Effects Of Nicotine Research Articles

Efficacy of nano-curcumin on nicotine-induced genotoxicity and immunomodulatory disruption in protein- malnourished female rats

Background: Aggravated DNA damage and immunomodulatory disruptions by nicotine are more prominent in female populations under protein-restricted conditions. Females are more susceptible to nicotine-induced complications due to their low innate immunity. Anti-inflammatory and anti-genotoxic curcumin, though it effectively works against nicotine-induced complications, still its therapeutic use is hindered due to its poor aqueous solubility and low bioavailability. Nano-curcumin would be a better therapeutic agent because of its increased aqueous solubility and higher bioavailability than curcumin. Materials: This study investigates the effects of nicotine (2.5 mg/kg body weight injected subcutaneously for 21 days) on genotoxicity and immunomodulatory disruptions in female rats maintained under a protein-restricted diet (5% casein) and determines the ameliorative efficacy of nano-curcumin after one hour of nicotine dosage. Results: It is observed that nicotine decreases hemoglobin content in blood and DNA content in tissues. It causes severe DNA damage and disrupts the immune system and endocrine functions under protein-restricted conditions. Nano-curcumin ameliorates the nicotine-mediated genotoxic effects, maintains the female sex hormone levels, and restores the normalcy of immune responses in protein-restricted diet rats more efficiently than curcumin. Conclusion: Nano-curcumin looks like a potential blocker of nicotine, which may be used as a prospective therapeutic herbal agent to protect the health of the protein-malnourished female population.

Effects of nicotine on microRNA-124 expression in bile duct ligation-induced liver fibrosis in rats

BackgroundNicotine, the main compound of smoking may exert its effects by changing the expression of microRNAs (miRNAs). This study was conducted to further investigate the molecular mechanisms of miRNA-dependent effects of nicotine in an animal model of liver fibrosis.MethodsThe bile duct ligation (BDL) approach was used to create a model of liver fibrosis. Twenty-four male Wistar rats were used in the study. The effects of nicotine administration on miRNA-124 expression, as well as alpha-smooth muscle actin (liver fibrosis marker) and chemokine ligand 2 (an inflammatory chemokine), were investigated using RT-qPCR. In addition, the mRNA and protein expression of signal transducer and activator of transcription 3 (STAT-3; as a potential target for miRNA-124) were investigated by RT-qPCR and immunofluorescence, respectively. Liver enzyme activity levels were measured using a colorimetric assay. In addition, the effects of nicotine on the process of liver fibrosis were investigated with histological studies.ResultsThe development of liver fibrosis in BDL rats and nicotine administration led to a decrease in miRNA-124 expression. The decrease in the expression is accompanied by the increase in the expression of fibrotic and proinflammatory genes. Also, an increase in STAT-3 mRNA and protein expression was observed in the fibrotic rats that received nicotine. In addition, the significant increase in bilirubin and liver enzymes in fibrotic rats worsens with nicotine administration. The results of histological studies also confirm these results.ConclusionConsidering that miRNA-124 is an anti-inflammatory miRNA, it can be concluded that the decrease in its expression due to nicotine exposure leads to an increase in inflammatory processes and subsequently to an increase in liver fibrosis.

Attenuation of Nicotine Effects on A549 Lung Cancer Cells by Synthetic α7 nAChR Antagonists APS7-2 and APS8-2.

Nicotine binds to nicotinic acetylcholine receptors (nAChRs) that are overexpressed in different cancer cells, promoting tumor growth and resistance to chemotherapy. In this study, we aimed to investigate the potential of APS7-2 and APS8-2, synthetic analogs of a marine sponge toxin, to inhibit nicotine-mediated effects on A549 human lung cancer cells. Our electrophysiological measurements confirmed that APS7-2 and APS8-2 act as α7 nAChR antagonists. APS8-2 showed no cytotoxicity in A549 cells, while APS7-2 showed concentration-dependent cytotoxicity in A549 cells. The different cytotoxic responses of APS7-2 and APS8-2 emphasize the importance of the chemical structure in determining their cytotoxicity on cancer cells. Nicotine-mediated effects include increased cell viability and proliferation, elevated intracellular calcium levels, and reduced cisplatin-induced cytotoxicity and reactive oxygen species production (ROS) in A549 cells. These effects of nicotine were effectively attenuated by APS8-2, whereas APS7-2 was less effective. Our results suggest that APS8-2 is a promising new therapeutic agent in the chemotherapy of lung cancer.

Stimulus mediation, specificity and impact of menthol in rats trained to discriminate puffs of nicotine e-cigarette aerosol from nicotine-free aerosol.

It is unclear if e-cigarettes have reduced abuse liability relative to traditional cigarettes, especially when considering advanced devices which deliver nicotine more efficiently. Translatable and predictive animal models are needed to addresses this question. Our goal was to explore the subjective stimulus effects of e-cigarettes by training rats to discriminate puffs of nicotine aerosol from vehicle aerosol using an aerosol delivery system designed to model e-cigarette use patterns in humans. Rats were trained to discriminate between ten, 10s puffs of aerosol generated from 3mg/ml nicotine e-liquid and nicotine-free e-liquid using a food-reinforced operant procedure. Following acquisition, tests were conducted to determine the specificity of the nicotine aerosol stimulus as well as the impact to the stimulus effects of nicotine resulting from the addition of menthol to e-liquid. Rats learned the nicotine aerosol puff vs vehicle puff discrimination in a mean of 25 training sessions. Injected nicotine fully substituted for the stimulus effects of nicotine aerosol. The stimulus effects of nicotine aerosol were blocked by the nicotinic receptor antagonist mecamylamine. The nicotinic receptor partial agonist, varenicline as well as the stimulant d-amphetamine substituted more robustly for nicotine aerosol puffs than did the NMDA antagonist, ketamine. Menthol enhanced the stimulus effects of nicotine aerosol without altering nicotine blood plasma levels. Nicotine aerosol puffs can function as a training stimulus in rats. The stimulus effects were CNS-mediated and receptor specific. Menthol appears to enhance the stimulus effects of nicotine aerosol through a pharmacodynamic rather than pharmacokinetic mechanism.

Abstract 5394: Nicotine-induced exosomal miR-3157-3p from prostate cancer cells promotes angiogenesis

Abstract Nicotine is a psychoactive component of cigarette smoke responsible for addictive properties of tobacco and is shown to promote cancer pathogenesis. We earlier reported that exosomes released from nicotine-treated prostate cancer cells played a key role in tumor angiogenesis, a process necessary to maintain the supply of nutrients and oxygen to the fast proliferating cancer cells. Here, we examined the molecular mechanisms underlying the exosome-mediated effect of nicotine on angiogenesis. For this, we screened the expression of angiogenesis-related miRNAs in the exosomes derived from LNCaP and C4-2 cells treated with vehicle or nicotine (400 nM). Highest and most differential abundance of miR-3157-3p was found in exosomes derived from nicotine-treated prostate cancer cells. Furthermore, the expression of TIMP-2 and KLF-2, established targets of miR-3157-3p, was also downregulated in endothelial cells transfected with exosomes derived from nicotine-treated prostate cancer cells or miR-3157-3p mimics. Studies are currently underway to establish direct targeting of TIMP-2 and KLF-2 by miR-3157-3p and confirm that their suppression is indeed associated with observed changes in endothelial cell growth, migration and capillary-forming ability. Citation Format: Shubhangi Singh, Mohammad Aslam Khan, Shashi Anand, Sirin Saranyutanon, Sanjeev Kumar Srivastava, Seema Singh, Ajay P. Singh, Kunwar Somesh Vikramdeo. Nicotine-induced exosomal miR-3157-3p from prostate cancer cells promotes angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5394.

Abstract 7581: Nicotine promotes the proliferation and metastasis of non-small cell lung cancer through c-Myc/EZH2 pathway

Abstract Objective: Lung cancer, particularly non-small cell lung cancer (NSCLC), continues to be a predominant contributor to global cancer-related mortality, with smoking emerging as a significant risk factor. Nicotine, which is one of the main chemicals from the tobacco smoke, is identified as carcinogen for lung cancer, especially for squamous carcinoma (LUSC). This study aims to investigates the intricate molecular mechanisms by which nicotine facilitates proliferation and migration in NSCLC through the c-Myc/EZH2 signaling pathway. Methods: Clinical tissue specimens were procured from surgical patients with lung cancer for immunohistochemical staining. Additionally, public databases were scrutinized to compare EZH2 expression between smokers and non-smokers. NSCLC cell lines underwent treatment with nicotine in a time- and concentration-dependent manner, and the impact on EZH2 was corroborated through Western Blot, Real-time PCR, and immunofluorescence staining. Proliferation and migration assays, encompassing CCK8 experiments, colony formation assays, EdU staining, and Transwell assays, were conducted to discern the effects of nicotine on NSCLC. Experimental techniques such as si-RNA and CHIP were deployed to investigate changes in c-Myc-mediated regulation of EZH2, elucidating the intricate role of the c-Myc/EZH2 pathway in nicotine-induced NSCLC proliferation and migration. Results: Smokers exhibited heightened EZH2 expression in tumor tissue compared to non-smokers. Nicotine treatment induced a concentration- and time-dependent upregulation of EZH2 in NSCLC cell lines. In 10 μM nicotine-treated NSCLC cells, concurrent treatment with 10 μM DZNep (EZH2 inhibitor) or si-EZH2 significantly augmented proliferation and migration. Moreover, the upregulation of EZH2 correlated with increased c-Myc expression, and siRNA-mediated c-Myc inhibition resulted in a corresponding reduction in EZH2 expression. Nicotine was identified as a promoter of NSCLC proliferation and migration through the c-Myc/EZH2 signaling pathway. This study establishes a robust association between nicotine and EZH2 in NSCLC cells, unveiling the novel regulatory axis of c-Myc/EZH2. Combined treatment with c-Myc and EZH2 inhibitors demonstrated efficacy in suppressing nicotine-induced promotion of NSCLC proliferation and migration. Conclusion: In summary, this study elucidates the mechanisms through which nicotine propels NSCLC development via the c-Myc/EZH2 pathway, providing a theoretical underpinning for future NSCLC treatment paradigms. The combined use of c-Myc and EZH2 inhibitors emerges as a promising therapeutic strategy, poised to inhibit nicotine-induced NSCLC proliferation and migration, offering enhanced treatment modalities for patients. Citation Format: Chen Ding, Hua Huang, Chen Chen, Yongwen Li, Hongyu Liu, Jun Chen. Nicotine promotes the proliferation and metastasis of non-small cell lung cancer through c-Myc/EZH2 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7581.

Methoxsalen Inhibits the Acquisition of Nicotine Self-Administration: Attenuation by Cotinine Replacement in Male Rats.

Cigarette smoking remains the leading preventable cause of disease and death. Nicotine is the primary reinforcing ingredient in cigarettes sustaining addiction. Cotinine is the major metabolite of nicotine that produces a myriad of neurobehavioral effects. Previous studies showed that cotinine-supported self-administration in rats and rats with a history of cotinine self-administration exhibited relapse-like drug-seeking behavior, suggesting that cotinine may also be reinforcing. To date, whether cotinine may contribute to nicotine reinforcement remains unknown. Nicotine metabolism is mainly catalyzed by hepatic CYP2B1/2 enzymes in rats and methoxsalen is a potent CYP2B1/2 inhibitor. The study examined nicotine metabolism, self-administration, and locomotor activity. The hypothesis is that methoxsalen inhibits nicotine self-administration and cotinine replacement attenuates the inhibitory effects of methoxsalen in male rats. Methoxsalen decreased plasma cotinine levels following a subcutaneous nicotine injection. Repeated daily methoxsalen treatments reduced the acquisition of nicotine self-administration, leading to fewer nicotine infusions, lower nicotine intake, and lower plasma cotinine levels. However, methoxsalen did not alter the maintenance of nicotine self-administration despite a significant reduction of plasma cotinine levels. Cotinine replacement by mixing cotinine with nicotine for self-administration dose-dependently increased plasma cotinine levels and enhanced the acquisition of self-administration. Neither basal nor nicotine-induced locomotor activity was altered by methoxsalen. These results indicate that methoxsalen inhibition of cotinine formation impaired the acquisition of nicotine self-administration, and cotinine replacement attenuated the inhibitory effects of methoxsalen on the acquisition of self-administration, suggesting that cotinine may contribute to the initial development of nicotine reinforcement. Smoking cessation medications targeting nicotine's effects are only moderately effective, making it imperative to better understand the mechanisms of nicotine misuse. Methoxsalen inhibited nicotine metabolism to cotinine and impaired the acquisition of nicotine self-administration. Cotinine replacement restored plasma cotinine and attenuated the methoxsalen inhibition of nicotine self-administration in rats. These results suggest that (1) the inhibition of nicotine metabolism may be a viable strategy in reducing the development of nicotine reinforcement, (2) methoxsalen may be translationally valuable, and (3) cotinine may be a potential pharmacological target for therapeutic development given its important role in the initial development of nicotine reinforcement.

Effect of chronic vapor nicotine exposure on affective and cognitive behavior in male mice

Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional cigarettes and promoted as devices to help traditional tobacco smokers reduce or quit smoking, they have instead contributed to increasing nicotine use among youths. Despite this, ENDS also represent a useful tool to create novel preclinical animal models of nicotine exposure that more accurately represent human nicotine use. In this study, we validated a chronic, intermittent, ENDS-based passive vapor exposure model in mice, and then measured changes in multiple behaviors related to nicotine abstinence. First, we performed a behavioral dose curve to investigate the effects of different nicotine inter-vape intervals on various measures including body weight, locomotor activity, and pain hypersensitivity. Next, we performed a pharmacokinetic study to measure plasma levels of nicotine and cotinine following chronic exposure for each inter-vape interval. Finally, we utilized a behavior test battery at a single dosing regimen that produces blood levels equivalent to human smokers in order to characterize the effects of chronic nicotine, vehicle, or passive airflow and identified nicotine-induced impairments in cognitive behavior.

Cigarette smoke and nicotine effect on human mesenchymal stromal cell wound healing and osteogenic differentiation capacity.

Mesenchymal stromal cells (MSCs) play a crucial role in promoting tissue regeneration and healing, particularly in bone tissue. Both smoking and nicotine use are known to delay and inhibit the healing process in patients. This study aims at delineating these cellular effects by comparing the impact of nicotine alone to cigarette smoke with equivalent nicotine content, and shedding light on potential differences in the healing process. We examined how cigarette smoke and nicotine affect the migration, proliferation, and osteogenic differentiation of human patient-derived MSCs in vitro, as well as the secretion of cytokines IL-6 and IL-8. We measured nicotine concentration of the cigarette smoke extract (CSE) to clarify the role of the nicotine in the effect of the cigarette smoke. MSCs exposed to nicotine-concentration-standardized CSE exhibited impaired wound healing capability, and at high concentrations, increased cell death. At lower concentrations, CSE dose-dependently impaired migration, proliferation, and osteogenic differentiation, and increased IL-8 secretion. Nicotine impaired proliferation and decreased PINP secretion. While there was a trend for elevated IL-6 levels by nicotine in undifferentiated MSCs, these changes were not statistically significant. Exposure of MSCs to equivalent concentrations of nicotine consistently elicited stronger responses by CSE and had a more pronounced effect on all studied parameters. Our results suggest that the direct effect of cigarette smoke on MSCs contributes to impaired MSC function, that adds to the nicotine effects. Cigarette smoke extract reduced the migration, proliferation, and osteogenic differentiation in MSCs in vitro, while nicotine alone reduced proliferation. Cigarette smoke impairs the osteogenic and regenerative ability of MSCs in a direct cytotoxic manner. Cytotoxic effect of nicotine alone impairs regenerative ability of MSCs, but it only partly explains cytotoxic effects of cigarette smoke. Direct effect of cigarette smoke, and partly nicotine, on MSCs could contribute to the smoking-related negative impact on long-term bone health, especially in bone healing.

Nicotine downregulates miR-375–3p via neurotrophic tyrosine receptor kinase 2 to enhance the malignant behaviors of laryngopharyngeal squamous epithelial cells

Nicotine exposure from smoking constitutes a significant global public health concern. Furthermore, smoking represents a pivotal risk factor for head and neck squamous cell carcinoma (HNSCC). However, the influence of nicotine on HNSCC remains relatively underexplored. Our aim was to unravel the molecular mechanisms that underlie the effect of nicotine on the metastatic cascade of HNSCC. In this study, we discovered a significant association between smoking and HNSCC metastasis and prognosis. Nicotine significantly enhanced HNSCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Analysis of TCGA-HNSCC and FDEENT-HNSCC cohorts revealed reduced miR-375–3p levels in HNSCC tumor tissues, particularly among current smokers. Additionally, miR-375–3p level was strongly correlated with both lymph node metastasis and tumor stage. By downregulating miR-375–3p, nicotine promotes HNSCC cell metastasis in vitro and hematogenous metastatic capacity in vivo. Utilizing transcriptomic sequencing, molecular docking, dual-luciferase reporter assay, and fluorescence in situ hybridization (FISH), we demonstrated that miR-375–3p specifically binds to 3′ untranslated region (3’UTR) of NTRK2 mRNA. Thus, this study uncovers a novel nicotine-induced mechanism involving miR-375–3p-mediated NTRK2 targeting, which promotes HNSCC metastasis. These findings have implications for improving the prognosis of patients with HNSCC, especially in smokers.

Low levels of nicotine and cotinine but not benzo[a]pyrene induce human trophoblast cell proliferation

E-cigarettes use constitutes a source of thirdhand nicotine exposure. The increasing use of electronic cigarettes in homes and public places increases the risk of exposure of pregnant women to thirdhand nicotine. The effects of exposure of pregnant women to very low levels of nicotine have not been studied in humans but detrimental in experimental animals. The objective of this study is to investigate the effect of nanomolar concentrations of nicotine and its metabolite cotinine on the proliferation of JEG-3, a human trophoblast cell line. We also studied the proliferative effect of nanomolar concentrations of benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon in tobacco smoke, for comparison.We treated JEG-3 cells in culture with nanomolar concentrations of nicotine, cotinine, and B[a]P. Their effect on cell proliferation was determined, relative to untreated cells, by MTT assay. Western blotting was used to assess the mitogenic signaling pathways affected by nicotine and cotinine.In contrast to the inhibitory effects reported with higher concentrations, we showed that nanomolar concentrations of nicotine and cotinine resulted in significant JEG-3 cell proliferation and a rapid but transient increase in levels of phosphorylated ERK and AKT, but not STAT3. Biphasic, non-monotonic effect on cell growth is characteristic of endocrine disruptive chemicals like nicotine. The mitogenic effects of nicotine and cotinine potentially contribute to increased villous epithelial thickness, seen in placentas of some smoking mothers. This increases the diffusion distance for oxygen and nutrients between mother and fetus, contributing to intrauterine growth restriction in infants of smoking mothers.

Exploring the Smoking-Epilepsy Nexus: a systematic review and meta-analysis of observational studies

BackgroundEpilepsy, characterized by recurrent unprovoked seizures, poses significant challenges to affected individuals globally. While several established risk factors for epilepsy exist, the association with cigarette smoking remains debated. This study aims to conduct systematic review and meta-analysis to elucidate the potential association between smoking and the likelihood of epilepsy.MethodsThe search was performed on March 31st, 2023, using the Medline, Embase, Web of Science, Scopus, and ScienceDirect. We included cohort, cross-sectional, and case–control studies in our meta-analysis, conducting subgroup analyses based on smoking history, sex, and epilepsy type to yield specific insights.ResultsWe identified 2550 studies, of which 17 studies were finally included in this study. The pooled odds ratio of epilepsy was 1.14 (0.96–1.36) in smokers compared to non-smokers. In current smokers compared to non-smokers, the odds ratio was 1.46 (1.13–1.89), while, in former smokers compared to non-smokers, the odds ratio was 1.14 (0.83–1.56).ConclusionsWhile the overall association between smoking and epilepsy did not reach statistical significance, a notable association was found among current smokers. The study emphasizes the importance of smoking cessation as a potential preventive measure against epilepsy, especially given the proconvulsive effects of nicotine. Future research should address limitations and explore specific clinical scenarios to enhance our understanding of the complex relationship between cigarette use and epilepsy.Systematic review registrationCRD42022342510.

In Vitro Assessment of Translocation and Toxicological Effects of Nicotine and Ethyl Maltol from e-Cigarettes Using Air–Liquid Interface-Cultured Bronchial Epithelial Cells

<i>In Vitro</i> Assessment of Translocation and Toxicological Effects of Nicotine and Ethyl Maltol from e-Cigarettes Using Air–Liquid Interface-Cultured Bronchial Epithelial Cells

The Combined Effects of Nicotine and Cannabis on Cortical Thickness Estimates in Adolescents and Emerging Adults.

Early life substance use, including cannabis and nicotine, may result in deleterious effects on the maturation of brain tissue and gray matter cortical development. The current study employed linear regression models to investigate the main and interactive effects of past-year nicotine and cannabis use on gray matter cortical thickness estimates in 11 bilateral independent frontal cortical regions in 223 16-22-year-olds. As the frontal cortex develops throughout late adolescence and young adulthood, this period becomes crucial for studying the impact of substance use on brain structure. The distinct effects of nicotine and cannabis use status on cortical thickness were found bilaterally, as cannabis and nicotine users both had thinner cortices than non-users. Interactions between nicotine and cannabis were also observed, in which cannabis use was associated with thicker cortices for those with a history of nicotine and tobacco product (NTP) use in three left frontal regions. This study sheds light on the intricate relationship between substance use and brain structure, suggesting a potential modulation of cannabis' impact on cortical thickness by nicotine exposure, and emphasizing the need for further longitudinal research to characterize these interactions and their implications for brain health and development.

Initial evidence of the acute effect of electronic nicotine delivery system use on energy intake.

Previous work has aimed to disentangle the acute effects of nicotine and smoking on appetite with mixed findings. Electronic nicotine delivery systems (ENDS) have yet to be examined in this regard despite evidence of use for weight control. The present study tested the influence of an ENDS on acute energy intake and associated subjective effects. Participants (n = 34; 18-65 years) with current ENDS use completed two randomly ordered clinical lab sessions after overnight abstinence from tobacco/nicotine/food/drinks (other than water). Sessions differed by the product administered over 20 min: active (20 puffs of a JUUL ENDS device; 5% nicotine tobacco-flavored pod) or control (access to an uncharged JUUL with an empty pod). About 40 min after product administration, participants were provided an ad lib buffet-style meal with 21 food/drink items. Subjective ratings were assessed at baseline, after product use, and before/after the meal. Energy intake (kcal) was calculated using pre-post buffet item weights. Repeated measures analyses of variance and pairwise comparisons were used to detect differences by condition and time (α < .05). Mean ± standard error of the mean energy intake did not differ significantly between active (1011.9 ± 98.8 kcal) and control (939.8 ± 88.4 kcal; p = .108) conditions. Nicotine abstinence symptoms significantly decreased after the active condition, while satiety significantly increased. Following the control condition, satiety remained constant while hunger significantly increased relative to baseline. Findings indicate that acute ENDS use did not significantly impact energy intake, but there was an ENDS-associated subjective increase in satiety and relative decrease in hunger. Results support further investigation of ENDS on appetite. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study.

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies.

Individual variations in motives for nicotine self-administration in male rats: evidence in support for a precision psychopharmacology

The significant heterogeneity in smoking behavior among smokers, coupled with the inconsistent efficacy of approved smoking cessation therapies, supports the presence of individual variations in the mechanisms underlying smoking. This emphasizes the need to shift from standardized to personalized smoking cessation therapies. However, informed precision medicine demands precision fundamental research. Tobacco smoking is influenced and sustained by diverse psychopharmacological interactions between nicotine and environmental stimuli. In the classical experimental rodent model for studying tobacco dependence, namely intravenous self-administration of nicotine, seeking behavior is reinforced by the combined delivery of nicotine and a discrete cue (nicotine+cue). Whether self-administration behavior is driven by the same psychopharmacological mechanisms across individual rats remains unknown and unexplored. To address this, we employed behavioral pharmacology and unbiased cluster analysis to investigate individual differences in the mechanisms supporting classical intravenous nicotine self-administration (0.04 mg/kg/infusion) in male outbred Sprague–Dawley rats. Our analysis identified two clusters: one subset of rats sought nicotine primarily for its reinforcing effects, while the second subset sought nicotine to enhance the reinforcing effects of the discrete cue. Varenicline (1 mg/kg i.p.) reduced seeking behavior in the former group, whereas it tended to increase in the latter group. Crucially, despite this fundamental qualitative difference revealed by behavioral manipulation, the two clusters exhibited quantitatively identical nicotine+cue self-administration behavior. The traditional application of rodent models to study the reinforcing and addictive effects of nicotine may mask individual variability in the underlying motivational mechanisms. Accounting for this variability could significantly enhance the predictive validity of translational research.

Toward a greener multifunctional pharmaceutical excipient: in vivo safety evaluation of nanofibrillated cellulose from tobacco stalk

Tobacco stalk is a cellulose-rich material and a sustainable alternative to be applied as a plant-based nanofibrillated cellulose (NFC) source. NFC use has garnered attention in the development of oral pharmaceutical forms, despite concerns about its safety due to the adverse effects of nicotine on health. Therefore, we aimed at establishing the safety of NFC derived from tobacco stalk for its potential use as a novel pharmaceutical excipient, exploring its potential functions for tablet production. We conducted acute and subchronic oral toxicity tests in adult female Wistar rats. Initially, individual animals received sequential doses (175–5,000 mg·kg−1) for 24 hours followed by a careful observation of any toxic effects. Subsequently, 20 rats were divided into four groups for a subchronic assay, evaluating toxicity signs, body weight changes, hematological, biochemical, and histopathological parameters. No deaths or other clinical toxicity signs were observed in either the acute or the subchronic assays. We noticed a significant reduction in body weight gain (p < 0.05) after 14 days. We found statistical differences for hematological and biochemical parameters, unrelated to dosage. There were no observed toxic effects, and tobacco stalk ingestion did not adversely affect organ morphology in the histopathological evaluation. The oral administration of NFC at 5,000 mg·kg−1 per day for 28 days was well-tolerated by treated rats, with no reported deaths. In conclusion, NFC derived from tobacco stalk has shown to be a sustainable and safe alternative for use as an excipient at experimental doses, demonstrating compatibility with its proposed applications.

Nicotine regulates abnormal macrophage polarization and trophoblast invasion associated with preterm labor via the α7nAChR/SIRT1 axis

IntroductionPreterm birth (PTB) frequently results from the syndrome of preterm labor (PTL). PTL is linked to an atypical maternal inflammatory response, as well as intrauterine inflammation and/or infection. In this study, we explored the mechanisms involved in nicotine-mediated abnormal macrophage polarization and trophoblast invasion associated with PTL. MethodsFirst, THP-1-M0 macrophages were generated by treating the human monocytic leukemia cell line (THP-1) with phorbol 12-myristate 13-acetate for a duration of 24 h. Afterward, nicotine treatment was administered, followed by coculturing with the HTR-8/SVneo trophoblast cell line (HTR-8) at a ratio of 1:1. Next, we transfected sh-α7nAChR and treated THP-1-M0 macrophages and HTR-8 cells with nicotine. In addition, we transfected THP-1-M0 macrophages with sh-NC or sh-SIRT1 or subjected them to 4 nM nicotinamide adenine dinucleotide (NAD) metabolic inhibitor FK866 treatment. Moreover, HTR-8 cells were treated with nicotine, after which THP-1-M0 macrophages were cocultured with HTR-8 cells. Finally, we constructed an in vivo RU486-induced PTL rat model to verify the effect of nicotine and the mechanisms involved. ResultsWe found that nicotine affected polarization and α7nAChR expression in HTR-8 cocultured THP-1-M0 macrophages. Knocking down α7nAChR blocked the effect of nicotine on the proliferation and invasion of HTR-8 cells. Furthermore, nicotine activated the α7nAChR/SIRT1 axis to regulate THP-1-M0 macrophage polarization through the cholinergic anti-inflammatory pathway. Additionally, NAD metabolism mediated the role of the α7nAChR/SIRT1 axis in nicotine-induced polarization of HTR-8 cocultured THP-1-M0 macrophages. In vivo experiments demonstrated that nicotine alleviated inflammation in PTL rats, which involved the α7nAChR/SIRT1 axis. ConclusionNicotine regulated abnormal macrophage polarization and trophoblast invasion associated with PTL via the α7nAChR/SIRT1 axis.

Tobacco or marijuana use and infertility: a committee opinion

In the United States, approximately 21% of adults report some form of tobacco use, although 18% report marijuana use. Although the negative impact of tobacco use in pregnancy is well documented, the impact of tobacco and marijuana on fertility and reproduction is less clear. This committee opinion reviews the potential deleterious effects of tobacco, nicotine, and marijuana use on conception, ovarian follicular dynamics, sperm parameters, gamete mutations, early pregnancy, and assisted reproductive technology outcomes. It also reviews the current status of tobacco smoking cessation strategies. This document replaces the 2018 American Society for Reproductive Medicine Practice Committee document entitled Smoking and Infertility: a committee opinion (Fertil Steril 2018).