Nicotine addiction is a concern worldwide. Most mechanistic investigations are on nicotine substance dependence properties based on its pharmacological effects. However, no effective therapeutic treatment has been established. Nicotine addiction is reinforced by environments or habits. We demonstrate the neurobiological basis of the behavioural aspect of nicotine addiction. We utilized the conditioned place preference to establish nicotine-associated behavioural preferences (NABP) in rats. Brain-wide neuroimaging analysis revealed that the medial prefrontal cortex (mPFC) was activated and contributed to NABP. Chemogenetic manipulation of µ-opioid receptor positive (MOR⁺) neurons in the mPFC or the excitatory outflow to the nucleus accumbens shell (NAcShell) modulated the NABP. Electrophysiological recording confirmed that the MOR⁺ neurons directly regulate the mPFC-NAcShell circuit via GABA_A receptors. Thus, the MOR⁺ neurons in the mPFC modulate the formation of behavioural aspects of nicotine addiction via direct excitatory innervation to the NAcShell, which may provide new insight for the development of effective therapeutic strategies.
Animals ; Nucleus Accumbens/drug effects* ; Prefrontal Cortex/drug effects* ; Nicotine/pharmacology* ; Receptors, Opioid, mu/metabolism* ; Male ; Rats ; Rats, Sprague-Dawley ; Tobacco Use Disorder/metabolism* ; Neurons/drug effects* ; Neural Pathways/drug effects*

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D₃ (VitD₃) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD₃, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11β-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD₃, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.
Rats ; Animals ; Glucocorticoids/metabolism* ; Rats, Sprague-Dawley ; Nicotine/metabolism* ; Hydrocortisone/metabolism* ; Muscle, Smooth, Vascular ; Dexamethasone/metabolism* ; Vascular Calcification/metabolism* ; Myocytes, Smooth Muscle/metabolism* ; Cells, Cultured

Blakeslea trispora is a natural source of carotenoids, including β-carotene and lycopene, which have industrial applications. Therefore, classical selective breeding techniques have been applied to generate strains with increased productivity, and microencapsulated β-carotene preparation has been used in food industry (Li et al., 2019). In B. trispora, lycopene is synthesized via the mevalonate pathway (Venkateshwaran et al., 2015). Lycopene cyclase, which is one of the key enzymes in this pathway, is a bifunctional enzyme that can catalyze the cyclization of lycopene to produce β-carotene and exhibit phytoene synthase activity (He et al., 2017).
Citric Acid Cycle ; Fermentation ; Gas Chromatography-Mass Spectrometry/methods* ; Lycopene/metabolism* ; Mucorales/metabolism* ; Nicotine/pharmacology* ; beta Carotene/biosynthesis*

BACKGROUND: Green tobacco sickness (GTS), an occupational disease in tobacco harvesters, is a form of acute nicotine intoxication by nicotine absorption through the skin from the wet green tobacco plant. We carried out a questionnaire survey and measured cotinine concentration, the metabolic product of nicotine, to determine the prevalence, incidence, and risk factors of GTS in Korean tobacco harvesters. METHODS: We measured cotinine concentrations, and administered a questionnaire survey to tobacco harvesters in Cheongsong-gun, Gyeongsangbuk-do, Korea. We repeatedly measured urine cotinine concentration five times with a questionnaire survey. RESULTS: Cotinine concentration at dawn was significantly higher than that at other times; it was significantly lower during the nonharvesting period than during the harvesting period. However, little change in cotinine concentration was detected in the daytime during the harvesting period. Study participants included 20 men and 20 women. The prevalence of GTS was 37.5% and was significantly higher in women than in men (55.0% vs. 20.0%, p < 0.01). GTS incidence according to number of workdays was 3.4 occurrences/100 person days. CONCLUSION: In this study, nicotine exposure and metabolism were experimentally determined from the time of cotinine exposure, and biological monitoring was performed in each season. In the future, this information may be valuable for medical decision-making in GTS prevention.
Absorption ; Clinical Decision-Making ; Cotinine ; Environmental Monitoring ; Farmers ; Female ; Gyeongsangbuk-do ; Humans ; Incidence ; Korea ; Male ; Metabolism ; Nicotine ; Occupational Diseases ; Plants ; Prevalence ; Risk Factors ; Seasons ; Skin ; Tobacco*

BACKGROUND: Nicotine is a major toxic component of tobacco smoke and has been recognized as a risk factor to induce oxidative tissue damage, which is a precursor to cardiovascular diseases, lung-related diseases, and cancers. Peaches (Prunus persica) have been used for the treatment of degenerative disorders, such as hypermenorrhea, dysmenorrhea, and infertility in Asian countries. In this study, we investigated the effects of white-fleshed peach on the excretion of nicotine metabolites and 1-hydroxypyrene in smokers and chronic nicotine-induced tissue damages in mice. METHODS: The concentrations of cotinine and 1-hydroxypyrene were measured in urine of smokers before or after intake of white-fleshed peaches. In addition, ICR mice were injected with nicotine (5 mg/kg body weight) and then orally administered with white-fleshed peach extracts (WFPE) (250 or 500 mg/kg body weight) for 36 days. The oxidative stress parameters and the activities of antioxidant enzymes were measured in liver and kidney tissues. Also, histological changes and nitrotyrosine expression were assessed. RESULTS: Intake of white-fleshed peaches increased the urinary concentration of nicotine metabolites and 1-hydroxypyrene in 91.67% and 83.33% of smokers, respectively. WFPE decreased the malondialdehyde levels and recovered the activities of antioxidant enzymes in nicotine-injected mice. In addition, WFPE inhibited nitrotyrosine expression and inflammatory responses in the liver, kidney, and lung tissues of nicotine-treated mice. CONCLUSIONS: White-fleshed peaches may increase the metabolism of toxic components in tobacco smoke in smokers and protect normal tissues against nicotine toxicity in mice. Therefore, supplementation of white-fleshed peaches might be beneficial to smokers.
Animals ; Asian Continental Ancestry Group ; Cardiovascular Diseases ; Cotinine ; Dysmenorrhea ; Female ; Humans ; Infertility ; Kidney ; Liver ; Lung ; Malondialdehyde ; Menorrhagia ; Metabolism ; Mice ; Mice, Inbred ICR ; Nicotine ; Oxidative Stress ; Prunus persica* ; Risk Factors ; Smoke ; Tobacco

OBJECTIVETo evaluate the impact of nicotine- and tar-free cigarette smoke extract (fCSE) on the serum testosterone (T) level and erectile function of male rats.

METHODSWe randomized 30 male SD rats to three groups of equal number to receive subcutaneous injection of PBS (1.0 ml / 300 g body weight per day), fCSE (1.0 ml/300 g body weight per day), and reduced glutathione hormone (GSH, 200 mg per kg body weight per day) in addition to fCSE (fCSE + GSH), respectively, all for 8 weeks. Then we evaluated the erectile function of the rats by measuring the maximal intracavernous pressure (MICP), mean arterial pressure (MAP), ICP/MAP ratio, time of stimulation to MICP (Tmax), and cavernosal filling fate (CFR). We determined the serum T level, the activities of superoxide dismutase (SOD) , malondialdehyde (MDA), and nitric oxide synthase (NOS) in the cavernosal tissue, and also observed the morphological changes of the corpus cavernosum.

RESULTSCompared with the controls, the rats of the fCSE group showed obvious decreases in the levels of serum T ([5.37 ± 1.43] vs [3.22 ± 1.11] μg/L), NOS ([2.90 ± 0.27] vs [1.67 ± 0.18] U/mg) , and SOD ([18.41 ± 1.09] vs [13.36 ± 1.18] U/mg prot) and erectile function-related indexes MICP ([85.92 ± 6.36] vs [58.99 ± 10.76] mmHg), MICP/MAP (0.86 ± 0.09 vs [0.56 ± 0.08]), and CFR (2.14 ± 0.44 vs 0.89 ± 0.44), but markedly increased Tmax ([29.90 ± 5.78] vs [42.90 ± 8.56]s), with a positive correlation between the serum T level and CFR (r = 0. 364, P < 0.05). Masson staining revealed a lower ratio of the corpus cavernosum smooth muscle tissue to collagen fiber in the fCSE group (0.27 ± 0.04) than in the control (0.98 ± 0.12). Compared with the fCSE group, the fCSE + GSH group exhibited significantly improved MICP ([58.99 ± 10.76 ] vs [77.95 ± 7.71] mmHg), MICP/MAP (0.56 ± 0.08 vs 0.77 ± 0.09), and CFR (0.89 ± 0.44] vs 1.76 ± 0.42) and shortened Tmax ([42.90 ± 8.56 ] vs [32.10 ± 5.84 ] s). The ratio of the corpus cavernosum smooth muscle tissue to collagen fiber was higher in the fCSE + GSH than in the fCSE group (0.77 ± 0.09 vs 0.27 ± 0.04) but still lower than in the control (0.98 ± 0.12).

CONCLUSIONNicotine- and tar-free cigarette smoke extract reduces the serum T level and erectile function of rats, which is related to oxidative stress. Antioxidant therapy can improve erectile function but has a limited value for morphological protection of the penile tissue.

Animals ; Erectile Dysfunction ; chemically induced ; Male ; Malondialdehyde ; metabolism ; Muscle, Smooth ; pathology ; Nicotine ; Nitric Oxide Synthase ; metabolism ; Penile Erection ; drug effects ; Penis ; pathology ; Rats ; Rats, Sprague-Dawley ; Smoke ; adverse effects ; Superoxide Dismutase ; metabolism ; Tars ; Tobacco ; adverse effects

Nicotine is the main component for smoking addiction. It is widely believed that nicotine dependence is heritable. Many studies are committed to study the effects of specific gene polymorphisms connect with nicotine dependence. Release of dopamine has been considered the most important channel for nicotine dependence. This paper provides a review for recent advance in studies on dopamine system related genetic polymorphisms associated with nicotine dependence.
Animals ; Dopamine ; metabolism ; Humans ; Nicotine ; metabolism ; Polymorphism, Genetic ; Tobacco Use Disorder ; genetics ; metabolism

OBJECTIVE: Cigarette smoking is associated with a variety of health problems including cardiovascular, pulmonary, neoplasms, endocrinopathies including diabetes, the metabolic syndrome, and chronic inflammation. Adiponectin is an adipocyte-derived plasma protein that is closely associated with insulin sensitivity and the metabolic syndrome. The aim of this study was to evaluate the changes of plasma adiponectin levels after smoking cessation. METHODS: Thirty seven smokers that wanted to stop smoking without any nicotine replacement therapy or medication were recruited for this study. Fifteen smokers succeeded in stopping smoking (validated by urine cotinine levels < or =50 ng/mL) and 22 smokers failed. Therefore, only the 15 that succeeded were included in the analysis. The plasma adiponectin levels were determined using a commercially available enzyme-linked immunosorbent assay. RESULTS: The mean age of the successful 15 was 35+/-9.3 years old. They were all males. The daily smoking habit was a mean of 13.5+/-5.4 cigarettes per day. The mean Nicotine Dependence Syndrome Scale (NDSS) and Fagerstrom Test for Nicotine Dependence (FTND) scores were 55.6+/-9.6 and 2.9+/-1.9. During the study period of three months, the mean body mass index (BMI), body fat mass (BFM), waist-hip ratio (WHR) and body weight increased by 1.1 kg/m2, 3.0%, 0.02%, and 2.9 kg, respectively. The baseline mean adiponectin level in the subjects was 11.9+/-5.2 mg/L. The mean adiponectin levels measured at one and three months were 16.0+/-5.1 mg/L and 14.7+/-4.5 mg/L respectively. The mean plasma adiponectin levels of the successful group was significantly increased after four weeks when compared to the baseline (z=-2.401, p=0.016). However, the decrease in plasma adiponectin levels at one and three months was not statistically significant. CONCLUSION: Even though the decrease over the next two months was not significant, these findings, the increase of plasma level of adiponectin after smoking cessation, provide preliminary data for future research on the possible mechanisms associated with smoking cessation and changes in body metabolism.
Adiponectin* ; Adipose Tissue ; Body Mass Index ; Body Weight ; Cotinine ; Enzyme-Linked Immunosorbent Assay ; Ghrelin ; Humans ; Inflammation ; Insulin Resistance ; Leptin ; Male ; Metabolism ; Nicotine ; Plasma* ; Smoke* ; Smoking Cessation* ; Smoking* ; Tobacco ; Tobacco Products ; Tobacco Use Disorder ; Waist-Hip Ratio

STUDY DESIGN: Experimental investigation in vitro. OBJECTIVES: To evaluate the relationship between the degeneration of intervertebral disc cells, and low back pain induced by degeneration of intervertebral disc cells and increases in use of proinflammatory mediators via nicotine stimulation. SUMMARY OF LITERATURE REVIEW: Smoking is a leading cause of degeneration of intervertebral disc cells and low back pain. According to the existing literature, nicotine, one of the main ingredients in cigarettes, causes the degeneration of intervertebral disk cells including decrease of glycoprotein through generation of carboxy-hemoglobin, vasoconstriction, and disability of fibrinolysis and changes of metabolism of nucleus pulposus cells. MATERIALS AND METHODS: Annulus fibrosus of intervertebral disc and knee joint cartilage were collected from pigs; these cells were acquired by gradual enzyme decomposition. Using Trypan blue, concentration and survival rate of cells were examined; cells were inserted on alginate beads for tertiary cultivation. Nicotine was then applied at 0, 50, 100, 200 and 300 nM, respectively, and the samples were cultivated for three, six and nine days, respectively. After collecting culture fluid, it was measured for interleukin(IL)-1beta, IL-6 and IL-8 with the ELISA Test. DNA of cells used for cultivation was quantitated and the amount of the resulting proinflammatory mediator was normalized. The results were then compared with the result of same study on cartilage of porcine knee joints. RESULTS: For changes of the inflammatory mediator based on the concentration of nicotine, in nicotine stimulation with low concentration of 50 nM and the control group, there was no significant change, while transient increases of inflammatory mediator showed in nicotine stimulation with concentrations of 100, 200 nM, respectively. There was not a significant increase of IL-1beta observed in all nicotine stimulation groups; these were the same results in porcine cartilage study. The level of IL-6 in 200, 300 nM nicotine concentration showed significant increases, respectively. The level of IL-8 in high dose nicotine stimulation groups also showed significant increases of DNA on the sixth day. And in porcine cartilage study group, significant changes were observed in 200, 300 nM, but the absolute value was lower than that of annulus fibrous cells group. CONCLUSION: Inflammatory mediators such as IL-6 and IL-8 increased as the result of tertiary cultivation of annulus fibrosus cells of porcine intervertebral disk and nicotine stimulation. It is believed that the cells of the disc annulus are more sensitive than articular chondrocytes to nicotine stimulation. This may be the focus of future long-term studies effects of nicotine other inflammatory cytokines.
Cartilage ; Chondrocytes ; Cytokines ; DNA ; Enzyme-Linked Immunosorbent Assay ; Fibrinolysis ; Glycoproteins ; Interleukin-6 ; Interleukin-8 ; Intervertebral Disc* ; Knee Joint ; Low Back Pain ; Metabolism ; Nicotine* ; Smoke ; Smoking ; Survival Rate ; Swine ; Tobacco Products ; Trypan Blue ; Vasoconstriction

A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).
Acetylcholinesterase ; metabolism ; Amyloid beta-Peptides ; antagonists & inhibitors ; metabolism ; Binding Sites ; Butyrylcholinesterase ; metabolism ; Cholinesterase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Nicotine ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology