Dietary Phytochemicals as Potential Chemopreventive Agents against Tobacco-Induced Lung Carcinogenesis.

Lung cancer is the second most common cancer in the world. Cigarette smoking is strongly connected with lung cancer. Benzo[a]pyrene (BaP) and 4-(N-methyl-N-nitrosamine)-1-(3-pyridyl)-butanone (NNK) are the main carcinogens in cigarette smoking. Evidence has supported the correlation between these two carcinogens and lung cancer. Epidemiology analysis suggests that lung cancer can be effectively prevented through daily diet adjustments. This review aims to summarize the studies published in the past 20 years exploring dietary phytochemicals using Google Scholar, PubMed, and Web of Science databases. Dietary phytochemicals mainly include medicinal plants, beverages, fruits, vegetables, spices, etc. Moreover, the perspectives on the challenges and future directions of dietary phytochemicals for lung cancer chemoprevention will be provided. Taken together, treatment based on the consumption of dietary phytochemicals for lung cancer chemoprevention will produce more positive outcomes in the future and offer the possibility of reducing cancer risk in society.

Effect of hyperhomocysteinemia on a murine model of smoke-induced pulmonary emphysema.

Hyperhomocysteinemia was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with hyperhomocysteinemia has not been fully elucidated. This study included 7- to 9-week-old C57BL6 male mice induced with hyperhomocysteinemia and were exposed to cigarette smoke (CS). A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and were exposed to cigarette smoke extract (CSE) to observe cell viability and expression of proteins related to the ER stress. After 6 months of CS exposure, pulmonary emphysema was more severely induced in the group under the condition of hyperhomocysteinemia compared to that in the control group. The apoptotic A549 cells increased as homocysteine concentration increased and that was enhanced by CSE. Protein expression levels of ER stress markers were significantly increased after simultaneous stimulation. Notably, vitamin B12 and folate supplementation improved ER stress after simultaneous stimulation of A549 cells. In this study, we showed that hyperhomocysteinemia exacerbates CS exposure-induced emphysema in mice, suggesting that hyperhomocysteinemia and CS stimulation enhance ER stress and subsequent induced apoptosis in alveolar epithelial cells. It was suggested that there is a synergistic effect between homocysteine and CS.

Lycopene Ameliorates Liver Inflammation and Redox Status in Mice Exposed to Long-Term Cigarette Smoke.

Cigarette smoke (CS) is the major cause of preventable death worldwide, and it can also cause damage to extrapulmonary organs, such as the liver, mainly due the generation of reactive oxygen species (ROS). The liver is an essential organ for human survival since it is mainly responsible for the body metabolism and among other things and it is the place where many endogenous and exogenous substances undergo biological transformation. Lycopene is a nonprovitamin A carotenoid found in red fruits and vegetables, and its role as a potent antioxidant is well known. In this study, we hypothesized that lycopene could protect mouse liver against long-term CS exposure. Thirty C57BL/6 mice were exposed to twelve cigarette smoke (12 cigarettes per day) for 60 days and pretreated with 25 mg/kg/day or 50 mg/kg/day of lycopene via orogastric gavage. After euthanasia, the hepatic tissue was collected for histopathological, antioxidant defense, oxidative stress, inflammatory, and collagen deposition analysis. Our analysis demonstrated that lycopene results in a suitable outcome to ameliorate the pathological changes, inflammatory and antioxidant profile in a mouse model of long-term CS exposure, and collagen accumulation in the hepatic extracellular matrix. This study demonstrates for the first time that supplementation of lycopene can be a possible pharmacological tool for the treatment of hepatic damage caused by exposure to long-term CS.

The MAPKinase Signaling and the Stimulatory Protein-1 (Sp1) Transcription Factor Are Involved in the Phototherapy Effect on Cytokines Secretion from Human Bronchial Epithelial Cells Stimulated with Cigarette Smoke Extract.

The present study was aimed to investigate the phototherapy effect with low-level laser on human bronchial epithelial cells activated by cigarette smoke extract (CSE). Phototherapy has been reported to actuate positively for controlling the generation/release of anti-inflammatory and pro-inflammatory mediators from different cellular type activated by distinct stimuli. It is not known whether the IL-8 and IL-10 release from CSE-stimulated human bronchial epithelium (BEAS) cells can be influenced by phototherapy. Human bronchial epithelial cell (BEAS) line was cultured in a medium with CSE and irradiated (660 nm) at 9 J. Apoptosis index was standardized with Annexin V and the cellular viability was evaluated by MTT. IL-8, IL-10, cAMP, and NF-κB were measured by ELISA as well as the Sp1, JNK, ERK1/2, and p38MAPK. Phototherapy effect was studied in the presence of mithramycin or the inhibitors of JNK or ERK. The IL-8, cAMP, NF-κB, JNK, p38, and ERK1/2 were downregulated by phototherapy. Both the JNK and the ERK inhibitors potentiated the phototherapy effect on IL-8 as well as on cAMP secretion from BEAS. On the contrary, IL-10 and Sp1 were upregulated by phototherapy. The mithramycin blocked the phototherapy effect on IL-10. The results suggest that phototherapy has a dual effect on BEAS cells because it downregulates the IL-8 secretion by interfering with CSE-mediated signaling pathways, and oppositely upregulates the IL-10 secretion through of Sp1 transcription factor. The manuscript provides evidence that the phototherapy can interfere with MAPK signaling via cAMP in order to attenuate the IL-8 secretion from CSE-stimulated BEAS. In addition, the present study showed that phototherapy effect is driven to downregulation of the both the IL-8 and the ROS secretion and at the same time the upregulation of IL-10 secretion. Besides it, the increase of Sp-1 transcription factor was crucial for laser effect in upregulating the IL-10 secretion. The dexamethasone corticoid produces a significant inhibitory effect on IL-8 as well as ROS secretion, but on the other hand, the corticoid blocked the IL-10 secretion. Taking it into consideration, it is reasonable to suggest that the beneficial effect of laser therapy on lung diseases involves its action on unbalance between pro-inflammatory and anti-inflammatory mediators secreted by human bronchial epithelial cells through different signaling pathway.

Smoking cessation.

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.

Early detection of skeletal muscle bioenergetic deficit by magnetic resonance spectroscopy in cigarette smoke-exposed mice.

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.

Financial incentives and proactive calling for reducing barriers to tobacco treatment among socioeconomically disadvantaged women: A factorial randomized trial.

Improved strategies and scalable interventions to engage low-socioeconomic status (SES) smokers in tobacco treatment are needed. We tested an intervention designed to connect low-SES smokers to treatment services, implemented through Minnesota's National Breast and Cervical Cancer Early Detection Program (Sage) in 2017; the trial was designed to last 3 months (July through October). Participants were female smokers who were 250% below the federal poverty level (randomized N = 3723; analyzed N = 3365). Using a factorial design, participants were randomized to six intervention groups consisting of a proactive call (no call vs call) and/or a financial incentive offered for being connected to treatment services ($0 vs $10 vs $20). Simple randomization was conducted using Stata v.13. All individuals received direct mail. Participants and staff were blinded to allocation. The outcome was connection via phone to QUITPLAN Services®, Minnesota's population-based cessation services. Groups that received $10 or $20 incentives had higher odds of treatment engagement compared to the no incentive group [respectively, OR = 1.94; 95% CI (1.19-3.14); OR = 2.18; 95% CI (1.36-3.51)]. Individuals that received proactive calls had higher odds of treatment engagement compared to individuals not called [OR = 1.59; 95% CI (1.11-2.29)]. Economic evaluation revealed that the $10 incentive, no call group had the best cost-benefit ratio compared to the no incentive, no call group. Direct mail with moderate incentives or proactive calling can successfully encourage connections to population-based tobacco treatment services among low-SES smokers. The intervention could be disseminated to similar programs serving low-SES populations. This trial is registered at ClinicalTrials.gov (NCT03760107).

Hypothalamic Neuropeptides Expression and Hypothalamic Inflammation in Adult Rats that Were Exposed to Tobacco Smoke during Breastfeeding: Sex-Related Differences.

The hypothalamus controls food intake and energy expenditure. In rats, maternal exposure to nicotine during breastfeeding alters the hypothalamic circuitry of the adult offspring, resulting in leptin resistance, neuropeptides changes and gliosis. Tobacco smoke exposure during lactation causes greater adiposity, hyperphagia and hyperleptinemia in the adult progeny. To understand the central mechanisms underlying the obese phenotype of adult rats that were directly and indirectly exposed to cigarette smoke during lactation, we investigated leptin signaling, orexigenic and anorexigenic neuropeptides expression, as well as astrocyte and microglia markers in hypothalamus. From postnatal day (PND) 3 to 21, Wistar lactating rat dams and their pups were divided into two groups: SE, smoke-exposed in a cigarette-smoking machine (four times/day); Crtl, exposed to filtered air. Offspring of both sexes were euthanized at PND180. The leptin pathway was not altered in SE animals from both sexes. SE males showed increased NPY (arcuate nucleus, ARC), CRH (paraventricular nucleus, PVN), as well as higher GFAP fiber density (ARC and PVN) and IL6 protein content. TRH (PVN) immunohistochemistry was reduced. SE females had lower CART-positive cells (ARC) and lower α-MSH immunostaining intensity (PVN and lateral hypothalamus), with no change of GFAP or IL-6. The protein contents of CX3CR1 (marker of activated microglia) and α7nAChR (anti-inflammatory marker) were not altered in both SE males and females. Neonatal cigarette smoke is deleterious to the hypothalamic circuitry, inducing changes in energy homeostasis favoring hyperphagia and decreased energy expenditure at adulthood in both sexes; however sex-dependent mechanisms were observed.

The plant flavonoid, fisetin alleviates cigarette smoke-induced oxidative stress, and inflammation in Wistar rat lungs.

In the present study, we tested the antioxidant and anti-inflammatory potential of the plant flavonoid, fisetin against cigarette smoke-induced oxidative stress, and inflammation in rat lungs. Male Wistar rats were chronically exposed to cigarette smoke (CS) with or without administration of fisetin. Fisetin administration to CS-exposed rats resulted in a significant reduction in neutrophils and macrophages in bronchoalveolar lavage fluid as well as malondialdehyde, 3-nitrotyrosine, 8-isoprostane, tumor necrosis factor-alpha, interleukin-1beta, granulocyte macrophage-colony stimulating factor, interleukin-4, and interleukin-10 levels in lung tissues compared to those in CS-exposed rats not treated with fisetin. Fisetin also significantly augmented lung hemoxinase-1, glutathione peroxidase-2, reduced glutathione, superoxide dismutase, nitric oxide, and nuclear factor erythroid 2-related factor (Nrf2) levels in CS-exposed rats. In addition, a marked reversal in CS-induced histopathological changes was noted in fisetin-treated rats. Collectively, these data demonstrate the potential of fisetin to blunt CS-induced oxidative stress and inflammation in the lung and to prevent tissue damage via the Nrf2-mediated upregulation of antioxidant gene expression. PRACTICAL APPLICATIONS: In the present study, we found that the plant flavonoid, fisetin significantly abrogated the oxidative stress, inflammation, and tissue damage induced by cigarette smoke, a powerful pro-oxidant in rat lungs. Additionally, fisetin markedly reversed cigarette smoke-induced increases in neutrophil and macrophage cell populations in bronchoalveolar lavage fluid. These findings are particularly significant considering the association of cigarette smoking with increased oxidative stress and inflammation, which are central to the pathologies of a wide variety of chronic diseases including chronic obstructive pulmonary disease, cancer, and cardiovascular diseases. Therefore, the present work underscores the beneficial effects of the regular consumption of plant-based foods with medicinal properties for the effective prevention of these chronic diseases.

Andrographolide simultaneously augments Nrf2 antioxidant defense and facilitates autophagic flux blockade in cigarette smoke-exposed human bronchial epithelial cells.

Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens oxidative stress and impairs autophagy, advancing COPD progression. Andrographolide is a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata which has been a traditional medicinal herb for respiratory diseases. As airway epithelial cells form the first interface to be exposed to cigarette smoke, this study aimed to explore the modulatory effects of andrographolide on oxidative stress and autophagy in human bronchial epithelial BEAS-2B cells exposed to cigarette smoke extract (CSE). CSE (2%) exposure increased autophagic markers p62 and LC3B-II levels in BEAS-2B cells. Andrographolide alone increased p62 and p-p62 (S349) but not LC3B-II in BEAS-2B cells. However, in the presence of CSE, andrographolide was able to simultaneously increase LC3B-II level and enhance antioxidant defense by decreasing oxidative stress and increasing total antioxidant capacity, through upregulation of nuclear Nrf2 via the p62-Nrf2 positive feedback loop. Using RFP-GFP-LC3B transfected BEAS-2B cells exposed to CSE, andrographolide was found to impair autophagosome fusion with lysosome, which may account for the moderate increase in activated caspase 3/7 and annexin V levels. Our findings revealed for the first time that andrographolide simultaneously upregulated antioxidant defense through the p62-Nrf2 loop and moderately induced apoptosis through impairment of autophagic flux in CSE-exposed bronchial epithelium. Andrographolide facilitated cigarette smoke-induced apoptosis may be a potential toxicological outcome or may protect against chronic inflammation and aberrant DNA repair. Validation of these in-vitro findings in an experimental COPD model by andrographolide is warranted.

Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: the role of Nrf2 antioxidant system in preventing oxidative stress.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been emerging as a great health problem in world. Cigarette smoke is known to cause oxidative stress and deplete glutathione (GSH) levels. Nuclear erythroid-related factor 2 (Nrf2) is involved in transcriptional regulation of glutamate-cysteine ligase catalytic subunit (GCLc). Antioxidant compounds may be of therapeutic value in monitoring disease progression. Crocin demonstrates antioxidant and anti-inflammatory functions. The aim of this study was to investigate the protective role of crocin against CSE-mediated oxidative stress, inflammatory process, Nrf2 modifications and impairment of cardiac function in rats with COPD. METHODS: Eighty rats were divided into four groups: Control, Cigarette smoke exposure (CSE), Crocin, Crocin+CS. Each group was divided into the two parts: 1) to evaluate lung inflammatory and oxidative process, 2) to evaluate the effect of Cigarette smoke induced-lung injuries on cardiac electrocardiogram (such as heart rate and QRS complex) and hemodynamic parameters (such as perfusion pressure and left ventricular developed pressure). RESULTS: CSE rats showed a significant increase in cotinine concentration (17.24 ng/ml), and inflammatory parameters and a decrease in PO2 (75.87 mmHg) and expression of PKC (0.86 fold), PI3K (0.79 fold), MAPK (0.87 fold), Nrf2 (0.8 fold) and GCLc (0.75 fold) genes, antioxidant activity, and finally cardiac abnormalities in electrocardiogram and hemodynamic parameters. Co-treatment whit crocin could restore all these values to normal levels. CONCLUSIONS: CS induced-COPD in rat model provides evidence that chronic CS exposure leads to lung injury and mediated cardiac dysfunction. Crocin co-treatment by modulating of Nrf2 pathway protected lung injury caused by COPD and its related cardiac dysfunction. In this study, we showed the importance of Nrf2 activators as a therapeutic target for the development of novel therapy for lung oxidative injuries.

Multielemental Analysis of Tobacco Plant and Tobacco Products by TXRF.

The aim of this research is to develop a fast analytical method for multielemental analysis of the tobacco plant Virginia tobacco (cultivated in Poland) and tobacco products (cigarettes, cigars, cigarillos, snuff and two kinds of properly crafted tobacco such as a shisha and cigarette tobacco) distributed in Polish markets by means of a low-power benchtop total reflection X-ray fluorescence (TXRF) system. For this purpose, a set of certified tobacco materials and real samples was employed. In leaves and stalks of V. tobacco and tobacco products, a concentration of 18 elements (P, S, Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Br, Rb, Sr and Pb) was determined. Analyzing elemental composition of tobacco plants, one can see that concentrations of S, Ca, Ti, Mn, Zn, Sr and Pb are higher in leaves, whereas the concentrations of P, Cl, K, Fe Cu and Br are higher in stalks; the levels of Cr, Ni, As and Rb are comparable in both these parts of the tobacco plant. All of the parameters affecting sample preparation and TXRF measurements conditions were carefully evaluated. The accuracy and precision of the TXRF measurements were verified using an internal standardization approach for quantification.

Pharmacological Investigation of the Anti-Inflammation and Anti-Oxidation Activities of Diallyl Disulfide in a Rat Emphysema Model Induced by Cigarette Smoke Extract.

Diallyl disulfide (DADS) is the main organosulfur ingredient in garlic, with known antioxidant and anti-inflammatory activities. The aim of the present study was to investigate the effect of DADS on reducing the inflammation and redox imbalance in a rat emphysema model that was induced by intraperitoneal injection of cigarette smoke extract (CSE). Briefly, DADS exerted an anti-inflammation effect on emphysema rats through decreasing cell influx in the bronchoalveolar lavage fluid (BALF) and suppressing pro-inflammation cytokine production including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) via inhibiting the NF-κB pathway. In addition, levels of oxidative stress markers including malondialdehyde (MDA) and myeloperoxidase (MPO) were reduced, while the activities of glutathione (GSH), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were markedly enhanced by DADS. Moreover, MMP-9 and TIMP-1 expression were down-regulated by DADS. Furthermore, the regulation effects of DADS on CD4⁺ and CD8⁺ T cells were observed. In conclusion, these encouraging findings suggest that DADS could be considered as a promising anti-inflammation and antioxidative agent for the treatment of emphysema.

[Claude Bernard and nicotinic receptors: from the neuromuscular junction to tobacco weaning]. / Claude Bernard et les récepteurs nicotiniques : de la jonction neuromusculaire au sevrage tabagique.

Claude Bernard (1813-1878) was fascinated by the pharmacological mechanisms of poisons. In particular, using a huge amount of ingenious and robust experiments, he demonstrated the peripheral toxic action of the natural compound curare. His work generated controversies in a period where scientific methodology and technical development followed the progression of concepts and ideas. From his intense debates with Albert Vulpian emerged the location of curare's toxicity at the neuromuscular junction. These two fascinating scientists could not imagine how important were these discoveries which allowed John Langley to propose the concept of receptor early in the 20th century. At the same time, the German immunologist Paul Ehrlich suggested that these receptors could be targeted by so-called "magic bullets", i.e., drugs that act on receptors, in order to treat patients. The molecular substrate of curare's activity was identified many years later as the nicotinic receptor of the motor end-plate. We now have curare molecules belonging to various chemical families that block receptors during anaesthesia. Suggamadex is the antidote for two of them, a drug that Claude Bernard perhaps dreamt of. We also have the recently marketed varenicline that acts as a partial agonist of nicotinic receptors in the central nervous system to treat patients from tobacco addiction. This rich story shows that biomedical research needs collaborations, imagination, perspicacity but also all results that it can have many years later, therefore challenging researchers about consequences of their discoveries.

Effects of Curcumin on Tobacco Smoke-induced Hepatic MAPK Pathway Activation and Epithelial-Mesenchymal Transition In Vivo.

Tobacco smoke is a major risk factor for hepatic cancer. Epithelial-mesenchymal transition (EMT) induced by tobacco smoke is crucially involved in the initiation and development of cancer. Mitogen-activated protein kinase (MAPK) pathways play important roles in tobacco smoke-associated carcinogenesis including EMT process. The chemopreventive effect of curcumin supplementation against cancers has been reported. In this study, we investigated the effects of tobacco smoke on MAPK pathway activation and EMT alterations, and then the preventive effect of curcumin was examined in the liver of BALB/c mice. Our results indicated that exposure of mice to tobacco smoke for 12 weeks led to activation of ERK1/2, JNK, p38 and ERK5 pathways as well as activator protein-1 (AP-1) proteins in liver tissue. Exposure of mice to tobacco smoke reduced the hepatic mRNA and protein expression of the epithelial markers, while the hepatic mRNA and protein levels of the mesenchymal markers were increased. Treatment of curcumin effectively attenuated tobacco smoke-induced activation of ERK1/2 and JNK MAPK pathways, AP-1 proteins and EMT alterations in the mice liver. Our data suggested the protective effect of curcumin in tobacco smoke-triggered MAPK pathway activation and EMT in the liver of BALB/c mice, thus providing new insights into the chemoprevention of tobacco smoke-associated hepatic cancer. Copyright © 2017 John Wiley & Sons, Ltd.

Effect of long-term maternal smoking on the offspring's lung health.

Maternal smoking during pregnancy contributes to long-term health problems in offspring, especially respiratory disorders that can manifest in either childhood or adulthood. Receptors for advanced glycation end products (RAGE) are multiligand receptors abundantly localized in the lung, capable of responding to by-products of reactive oxygen species and proinflammatory responses. RAGE signaling is a key regulator of inflammation in cigarette smoking-related pulmonary diseases. However, the impact of maternal cigarette smoke exposure on lung RAGE signaling in the offspring is unclear. This study aims to investigate the effect of maternal cigarette smoke exposure (SE), as well as mitochondria-targeted antioxidant [mitoquinone mesylate (MitoQ)] treatment, during pregnancy on the RAGE-mediated signaling pathway in the lung of male offspring. Female Balb/c mice (8 wk) were divided into a sham group (exposed to air), an SE group (exposed to cigarette smoke), and an SE + MQ group (exposed to cigarette smoke with MitoQ supplement from mating). The lungs from male offspring were collected at 13 wk. RAGE and its downstream signaling, including nuclear factor-κB and mitogen-activated protein kinase family consisting of extracellular signal-regulated kinase 1, ERK2, c-JUN NH2-terminal kinase (JNK), and phosphorylated JNK, in the lung were significantly increased in the SE offspring. Mitochondrial antioxidant manganese superoxide dismutase was reduced, whereas IL-1ß and oxidative stress response nuclear factor (erythroid-derived 2)-like 2 were significantly increased in the SE offspring. Maternal MitoQ treatment normalized RAGE, IL-1ß, and Nrf-2 levels in the SE + MQ offspring. Maternal SE increased RAGE and its signaling elements associated with increased oxidative stress and inflammatory cytokines in offspring lungs, whereas maternal MitoQ treatment can partially normalize these changes.

Cigarette Smoke Extract: A Preclinical Model of Tobacco Dependence.

Animal models are used to study many human diseases, one of which is tobacco addiction. Most preclinical models use nicotine alone, although there are >7000 constituents present in tobacco smoke. The clinical literature suggests that cigarettes have a strong addictive potential, which is not paralleled in preclinical studies using nicotine alone. In order to address the gap between clinical and preclinical literature on tobacco dependence, cigarette smoke extracts containing tobacco constituents have been developed. This unit describes a procedure for producing an aqueous cigarette smoke extract (CSE) which animals readily self-administer. In addition, we describe how to make the apparatus for producing CSE and how to analyze the solution for nicotine content. © 2016 by John Wiley & Sons, Inc.

Cigarette Smoke-mediated Perturbations of the Immune Response: A New Therapeutic Approach with Natural Compounds.

Cigarette smoke (CS) accounts for the outcome of several pathologies, even including lung cancer, cardiovascular disease and chronic obstructive pulmonary disease (COPD). Under healthy conditions, lung immune system becomes tolerant in response to various external stimuli. CS exposure alters the pulmonary immune equilibrium, thus leading to a condition of hyper activation of the local innate and adaptive immunity. COPD is one of the major complications of chronic CS exposure where a pro-inflammatory profile of the pulmonary and systemic immunity is predominant. In this review, alternative treatments with natural products to mitigate CS-mediated pulmonary inflammation are proposed. In particular, polyphenols, a class of natural compounds largely present in fruits and vegetables, have been shown to act as anti-inflammatory agents. Accordingly, recent experimental and clinical evidences support polyphenol-mediated potential health benefits in smokers. For instance, pomegranate juice is able to attenuate the damage provoked by CS on cultured human alveolar macrophages. In addition, maqui beery extract has been proven to normalize H2O2 and interleukin-6 levels in exhaled breath condensate in healthy smokers. However, some limitations of alternative treatments are represented by a better knowledge of the mechanism(s) of action exerted by polyphenols and by the lack of animal models of COPD. In any case, the potential targets of polyphenols in the course of COPD will be outlined with special reference to the activation of T regulatory cells as well as to the inhibition of the polymorphonuclear cell and monocyte respiratory burst and of the NF-κB pathway, respectively.

Evaluation of anti-aphthous activity of decoction of Nicotiana tabacum leaves as a mouthwash: a placebo-controlled clinical study.

OBJECTIVE: To determine the effects of decoction derived from the leaves of Nicotiana tabacum (L.) as a mouthwash on minor recurrent aphthous. METHODS: A randomized double-blinded placebo-controlled clinical trial was conducted on 60 patients with minor recurrent aphthous. Treatment comprised of application of tobacco or placebo mouthwash (10 mL 3 times a day) for 5 days. Clinical evaluation included pain level using a visual analog scale and ulcer size on days 1, 3, and 5 were measured. Adverse effects after mouthwash application were recorded, and the oral mucosa was examined by the investigator at each visit. RESULTS: A total of 54 subjects with the mean age (38 ± 10) years fulfilled the study. No minor and major adverse effects were observed. In the treatment group, ulcer pain score was decreased by 79.2% and 93.8% and ulcer size was reduced by 69.1% and 92.2% (days 3 and 5, respectively), which was significantly greater than the control group (P < 0.01). CONCLUSION: The decoction prepared with of Nicotiana tabacum leaves, used as mouthwash are well-tolerated and safe, and can be used for the management of recurrent aphthous.

2-Phenethyl Isothiocyanate, Glutathione S-transferase M1 and T1 Polymorphisms, and Detoxification of Volatile Organic Carcinogens and Toxicants in Tobacco Smoke.

Cigarette smoke contains relatively large quantities of volatile organic toxicants or carcinogens such as benzene, acrolein, and crotonaldehyde. Among their detoxification products are mercapturic acids formed from glutathione conjugation, catalyzed in part by glutathione S-transferases (GST). A randomized phase II clinical trial with a crossover design was conducted to evaluate the effect of 2-phenethyl isothiocyanate (PEITC), a natural product formed from gluconasturtiin in certain cruciferous vegetables, on the detoxification of benzene, acrolein, and crotonaldehyde in 82 cigarette smokers. Urinary mercapturic acids of benzene, acrolein, and crotonaldehyde at baseline and during treatment were quantified. Overall, oral PEITC supplementation increased the mercapturic acid formed from benzene by 24.6% (P = 0.002) and acrolein by 15.1% (P = 0.005), but had no effect on crotonaldehyde. A remarkably stronger effect was observed among subjects with the null genotype of both GSTM1 and GSTT1: in these individuals, PEITC increased the detoxification metabolite of benzene by 95.4% (P < 0.001), of acrolein by 32.7% (P = 0.034), and of crotonaldehyde by 29.8% (P = 0.006). In contrast, PEITC had no effect on these mercapturic acids in smokers possessing both genes. PEITC had no effect on the urinary oxidative stress biomarker 8-iso-prostaglandin F2α or the inflammation biomarker prostaglandin E2 metabolite. This trial demonstrates an important role of PEITC in detoxification of environmental carcinogens and toxicants which also occur in cigarette smoke. The selective effect of PEITC on detoxification in subjects lacking both GSTM1 and GSTT1 genes supports the epidemiologic findings of stronger protection by dietary isothiocyanates against the development of lung cancer in such individuals. Cancer Prev Res; 9(7); 598-606. ©2016 AACR.