Effects Of Chronic Nicotine Exposure Research Articles

Nicotine inhalant via E-cigarette facilitates sensorimotor function recovery by upregulating neuronal BDNF-TrkB signalling in traumatic brain injury.

Traumatic brain injury (TBI) causes lifelong physical and psychological dysfunction in affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarettes (E-cig) (vaping) on TBI-associated behavioural and biochemical changes. Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cig vapour for 6 weeks. Sensorimotor functions, locomotion, and sociability were subsequently evaluated by nesting, open field, and social approach tests, respectively. Immunoblots were conducted to examine the expression of mature brain-derived neurotrophic factor (mBDNF) and associated downstream proteins (p-Erk, p-Akt). Histological analyses were performed to evaluate neuronal survival and neuroinflammation. Post-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histological analysis revealed increased survival of cortical neurons in the perilesion cortex with chronic nicotine exposure. Immunoblots revealed that chronic nicotine exposure significantly up-regulated mBDNF, p-Erk and p-Akt expression in the perilesion cortex of CCI mice. Immunofluorescence microscopy indicated that elevated mBDNF and p-Akt expression were mainly localized within cortical neurons. Immunolabelling of Iba1 demonstrated that chronic nicotine exposure attenuated microglia-mediated neuroinflammation. Post-injury chronic nicotine exposure via vaping facilitates recovery of sensorimotor function by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signalling. These findings suggest potential neuroprotective properties of nicotine despite its highly addictive nature. Thus, understanding the multifaceted effects of chronic nicotine exposure on TBI-associated symptoms is crucial for paving the way for informed and properly managed therapeutic interventions.

Chronic Nicotine Consumption and Withdrawal Regulate Melanocortin Receptor, CRF, and CRF Receptor mRNA Levels in the Rat Brain.

Alterations in the various neuropeptide systems in the mesocorticolimbic circuitry have been implicated in negative effects associated with drug withdrawal. The corticotropin-releasing factor (CRF) and α-melanocyte-stimulating hormone are two peptides that may be involved. This study investigated the regulatory effects of chronic nicotine exposure and withdrawal on the mRNA levels of melanocortin receptors (MC3R, MC4R), CRF, and CRF receptors (CRFR1 and CRFR2) expressed in the mesocorticolimbic system. Rats were given drinking water with nicotine or without nicotine (control group) for 12 weeks, after which they continued receiving nicotine (chronic exposure) or were withdrawn from nicotine for 24 or 48 h. The animals were decapitated following behavioral testing for withdrawal signs. Quantitative real-time PCR analysis demonstrated that nicotine exposure (with or without withdrawal) increased levels of CRF and CRFR1 mRNA in the amygdala, CRF mRNA in the medial prefrontal cortex, and CRFR1 mRNA in the septum. Nicotine withdrawal also enhanced MC3R and MC4R mRNA levels in different brain regions, while chronic nicotine exposure was associated with increased MC4R mRNA levels in the nucleus accumbens. These results suggest that chronic nicotine exposure and withdrawal regulate CRF and melanocortin signaling in the mesocorticolimbic system, possibly contributing to negative affective state and nicotine addiction.

Chronic nicotine impairs the angiogenic capacity of human induced pluripotent stem cell-derived endothelial cells in a murine model of peripheral arterial disease

ObjectiveLifestyle choices such as tobacco and e-cigarette use are a risk factor for peripheral arterial disease (PAD) and may influence therapeutic outcomes. The effect of chronic nicotine exposure on the angiogenic capacity of human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) was assessed in a murine model of PAD. MethodsMice were exposed to nicotine or phosphate-buffered saline (PBS) for 28 days, followed by induction of limb ischemia and iPSC-EC transplantation. Cells were injected into the ischemic limb immediately after induction of hindlimb ischemia and again 7 days later. Limb perfusion was assessed by laser Doppler spectroscopy, and transplant cell survival was monitored for 14 days afterward using bioluminescence imaging, followed by histological analysis of angiogenesis. ResultsTransplant cell retention progressively decreased over time after implantation based on bioluminescence imaging, and there were no significant differences in cell survival between mice with chronic exposure to nicotine or PBS. However, compared with mice without nicotine exposure, mice with prior nicotine exposure had had an impaired therapeutic response to iPSC-EC therapy based on decreased vascular perfusion recovery. Mice with nicotine exposure, followed by cell transplantation, had significantly lower mean perfusion ratio after 14 days (0.47 ± 0.07) compared with mice undergoing cell transplantation without prior nicotine exposure (0.79 ± 0.11). This finding was further supported by histological analysis of capillary density, in which animals with prior nicotine exposure had a lower capillary density (45.9 ± 4.7 per mm2) compared with mice without nicotine exposure (66.5 ± 8.1 per mm2). Importantly, the ischemic limbs mice exposed to nicotine without cell therapy also showed significant impairment in perfusion recovery after 14 days, compared with mice that received PBS + iPSC-EC treatment. This result suggested that mice without chronic nicotine exposure could respond to iPSC-EC implantation into the ischemic limb by inducing perfusion recovery, whereas mice with chronic nicotine exposure did not respond to iPSC-EC therapy. ConclusionsTogether, these findings show that chronic nicotine exposure adversely affects the ability of iPSC-EC therapy to promote vascular perfusion recovery and angiogenesis in a murine PAD model.

Nicotine withdrawal after chronic exposure in adulthood blunts the ventilatory response to hypoxia in rats

Nicotine is one of the most addictive substances known, and it is estimated that 50.6 million US adults use nicotine in some form. It is well known that smoking, the most common form of nicotine exposure, alters lung structure and function. In contrast, the impact of chronic nicotine exposure during adulthood on neural structures involved in the control of breathing is largely unknown. In preliminary experiments in adult rats, we used plethysmography to study the effects of chronic nicotine exposure on the ventilatory response to hypoxia, which is a critical respiratory chemoreflex that enhances breathing and limits arterial O2 desaturation. Four weeks of chronic nicotine exposure through drinking water had no effect on the ventilatory response to a brief, 5‐ minute episode of hypoxia (10%) (Minute ventilation: One‐way ANOVA, Control vs Nicotine Exposure; P=0.6533). In contrast, nicotine exposed rats show a significantly blunted ventilatory response to hypoxia following 48 hours of nicotine withdrawal (Control vs Nicotine Withdrawal, P=0.0447). The reduced ventilatory response was due to a blunted increase in tidal volume (Amplitude: One‐way ANOVA, Control vs Nicotine Withdrawal; P=0.007), with a normal frequency response (Control vs Nicotine Withdrawal; P=0.2518. This has important clinical ramifications, as hypoxia is a commonly encountered medical complication, and withdrawal symptoms are often observed in hospitalized patients as it is common for them to abstain from smoking during periods of worsening health or in preparation for surgery.

Chronic Nicotine Exposure Increases Hematoma Expansion following Collagenase-Induced Intracerebral Hemorrhage in Rats

Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure (as a surrogate for tobacco use) on outcomes following sICH. Young male and female rats were randomly assigned to either nicotine (4.5 mg/kg b.w. per day) or vehicle (saline) treatment (2–3 weeks) groups. sICH was induced by injecting collagenase into the right striatum. Neurological score and hematoma volume were determined 24 h post-sICH. The hematoma volumes in nicotine-treated male and female rats were significantly higher by 42% and 48% when compared to vehicle-treated male and female rats, respectively. Neurological deficits measured in terms of neurological score for the nicotine-treated male and female groups were significantly higher when compared to the respective vehicle-treated male and female groups. Our results show that chronic nicotine exposure increases hematoma volume post-sICH in rats of both sexes. Identifying the mechanism of nicotine-dependent increase in hematoma growth post-sICH will be crucial to understanding the detrimental effect of tobacco use on the severity of bleeding following intracerebral hemorrhage.

Extraction and High Purification of Nicotine from Iraqi Tobacco Leaf Formanufacturing, Pharmaceutical, and Medicinal Uses

Bachground: Nicotine is highly addictive plant derived alkaloid and the most important species in humanuse today is Nicotianatabacum. There are direct health effects of chronic nicotine exposure. Even in lowdoses, nicotine causes vasoconstriction and other cardiovascular effects related to catecholamine release andpromote angiogenesis, neuroteratogenicity, and possibly some cancers. Methods: A preliminary investigationto analyze the nicotine contained in Iraqi tobacco leaves was carried out using gas chromatography-massspectrometry (GC-MS). Nicotine is an alkaloid, and alkali methanol and Lipophilic solventsystem methods(LSS) have been extracted and determined by GC-MS from tobacco leaves. Results: The detection limit fornicotine was for non-selective monitoring at the ppm level and for selective detection at the nanogram level.This is a simple method of thin layer chromatography (TLC) and chromatography mass spectrometry (GCMS)for the tobacco leave analysis of nicotine. The final purity of nicotine is 99%. Conclusion :the methodswhich used in this study gave very high purity of nicotineafter converting the crude nicotine to its esters.

B-PO04-010 THE EFFECT OF CHRONIC NICOTINE EXPOSURE ON CARDIAC ELECTROPHYSIOLOGY IN THE RABBIT HEART

Tobacco smoke exposure is associated with increased risk for atrial and ventricular arrhythmias. However, the individual components of tobacco smoke that may promote arrhythmias and the underlying electrophysiological mechanisms responsible are unknown. Nicotine (NIC) is a major component of tobacco smoke and emerging tobacco products, including e-cigarettes. To determine the effects of chronic NIC exposure on autonomic and electrophysiological remodeling in the rabbit heart. Fully innervated hearts from rabbits exposed to NIC (21mg/day, transdermal patch, 28 days, n=7) or control (CT, n=4) rabbit hearts were optically mapped using voltage- (RH237) and calcium-sensitive (Rhod2-AM) indicators. Sympathetic nerve stimulation (SNS) was performed with electrical stimulation at the first thoracic vertebrae in which voltage was kept constant (7 V) and frequency was increased in 0.5 Hz increments until a 15% increase in heart rate (HR) was achieved. B-adrenergic (B-AR) responsiveness was evaluated with norepinephrine (500nM, NE). Baseline HR was higher in NIC vs. CT (215.8 BPM vs. 151 BPM, p<0.05). SNS stimulation thresholds necessary to produce an increase in HR were higher in NIC vs. CT (4.17 Hz vs. 1.38 Hz, p<0.05). Maximal HR increase after 40s of SNS trended lower in NIC vs. CT (19.38 vs. 54.30% increase, p=0.1). SNS also tended to produce a smaller change in action potential duration (APD80: -8.14 vs. -16.68% decrease, p=NS) and in calcium transient duration (CaTD80: -7.80 vs. - 20.74% decrease, p=NS) in NIC vs. CT. B-AR responsiveness was decreased in NIC vs. CT (33.38 vs. 75.77% increase in HR with NE, p=0.12). These results suggest that chronic NIC exposure may cause baseline sympathetic hyperactivity reduced B-AR sensitivity. Findings from this study will have significant implications for youth and young adults who represent the fastest growing group of nicotine users and the cardiac effects of nicotine on this potentially vulnerable population is unknown. Thus, data from this study may have implications for tobacco products and other nicotine containing products.

Chronic, Episodic Nicotine Alters Hypoglossal Motor Neuron Function at a Critical Developmental Time Point in Neonatal Rats.

Developmental nicotine exposure (DNE), alters brainstem neurons that control breathing, including hypoglossal motor neurons (XIIMNs), which innervate the tongue. Here, we tested the hypothesis that chronic, episodic DNE (eDNE), which mimics nicotine replacement therapies such as e-cigarettes or nicotine gum, alters the function of nicotinic acetylcholine receptors (nAChRs), XIIMN intrinsic properties, and tongue muscle function in vivo similar to what we have observed with a chronic, sustained exposure model. We delivered nicotine to pregnant Sprague Dawley rats through drinking water and studied pups of either sex in two age groups: postnatal day (P)1–P5 and P10–P12, which encompasses a critical period in brain development. At P1–P5, eDNE was associated with delayed recovery of nAChRs from desensitization; however, there were no changes in the magnitude of desensitization, XIIMN intrinsic properties, or tongue muscle function in vivo. By P10–P12, eDNE XIIMNs had lower peak firing frequencies in response to depolarizing current injection, larger delayed rectifier potassium currents, and continued to exhibit delayed nAChR recovery. Moreover, this age group exhibited a blunted and delayed tongue muscle response to nasal occlusion in vivo, indicating that changes to XIIMN intrinsic properties is an important mechanism behind this effect, as it is not produced by altered nAChR function alone. Together, these results show that eDNE alters XIIMNs and tongue muscle function during a critical period in brain development and that the specific effects of chronic nicotine exposure may be pattern dependent.

Linalyl acetate as a potential preventive agent against muscle wasting in rheumatoid arthritis rats chronically exposed to nicotine

Cigarette smoking has detrimental effects on rheumatoid arthritis (RA), characterized by muscle wasting. Linalyl acetate (LA), the main component of Lavandula angustifolia Mill (lavender) oil, has anti-inflammatory properties. We investigated the detrimental effects of chronic nicotine exposure in rats with RA, as well as the abilities of lavender oil and LA to prevent muscle wasting. Rats with RA induced by type II collagen were exposed to nicotine for 22 days from day 1. Lavender oil or LA was administered twice a week during the experiment. Compared with control, collagen-induced arthritis (CIA) and chronic nicotine exposure plus CIA (NicoCIA) showed increases in hind paw thickness and serum interleukin (IL)-6 and decreases in body weight and serum insulin-like growth factor (IGF)-1 levels. Moreover, weight and fiber cross-sectional area of the gastrocnemius muscle were much lower, and mitochondrial membrane potential of the gastrocnemius muscle was higher, in the NicoCIA than in the CIA. These alterations in the NicoCIA were prevented by lavender oil and LA. Importantly, LA showed greater activity than lavender oil in preventing IGF-1 reduction in the NicoCIA. These findings suggest that lavender oil and LA may have preventive benefit in RA by counteracting muscle wasting associated with chronic nicotine exposure.

Effects of Chronic Nicotine Exposure and 24h Withdrawal on Synaptosomal Protein Expression in the Mouse Ventral Hippocampus

Despite cigarette smoking being the leading cause of preventable death in the United States 20% of Americans continue to smoke. We now know that 80% of smokers desire to quit; however, less than 5% of them are successful. The low success rate of smoking cessation is partially due to current pharmacotherapies only addressing a subset of nicotine withdrawal symptoms, which is the primary driver of smoking relapse. A prominent, yet unaddressed, symptom of nicotine withdrawal is affective dysfunction. Affective symptoms, such as increased anxiety and reduced emotional regulation, are underpinned by discrete disruption of select brain circuits. For example, the ventral hippocampus (VHIPP) has a well-described role sub-serving the interface between contextual learning and affective responding, suggesting it as a potential circuitry target for examination of molecular alterations during nicotine withdrawal. Therefore, we explored this by treating 18-week-old mice for two weeks with either saline, nicotine (18 mg/kg/day), or 24h withdrawal from nicotine (18 mg/kg/day) via osmotic minipumps (Alzet 2002 model). Following treatment, the subjects were sacrificed and the VHIPP was collected and synaptosomes were prepared. These samples were analyzed via liquid chromatography-mass spectrometry to quantify changes in synaptosomal protein expression. These results were then analyzed using Enrichr pathway and transcriptional factor databases. Our results indicate changes in the axon guidance, vesicle-mediated transport, and transmission across chemical synapses pathways in both nicotine versus saline and withdraw versus saline synaptosomal protein comparisons. However, upon qPCR analysis mRNA expression of key genes associated with the pathways of interest remained unchanged for each treatment group. Further experiments will utilize western blotting to validate changes in total and phosphorylated proteins of interest in the aforementioned pathways.

The impact of chronic daily nicotine exposure and its overnight withdrawal on the structure of anxiety-related behaviors in rats: Role of the lateral habenula

Tobacco smoking is a serious health problem worldwide and a leading cause of mortality. Nicotine, the addictive component of tobacco, affects a range of emotional responses, including anxiety-related behaviors. Although perceived by smokers to be anxiolytic, evidence suggests that smoking increases anxiety and that mood fluctuates with nicotine intake. Thus, nicotine addiction may depend on easing the psychobiological distress caused by its abuse. The lateral habenula (LHb) has been implicated as a neural substrate for acute nicotine-induced anxiety, but its role in anxiety-like behaviors associated with chronic nicotine exposure has not been explored. Here, we assessed the effect of chronic nicotine exposure and its subsequent overnight withdrawal on anxiety-like behavior using both quantitative and multivariate T-pattern analysis in rats tested using the hole-board apparatus. Additionally, we explored the role of the LHb by comparing the behavioral effects of short-term nicotine withdrawal in chronically treated LHb-lesioned rats. Quantitative analysis revealed increased anxiety-like behavior in chronically treated overnight nicotine-deprived rats, as manifested in reduced general and focused exploratory behaviors, which was eased in animals that received nicotine. Quantitative analysis failed to reveal a role of the LHb in overnight nicotine deprivation-induced anxiety. Conversely, T-pattern analysis of behavioral outcomes revealed that chronic nicotine-treated rats still show anxiety-like behavior following nicotine challenge. Moreover, it demonstrated that the LHb lesion induced a stronger anxiolytic-like response to the acute challenge of nicotine in chronically nicotine-exposed animals, implicating the LHb in the anxiogenic effect of chronic nicotine exposure. These data further highlight the LHb as a promising target for smoking cessation therapies and support the importance of T-pattern analysis for behavioral analysis.

Tobacco Toxicity in Tobacco Chewers

Nicotine is highly addictive plant derived alkaloid and the most important species in human use today is&#x0D; Nicotiana tabacum. There are direct health effects of chronic nicotine exposure. Even in low doses, nicotine&#x0D; causes vasoconstriction and other cardiovascular effects related to catecholamine release and promote&#x0D; angiogenesis, neuroteratogenicity, and possibly some cancers¹. Periodontal disease and dental cavities&#x0D; and have up to 48 times the risk of oropharyngeal cancers compared with people who do not use tobacco&#x0D; products². Low doses exposure produces fine tremor, cutaneous vasoconstriction, increased GI motility, and&#x0D; increase in heart rate, respiratory rate and blood pressure³. Low dose nicotine also increases mental alertness&#x0D; and produces euphoria and desired psychoactive effects³. Metabolism is via the hepatic cytochrome oxidase&#x0D; system. The half life of nicotine in the body is 1 to 4 hours and decreases with repeated nicotine exposure4.

Effects of chronic nicotine exposure on Δ9-tetrahydrocannabinol-induced locomotor activity and neural activation in male and female adolescent and adult rats

RationaleHigh rates of comorbid tobacco and cannabis use in adolescents and young adults may be related to functional interactions between the nicotinic cholinergic and cannabinoid systems in the brain during development. This study examined the effects of chronic exposure to nicotine (the psychoactive component in tobacco) on acute exposure to delta-9-tetrahydrocannabinol (THC) (the psychoactive component of cannabis). MethodsMale and female adolescent and adult Sprague-Dawley rats (N = 112) were injected daily with nicotine (1 mg/kg, i.p.) or vehicle for 14 days, followed by a 14-day drug-free period. On test day, rats were injected with THC (5 mg/kg, i.p.) or vehicle, locomotor activity was recorded for 2 h, and brains harvested for c-Fos immunoreactivity (IR). ResultsLocomotor activity and c-Fos IR changes induced by THC challenge were altered by nicotine pre-exposure and modified by age and sex. THC-induced suppression of locomotor activity was attenuated by nicotine pre-exposure in adult but not adolescent males. THC-induced suppression of locomotor activity was potentiated by nicotine pre-exposure in female adolescents, with no effects of THC or nicotine observed in female adults. THC increased c-Fos IR in the caudate, nucleus accumbens, stria terminalis, septum, amygdala, hypothalamus, and thalamus. Nicotine pre-exposure potentiated this effect in all regions. Several brain regions showed age and sex differences in c-Fos IR such that expression was greater in adults than adolescents and in females than males. ConclusionsChronic nicotine pre-exposure produces lasting effects on cannabinoid-mediated signalling in the brain and on behaviour that are mediated by age and sex. Funding supportNSERC.

Effect of Chronic Nicotine Exposure on Maternal Renal Adaptations in Pregnant Rats: The Possible Role of Nitric Oxide

Abstract Background: Nicotine exposure during pregnancy contin-ues to be a widespread public health problem, impacting both fetal and postnatal health. Although the deleterious effects of nicotine on fetal development and the newborn have been extensively investigated, few studies have focused on its negative effects on the maternal adaptations to pregnancy especially relevant on renal functions. Aim of Study: To study the effects of chronic nicotine exposure on the maternal renal adaptations during pregnancy and the possible underlying mechanisms. Material and Methods: Thirty six adult virgin female albino rats, divided into two main groups, each subdivided into three subgroups; all received treatment for four weeks. Group I (virgin): Subdivided into; saline treated: Received daily subcutaneous saline injections, nicotine treated: Received daily nicotine bitartrate (1mg/kg) subcutaneous injections, combined with transdermal nicotine patches (5.2mg nico-tine/day) application, and nicotine and L-arginine treated: Received the same nicotine therapy plus 0.25% L-arginine added to drinking. Group II (pregnant): Subdivided into; saline treated: Received daily subcutaneous injections of saline (2 weeks prior to mating and 1 st two weeks of gestation), nicotine treated: Received daily subcutaneous injections of nicotine bitartrate (1mg/kg), with transdermal nicotine patches, and nicotine and L-arginine treated): Received same nicotine therapy plus 0.25% L-arginine added to drinking water. Results: Physiological effects of the pregnancy on renal function were significantly improved by L-argini ne. Similarly, nicotine exposure to virgin group produced a significant increase in serum and urinary Na+, significant decrease in renal total protein, nitric oxide with renal oxidative stress compared to their control group. Co-administration of nicotine and L-arginine to virgin group produced a significant decrease in serum Na+, urinary albumin and renal MDA levels, and significant increase in the urinary Na+ level, renal total protein, NO and GSH levels compared to the virgin nicotine group. Similarly, nicotine administration to pregnant group produced a significant increase in serum and urinary Na+, FENa, urinary albumin levels, together with significant de-crease in GFR, UFR and renal total protein, NO and GSH levels. While co-administration of nicotine and L-arginine to pregnant group produced a significant decrease in serum Na+, FENa, urinary albumin levels, with significant increase in the GFR, UFR and renal total protein, NO and GSH levels. Conclusion: We concluded that chronic nicotine exposure potentially impaired maternal renal adaptation to pregnancy which was improved greatly by L-arginine, implicating NO as crucial player.

Chronic Nicotine Exposure Alters Metabotropic Glutamate Receptor 5: Longitudinal PET Study and Behavioural Assessment in Rats.

Using positron emission tomography (PET), a profound alteration of the metabotropic glutamate receptor 5 (mGluR5) was found in human smoking addiction and abstinence. As human PET data either reflect the impact of chronic nicotine exposure or a pre-existing vulnerability to nicotine addiction, we designed a preclinical, longitudinal study to investigate the effect of chronic nicotine exposure on mGluR5 with the novel radiotracer [18F]PSS232 using PET. Twelve male dark Agouti rats at the age of 6weeks were assigned randomly to three groups. From day 0 to day 250 the groups received 0mg/L, 4mg/L, or 8mg/L nicotine solution in the drinking water. From day 250 to 320 all groups received nicotine-free drinking water. PET scans with [18F]PSS232 were performed in all animals on days 0, 250, and 320. To assess locomotion, seven tests in square open field arenas were carried out 72days after the last PET scan. During the first four tests, rats received 0mg/L nicotine and for the last three tests 4mg/L nicotine in the drinking water. After 250days of nicotine consumption [18F]PSS232 binding was reduced in the striatum, hippocampus, thalamus, and midbrain. At day 320, after nicotine withdrawal, [18F]PSS232 binding increased. These effects were more pronounced in the 4mg/L nicotine group. Chronic administration of nicotine through the drinking water reduced exploratory behaviour. This preliminary longitudinal PET study demonstrates that chronic nicotine administration alters behaviour and mGluR5 availability. Chronic nicotine administration leads to decreased [18F]PSS232 binding which normalizes after prolonged nicotine withdrawal.

Nicotine-induced oxidative stress contributes to EMT and stemness during neoplastic transformation through epigenetic modifications in human kidney epithelial cells

Nicotine is a component of cigarette smoke and mounting evidence suggests toxicity and carcinogenicity of tobacco smoke in kidney. Carcinogenicity of nicotine itself in kidney and the underlying molecular mechanisms are not well-understood. Hence, the objective of this study was to determine the carcinogenic effects of chronic nicotine exposure in Hk-2 human kidney epithelial cells. The effects of nicotine exposure on the expression of genes for cellular reprogramming, redox status, and growth signaling pathways were also evaluated to understand the molecular mechanisms. Results revealed that chronic exposure to nicotine induced growth and neoplastic transformation in HK-2 cells. Increased levels of intracellular reactive oxygen species (ROS), acquired stem cell-like sphere formation, and epithelial-mesenchymal-transition (EMT) changes were observed in nicotine exposed cells. Treatment with antioxidant N-acetyl cysteine (NAC) resulted in abrogation of EMT and stemness in HK-2 cells, indicating the role of nicotine-induced ROS in these morphological changes. The result also suggests that ROS controls the stemness through regulation of AKT pathway during early stages of carcinogenesis. Additionally, the expression of epigenetic regulatory genes was altered in nicotine-exposed cells and the changes were reversed by NAC. The epigenetic therapeutics 5-aza-2′-deoxycytidine and Trichostatin A also abrogated the stemness. This suggests the nicotine-induced oxidative stress caused epigenetic alterations contributing to stemness during neoplastic transformation. To our knowledge, this is the first report showing the ROS-mediated epigenetic modifications as the underlying mechanism for carcinogenicity of nicotine in human kidney epithelial cells. This study further suggests the potential of epigenetic therapeutics for pharmacological intervention in nicotine-induced kidney cancer.

Chronic Nicotine Exposure Alters Uninjured Tendon Vascularity and Viscoelasticity.

Background:Although nicotine and tobacco use are well established to have adverse health effects, the effects on tendons are less well understood. The purpose of this study was to investigate the effect of chronic nicotine exposure on Achilles tendon (AT) and supraspinatus tendon (SS) physiologic and mechanical properties in a rodent model.Methods:Sprague-Dawley rats (n = 20) were exposed to either 0.9% saline or 36 mg/mL nicotine through an implantable osmotic pump for 12 weeks. At 12 weeks, the AT was imaged in vivo with contrast-enhanced ultrasound (CE-US) to assess vascularity. Bilateral AT and SS were then harvested for ex vivo biomechanical analysis. Statistical analysis was performed using Student t test and Mann Whitney U test.Results:AT CE-US demonstrated a significantly increased wash-in rate in the nicotine group compared to the saline group, indicating an increase in tissue perfusion rate in the nicotine group. AT percent stress relaxation, a measure of tendon viscoelasticity, was significantly increased in the nicotine group compared to the saline group. Similarly, there was a trend toward increased SS percent stress relaxation in the nicotine group compared to the saline group. No differences in other mechanical properties were observed.Conclusion:AT perfusion rate increased and both AT and SS viscoelasticity were altered with chronic nicotine exposure at a clinically relevant dose that models the average smoker in the United States (14 cigarettes per day). Further studies are necessary to link these properties with tendon degeneration and injury.Clinical Relevance:Chronic nicotine exposure affects tendon health. Patients should be counseled as such.

Adverse effects of chronic nicotine exposure on the kidney: Potential human health implications of experimental findings .

With the increasing popularity of E-cigarettes, chronic exposure to nicotine (NIC) is emerging as a novel risk factor for the kidney. NIC increases oxidative stress in the kidneys, which impairs the viability and function of renal tubular and endothelial cells, alters renal hemodynamics, and compromises overall kidney function. Moreover, long-term NIC exposure increases the risk of development and progression of chronic kidney diseases and may escalate the impact of coexisting morbidities such as obesity-associated renal disease, hypertension, renal transplant status, or the toxicity of various anticancer agents. In this review, we summarize experimental findings describing increased renal risk of chronic NIC exposure and explore therapeutic interventions to alleviate adverse effects of NIC. .

Adolescent Nicotine Exposure Induces Dysregulation of Mesocorticolimbic Activity States and Depressive and Anxiety-like Prefrontal Cortical Molecular Phenotypes Persisting into Adulthood.

Considerable evidence demonstrates strong comorbidity between nicotine dependence and mood and anxiety disorders. Nevertheless, the neurobiological mechanisms linking adolescent nicotine exposure to mood and anxiety disorders are not known. Disturbances in the mesocorticolimbic dopamine (DA) system, comprising the prefrontal cortex (PFC), ventral tegmental area (VTA), and nucleus accumbens (NAc), are correlates of mood and anxiety-related symptoms and this circuitry is strongly influenced by acute or chronic nicotine exposure. Using a combination of behavioral pharmacology, in vivo neuronal electrophysiology and molecular analyses, we examined and compared the effects of chronic nicotine exposure in rats during adolescence versus adulthood to characterize the mechanisms by which adolescent nicotine may selectively confer increased risk of developing mood and anxiety-related symptoms in later life. We report that exposure to nicotine, selectively during adolescence, induces profound and long-lasting neuronal, molecular and behavioral disturbances involving PFC DA D1R and downstream extracellular-signal-related kinase 1-2 (ERK 1-2) signaling. Remarkably, adolescent nicotine induced a persistent state of hyperactive DA activity in the ventral tegmental area (VTA) concomitant with hyperactive neuronal activity states in the PFC. Our findings identify several unique neuronal and molecular biomarkers that may serve as functional risk mechanisms for the long-lasting neuropsychiatric effects of adolescent smoking behaviors.

Chronic nicotine exposure in preadolescence enhances later spontaneous recovery of fear memory.

Preadolescent mice have been shown to be differentially susceptible to the effects of both acute and chronic nicotine exposure on contextual fear learning relative to adults. For this study, we tested the effects of chronic nicotine exposure in preadolescence on adulthood extinction and spontaneous recovery of fear memory in a model in which contextual fear acquisition occurred prior to nicotine exposure. Preadolescent (postnatal day 23) and adult (postnatal day 53) male C57BL/6J mice underwent contextual fear conditioning and were then exposed to chronic nicotine at 12.6 mg/kg/day for 12 days via osmotic minipump. Eighteen days following the removal of nicotine, both groups of mice underwent fear extinction, followed by a spontaneous recovery session a week later. History of chronic nicotine did not affect later extinction of fear memory in adult-trained mice, whereas adolescent-trained mice exhibited a global impairment in retention of fear memory that precluded detection of effects of early nicotine on later fear extinction. However, it was found that adult spontaneous recovery of fear memory was impaired in mice exposed to nicotine as adults and enhanced in mice exposed to nicotine as preadolescents. These results may indicate greater vulnerability to recurrence of traumatic memory as well as compromised inhibitory control in young smokers. (PsycINFO Database Record