alkenylbenzenes require bioactivation to form electrophilic intermediates, which form DNA adducts. The results of this study suggest that an in silico prediction for the mouse lymphoma assay L5178Y, may serve as a surrogate endpoint to help predict DNA adduct formation for chemicals found in tobacco products such as flavors and byproducts., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Published by Elsevier Inc.)

Competing Interests: None

Background: Recent epidemiologic studies identified credible associations between marijuana smoking and risk of nonseminomatous testicular germ cell tumors (TGCTs), but did not distinguish exposure to cannabinoid compounds from exposure to other constituents of smoke., Methods: We implemented a systematic review of scholarly literature followed by random effects meta-analysis to quantitatively synthesize published data relating incident TGCT to each of 2 exposure histories: ever using marijuana, and ever smoking tobacco., Results: We identified four epidemiologic studies of marijuana use and 12 of tobacco smoking. Summary data concur with earlier reports of a specific association of marijuana use with nonseminoma, summary odds ratio [sOR] = 1.71 (95% confidence interval [CI] 1.12-2.60), and identify a positive association, sOR = 1.18 (95% CI 1.05-1.33), between tobacco smoking and all TGCT., Conclusions: Available data accord with positive associations between incident TGCT and each exposure, implicating both cannabinoid compounds and other constituents of smoke. Etiologic interpretation awaits epidemiologic studies that assess associations between tobacco smoking and nonseminomatous TGCT, investigating not only these exposures but also both co-use of tobacco and marijuana and smoke-free sources of cannabinoids, while adequately evaluating potential confounding among all of these exposures., Competing Interests: Conflicts of interest The authors declare no conflicts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Radiotherapy and cisplatin lead to cell killing in head and neck squamous cell carcinoma patients, but adverse events and response to treatment are not the same in patients with similar clinicopathological aspects. The aim of this prospective study was to evaluate the roles of TP53 c.215G > C, FAS c.-671A > G, FAS c.-1378G > A, FASL c.-844 C > T, CASP3 c.-1191A > G, and CASP3 c.-182-247G > T single nucleotide variants in toxicity, response rate, and survival of cisplatin chemoradiation-treated head and neck squamous cell carcinoma patients. Genomic DNA was analyzed by polymerase chain reaction for genotyping. Differences between groups of patients were analyzed by chi-square test or Fisher's exact test, multiple logistic regression analysis, and Cox hazards model. One hundred nine patients with head and neck squamous cell carcinoma were enrolled in study. All patients were smokers and/or alcoholics. Patients with FAS c.-671GG genotype, FAS c.-671AG or GG genotype, and FASL c.-844CC genotype had 5.52 (95% confidence interval (CI): 1.42-21.43), 4.03 (95% CI: 1.51-10.79), and 5.77 (95% CI: 1.23-27.04) more chances of presenting chemoradiation-related anemia of grades 2-4, lymphopenia of grade 3 or 4, and ototoxicity of all grades, respectively, than those with the remaining genotypes. FAS c.-671GG genotype was also seen as an independent predictor of shorter event-free survival (hazard ratio (HR): 2.05; P   =  0.007) and overall survival (HR: 1.83; P   =  0.02) in our head and neck squamous cell carcinoma patients. These findings present, for the first time, preliminary evidence that inherited abnormalities in apoptosis pathway, related to FAS c.-671A > G and FASL c.-844 C > T single nucleotide variants, can alter toxicity and survival of tobacco- and alcohol-related head and neck squamous cell carcinoma patients homogeneously treated with cisplatin chemoradiation.

Background: India poses a novel tobacco problem with majority of the tobacco users consuming smokeless form of tobacco (21.4%). Gul is one such Smokeless Tobacco (ST) product that is manufactured commercially as a dentifrice to be applied to the teeth and then to gums many times during the day, making it a cheap and easy tobacco source. Hence, the aim of the present study was to estimate the usage of Gul and its social determinants among adults in the capital city of India, Delhi., Methods: The cross-sectional study was conducted among 1300 adults across 27 Delhi government dispensaries across 3 districts of Delhi through multistage stratified random sampling. A structured, close-ended, validated questionnaire inquiring about the tobacco practices was used for all the participants and a specially constructed, structured, close-ended, validated proforma was used for Gul users to assess practice and pattern of use., Results: The overall prevalence of Gul users was found to be 4.9% with a mean usage duration of 6.28 ± 6.75 years. The usage was found to be more among males (67.7%) and unskilled workers (45.2%). 74.9% started using Gul to treat dental pain with 93.47% of them reporting pain relief., Conclusion: Gul usage is an emerging menace in Delhi. Awareness programs and initiatives are the need of the hour to bring this tobacco product under the tobacco control policy radar and at the same time educate people about the actual contents and ill effects of Gul usage., Competing Interests: None

Introduction: This study investigated the systemic response of serum bone alkaline phosphatase (SBAP) and urinary N-telopeptide (UNTX) to tobacco exposure and environmental tobacco smoke (ETS) and the possible effect modification (and variability) of this response by racial/ethnic origin. Methods: Data (n   =   5411) were obtained from the National Health and Nutrition Examination Survey, with data analysis done on adults aged ≥ 20   years. Outcome variables were SBAP and UNTX. Independent variable was tobacco exposure measured using serum cotinine levels and adjusted for covariates. Generalized linear models were used to explore associations. Results: A percentage increase in log transformed serum cotinine was associated with a 0.005 percentage increase in log transformed SBAP (CI: 0.002, 0.008) and 0.02 percentage increase in log transformed UNTX (CI: -0.01, 0.04) with interaction between cotinine and race/ethnicity ( p   =   0.01). Stratifying by race/ethnicity, tobacco exposure was associated with significant decreases in UNTX among non-Hispanic Whites - 0.008(-0.014, -0.002) and Mexican Americans -0.014 (-0.025, -0.002) only. Categories of serum cotinine were associated with a monotonic increase in SBAP ( p for trend <0.001) and monotonic non-linear decrease in UNTX ( p for trend   >   0.05). Conclusions: Tobacco and environmental tobacco exposure are associated with SBAP and increased bone formation. The response of UNTX to these exposures is modified by race/ethnicity with non-Hispanic Whites and Mexican-Americans less sensitive to the resorptive effects of tobacco exposure on bone.

Even if cancer and cardiovascular diseases are considered two distinct diseases, an intricate interconnection between these conditions has been established. Increased risk of malignancy has been identified in patients with cardiovascular disease, as well as a greater propensity to the development of cardiovascular diseases has been observed in patients with cancer. The development of cardiotoxicity following exposure to certain anticancer drugs only partially explains this relationship. Shared risk factors and common pathogenic mechanisms suggest the existence of a common biology and a complex interplay between these two conditions. Due to improving longevity and therapeutic advances, the number of patients affected or potentially at risk of developing these two diseases is constantly increasing and currently, several drugs against cancer from anthracyclines to checkpoint inhibitors, can also cause a wide range of unexpected cardiovascular side effects. Management of these issues in clinical practice is an emerging challenge for cardiologists and oncologists, and led to the development of a new dedicated discipline called cardio-oncology. Surveillance and prevention strategies as well as interventions to reduce cardiovascular risk and prevent cardiotoxicities are the primary objectives of cardio-oncology. In this review, we explore the etiopathogenesis common to cardiovascular disease and cancer and the complex interplay between them. We also report the main characteristics of the drugs responsible for cardiotoxicity, highlighting the available strategies for optimal patient management based on a multidisciplinary approach in the cardio-oncology setting.

Background and Objectives : Smoking has been found to interfere with wound healing processes. Therefore, the purpose of this study was to compare surgical treatment of oroantral fistulae (OAFs) in smokers and non-smokers. Materials and Methods: Medical records of all consecutive patients who underwent surgical closure of OAFs between 2003 and 2016 at the oral and maxillofacial surgery department, Rabin Medical Center, Israel were reviewed. Patients' demographic data, preoperative signs and symptoms, surgical method of repair, and postoperative complications were recorded. Results: The cohort consisted of 38 smokers and 59 non-smokers. Age and gender distributions were similar in both groups. The main etiology in both groups was tooth extraction, followed by pre-prosthetic surgery in smokers and odontogenic infection in non-smokers ( p = 0.02). Preoperative conditions were not significantly different between smokers and non-smokers in terms of size of soft tissue fistula and bony defect, chronic sinusitis and foreign bodies inside the sinus. OAFs were repaired by local soft tissue flaps without consideration of smoking status. Smokers experienced more moderate-severe postoperative pain ( p = 0.05) and requested more weak opioids ( p = 0.06). Postoperative complications included infection, delayed wound healing, residual OAF, pain, sensory disturbances and sino nasal symptoms. These were mostly minor and tended to be more frequent in smokers ( p = 0.35). Successful closure of OAFs was obtained in all patients except one smoker who required revision surgery. Conclusions: Smokers may be more susceptible to OAFs secondary to preprosthetic surgery. In this cohort, there was no statistically significant difference in outcome between smokers and non-smokers in terms of failure. However, smokers tended to have more severe postoperative pain and discomfort and to experience more postoperative complications. Further studies with larger sample sizes should be conducted to validate these results.

Skeletal muscle dysfunction is a common complication and an important prognostic factor in patients with chronic obstructive pulmonary disease (COPD). It is associated with intrinsic muscular abnormalities of the lower extremities, but it is not known whether there is an easy way to predict its presence. Using a mouse model of chronic cigarette smoke exposure, we tested the hypothesis that magnetic resonance spectroscopy allows us to detect muscle bioenergetic deficit in early stages of lung disease. We employed this technique to evaluate the synthesis rate of adenosine triphosphate (ATP) and characterize concomitant mitochondrial dynamics patterns in the gastrocnemius muscle of emphysematous mice. The fibers type composition and citrate synthase (CtS) and cytochrome c oxidase subunit IV (COX4) enzymatic activities were evaluated. We found that the rate of ATP synthesis was reduced in the distal skeletal muscle of mice exposed to cigarette smoke. Emphysematous mice showed a significant reduction in body weight gain, in the cross-sectional area of the total fiber and in the COX4 to CtS activity ratio, due to a significant increase in CtS activity of the gastrocnemius muscle. Taken together, these data support the hypothesis that in the early stage of lung disease, we can detect a decrease in ATP synthesis in skeletal muscle, partly caused by high oxidative mitochondrial enzyme activity. These findings may be relevant to predict the presence of skeletal bioenergetic deficit in the early stage of lung disease besides placing the mitochondria as a potential therapeutic target for the treatment of COPD comorbidities., Competing Interests: The authors have declared that no competing interests exist

Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.

Background: Tobacco exposure (TE) is the major contributor for CVD mortality, but few published studies on CVD mortality attributable to TE have analyzed the potential reasons underlying long-term trends in China. Our studysought to find the potential reasons and compared CVD mortality attributable to TE in China, Japan, the United States of America (USA), and the world between 1990 and 2017., Methods: The mortality data in China, Japan, the USA, and the world were obtained from Global Burden of Disease Study 2017(GBD 2017). Joinpoint regression was used to assess the trend magnitude and directions over time for CVD mortality, while the age-period-cohort method was used to analyzethe temporal trends of CVD mortality according to age, period, and cohort., Results: A significant downward trend was found in the age-standardised mortality rate (ASMR) of CVD attributable to smoking in four regions. China had the smallest decline and the Chinese ASMR became the highest in 2017. All the annual net drifts in the four regions were negative and the local drifts were below zero. The longitudinal age curves of CVD mortality attributable to smoking increased in four regions,with China having the largest increase. The period or cohort RRs indicated a decline, and China had the smallest decline. The researchers further analyzed the IHD and stroke trends, finding that the morality and period or cohort RR of IHD in China was always at a high level., Conclusions: CVD mortality attributable to TE declined in four regions, and was highest in China. The proportion of IHD mortality attributable to TE was similar to stroke, which significantly changed the traditional cognition of CVD composition, but the control measure was not sufficient for IHD in China.

Purpose: ¡Activate Ya! was a group-randomized controlled intervention trial aimed at developing and evaluating the impact of a school-based intervention on preventing cigarette smoking and promoting physical activity (PA) in secondary school students in Uruguay. Secondary aims were to evaluate the program's impact on students' smoking- and PA-related psychosocial risk and protective factors., Methods: Sixteen schools and n = 654 students participated in the study. The one-year intervention included a classroom-based curriculum, an afterschool program, activity breaks, and final showcase event. A self-administered questionnaire measured outcomes at three time points. Fixed effects regression models tested for differences in outcomes by study condition., Results: While positive intervention effects were found for selected psychosocial-related smoking outcomes, no impact on past-year smoking or smoking susceptibility was detected. Past 7-day PA, measured by the PAQ-C, was significantly higher among intervention school students overall ( p = .048) and for girls ( p = .03) at posttest, and intervention girls reported significantly higher athletic identity PA competence, friend and teacher PA support at posttest, and PA enjoyment at follow-up ( p < .05)., Conclusion: The positive short-term effects of ¡Activate Ya! on PA and related outcomes for girls support the utility of school-based health promotion in Uruguay. Additional research is needed to determine the most effective strategies to prevent tobacco use among students and promote PA among boys in this setting.

Inflammation is an important cause of chronic obstructive pulmonary disease (COPD) and its acute exacerbation. However, the critical role of C-C chemokine receptor (CCR)1 in progression of cigarette smoke-induced chronic inflammation remains unclear. We studied CCR1 expression using immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction (RT-PCR) in COPD patients and controls. Cytokine levels in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, we investigated Janus kinase/signal transducers and activators of transcription (JAK/STAT)/nuclear factor-κB (NF-κB) signaling in cigarette smoke extract-induced or CCR1 deficiency/overexpressed mouse macrophage cell line MH-S by RT-PCR and western blot, and measured the cytokine levels in the supernatant with ELISA. We found that CCR1 expression was upregulated in COPD patients and there was a negative correlation between CCR1 mRNA levels and predicted % forced expiratory volume in 1 min. Inflammatory cytokine levels in the peripheral blood were higher in COPD patients than controls, and these were positively correlated with CCR1 levels. CCR1 was shown to play a critical role in regulating smoke-induced inflammation via JAK/STAT3/NF-κB signaling in vitro. CCR1 may play a critical role in airway inflammation in COPD. Additionally, understanding the molecular mechanism may help develop novel methods for the treatment of COPD.

Purpose: The effects of cigarette smoking on male semen quality are controversial, and the molecular mechanisms underlying how cigarette smoking affects semen quality are not clear yet., Methods: In this study, semen samples from 70 heavy smokers and 75 non-smokers receiving infertility treatment were included. Basic semen parameters in non-smokers and heavy smokers were evaluated. Levels of glutathione (GSH), lipid reactive oxygen species (ROS), iron and GSH-dependent peroxidase 4 (GPX4) protein level were observed in human seminal plasma and in GC-2Spd cells exposed to cigarette smoke condensate (CSC)., Results: Heavy smokers had significantly higher abnormalities (sperm viability and sperm progressive motility) than non-smoking counterparts. Comparing non-smokers group, GSH level was reduced in the group of heavy smokers (P < 0.05). However, the level of lipid ROS and iron were significantly increased (P < 0.05). Besides, GSH level was reduced following treatment with CSC for 24 h, while lipid ROS and iron levels were increased (P < 0.05). However, the levels were reduced after being co-cultured with Ferrostatin-1 (Fer-1) (P < 0.05). The level of GPX4 protein was reduced after being treated with CSC in 24 h, and increased after being co-cultured with Fer-1(P < 0.05)., Conclusion: Cigarette smoking is associated with high level of ferroptosis in seminal plasma and affect semen quality.

Cigarette smoke exposure is a risk factor for many pulmonary diseases, including Chronic Obstructive Pulmonary Disease (COPD). Cigarette smokers are more prone to respiratory infections with more severe symptoms. In those with COPD, viral infections can lead to acute exacerbations resulting in lung function decline and death. Epithelial cells in the lung are the first line of defense against inhaled insults such as tobacco smoke and are the target for many respiratory pathogens. Endocytosis is an essential cell function involved in nutrient uptake, cell signaling, and sensing of the extracellular environment, yet, the effect of cigarette smoke on epithelial cell endocytosis is not known. Here, we report for the first time that cigarette smoke alters the function of several important endocytic pathways in primary human small airway epithelial cells. Cigarette smoke exposure impairs clathrin-mediated endocytosis and fluid phase macropinocytosis while increasing caveolin mediated endocytosis. We also show that influenza virus uptake is enhanced by cigarette smoke exposure. These results support the concept that cigarette smoke-induced dysregulation of endocytosis contributes to lung infection in smokers. Targeting endocytosis pathways to restore normal epithelial cell function may be a new therapeutic approach to reduce respiratory infections in current and former smokers., Competing Interests: Thomas H Thatcher is a member of the PLOS ONE editorial board. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. No other authors have competing interests to declare.

Although tobacco (TOB) and marijuana (MJ) are often co-used in pregnancy, little is known regarding the joint impact of MJ + TOB on offspring development, including the developing neuroendocrine stress system. Further, despite evidence for sex-specific impacts of prenatal exposures in preclinical models, the sex-specific impact of prenatal MJ + TOB exposure on offspring neuroendocrine regulation in humans is also unknown. In the current study, overall and sex-specific influences of MJ + TOB co-use on offspring cortisol regulation were investigated over the first postnatal month. 111 mother-infant pairs from a low-income, racially and ethnically diverse sample participated. Based on Timeline Followback data with biochemical verification, three groups were identified: (1) prenatal MJ + TOB, (2) TOB only, and (3) controls. Baseline cortisol and cortisol stress response were assessed at seven points over the first postnatal month using a handling paradigm in which saliva cortisol was assessed before, during, and following a standard neurobehavioral assessment (NICU Network Neurobehavioral Scale). A significant exposure group by offspring sex interaction emerged for baseline cortisol over the first postnatal month (p = .043); MJ + TOB-exposed males showed 35-36% attenuation of baseline cortisol levels vs. unexposed and TOB-exposed males (ps ≤ .003), while no effects of exposure emerged for females. Both MJ + TOB and TOB-exposed infants showed a 22% attenuation of cortisol stress response over the first postnatal month vs. unexposed infants (ps < .03), with evidence for sex-specific effects in exploratory analyses. Although results are preliminary, this is the first human study to investigate the impact of prenatal MJ exposure on infant cortisol and the first to reveal a sex-specific impact of prenatal MJ + TOB on cortisol regulation in humans. Future, larger-scale studies are needed to elucidate mechanisms and consequences of sex-specific effects of MJ and MJ + TOB on the developing neuroendocrine stress system., Competing Interests: Declaration of competing interest The authors have no biomedical financial interests or potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Varenicline tartrate is superior for smoking cessation to other tobacco cessation therapies by 52 weeks, in the outpatient setting. We aimed to evaluate the long-term (104 week) efficacy following a standard course of inpatient-initiated varenicline tartrate plus Quitline-counselling compared to Quitline-counselling alone., Methods: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to one of three hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling, (n = 196) or Quitline-counselling alone, (n = 196), with continuous abstinence from smoking assessed at 104 weeks., Results: A total of 1959 potential participants were screened for eligibility between August 2008 and December 2011. The proportion of participants who remained continuously abstinent (intention-to-treat) at 104 weeks were significantly greater in the varenicline tartrate plus counselling arm (29.2% n = 56) compared to counselling alone (18.8% n = 36; p = 0.02; odds ratio 1.78; 95%CI 1.10 to 2.86, p = 0.02). Twenty-two deaths occurred during the 104 week study (n = 10 for varenicline tartrate plus counselling and n = 12 for Quitline-counselling alone). All of these participants had known or developed underlying co-morbidities., Conclusions: This is the first study to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting. Varenicline tartrate plus Quitline-counselling was found to be an effective opportunistic treatment when initiated for inpatient smokers who had been admitted with tobacco-related disease., Competing Interests: The authors have read the journal’s policy and have the following potential competing interests: KVCC was paid an honorarium and provided with economy airfares and accommodation by Pfizer Australia to present at the 2019 Smoking Exchange Summit in New South Wales where she spoke about ‘cultural-specific issues in smoking cessation’ and as an invited panellist in a plenary session about ‘a national approach to smoking cessation’. In 2017 she received an honorarium and provided with economy airfares and accommodation to speak about 12-month results of the STOP trial at the annual Pfizer Australia conference in New South Wales, Hunter Valley. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Background: It is well established that airway remodeling and inflammation are characteristics for chronic obstructive pulmonary disease (COPD). Moreover, cigarette smoke extract (CSE) promots inflammation, apoptosis and oxidative stress in COPD. And, there is evidence suggested that alantolactone (ALT), a sesquiterpene lactone isolated from Inula helenium, plays an adverse role in inflammation, apoptosis and oxidative stress. However, few studies have investigated the function and mechanism of ALT treatment on the COPD pathological process., Methods: The levels of IL-1 β, TNF-α, IL-6 and IFN-γ were examined by ELISA. Cells' apoptosis and caspase-3 activity were detected by Cell Death Detection PLUS enzyme-linked immunosorbent assay and caspase-Glo 3/7 Assay, respectively. The content of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using MDA and SOD assay kits. Reactive oxygen species (ROS) generation was measured by DCFH-DA assay. Protein expression was assayed by Western blot., Results: In the present study, we aimed to observe the protective effects of ALT against inflammation, apoptosis and oxidative stress in human bronchial epithelial Beas-2B and NHBE cells. Our results showed that different doses of CSE exposure induced Beas-2B and NHBE cell inflammatory cytokines IL-1 β, TNF-α, IL-6 and IFN-γ expression, cell apoptosis, caspase-3 activity and mediated oxidative stress markers MDA, ROS and SOD levels, while ALT treatment counteracted the effects of CSE. Further studies suggested that ALT attenuated NF-κB pathway activation. ALT also activated the Nrf2/HO-1 signal pathway through promoting Nrf2 nuclear aggregation and downstream HO-1 protein expression. HO-1 inhibitor tin protoporphyrin IX (SnPP IX) reversed the effects of ALT on Beas-2B and NHBE cell inflammation, apoptosis and oxidative stress., Conclusions: The above results collectively suggested that ALT suppressed CSE-induced inflammation, apoptosis and oxidative stress by modulating the NF-ĸB and Nrf2/ HO-1 axis.

Rationale: Chronic smoke exposure is associated with weight loss in patients with Chronic Obstructive Pulmonary Disease (COPD). However, the biological contribution of chronic smoking and sex on the cecal microbiome has not been previously investigated., Methods: Adult male, female and ovariectomized mice were exposed to air (control group) or smoke for six months using a standard nose-only smoke exposure system. DNA was extracted from the cecal content using the QIAGEN QIAamp® DNA Mini Kit. Droplet digital PCR was used to generate total 16S bacterial counts, followed by Illumina MiSeq® analysis to determine microbial community composition. The sequencing data were resolved into Amplicon Sequence Variants and analyzed with the use of QIIME2®. Alpha diversity measures (Richness, Shannon Index, Evenness and Faith's Phylogenetic Diversity) and beta diversity (based on Bray-Curtis distances) were assessed and compared according to smoke exposure and sex., Results: The microbial community was different between male and female mice, while ovariectomy made the cecal microbiome similar to that of male mice. Chronic smoke exposure led to significant changes in the cecal microbial community in both male and female mice. The organism, Alistipes, was the most consistent bacteria identified at the genus level in the cecal content that was reduced with chronic cigarette exposure and its expression was positively related to the whole-body weight of these mice., Conclusion: Chronic smoke exposure is associated with changes in the cecal content microbiome; these changes may play a role in the weight changes that are observed in cigarette smokers., Competing Interests: The authors have declared that no competing interests exist.

The level of concentration of heavy metal (loids) in tobacco-growing soils is detrimental to soil quality. In this study, 256 topsoil samples were collected from Zunyi city to understand the concentration, spatial distribution characteristics, sources and health risks of heavy metal (loids) by using mathematical statistics, geostatistical analyst, and conditional inference tree (CIT). The results showed that the average contents of Hg, Pb, Zn, and Cd in tobacco-growing soils were high with 1.7, 1.2, 1.1 and 1 times the background value, respectively. While, Ni, Cr, Cu and As were temporarily within the permissible limits. Concentrations of Hg, Cd, Pb, and Zn in the soils of Wuchuan, Tongzi, Daozhen, and Yuqing were much higher than the other regions due to human activities. According to the CIT, the main nodes were 1) distance from sampling to the main road, 2) organic matter, 3) factories, and 4) soil types. The results indicated that for Pb and Zn, the sources of pollution might be transportation; for Cu, As, and Cd, the sources were utilization of phosphate, tobacco-specific fertilizers, and organic fertilizers; and the sources of Hg were coal combustion and metals smelting. In addition, high background values of heavy metal (loids) in karst landforms were responsible for the accumulation of Cd. With respect to Hazard Quotient and Lifelong Carcinogenic Risk, the exposed individual was unlikely to experience obvious adverse health effect due to the heavy metal (loids) pollution, except Cr, which should be particularly considered in further risk control., Competing Interests: Declaration of competing interest This manuscript is an original work, it has not been previously published, and it is not under consideration for publication elsewhere. All authors have read the manuscript, agree that the work is ready for submission to a journal, and accept responsibility for the manuscript’s contents. All authors have disclosed any competing financial interests in this work, and in fact, there were none., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease-modifying treatment. The biggest drawback of today's COPD treatment regimen is the 'one size fits all' pharmacological intervention, mainly based on disease severity and symptoms and not the individual's disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age-related changes, structural changes in the small airways and the role of sex-related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2020 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Cigarette smoke (CS) has a negative impact on women's health and fertility. Studies have shown that histone deacetylases 1 and 2 (HDAC1/2) were involved in oocyte development. However, the roles of HDAC1/2 in ovarian toxicity caused by CS exposure and the therapeutic potential of trichostatin A (TSA, a HDAC inhibitor) for ovarian tissue damage have not been investigated. In this study, Female C57BL/6 mice were exposed to CS from six cigarettes mixed with indoor air for 120 min (one cigarette for 20 min) using a whole-body mainstream smoke exposure system twice daily for 30 days. TSA (0.6 mg/kg body weight) was injected intraperitoneally into mice in the Control + TSA group and CS + TSA group every two days for 30 days. We found that exposure to CS resulted in ovarian tissue damage and HDAC1/2 over-expression. TSA alleviated the structural changes of ovarian tissue induced by smoking and prevented the activation of HDAC1/2. Exposure to CS caused autophagy inhibition and pyroptosis activation. TSA treatment restored the expression of autophagy-associated proteins and decreased the levels of pyroptosis-related proteins induced by CS exposure. The TSA effect may be mediated by inhibition of HDAC1/2 involved in autophagy and pyroptosis process., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Information on the long-term safety of electronic cigarettes (e-cig) is still limited. We report the results after six years of follow-up of the first observational study assessing e-cig long-term effectiveness and safety., Patients and Methods: Participants were adults who smoked ≥1 tobacco cigarette/day (tobacco smokers); or used any type of e-cig inhaling ≥50 puffs weekly (e-cig users); or used both (dual users). Participants were contacted directly or by phone and/or internet interviews. Hospital discharge abstract data and carbon monoxide level tests were also used., Results: Data were available for 228 e-cig users (all ex-smokers), 469 tobacco smokers, 215 dual users. A possibly smoking-related disease (PSRD) was recorded in 90 subjects (9.9%); 11 deceased (1.2%). No differences were observed across groups in PSRD rates, with minor changes in self-reported health. Among e-cig users, 64.0% remained tobacco abstinent. Dual users and tobacco smokers did not significantly differ in the rate of cessation of tobacco (38.6% vs. 33.9%, respectively) and all products (23.7% vs. 26.4%). A comparable decrease in daily cigarettes was also observed. 39.5% of the sample switched at least once (tobacco smokers: 15.1%; dual users: 83.3%)., Conclusions: After six years, no evidence of harm reduction was found among e-cig or dual users. The complete switch to e-cig might support tobacco quitters remain abstinent, but the use of e-cig in addition to tobacco did not improve smoking cessation or reduction.

Chronic obstructive pulmonary fibrosis (COPD) is a chronic and fatal lung disease with few treatment options. Sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H 2 S), was found to alleviate cigarette smoke (CS)-induced emphysema in mice, however, the underlying mechanisms have not yet been clarified. In this study, we investigated its effects on COPD in a CS-induced mouse model in vivo and in cigarette smoke extract (CSE)-stimulated alveolar epithelial A549 cells in vitro. The results showed that NaHS not only relieved emphysema, but also improved pulmonary function in CS-exposed mice. NaHS significantly increased the expressions of tight junction proteins (i.e., ZO-1, Occludin and claudin-1), and reduced apoptosis and secretion of pro-inflammatory cytokines (i.e., TNF-α, IL-6 and IL-1β) in CS-exposed mouse lungs and CSE-incubated A549 cells, indicating H 2 S inhibits CS-induced inflammation, injury and apoptosis in alveolar epithelial cells. NaHS also upregulated prolyl hydroxylase (PHD)2, and suppressed hypoxia-inducible factor (HIF)-1α expression in vivo and in vitro, suggesting H 2 S inhibits CS-induced activation of PHD2/HIF-1α axis. Moreover, NaHS inhibited CS-induced phosphorylation of ERK, JNK and p38 MAPK in vivo and in vitro, and treatment with their inhibitors reversed CSE-induced ZO-1 expression and inflammation in A549 cells. These results suggest that NaHS may prevent emphysema via the suppression of PHD2/HIF-1α/MAPK signaling pathway, and subsequently inhibition of inflammation, epithelial cell injury and apoptosis, and may be a novel strategy for the treatment of COPD., (Copyright © 2019. Published by Elsevier B.V.)