The roles of microRNAs in the pathogenesis of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and irreversible airflow obstruction, with an abnormal lung function. The etiology of COPD correlates with complex interactions between environmental and genetic determinants. However, the exact pathogenesis of COPD is obscure although it involves multiple aspects including oxidative stress, imbalance between proteolytic and anti-proteolytic activity, immunity and inflammation, apoptosis, and repair and destruction in both airways and lungs. Many genes have been demonstrated to be involved in those pathogenic processes of this disease in patients exposed to harmful environmental factors. Previous reports have investigated promising microRNAs (miRNAs) to disclose the molecular mechanisms for COPD development induced by different environmental exposure and genetic predisposition encounter, and find some potential miRNA biomarkers for early diagnosis and treatment targets of COPD. In this review, we summarized the expression profiles of the reported miRNAs from studies of COPD associated with environmental risk factors including cigarette smoking and air pollution exposures, and provided an overview of roles of those miRNAs in the pathogenesis of the disease. We also highlighted the potential utility and limitations of miRNAs serving as diagnostic biomarkers and therapeutic targets for COPD.     

吸烟对血液过氧化与抗氧化平衡的影响

比较吸烟与不吸烟人静脉血血浆及红细胞脂质过氧化物-丙二醛（MDA）含量，血浆及红细胞超氧化物歧化酶（SOD）活力、全血谷胱甘肽过氧化物酶（GSH－Px）活力及血浆总抗氧化能力（AOA）．结果表明：吸烟组血浆及红细胞MDA的含量高于不吸烟组（P＜0．01），红细胞SOD含量高于不吸烟组（P＜0．01），血浆SOD、全血GSH－Px活力．血浆AOA均低0于不吸烟组（P＜0．01，P＜0．05，P＜0.05）．提示长期吸烟可使血中氧化与抗氧化失去平衡。     

Smoking enhances asbestos-induced genotoxicity,relative involvement of chromosome 1: a study using multicolor FISH with tandem labeling

Several experimental and epidermological studies have indicated augmentation of asbestos induced diseases by cigarette smoke by the mechanisms, which are still unknown. To determine whether smoking affects genetic system of the cells and further modifies asbestos induced genotoxicity, whole blood from non-smokers and smokers was exposed to asbestos fibres separately in vitro and micronucleus test was performed. The number of micronuclei was found to be significantly higher (P<0 05) in cases of smoker's lymphocytes, asbestos exposed non-smokers lymphocytes as well as asbestos exposed smokers lymphocytes, as compared with unexposed non-smokers lymphocytes. Further we investigated involvement of chromosome 1 in the damaging process using multicolor FISH technique. FISH is fast and reliable method, distinguishing both structural and numerical alterations. The centric/pericentric regions of chromosome 1 (cen-q12) were labeled, as the pericentric heterochromatin region 1 (q12) is quite large, highly repetitive and prone to breakage. Multicolor FISH assay suggested that the genetic damage by asbestos fibres mainly involve chromosome 1 but in case of cigarette smoking the damage is not strictly connected to chromosome 1 only, but also involves damage to other chromosomes. Further the study suggested that smoking makes genetic system of the cells more vulnerable to the deleterious effects of asbestos.     

The effects of cigarette smoking on the response to stress in a driving simulator

1. Some behavioural and physiological responses of cigarette smokers and non-smokers exposed to varying degrees of stress in a driving simulator were compared.2. When the smokers were smoking a cigarette, some of their reaction times to light signals differed significantly from those of non-smokers, some being longer and some shorter. These differences disappeared when the smokers were not smoking.3. Of the physiological measurements, only heart rate differed significantly between smokers and non-smokers, being higher at all levels of stress in the smokers. There were no significant differences in blood pressure, calf blood flow and respiration rate between smokers and non-smokers.4. The results of the Cattell Sixteen Personality Factor Questionnaire showed that the smokers were significantly more extroverted and self-reliant than the non-smokers.5. The results are discussed in relation to the pharmacology of cigarette smoking. It is concluded that the differences in reaction times and heart rates between smokers and non-smokers were a consequence of cigarette smoking.     

WHOLE BLOOD AGGREGATION AND PLASMA LYSO-PAF RELATED TO SMOKING AND ATHEROSCLEROSIS

1. Aggregation of diluted whole blood (impedance method) and thromboxane B2 production during aggregation were measured in cigarette smokers and non-smokers, aged 41-68 years, with (n = 14) and without (n = 15) major symptomatic peripheral vascular disease. The plasma level of the lyso derivative of platelet activating factor (lyso-PAF) was also measured using a bioassay with 14C-serotonin labelled rabbit platelets, after extraction and acetylation to active PAF. 2. Aggregation to ADP and collagen was significantly less in non-smokers without vascular disease (n = 8) than in the other three groups (P less than 0.01; ANOVA). Thromboxane B2 production was not significantly different between the groups. There was no significant difference in plasma lyso-PAF between groups. No change was found in any variable after smokers smoked two cigarettes. 3. In these older age subjects, both vascular disease and the smoking habit were associated with greater whole blood aggregation. However, current smoking and the smoking of two cigarettes did not affect aggregation in subjects with vascular disease and plasma lyso-PAF levels were not consistently related to either smoking or vascular disease.     

Does smoking influence the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine?

Twelve healthy habitual cigarette smokers and eight non-smokers participated in a double-blind placebo controlled study to determine the effect of smoking on the pharmacokinetics and pharmacodynamics of the H2-receptor antagonist famotidine. In smokers, cigarette smoking was standardised and started 1 h before (A), or 2 h after (B) drug administration, or was prohibited (C). Intragastric pH-levels (IGpH) were measured with an ambulatory pH-recorder. Famotidine (40 mg orally) significantly raised median 22 h IGpH in non-smokers and smokers in all study periods. The smoking sequence (A, B, C) did not significantly influence median 22 h IGpH in both placebo-treated and famotidine-treated smokers, and no significant difference in median 22 h IGpH was shown between smokers and non-smokers. Plasma drug concentrations were similar in the various experiments, although famotidine was detected earlier in plasma from non-smokers compared with smokers (P less than 0.05). Smoking did not interfere significantly with the pharmacokinetics and pharmacodynamics of famotidine.     

Targeted Stage-Specific Inflammatory microRNA Profiling in Urine During Disease Progression in Experimental Autoimmune Encephalomyelitis: Markers of Disease Progression and Drug Response

Recently, microRNAs (miRNAs) have been implicated in regulating neuroinflammatory and demyelinative responses in multiple sclerosis (MS) and its mouse model of experimental autoimmune encephalomyelitis (EAE). miRNAs have also been studied as biomarkers of disease pathology and drug-response in MS. However, no complete miRNA profiling at various stages of EAE disease has been examined, especially in the urine. We carried out a systematic analysis of miRNAs in the urine exosomes as well as in the plasma and spinal cord at pre-onset, onset and peak stages of EAE established in the chronic B6 mice model. For the first time, we provide evidence that urine exosomes can be a specific and sensitive source of miRNA biomarkers for all 3 stages of EAE disease. In a significant observation, we observed that miR-155-5p expression increased in urine exosomes, plasma and spinal cord 6 days before the onset of disease, suggesting its early involvement in the pathology of EAE disease. We also analyzed the effect of Glatiramer acetate (GA; copaxone) treatment, an approved treatment for MS patients, in modulating miRNA expression at the peak of EAE disease. We identified miR-155-5p, miR-27a-3p, miR-9-5p and miR-350-5p as putative GA-treatment responsive miRNA biomarkers. Since, EAE is a mainly CD4 cells mediated disease, we also examined the above set of miRNAs and found to be significantly altered in T cells polarized to Th1 and Th17 phenotype, similar to urine exosomes. Thus, urine exosome miRNAs hold the potential to be defined as novel accessible stage-specific biomarkers of EAE (MS) disease as well as treatment response.     

Effect of cigarette smoking on salivary epidermal growth factor (EGF) and EGF receptor in human buccal mucosa.

The mouth acts as a primary target for cigarette smoke which is associated with several oral diseases and cancer. The present study investigated the effect of cigarette smoking on salivary EGF and the buccal EGF receptor. Samples of whole saliva and buccal biopsy were obtained from 15 healthy volunteers (10 smokers and 5 non-smokers). The smokers smoked 20 or more cigarettes/day for more than 5 years. Salivary cotinine (a major metabolite of nicotine) was determined by radioimmunoassay (RIA). The salivary cotinine level was consistent with the self-reported smoking status (smokers, 106-530 ng/ml saliva; non-smokers, < 2 ng/ml saliva). As compared to the non-smokers, the salivary EGF concentration (determined by RIA) was 32% lower in those smokers whose salivary cotinine level was 250 ng/ml or higher (non-smokers, 2.21 +/- 0.16; smokers, 1.57 +/- 0.09 ng/ml saliva; mean +/- S.E.M., P < 0.01). There was no significant difference in 125I-labeled EGF binding to the buccal receptor between the two groups. However, EGF stimulated the autophosphorylation of a 170-kDa protein band in the sample of non-smokers, but not in the smokers. The immunoblot analysis using anti-EGF receptor antibody indicated that the smoking-related deficiency in EGF receptor autophosphorylation was due to the functional alteration of the receptor proteins. In conclusion, cigarette smoking reduces the salivary EGF level and impairs the function of buccal EGF receptor, which may be associated with the pathology of smoking-related oral disease.     

Urinary hydroxyproline excretion in smokers, non-smokers and passive smokers

The hydroxyproline/creatinine ratio in urine was investigated in 200 cigarette smokers, 199 pipe and/or cigar smokers and 24 non-smokers. For cigarette smokers a statistically significant positive correlation is found between this ratio and daily cigarette consumption, COHb, serum cotinine and nicotine excretion in urine. This smoking-related increase in the hydroxyproline/creatinine ratio is, for the most part or completely, due to the fact that creatinine urine concentrations inversely correlate with the smoke uptake variables. Neither pipe and/or cigar smoking nor passive smoke exposure of non-smokers seem to affect the hydroxyproline/creatinine ratio. A seasonal influence is found in these studies as well as in two experiments with limited numbers of subjects: the hydroxyproline/creatinine ratio is higher in winter than in summer for both smokers and non-smokers. Our data do not favour the idea that measuring hydroxyproline/creatinine ratios in urine is an accurate method of investigating early effects of smoking, passive smoking and air pollution in man.     

Cigarette smoking as a stigma: Evidence from France

BackgroundThere is growing evidence that cigarette smoking has become a stigmatized behaviour, at least in western countries, and there is ongoing debate among experts about whether or not such stigma should be an instrument of anti-tobacco policy.MethodsWe investigated French non-smokers attitudes toward cigarette smokers, using data from a telephone survey carried out in 2010 among a representative random sample of non-smokers aged 15–75 (N = 3091). We carried out a cluster analysis to build contrasted attitudinal profiles and we also computed a score of stigmatization.ResultsWe found evidence for the existence of stigma associated with cigarette smoking in France: a majority of French non-smokers would not date a smoker, nor hire one to take care of their children. The cluster analysis identified four contrasting profiles, corresponding to different levels of stigmatization, including one cluster whose respondents demonstrated strong levels of moral condemnation and social rejection of smokers. Older people, those with a lower educational level and those reporting financial difficulties were more prone to stigmatize smokers, while those who reported that somebody smoked in their home were less likely to do so. Those who had never smoked and those who abstained from alcohol were more prone to stigmatize smokers. Obese people were also more likely to do so (in bivariate analysis only).ConclusionThe process of tobacco stigmatization seems well-advanced in France, despite a cultural context that may be less permeable to this process. Further research is needed as our results raise some questions regarding its efficiency as a policy tool. First, people who are familiar with smokers are less prone to stigmatize them. More generally, simultaneously stigmatizing several categories of people may provide each of these same categories with stereotyped ‘others’ onto whom they can deflect their stigma.     

Relationship between machine-derived smoke yields and biomarkers in cigarette smokers in Germany

In order to determine whether smokers of cigarettes in the contemporary yield ranges of the German market (0.1-1.0mg nicotine, 1-10mg tar) differ in their actual exposure to various smoke constituents, we performed a field study with 274 smokers and 100 non-smokers. The following biomarkers were determined: In 24-h urine: Nicotine equivalents (molar sum of nicotine, cotinine, trans-3'-hydroxycotinine and their respective glucuronides), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK), 3-hydroxypropylmercapturic acid (metabolite of acrolein), trans,trans-muconic acid, S-phenylmercapturic acid (metabolites of benzene), 1-hydroxypyrene (metabolite of pyrene); in saliva: Cotinine and trans-3'-hydroxycotinine; in exhaled air: Carbon monoxide; in blood: Methyl-, hydroxyethyl-, cyanoethyl- (biomarker of acrylonitrile) and carbamoylethylvaline (biomarker of acrylamide) hemoglobin adducts. All biomarkers were found to be significantly higher in smokers compared to non-smokers and showed strong correlations with the daily cigarette consumption. Biomarker levels and per cigarette increases in smokers were at most weakly related to the machine-derived smoke yields. It is concluded that machine-derived yields of cigarettes from the contemporary German cigarette market have little or no impact on the actual smoking-related exposure determined by suitable biomarkers.     

Reduced platelet vesicular monoamine transporter density in smoking schizophrenia patients.

Brain vesicular monoamine transporter 2 (VMAT2) has a critical role in the regulation of monoaminergic neurotransmission. In our previous study we have found decreased platelet VMAT2 density in healthy habitual smokers. Schizophrenia is associated with high rate of cigarette smoking. In the present study we assessed platelet VMAT2 pharmacodynamic characteristics in a population of medicated schizophrenia patients (n=36) comparing smokers (n=23) vs. non-smokers (n=13). A significant decrease in platelet VMAT2 density (24%, p=0.005) was found in the smokers compared to the non-smokers . This decrease was not ascribed to the pharmacotherapy. An inverse correlation was found in the smokers between the platelet VMAT2 density and the severity of schizophrenia as assessed by the positive and negative syndrome scale (PANSS). Our observation in schizophrenia patients is consistent with that found in healthy smokers. The complex relationship between VMAT2 expression, cigarette smoking and schizophrenia merits a further large scale study.     

Role of microRNAs in gynecological pathology

microRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in biological processes. These small molecules bind to target mRNAs, leading to translational repression and/or mRNA degradation. Aberrant miRNA expression is associated with several human diseases such as cancer, cardiovascular disorders, inflammatory diseases and gynecological pathology. The present article reviews the role of miRNAs in four gynecological disorders that affect the ovary or the uterus, one benign and frequent disease (endometriosis) that is classified as a tumor-like lesion and three malignant gynecological diseases (endometrial, cervical and ovarian cancers). Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent benign gynecological diseases. Similarly to tumor metastasis, endometriotic implants require neovascularization to proliferate, invade the extracellular matrix and establish an endometriotic lesion. Despite its high prevalence and incapacitating symptoms, the exact pathogenic mechanism of endometriosis remains unsolved. A relationship between endometriosis and gynecological cancer, especially ovarian cancer, has been reported. Endometriosis is a multifactorial and polygenic disease, and emerging data provide evidence that a dysregulation of miRNA expression may be involved. miRNAs appear to be potent regulators of gene expression in endometriosis, raising the prospect of using miRNAs as biomarkers and therapeutic tools in this disease. In cancer, miRNAs have an important role as regulatory molecules, acting as oncogenes (oncomiRs) or tumor suppressors. Endometrial cancer is one of the most frequent gynecological malignancies in the developed countries. Cervical cancer, also one of the most common cancers in women, is associated with high-risk human papillomaviruses although this infection alone may not be enough to induce the malignant transformation. Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. Over 80% of cases are diagnosed at an advanced stage, with a reduced five-year survival rate. Recent studies have shown that miRNAs are aberrantly expressed in different human cancer types, including endometrial, cervical and ovarian cancer, and that specific dysregulated miRNAs may act as biomarkers of patients' outcome. Recently, miRNAs have been detected in serum and plasma, and circulating miRNA expression profiles have now been associated with a range of different tumor types. Their accessibility in peripheral blood and stability given the fact that miRNAs circulate confined within exosomes, make researchers foster hope in their role as emerging biomarkers of cancer and other disorders. The development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for any of the aforementioned gynecological disorders.     

Lack of effect of smoking on the metabolism and pharmacokinetics of quinidine in patients

The urinary metabolite profile of quinidine and the oral clearance of this drug were studied under steady state conditions in five smoking and nine non-smoking patients. No significant differences were observed in the urinary recovery of unchanged quinidine, 3S-3-hydroxyquinidine, 2'-oxoquinidinone or quinidine-N-oxide between smokers and non-smokers. In addition, the plasma clearance of quinidine was not affected by the smoking status of subjects. These results suggest that cigarette smoke does not induce any of the main pathways for quinidine metabolism in a typical patient population and that the consideration of smoking status is of little utility in aiding in the selection of initial dosage regimens for this drug.     

Why do young women smoke? III. Attention and impulsivity as neurocognitive predisposing factors

Since nicotine has been shown to facilitate sustained attention and control of impulsivity, impairment in these domains may influence individuals who initiate smoking for various reasons to continue to smoke cigarettes. The purpose of this study was to determine whether young women who smoke regularly but are not abstinent at the time of testing, differ in their cognitive functioning from non-smokers and whether they resemble women who smoked in the past but quit. Female undergraduate students aged 20-30 years were recruited by advertisement from institutes of higher education in the Jerusalem area. The study sample consisted of 91 current smokers (CS), 40 past smokers (PS) and 151 non-smokers (NS). 46 occasional smokers (OS) were also tested. Confounding by withdrawal state was neutralized by including only CS and OS who smoked their last cigarette less than 90 min before testing. Subjects performed a computerized neurocognitive battery, which tests the domains of attention, memory, impulsivity, planning, information processing and motor performance. Analyses were controlled for age. The results showed that CS made significantly more errors than NS on the Continuous Performance Task (CPT), Matching Familiar Figures Test (MFFT) and Tower of London (TOL) test. PS were significantly worse than NS on the MFFT and TOL test. PS did not differ significantly from CS on any test. No association was found between duration of smoking and performance. These findings suggest that a neurocognitive profile characterized by impairments in sustained attention and control of impulsivity may be one of the factors that predispose young women who initiate cigarette smoking to maintain the habit.     

Recent progress in the use of microRNAs as biomarkers for drug-induced toxicities in contrast to traditional biomarkers: A comparative review

microRNAs (miRNAs) are small non-coding RNAs with 18–25 nucleotides. They play key regulatory roles in versatile biological process including development and apoptosis, and in disease pathogenesis, for example carcinogenesis, by negatively regulating gene expression. miRNAs often exhibit characteristics suitable for biomarkers such as tissue-specific expression patterns, high stability in serum/plasma, and change in abundance in circulation immediately after toxic injury. Since the discovery of circulating miRNAs in extracellular biological fluids in 2008, there have been many reports on the use of miRNAs as biomarkers for various diseases including cancer and organ injury in humans and experimental animals. In this review article, we have summarized the utility and limitation of circulating miRNAs as safety/toxicology biomarkers for specific tissue injuries including liver, skeletal muscle, heart, retina, and pancreas, by comparing them with conventional protein biomarkers. We have also covered the discovery of miRNAs in serum/plasma and their stability, the knowledge of which is essential for understanding the kinetics of miRNA biomarkers. Since numerous studies have reported the use of these circulating miRNAs as safety biomarkers with high sensitivity and specificity, we believe that circulating miRNAs can promote pre-clinical drug development and improve the monitoring of tissue injuries in clinical pharmacotherapy.     

miR-27a在妇科肿瘤中的研究进展 #br#

微小 RNA（miRNA）是一类内源性的非编码小 RNA,通常可通过特异性降解 mRNA或抑制蛋白质的翻译, 在转录后水平调控靶基因的表达,参与机体的多个生理或病理过程。miRNA可通过调节癌基因和抑癌基因的表达 来参与肿瘤的发生发展,在不同类型的肿瘤中及肿瘤的不同发展阶段,miRNA分子的表达谱呈现不同的特征。其 中,miR-27a定位于人类 19号染色体,在子宫内膜癌、宫颈癌、卵巢癌等多种妇科肿瘤中异常表达。本文对 miR-27a 在子宫内膜癌、宫颈癌和卵巢癌中的作用及其临床应用进展进行综述,为开发新型的肿瘤分子标志物或靶向药物提 供理论依据。     

Effects of Smoking and Smoking Deprivation on the Articulatory Loop of Working Memory

This study examined the effects of smoking and smoking deprivation on the articulatory loop of working memory. Forty subjects (20 smokers and 20 non-smokers) performed tasks involving serial recall of letters on two occasions 1 week apart. In each test one part was conducted with articulatory suppression and the other without it. The smokers completed one test following 12 h of smoking deprivation, and the other after smoking a cigarette. The order of suppression/non-suppression conditions and the order of smoking and smoking deprivation were balanced across subjects. The results showed that deprived smokers performed significantly worse than both smoking smokers and non-smokers in the task without suppression. Although all the subjects performed significantly worse whilst under articulatory suppression, smoking status was not found to influence performance here. These results imply that smoking has the effect of returning the smoker to a comparable level of performance to that seen in non-smokers, and suggest that smoking abstinence has a negative effect when performance involves the articulatory loop. © 1997 John Wiley & Sons, Ltd.