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1.
Life Sci ; 243: 117301, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953160

RESUMO

AIM: Pancreatic stellate cells (PSCs) are the main functional cells leading to pancreatic fibrosis. Nicotine is widely considered as an independent risk factor of pancreatic fibrosis, but the mechanism is still unclear. Our study was aimed to explore the effects of nicotine on human pancreatic stellate cells (hPSCs) and involved pathways. MATERIALS AND METHODS: Primary human PSCs were cultured and treated with nicotine (0.1 µM and 1 µM). The proliferation, apoptosis, α-SMA expression, extracellular matrix metabolism and autophagy of hPSCs were detected by CCK-8 assay, flow cytometry, real-time PCR and Western blotting analysis. The α7nAChR-mediated JAK2/STAT3 signaling pathway was also examined, and an α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. KEY FINDINGS: The proliferation, α-SMA expression and autophagy of hPSCs were significantly promoted by 1 µM nicotine. Meanwhile, the apoptosis of hPSCs was significantly reduced. The extracellular matrix metabolism of hPSCs was also regulated by nicotine. Moreover, the α7nAChR-mediated JAK2/STAT3 signaling pathway was activated by nicotine, this pathway and effects of nicotine can be blocked by α-BTX. SIGNIFICANCE: Our finding suggests that nicotine can promote activation of human pancreatic stellate cells (hPSCs) through inducing autophagy via α7nAChR-mediated JAK2/STAT3 signaling pathway, providing a new insight into the mechanisms by which nicotine affects pancreatic fibrosis.


Assuntos
Autofagia/efeitos dos fármacos , Janus Quinase 2/metabolismo , Nicotina/farmacologia , Células Estreladas do Pâncreas/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Actinas/metabolismo , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Células Estreladas do Pâncreas/metabolismo
2.
Nat Commun ; 11(1): 306, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949158

RESUMO

With the rise of e-cigarette use, teen nicotine exposure is becoming more widespread. Findings from clinical and preclinical studies show that the adolescent brain is particularly sensitive to nicotine. Animal studies have demonstrated that adolescent nicotine exposure increases reinforcement for cocaine and other drugs. However, the mechanisms that underlie these behaviors are poorly understood. Here, we report reactive microglia are critical regulators of nicotine-induced increases in adolescent cocaine self-administration. Nicotine has dichotomous, age-dependent effects on microglial morphology and immune transcript profiles. A multistep signaling mechanism involving D2 receptors and CX3CL1 mediates nicotine-induced increases in cocaine self-administration and microglial activation. Moreover, nicotine depletes presynaptic markers in a manner that is microglia-, D2- and CX3CL1-dependent. Taken together, we demonstrate that adolescent microglia are uniquely susceptible to perturbations by nicotine, necessary for nicotine-induced increases in cocaine-seeking, and that D2 receptors and CX3CL1 play a mechanistic role in these phenomena.


Assuntos
Cocaína/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Nicotina/farmacologia , Aminopiridinas/farmacologia , Animais , Quimiocina CX3CL1/metabolismo , Modelos Animais de Doenças , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Minociclina/farmacologia , Fenótipo , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/efeitos dos fármacos , Reforço Psicológico , Recompensa , Autoadministração , Sinaptofisina
3.
Chem Biol Interact ; 317: 108943, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926917

RESUMO

Epidemiological studies have shown that cigarette smoking is beneficial in ulcerative colitis and that nicotine may be responsible for this effect. However, the mechanism remains unclear. In a previous study, nicotine was found to induce autophagy in intestinal cells. Here, we evaluated the effect of nicotine-induced autophagy in a dextran sodium sulfate (DSS)-induced colitis mouse model. C57BL/6 adult male mice drank DSS water solution freely for seven consecutive days, and then tap water was administered. The effect of nicotine treatment was examined in the DSS model, including colon length, disease severity, histology of the colon tissue, and inflammation levels. Moreover, autophagy levels were detected by Western blot analysis (LC3II/LC3I, p62, and beclin-1). The levels of DSS-induced colitis were significantly decreased following nicotine treatment. The disease activity score, body weight, histologic damage scores, and the level of colonic inflammatory factors of nicotine-treated mice all decreased compared to those of the control mice. Additionally, nicotine enhanced the expression of LC3II/LC3I and beclin-1 but decreased the p62 protein level. Inhibiting autophagy by 3-MA attenuated the protective effects of nicotine on colitis. Additionally, both in vitro and in vivo experiments showed changes in AMPK-mTOR-P70S6K during this process. These results suggest that nicotine improved colitis by regulating autophagy and provided a protective effect against DSS-induced colitis.


Assuntos
Adenilato Quinase/metabolismo , Autofagia/efeitos dos fármacos , Colite/prevenção & controle , Nicotina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/genética , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/genética
4.
Int J Cancer ; 146(2): 496-509, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125123

RESUMO

The biological role of vacuolar protein sorting 33B (VPS33B) has not been examined in colorectal cancer (CRC). We report that VPS33B was downregulated in dextran sulfate sodium/azoxymethane (DSS/AOM) -induced CRC mice models and nicotine-treated CRC cells via the PI3K/AKT/c-Jun pathway. Reduced VPS33B is an unfavorable factor promoting poor prognosis in human CRC patients. VPS33B overexpression suppressed CRC proliferation, intrahepatic metastasis and chemoresistance of cisplatin (DDP) in vivo and in vitro through modulating the epidermal growth factor receptor (EGFR)/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and the downstream cell cycle or EMT-related factors. Furthermore, NESG1 as a newly identified tumor suppressor interacted with VPS33B via colocalization in the cytoplasm, and it was stimulated by VPS33B through the downregulation of RAS/ERK/c-Jun-mediated transcription. NESG1 also activated VPS33B expression via the RAS/ERK/c-Jun pathway. Suppression of NESG1 increased cell growth, migration and invasion via the reversion of the VPS33B-modulating signal in VPS33B-overexpressed cells. Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and thus suppress the malignant phenotype of CRC.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes Supressores de Tumor/efeitos dos fármacos , Nicotina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas de Transporte Vesicular/genética , Animais , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HT29 , Humanos , Camundongos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética
5.
Food Chem Toxicol ; 135: 111057, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31846720

RESUMO

Prenatal nicotine exposure (PNE) may lead to offspring's testicular dysplasia. Here, we confirmed the intergenerational effect of PNE on testosterone synthetic function and explored its epigenetic programming mechanism. Pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg.d) from gestational day 9-20. Some dams were anesthetized to obtain fetal rats, the rest were allowed to spontaneous labor to generate F1 and F2 generation. In utero, PNE impaired testicular development and testosterone production. Meanwhile, the expression of steroidogenic acute regulatory protein (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were decreased both in F1 and F2 generations. Furthermore, PNE enhanced the expression of fetal testicular nicotinic acetylcholine receptors (nAChRs) and histone deacetylase 4 (HDAC4), while obviously weakened histone 3 lysine 9 acetylation (H3K9ac) level of StAR/3ß-HSD promoter from GD20 to postnatal week 12 and even in F2 generation. In vitro, nicotine increased nAChRs and HDAC4 expression, and decreased the StAR/3ß-HSD H3K9ac level and expression, as well as the testosterone production in Leydig cells. Antagonism of nAChRs and inhibition of HDAC4 reversed the aforementioned changes. In conclusion, PNE programmed testicular low steroidogenesis and its heritability in male offspring rats. The underlying mechanism was associated to the low-level programming of StAR/3ß-HSD H3K9ac via nAChR/HDAC4.


Assuntos
Epigênese Genética/efeitos dos fármacos , Histona Desacetilases/metabolismo , Comportamento Materno , Nicotina/administração & dosagem , Receptores Nicotínicos/metabolismo , Testículo/efeitos dos fármacos , Testosterona/biossíntese , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Nicotina/farmacologia , Gravidez , Ratos , Ratos Wistar , Testículo/embriologia , Testículo/metabolismo
6.
Chem Biol Interact ; 316: 108929, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31857090

RESUMO

Fatty liver is the hepatic consequence of chronic insulin resistance (IR) and related syndromes. It is mostly accompanied by inflammatory and oxidative molecules. Increased activity of xanthine oxidase (XO) exerts both inflammatory and oxidative effects and has been implicated in metabolic derangements including non-alcoholic fatty liver disease. Short chain fatty acids (SCFAs) elicit beneficial metabolic alterations in IR and related syndromes. In the present study, we evaluated the preventive effects of a SCFA, acetate, on nicotine-induced dysmetabolism and fatty liver. Twenty-four male Wistar rats (n = 6/group): vehicle-treatment (p.o.), nicotine-treated (1.0 mg/kg; p.o.), sodium acetate-treated (200 mg/kg; p.o.) and nicotine + sodium acetate-treated groups. The treatments lasted for 8 weeks. IR was estimated by oral glucose tolerance test and homeostatic model assessment of IR. Plasma and hepatic free fatty acid, triglyceride (TG), glutathione peroxidase, adenosine deaminase (ADA), XO and uric acid (UA) were measured. Nicotine exposure resulted in reduced body weight, liver weight, visceral adiposity, glycogen content and glycogen synthase activity. Conversely, exposure to nicotine increased fasting plasma glucose, lactate, IR, plasma and hepatic TG, free fatty acid, TG/HDL-cholesterol ratio, lipid peroxidation, liver function enzymes, plasma and hepatic UA, XO and ADA activities. However, plasma and hepatic glucose-6-phosphate dehydrogenase-dependent antioxidant defense was not affected by nicotine. Concomitant treatment with acetate ameliorated nicotine-induced effects. Taken together, these results indicate that nicotine exposure leads to excess deposition of lipid in the liver by enhancing XO activity. The results also imply that acetate confers hepatoprotection and is accompanied by decreased XO activity.


Assuntos
Lipídeos/análise , Fígado/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Acetato de Sódio/farmacologia , Xantina Oxidase/metabolismo , Animais , Área Sob a Curva , Ácidos Graxos não Esterificados/sangue , Teste de Tolerância a Glucose , Resistência à Insulina , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Nicotina/farmacologia , Curva ROC , Ratos , Ratos Wistar , Triglicerídeos/sangue , Xantina Oxidase/sangue
7.
J Pharmacol Sci ; 142(1): 9-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771811

RESUMO

Varenicline is a widely used and effective drug for smoking cessation. We previously reported that varenicline aggravates atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. However, it remains unknown whether varenicline affects cardiovascular events in patients with nicotine addiction. Here, we examined the effect of varenicline on atherosclerotic plaque formation in nicotine-pretreated ApoE KO mice and oxidized low-density lipoprotein (oxLDL) uptake in nicotine-treated peritoneal macrophages. Varenicline caused significant progression of plaque formation in the whole aorta and aortic root and further accelerated the increased formation of a macrophage-rich plaque area in the aortic root in nicotine-pretreated ApoE KO mice. Varenicline (10 µM) enhanced oxLDL uptake in peritoneal macrophages. Furthermore, this treatment significantly further lowered the decreased protein levels of ATP-binding cassette (ABC) transporter without affecting the expression of scavenger receptors LOX-1 and CD36 in RAW264.7 cells treated with 100 nM nicotine. Varenicline enhanced nicotine-induced oxLDL uptake in macrophages through decreased expression of cholesterol efflux transporters ABCA1 and ABCG1 and thereby progressed atherosclerotic plaque formation. Taken together, we tentatively conclude that nicotine exposure before and/or during varenicline treatment can aggravate varenicline-increased atherosclerotic plaque formation and progression. Therefore, this enhanced risk requires special consideration when prescribing varenicline to smoker patients.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Macrófagos/metabolismo , Nicotina/farmacologia , Placa Aterosclerótica/etiologia , Vareniclina/toxicidade , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Nicotina/agonistas , Células RAW 264.7 , Agentes de Cessação do Hábito de Fumar/toxicidade
8.
Ophthalmic Surg Lasers Imaging Retina ; 50(11): 691-700, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755968

RESUMO

BACKGROUND AND OBJECTIVE: To evaluate the acute effects of nicotine on macular microvasculature by optical coherence tomography angiography (OCTA). PATIENTS AND METHODS: Non-smokers who were administered 4 mg nicotine gum (study group) or placebo gum (control group) were enrolled, 18 individuals in each group. All participants underwent OCTA at baseline and 1 hour after gum chewing. Macular flow area, macular vessel density, foveal avascular zone area, central foveal thickness, and subfoveal choroidal thickness were analyzed. RESULTS: Macular flow area, vessel density, and subfoveal choroidal thickness decreased in the nicotine group (P < .05). No statistically significant difference observed in central foveal thickness, when compared with baseline measurement (P > .05). CONCLUSIONS: Nicotine causes a significant decrease in macular microcirculation. Deterioration of macular microcirculation can be quantitatively detected by OCTA noninvasively. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:691-700.].


Assuntos
Macula Lutea/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Nicotina/farmacologia , Adulto , Corioide/efeitos dos fármacos , Feminino , Angiofluoresceinografia , Fóvea Central/irrigação sanguínea , Humanos , Masculino , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasos Retinianos/efeitos dos fármacos , Tomografia de Coerência Óptica
9.
Physiol Int ; 106(3): 272-282, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31564117

RESUMO

Nicotine and cocaine- and amphetamine-regulated transcripts (CART) have several overlapping functions, such as the regulation of reward, feeding behavior, stress response, and anxiety. Previous studies showed that nicotine regulates CART expression in various brain regions. However, the molecular mechanisms underlying this regulation are not known. This study investigated the regulatory effect of nicotine on promoter activity of the CART gene in PC12 cells, which were differentiated into a neuronal phenotype by nerve growth factor (NGF) treatment. Two vectors containing reporter genes (Gaussia luciferase or mCherry) and the 1,140-bp upstream of the transcriptional start site of the mouse CART gene are used to analyze the CART promoter activity. Transient transfection of PC12 cells with either vector displayed strong promoter activity in both undifferentiated and differentiated PC12 cells. CART promoter activity in the PC12 cell line is increased by forskolin or NGF treatment. In differentiated PC12 cells, exposure to 50 nM nicotine for 6 h increased CART promoter activity. However, treatment with higher nicotine doses for 6 h and treatment with all nicotine doses for 24 h showed no effect. A nicotine concentration of 50 nM is comparable to brain nicotine levels experienced by chronic smokers over long periods of time. Taken together, these data indicate that nicotine may exert some of its actions through the regulation of CART transcription in the brain.


Assuntos
Fator de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/efeitos dos fármacos , Nicotina/farmacologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Genes Reporter/efeitos dos fármacos , Genes Reporter/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Células PC12 , Regiões Promotoras Genéticas/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética , Transfecção/métodos
10.
Nat Commun ; 10(1): 4037, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492869

RESUMO

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Nicotina/farmacologia , Receptores Opioides kappa/metabolismo , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Estimulantes Ganglionares/administração & dosagem , Estimulantes Ganglionares/farmacologia , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Nicotina/administração & dosagem , Ratos Sprague-Dawley , Receptores Opioides kappa/genética , Proteína Desacopladora 1/metabolismo
11.
Eur Cytokine Netw ; 30(2): 59-66, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486397

RESUMO

Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats. Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1ß), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves. Treatment with nicotine decreased local levels of TNF-α and IL-1ß, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR. These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.


Assuntos
Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Nicotina/farmacologia , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Animais , Modelos Animais de Doenças , Proteína GAP-43/metabolismo , Interleucina-1beta/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
12.
Arch Oral Biol ; 108: 104537, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31525533

RESUMO

OBJECTIVE: Tobacco smoking is one of the main risk factors for oral squamous cell carcinoma (OSCC) and can induce generation of reactive oxygen species (ROS). In our previous studies, we demonstrated that nicotine, the major ingredient in tobacco, can upregulate an important antioxidant enzyme Peroxiredoxin 1 (Prx1), in oral leukoplakia (OLK), an oral precancerous lesion. The underlying regulatory mechanisms, however, remain unclear. This study aims to identify regulatory mechanisms of nicotine and identify Prx1 interacting proteins in nicotine-associated OLK. DESIGN: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with bioinformatics analysis was conducted to profile Prx1 binding proteins in human dysplastic oral keratinocyte (DOK) cells. Candidate interaction proteins were further verified using Co-immunoprecipitation (Co-IP), Western blot or Duolink assay in 4-nitro-quinoline-1-oxide (4NQO)-induced OLK in mice and human OLK tissues. RESULTS: We identified Thioredoxin (Trx), Nucleolar GTP-binding protein 1 (GTPBP4), GTP-binding protein Di-Ras2 (DIRAS2) and apoptosis signal-regulating kinase 1 (ASK1) as key Prx1 interacting proteins regulated by nicotine. Our data showed that nicotine upregulated Trx, GTPBP4, DIRAS2, and downregulated ASK1 in 4NQO-induced OLK in mice, at least in part dependent on Prx1. The modulations of Trx, GTPBP4, DIRAS2 and ASK1 by nicotine were also found in OLK smokers compared to OLK non-smokers. The in-situ interaction of Trx, GTPBP4, DIRAS2 and ASK1 with Prx1 were validated in human OLK tissues. CONCLUSION: Nicotine may promote OLK development via regulating Prx1 binding proteins Trx, GTPBP4, DIRAS2 and ASK1. The results of this study will help to develop therapeutic approaches for OLK in humans targeting Prx1 interacting protein network.


Assuntos
Carcinoma de Células Escamosas , Proteínas de Homeodomínio , MAP Quinase Quinase Quinase 5 , Neoplasias Bucais , Nicotina , Proteínas rho de Ligação ao GTP , Animais , Carcinoma de Células Escamosas/metabolismo , Cromatografia Líquida , Proteínas de Ligação ao GTP , Proteínas de Homeodomínio/metabolismo , Humanos , Leucoplasia Oral , MAP Quinase Quinase Quinase 5/metabolismo , Camundongos , Neoplasias Bucais/metabolismo , Nicotina/farmacologia , Proteínas Nucleares , Peroxirredoxinas , Proteoma , Fumar/efeitos adversos , Espectrometria de Massas em Tandem , Proteínas rho de Ligação ao GTP/metabolismo
13.
Pharmacol Biochem Behav ; 185: 172764, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449820

RESUMO

Zebra finches are songbirds that learn vocal patterns during a sensitive period of development that approximates adolescence. Exposure of these animals to a cannabinoid agonist during their period of sensorimotor vocal learning alters song patterns produced in adulthood. Thus, songbirds have unique value in studying developmental effects of drug exposure on a naturally learned behavior. A missing feature of this animal model has been a method to study drug reinforcement of behavior. To address this gap we have adapted place conditioning methods, used previously to determine that singing behavior is rewarding, to study cocaine reinforcement of behavior. We have found that cocaine dose-dependently reinforces both place conditioning and aversion at potencies consistent with those observed in mammalian species. Use of this place conditioning method has allowed us to determine that, when administered during periods of sensorimotor vocal learning, delta-9-THC, but not nicotine persistently increases sensitivity to cocaine through adulthood. Establishment of this method significantly expands the songbird drug exposure model, and holds promise for better appreciation of mechanisms important to sensorimotor learning that is dependent upon successful progress through sensitive periods of CNS development.


Assuntos
Cocaína/farmacologia , Dronabinol/farmacologia , Tentilhões/crescimento & desenvolvimento , Aprendizagem/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cocaína/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Feminino , Masculino , Nicotina/administração & dosagem , Nicotina/farmacologia , Recompensa , Córtex Sensório-Motor/efeitos dos fármacos , Fatores Sexuais
14.
Pan Afr Med J ; 33: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384352

RESUMO

Introduction: Osteoporosis is characterized by low bone mass and density, as well as change in microarchitecture of bone tissue leading to decreased bone strength. In vitro research shows nicotine can increase osteoblast activity and proliferation, also suppress osteoclast activity. Therefore we explore nicotine anti-resorptive property by in vivo true experimental and randomized posttest only controlled group research that was conducted in 18-20 weeks old Rattus norvegicus. Methods: Twenty-five female rats were divided into five groups, with 5 rats per group. The first group represented normal rats (Sham), while the second to fifth group underwent bilateral ovariectomy. The second group serves as positive control group (ovariectomy-only/OVX). The third to fifth group serve as dose 1 (P1-0.25mg/kg), dose 2 (P2-0.5 mg/kg), and Dose 3 (P3-0.75 mg/kg) treatment group receiving daily per-oral nicotine for 28 days, started 3 weeks post- ovariectomy. After 28 days treatment, the serum was checked. Results: Nicotine has dose-dependent manner on serum osteocalcin and serum DPD level. Level of osteocalcin in P2 group was significantly lower (Mann-Whitney, p = 0.008) compared to OVX group (59.4% lower). Level of DPD in all group was not significantly different (ANOVA, p < 0.05) but shows lowest level in P2 group. For serum calcitonin level, there's no significant different between groups. Conclusion: Nicotine at right low-dose might be able to inhibit osteoclast activity, thus open a possibility of anti-resorptive property of nicotine.


Assuntos
Densidade Óssea/efeitos dos fármacos , Nicotina/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoporose/prevenção & controle , Aminoácidos/sangue , Animais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Nicotina/administração & dosagem , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/sangue , Osteoclastos/metabolismo , Osteoporose/patologia , Ovariectomia , Ratos , Ratos Wistar
15.
Pharmacol Biochem Behav ; 184: 172741, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31336109

RESUMO

RATIONALE: Cannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. OBJECTIVE: To further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. METHODS: Blood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. RESULTS: Vapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. CONCLUSIONS: The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.


Assuntos
Canabidiol/administração & dosagem , Canabidiol/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Administração por Inalação , Animais , Temperatura Corporal/efeitos dos fármacos , Canabidiol/sangue , Cannabis/química , Estudos de Coortes , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Hipotermia/induzido quimicamente , Masculino , Modelos Animais , Nicotina/administração & dosagem , Nicotina/farmacologia , Nociceptividade/efeitos dos fármacos , Extratos Vegetais/sangue , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo
16.
Pharmacol Biochem Behav ; 184: 172739, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31283908

RESUMO

The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5 mg]; nicotine [6 mg]; and nicotine + nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/análogos & derivados , Potenciais Evocados Auditivos/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Estimulação Acústica/métodos , Adulto , Agonistas de Receptores de Canabinoides/administração & dosagem , Método Duplo-Cego , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Quimioterapia Combinada/métodos , Eletroencefalografia/métodos , Eletroculografia/métodos , Lobo Frontal/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamento farmacológico , Lobo Temporal/efeitos dos fármacos , Adulto Jovem
17.
Biol Sex Differ ; 10(1): 37, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315660

RESUMO

BACKGROUND: Nicotine exposure enhances Pavlovian conditioned approach (PCA), or the learned approach to reward-predictive cues. While females show elevated approach to conditioned stimuli compared to males, potentially indicating heightened addiction vulnerability, it is unknown how sex may interact with nicotine to influence approach behavior. Additionally, brain-derived neurotrophic factor (BDNF) levels can be altered significantly after repeated nicotine exposure, suggesting a potential mechanism contributing to nicotine-induced behavioral phenotypes. The present study investigated the role of sex on nicotine-induced changes to stimulus-response behavior and associated BDNF protein levels. METHODS: Male and female rats were exposed to nicotine (0.4 mg/kg, subcutaneously) or saline 15 min prior to each PCA session. PCA training consisted of 29 sessions of 15 trials, in which a 30-s cue presentation ended concurrently with a sucrose reward (20% w/v in water, 100 µL), and a 120-s variable intertrial interval occurred between trials. Approach behavior to the cue and reward receptacle was recorded. Preference toward the reward receptacle indicated a goal-tracking phenotype, and preference toward the cue indicated a sign-tracking phenotype, demonstrating that the cue had gained incentive salience. Twenty-four hours after the last PCA session, brain tissue was collected and BDNF levels were measured in the basolateral amygdala, orbitofrontal cortex, and nucleus accumbens using Western blot analysis. RESULTS: Nicotine exposure enhanced both sign- and goal-tracking conditioned approach, and females showed elevated sign-tracking compared to males. There were no sex-by-drug interactions on conditioned approach. Day-to-day variability in conditioned approach was similar between sexes. In contrast to prior studies, neither repeated exposure to nicotine nor sex significantly affected BDNF expression. CONCLUSIONS: Drug-naïve females exhibited heightened sign-tracking compared to males, and nicotine enhanced conditioned approach similarly in males and females. Further, non-significant changes to BDNF expression in brain regions highly associated with PCA indicate that BDNF is unlikely to drive nicotine-enhanced conditioned behavior.


Assuntos
/efeitos dos fármacos , Nicotina/farmacologia , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais
18.
Medicina (Kaunas) ; 55(7)2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31284668

RESUMO

Background and objectives: Exercise can help ease withdrawal symptoms of smokers. However, there is little information about the physiological responses, such as cardiorespiratory and lactate (La) responses, during exercise from light to moderate intensity combined with transdermal nicotine patches (TNPs) in smokers. This study aimed to investigate the effect of TNPs on the cardiorespiratory and La responses during exercise at light to moderate intensity. Materials and Methods: Fourteen young men (8 non-smokers, 6 current smokers) aged 20 to 26 years participated in this study. They performed an incremental graded submaximal exercise test using an electromagnetic cycle ergometer set from 30 to 210 W with (TNP condition) or without a TNP (control condition) in a random order. The TNP was applied to the left arm 8-10 h prior to starting the exercise to achieve the peak level of blood nicotine concentration. Heart rate (HR), rate of perceived exertion (RPE), oxygen consumption (VO2), ventilation (VE), and blood La at rest and during exercise were measured and analyzed. Results: The HR at rest was significantly higher in the TNP condition than in the control condition (TNP; 74.7 ± 13.8 bpm, control; 65.3 ± 10.8 bpm, p < 0.001). There was no interaction (condition × exercise intensity) between any of the variables, and VO2, VE, RPE, and La during exercise were not significantly different between the conditions. However, HR during exercise was 6.7 bpm higher on average in the TNP condition. Conclusions: The HR during exercise was greater at light to moderate intensity with a TNP. Our study results will guide clinicians or health professionals when prescribing exercise programs combined with TNPs for healthy young smokers.


Assuntos
Aptidão Cardiorrespiratória/fisiologia , Exercício Físico/fisiologia , Ácido Láctico/análise , Nicotina/efeitos adversos , Dispositivos para o Abandono do Uso de Tabaco/efeitos adversos , Adulto , Teste de Esforço/métodos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Ácido Láctico/sangue , Masculino , Nicotina/farmacologia , Nicotina/uso terapêutico , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Abandono do Hábito de Fumar/métodos , Agentes de Cessação do Hábito de Fumar/efeitos adversos , Agentes de Cessação do Hábito de Fumar/farmacologia , Agentes de Cessação do Hábito de Fumar/uso terapêutico
19.
Molecules ; 24(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344816

RESUMO

Neuronal α4ß2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4ß2 nAChRs subtypes. The most important therapeutic use for α4ß2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4ß2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4ß2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.


Assuntos
Nicotina/química , Nicotina/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/química , Ligação Competitiva , Relação Dose-Resposta a Droga , Humanos , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Nicotina/análogos & derivados , Ligação Proteica , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 20(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349586

RESUMO

Uridine diphosphate (UDP)-glycosyltransferases (UGTs) are major phase II detoxification enzymes involved in glycosylation of lipophilic endobiotics and xenobiotics, including phytoalexins. Nicotine, one of the most abundant secondary plant metabolites in tobacco, is highly toxic to herbivorous insects. Plant-herbivore competition is the major impetus for the evolution of large superfamilies of UGTs and other detoxification enzymes. However, UGT functions in green peach aphid (Myzus persicae) adaptation are unknown. In this study, we show that UGT inhibitors (sulfinpyrazone and 5-nitrouracil) significantly increased nicotine toxicity in M. persicae nicotianae, suggesting that UGTs may be involved in nicotine tolerance. In total, 101 UGT transcripts identified in the M. persicae genome/transcriptome were renamed according to the UGT Nomenclature Committee guidelines and grouped into 11 families, UGT329, UGT330, UGT339, UGT341-UGT345, and UGT348-UGT350, with UGT344 containing the most (57). Ten UGTs (UGT330A3, UGT339A2, UGT341A6, UGT342B3, UGT343C3, UGT344D5, UGT344D8, UGT348A3, UGT349A3, and UGT350A3) were highly expressed in M. persicae nicotianae compared to M. persicae sensu stricto. Knockdown of four UGTs (UGT330A3, UGT344D5, UGT348A3, and UGT349A3) significantly increased M. persicae nicotianae sensitivity to nicotine, suggesting that UGT expression in this subspecies may be associated with nicotine tolerance and thus host adaptation. This study reveals possible UGTs relevant to nicotine adaptation in tobacco-consuming M. persicae nicotianae, and the findings will facilitate further validation of the roles of these UGTs in nicotine tolerance.


Assuntos
Adaptação Biológica , Afídeos/fisiologia , Glucuronosiltransferase/metabolismo , Nicotina/metabolismo , Sequência de Aminoácidos , Animais , Afídeos/classificação , Afídeos/efeitos dos fármacos , Sequência Conservada , Resistência a Medicamentos/genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/química , Glucuronosiltransferase/genética , Família Multigênica , Nicotina/farmacologia , Filogenia , Domínios Proteicos
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