Effect of cigarette smoke on protein synthesis in brain and liver

The rates of protein synthesis in brain and liver were determined in 2 inbred mouse strains (BALB/c and CXBH) during 1 hr of smoke exposure, and after 3 and 6 days of cigarette smoke treatment. Exposure to cigarette smoke reduced valine incorporation into brain and liver protein by 12 and 30% respectively. The greatest part of this reduction in synthesis was due to the hypothermie effect of smoke exposure, which was an approx. 8% change in the synthesis rate for each degree of reduction in body temperature, though a significant smoke effect was still evident. Two major components of cigarette smoke, nicotine and carbon monoxide, were individually tested. Injections of nicotine produced a similar inhibition of brain protein synthesis, with no effect on liver protein synthesis. After extraction of nicotine from the smoke by use of a Cambridge filter, only slight inhibition of brain protein synthesis was observed, which was due to the decrease in body temperature; there was still a significant inhibition in the liver. Incorporation measured, not during but after smoke exposure, was still significantly reduced, although reduction in the liver was smaller than that measured during smoke exposure. Carboxyhemoglobin at levels 50% higher than that achieved by smoke exposure had no effect on brain or liver protein synthesis; higher carboxyhemoglobin levels (300–400% higher than levels during smoke exposure) produced inhibition of liver protein synthesis. The results suggest that the slight and significant inhibition of brain protein synthesis is due to nicotine, whereas the effect on the liver is probably due to anoxia. Smoke treatment for 3–6 days suggests that there is no adaptation to these effects. Strain differences in smoke sensitivity are not related to the effect of nicotine on protein synthesis, suggesting that other mechanisms are involved in smoke sensitivity.     

烟碱和大脑功能障碍(英文)

During the last decade, brain nicotinic acetylcholine receptors were extensively characterized from electrophys-iological and pharmacological points of view. These receptors play important roles in memory and cognition and participate in the pathogenesis of several brain disorders (Parkinson's and Alzheimer's diseases, Tourette's syndrome, schizophrenia, depression, attention deficit disorder) . In the same diseases, clinical studies showed that nicotine had beneficial effects, both as therapeutic and prophylactic agent. This review presents recent data concerning the structure and properties of neuronal nicotinic receptors, their involvement in the pathogenesis of various brain disorders and the beneficial effects of nicotine as therapeutic agent.     

Nicotine dependence and withdrawal in alcoholic and nonalcoholic ever-smokers

We compared nicotine dependence and withdrawal in male alcoholic and control ever-smokers, controlling for relevant demographic and clinical variables. Alcoholics were more likely to meet criteria for moderate or severe nicotine dependence and endorse more nicotine dependence symptoms. Symptoms reported more frequently by alcoholics included: (a) using nicotine in larger amounts or over a longer time than intended; (b) continued use despite problems caused or exacerbated by nicotine; (c) marked tolerance; and (d) experiencing characteristic nicotine withdrawal symptoms. Alcoholics also smoked more heavily. Other than “headaches,” and “decreased heart rate,” alcoholics consistently endorsed nicotine withdrawal symptoms at a higher rate. After controlling for demographic and clinical variables and level of nicotine dependence, only “feel depressed” differed significantly between groups. Our research supports previous findings suggesting that nicotine dependence is more severe in those with a history of alcohol dependence. As a result, alcoholics may experience greater discomfort from nicotine withdrawal upon smoking cessation.     

Nicotine dose-concentration relationship and pregnancy outcomes in rat: biologic plausibility and implications for future research

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.     

Effect of cigarette smoke components on vascular smooth muscle cell migration toward platelet-derived growth factor BB

Cigarette smoking is one of the factors causing accumulation of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques. Changes in cell migration toward platelet-derived growth factor BB were investigated using a Boyden chamber after 48-h preincubation of GBaSM-4 VSMCs with nicotine or nicotine-free cigarette smoke extract (CSE). A nicotine concentration of 0.1 μM maximally promoted cell migration; 0.1% CSE also promoted cell migration, while high CSE concentrations damaged GBaSM-4 cells. Fetal bovine serum (FBS) long-depletion induced decrease in migration of GBaSM-4 cells. Our results suggest that nicotine and some CSE components can induce GBaSM-4 cell migration.     

Evidence for carbon monoxide as the major factor contributing to lower fetal weights in rats exposed to cigarette smoke.

One of the major effects of cigarette smoking during pregnancy is bearing a child with lower birth weight. It has previously been demonstrated under experimental conditions in rats that exposure to reference cigarette smoke results in reduced birth weight (E. L. Carmines et al., 2003, Toxicol. Sci. 75, 134-147; C. L. Gaworski et al., 2004, Toxicol. Sci. 79, 157-169). The role of various smoke constituents on lower birth weight was evaluated by exposing time-pregnant Sprague-Dawley rats at the concentrations found in cigarette smoke. The rats were exposed for 2 h/day 7 days/week by nose-only inhalation. The target concentrations were designed to produce the same plasma levels of biomarkers as exposure to 2R4F reference cigarette smoke at a concentration of 600 mg/m(3) total particulate matter. The smoke constituents evaluated included carbon monoxide (CO), nicotine, and a mixture of aldehydes (acrolein, acetaldehyde, and formaldehyde). The smoke constituents were tested individually as well as in mixtures to evaluate potential interactions. Exposure to cigarette smoke during gestation produced a reduction in both maternal body weight gain and fetal weights. Exposure to nicotine reduced maternal body weight gain but had no effect on fetal weight. Exposure to CO had no effect on maternal body weight gain but reduced fetal weight to a degree comparable to cigarette smoke. Exposure to a mixture of aldehydes (acrolein, acetaldehyde, and formaldehyde) had no effect on either maternal body weight gain or fetal weight. Exposure to mixtures of nicotine and CO or nicotine, CO, and aldehydes did not demonstrate any interactions. The results of this study suggest that the observed reduction in fetal weight after exposure to cigarette smoke in rats is due to CO toxicity and not nicotine toxicity.     

Nicotine administration in rabbits using Habitrol nicotine patches and nicotine nasal spray

1. Several methods are used to provide predictable and effective nicotine to experimental animals in scientific studies. Due to the expense and technical challenges of these methods, we sought suitable alternatives. Consequently, the purpose of the present study was to develop a reliable experimental nicotine protocol in rabbits that included either Habitrol nicotine patches (Novartis Consumer Health Inc., Summit, NJ, USA) or nicotine nasal spray. 2. Administration of one of three doses of nicotine (2.5, 5, or 10 mg) was accomplished daily on 13 rabbits divided between either the patch or spray groups. Systemic nicotine and cotinine levels at 0 h, 15 min and 8 and 24 h were assayed. Data were analysed by a Fisher's protected least significant difference test at P = 0.05. 3. Rabbits treated with Habitrol patches exhibited consistent and predictable systemic nicotine levels. The nicotine nasal spray produced an immediate dose-dependent response with no measurable nicotine serum levels at 8 h. 4. For nicotine administration in rabbits, nicotine patches are easy to administer and provide a nicotine serum level between 5 and 25 ng/mL, which is consistent with the average daily level found in a patient who smokes cigarettes.     

Commonly used air filters fail to eliminate secondhand smoke induced oxidative stress and inflammatory responses

Secondhand smoke (SHS) causes approximately 50,000 deaths per year. Despite all the health warnings, smoking is still allowed indoors in many states exposing both workers and patrons to SHS on a daily basis. The opponents of smoking bans suggest that present day air filtration systems remove the health hazards of exposure to SHS. In this study, using an acute SHS exposure model, we looked at the impact of commonly used air filters (MERV-8 pleated and MERV-8 pleated activated charcoal) on SHS by assessing the inflammatory response and the oxidative stress response in C57BL/6 mice. In order to assess the inflammatory response, we looked at the tumor necrosis factor alpha (TNF-α) cytokine production by alveolar macrophages (AMs), and for the oxidative response, we quantified the products of lipid peroxidation and the total glutathione (tGSH) production in lung homogenates. Our results showed that SHS caused significant immune and oxidative stress responses. The tested filters resulted in only a modest alleviation of inflammatory and oxidative responses due to SHS exposure. Our data show that these air filters cannot eliminate the risk of SHS exposure and that a short-term exposure to SHS is sufficient to alter the inflammatory cytokine response and to initiate a complex oxidative stress response. Our results are consistent with the statement made by the Surgeon General’s reports that there is no risk free level of exposure to SHS.     

卷烟烟气中木犀草素和黄芩苷混合物对呼吸系统作用的研究

目的研究卷烟烟气中木犀草素和黄芩苷对呼吸系统的作用。方法将木犀草素和黄芩苷混合物加入卷烟制成特制卷烟,以动物吸烟机使混合物通过烟气接触动物呼吸系统。采用小鼠氨水引咳法制作咳嗽模型;以小鼠酚红排泄法评价气道分泌液量;以豚鼠整体动物药物引喘法评价对支气管痉挛的作用;并进行木犀草素和黄芩苷混合物经消化道给药和特制卷烟的急性毒性试验。结果与对照卷烟比较,特制卷烟可明显减少咳嗽,增加气道分泌液量,减轻动物呼吸道刺激。结论特制卷烟中木犀草素和黄芩苷能降低卷烟的呼吸系统危害性。     

Distribution of toxic chemicals in particles of various sizes from mainstream cigarette smoke

To accurately estimate the risk of inhaling cigarette smoke containing toxic chemicals, it is important that the distribution of these chemicals is accurately measured in cigarette smoke aerosol particles of various sizes. In this study, a single-channel smoking machine was directly coupled to an electrical low-pressure impactor. The particles of mainstream cigarette smoke were collected using 12 polyester films, and the particulate matter (PM) was characterized. Nicotine, tobacco-specific N-nitrosamines (TSNAs, including NNN, NAT, NAB, and NNK), polycyclic aromatic hydrocarbons (PAHs, including benzo(a)pyrene (BaP), benzo(a)anthracene, and chrysene), and heavy metals (including Cr, As, Cd, and Pb) present in the particles of different sizes were analyzed by GC, HPLC-MS/MS, GC/MS, or ICP-MS, respectively. The results demonstrated that the nicotine, TSNAs, PAHs, and heavy metals in mainstream cigarette smoke were dispersed over a particle size ranging from 0.1?μm to 2.0?μm, and the concentration of these toxic chemicals initially increased and then decreased the particle size grew. The distribution of nicotine was uniform for the PM in the size ranges of less than 0.1?μm, 0.1–1.0?μm, and 1.0–2.0?μm, TSNAs and heavy metals in particles of less 0.1?μm were more abundant, and PAHs in fine particles were also more abundant.     

Nicotine, its metabolism and an overview of its biological effects.

Nicotine is a naturally occurring alkaloid found in many plants. The principal sources of nicotine exposure is through the use of tobacco, nicotine containing gum and nicotine replacement therapies. Nicotine is an amine composed of pyridine and pyrrolidine rings. It has been shown that nicotine crosses biological membranes and the blood brain barrier easily. The absorbed nicotine is extensively metabolized in the liver to form a wide variety of metabolites including nicotine N'-oxide and cotinine N'-oxide. These are the products of mixed function oxidase system. Nicotine is also converted to some biologically important compounds during harvesting. Among these are the nitrosamines specific to tobacco. Nicotine has been shown to affect a wide variety of biological functions ranging from gene expression, regulation of hormone secretion and enzyme activities. The objective of this study was to overview the biological effects and metabolism of nicotine.     

Cigarette smoke inhibits macrophage sensing of Gram-negative bacteria and lipopolysaccharide: relative roles of nicotine and oxidant stress

BACKGROUND AND PURPOSE: Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smokers are more prone to infections. This has been associated with a suppression of the immune system by smoke. However, it is not clear how cigarette smoke affects the ability of immune cells to sense pathogens. Cigarette smoke contains a large number of molecules which may mediate responses on immune cells and of these, nicotine and oxidants have both been identified as inhibitory for the sensing of bacterial lipopolysaccharide (LPS). Nitric oxide synthase (NOS) and tumour necrosis factor (TNF)-alpha are both induced in macrophages on stimulation with Gram negative bacteria or LPS. EXPERIMENTAL APPROACH: We used murine macrophages stimulated with whole heat-killed bacteria or LPS. We measured output of NO (as nitrite) and TNFalpha, NOS protein by Western blotting and cellular oxidant stress. KEY RESULTS: Cigarette smoke extract suppressed the ability of murine macrophages to release NO, but not TNFalpha in response to whole bacteria. Cigarette smoke extract also inhibited nitric oxide synthase II protein expression in response to LPS. The effects of cigarette smoke extract on nitrite formation stimulated by LPS were unaffected by inhibition of nicotinic receptors with alpha-bungarotoxin (100 units ml(-1)). However, the effects of cigarette smoke extract on LPS-induced nitrite formation were mimicked by hydrogen peroxide and reversed by the anti-oxidants N-acetyl cysteine and glutathione. CONCLUSIONS AND IMPLICATIONS: We suggest that cigarette smoke exerts its immunosuppressive effects through an oxidant-dependent and not a nicotine-dependent mechanism.     

Effects of Chronic Varenicline Treatment on Nicotine,Cocaine, and Concurrent Nicotine+Cocaine Self-Administration

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004–0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7–10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05–0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.     

PDE7 inhibitors as new drugs for neurological and inflammatory disorders

Background: Phosphodiesterase 7 (PDE7) is a high affinity cAMP-specific PDE whose functional role in T cells has been the subject of some controversy. Recent findings on tissue distribution, however, support the hypothesis that PDE7 could be a good target for the treatment of airway diseases, T-cell related diseases or even CNS disorders. Objective/method: This review discloses recent discoveries of selective PDE7 and PDE4/PDE7 dual inhibitors with special emphasis on their potential for neurological and inflammatory diseases. Conclusion: PDE7 inhibitors constitute a new approach to be explored for the treatment of neurodegenerative disorders.     

A transport model for nicotine in the tracheobronchial and pulmonary region of the lung

Nicotine in mainstream cigarette smoke is predominantly present in the particulate phase. Interestingly, however, the deposition efficiency of smoke particles in the respiratory tract is less effective than is the nicotine retention. In the literature, four nicotine deposition mechanisms are identified: (a) direct gas deposition, (b) evaporative gas deposition, (c) particle deposition with evaporation, and (d) particle deposition with diffusion. In this article we present a physically motivated fundamental model to address nicotine deposition mechanisms (b) and (c) from the vapor phase. The model incorporates nicotine mass transport through estimates for the diffusion time across the epithelial layer and the time for nicotine vapor diffusion from the gas volume to the tissue surfaces in the tracheobronchial and pulmonary regions of the respiratory tract. The model comprises four mass transfer processes for nicotine at the surface of the respiratory tract epithelium: (1) conversion of free base nicotine from protonated nicotine; (2) free base nicotine transport across the epithelium; (3) free base nicotine evaporation; and (4) diffusion of free base nicotine vapor from the surface gas layer into the airway lumen. Results of the nicotine mass transport model suggest that the principal mechanism of nicotine delivery to the lung is by direct deposition of particles to the alveolar fluid lining, followed rapidly by evaporation into the lumen and then gas diffusion back to the surface as nicotine depletes in the surface layer through its transport across the epithelium.     

Acute exposure to waterpipe tobacco smoke induces changes in the oxidative and inflammatory markers in mouse lung

Context: Tobacco smoking represents a global public health threat, claiming approximately 5 million lives a year. Waterpipe tobacco use has become popular particularly among youth in the past decade, buttressed by the perception that the waterpipe “filters” the smoke, rendering it less harmful than cigarette smoke.

Objective: In this study, we examined the acute exposure of waterpipe smoking on lung inflammation and oxidative stress in mice, and compared that to cigarette smoking.

Materials and methods: Mice were divided into three groups; fresh air control, cigarette and waterpipe. Animals were exposed to fresh air, cigarette, or waterpipe smoke using whole body exposure system one hour daily for 7 days.

Results: Both cigarette and waterpipe smoke exposure resulted in elevation of total white blood cell count, as well as absolute count of neutrophils, macrophages, and lymphocytes (P < 0.01). Both exposures also elevated proinflammatory markers such as TNF-α and IL-6 in BALF (P < 0.05), and oxidative stress markers including GPx activity in lungs (P < 0.05). Moreover, waterpipe smoke increased catalase activity in the lung (P < 0.05). However, none of the treatments altered IL-10 levels.

Discussion and conclusion: Results of cigarette smoking confirmed previous finding. Waterpipe results indicate that, similar to cigarettes, exposure to waterpipe tobacco smoke is harmful to the lungs.     

废弃烟草中茄尼醇和烟碱的提取

从废弃烟草中提取得到茄尼醇浸膏和烟碱提取液，茄尼醇浸膏皂化后用柱色谱方法，可得纯度95．7％的茄尼醇，收率80％。烟碱提取液，以正己烷作为萃取剂，可直接提取得到纯度98．9％的烟碱，收率75％。二者结构由IR、UV和MS确证。     

An Assessment of Nicotine Dependence Among Pregnant Adolescents

Studies have reported that between 28 and 62% of pregnant teenagers smoke (Cornelius and Trollestrup). Because smoking is prevalent among pregnant teenagers, the purpose of this research is to assess nicotine dependence in this high-risk group. This study analyzed baseline data from a sample of pregnant teen smokers who had volunteered to participate in a smoking cessation study (N = 94). Nicotine dependence was measured by adapting the Fagerstrom Tolerance Questionnaire (FTQ; Prokhorov, Pallonen, Fava, Ding, & Niaura, 1996), and by a 6-item withdrawal symptom scale. The overall FTQ score found among pregnant adolescents was 3.10 (SD = 2.3) compared to the mean overall FTQ score among vocational-technical students of 4.27 (SD = 2.2) (Prokhorov et al., 1996). Duration of smoking in years was significantly correlated with the overall FTQ score (r = 0.43, p < .01). Quantity of smoking, as measured by average number of cigarettes smoked, significantly correlated with overall FTQ scores (r = 0.67, p < .01). Lighter smokers were more likely to have previously attempted to quit, however, among the quit attempters, those who smoked 10 + cigarettes per day reported greater severity of withdrawal symptoms than those who smoked less per day. Prenatal education and smoking cessation programs for pregnant teenagers, and pregnant women in general, need to consider that nicotine dependence is an important issue. Early pregnancy may be an opportune time to intervene among pregnant smokers; incentives may be necessary to attract those women who are the heaviest smokers, and possibly the most dependent on nicotine.     

反相高效液相色谱法测定复方戒烟贴片中尼古丁和可乐定的含量

目的 :建立反相高效液相色谱法检测复方戒烟贴片中尼古丁和可乐定的含量。方法 :用LichrosorbC8柱 ,甲醇 -磷酸盐缓冲液 (0 0 0 2 2mol·L- 1 磷酸二氢钾 - 0 0 16mol·L- 1 磷酸氢二钠溶液 ) (5 2∶48)为流动相 ,检测波长 2 6 8nm。结果 :该方法回收率尼古丁为 95 4% ,RSD为 3 8% (n =5 ) ;可乐定为 98 9% ,RSD为 4 8% (n =5 )。结论 :本法较简便 ,准确可靠 ,可作为复方戒烟贴片的质量控制方法。