RESUMO
Introduction. Peri-implantitis is a plaque-associated disease that leads to implant loss and arises from bacterial biofilms on the surface of the implant. Smoking is a risk factor for peri-implantitis and impedes treatment effectiveness. Additionally, aryl hydrocarbon receptor (AHR), IL-6, and IL-22 levels are related to peri-implantitis.Aim. We aimed to investigate the effects of nicotine on inflammatory response, bacterial growth and biofilm formation.Hypothesis/Gap Statement. We hypothesized that nicotine promoted pathogenic bacterial growth and biofilm formation, thereby aggravating inflammation.Methodology. The expression of AHR, IL-6 and IL-22 was measured in peri-implant sulci fluid using quantitative PCR and Western blot analyses. The cementum was incubated with bacterial suspension including Porphyromonas gingivalis, Streptococcus sanguinis and Fusobacterium nucleatum and treated with 100, 200, 250 and 300 µg ml-1 nicotine, and then, the absorbance and number of colony-forming units were detected. Biofilm formation was evaluated using the tissue culture plate method and safranin O staining. Carbohydrates and proteins were measured by the phenol-sulfuric acid method and the bicinchoninic acid method, respectively.Results. The results indicated that smoking increased the levels of AHR, IL-6 and IL-22. Functionally, nicotine promoted the growth of P. gingivalis, S. sanguinis and F. nucleatum. Additionally, it promoted the biofilm formation of these bacteria and increased the contents of carbohydrates and proteins.Conclusion. Nicotine promoted bacterial growth and biofilm build-up, suggesting that smoking may aggravate the progression of peri-implantitis.
Assuntos
Biofilmes , Nicotina , Peri-Implantite , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Nicotina/farmacologia , Humanos , Peri-Implantite/microbiologia , Fusobacterium nucleatum/efeitos dos fármacos , Fusobacterium nucleatum/crescimento & desenvolvimento , Fusobacterium nucleatum/fisiologia , Porphyromonas gingivalis/efeitos dos fármacos , Porphyromonas gingivalis/crescimento & desenvolvimento , Masculino , Implantes Dentários/microbiologia , Feminino , Interleucina-6/metabolismo , Pessoa de Meia-Idade , Interleucinas/metabolismo , Streptococcus sanguis/efeitos dos fármacos , Streptococcus sanguis/crescimento & desenvolvimento , Bactérias/efeitos dos fármacos , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Fumar/efeitos adversosRESUMO
High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds' potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain-derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward. Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti-inflammatory properties, among others. This work aims to examine the potential anxiety-reducing properties of CBD in a well-established experimental mouse model of anxiety-like behavior induced by high doses of nicotine on male C57BL/6 mice. In this context, the open-field behavioral test was specially conducted to assess CBD's effects on anxiety-like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood's metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro-inflammatory cytokine assessments were conducted to evaluate redox status and immune system function. Our research suggests that CBD shows potential in reducing anxiety-like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue's systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro-inflammatory cytokines (TNF-alpha and IL-6).
Assuntos
Ansiedade , Fator Neurotrófico Derivado do Encéfalo , Canabidiol , Camundongos Endogâmicos C57BL , Nicotina , Estresse Oxidativo , Animais , Canabidiol/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Camundongos , Nicotina/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/induzido quimicamente , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Animal/efeitos dos fármacosRESUMO
Nicotine dependence is an important cause of excessive exposure to tobacco combustion compounds in most smokers. Nicotine replacement therapy is the main method to treat nicotine dependence, but it still has its shortcomings, such as the inability to mitigate withdrawal effects and limited applicability. It has been hypothesized that a combination of low-dose nicotine and caffeine could achieve the same psychological stimulation effect as a high dose of nicotine without causing nicotine withdrawal effects. To establish a model of nicotine dependence, male C57BL/6J mice were subcutaneously injected four times a day with nicotine (2 mg/kg) for 15 days and fed with water containing nicotine at the same time. They were randomly divided into four groups. After 24 h of withdrawal, different groups were injected with saline, nicotine (0.25 mg/kg or 0.1 mg/kg), or nicotine (0.1 mg/kg) and caffeine (20 mg/kg). Behavioral and physiological changes were evaluated by an assessment of physical signs, open field tests, elevated plus maze experiments, forced swimming tests, hot plate tests, and new-object-recognition tests. The changes in dopamine release in the prefrontal cortex (PFC) and ventral tegmental area (VTA) in the midbrain were analyzed using ELISA. The results showed that a combination of caffeine and nicotine could effectively relieve nicotine withdrawal syndrome, increase movement ability and pain thresholds, reduce anxiety and depression, enhance memory and cognitive ability, and increase the level of dopamine release in the PFC and VTA. Thus, caffeine combined with nicotine has potential as a stable and effective treatment option to help humans with smoking cessation.
Assuntos
Cafeína , Camundongos Endogâmicos C57BL , Nicotina , Síndrome de Abstinência a Substâncias , Tabagismo , Animais , Cafeína/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Nicotina/farmacologia , Masculino , Camundongos , Tabagismo/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Ansiedade/tratamento farmacológico , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Modelos Animais de DoençasRESUMO
Nicotine use is driven by pleasurable effects, but following chronic exposure, nicotine use becomes largely driven by the desire need to avoid withdrawal symptoms. Current cessation strategies focusing on alleviating withdrawal, but current cessation interventions are less effective for women than men. Also, hormone fluctuations across the menstrual cycle appear to impact use patterns, withdrawal severity, and treatment efficacy. This raises important questions regarding optimal quit dates and the application of hormone interventions to alleviate withdrawal in women. This review surveys the existing literature assessing the impact of ovarian hormones on nicotine withdrawal severity. This is an important issue because women seeking cessation treatments may be using hormone-based contraceptives or hormone replacement post-menopause. Hormone interventions may also offer a novel treatment avenue that is more effective than current cessation approaches. Future work in this area is important for reducing health disparities produced by excessive nicotine use in women.
Assuntos
Nicotina , Humanos , Feminino , Nicotina/farmacologia , Nicotina/administração & dosagem , Síndrome de Abstinência a Substâncias , Tabagismo , Ovário/efeitos dos fármacos , Ovário/fisiologia , Ciclo Menstrual/fisiologia , Ciclo Menstrual/efeitos dos fármacos , Abandono do Hábito de Fumar/métodosRESUMO
Nicotine is developmentally toxic. Prenatal nicotine exposure (PNE) affects the development of multiple fetal organs and causes susceptibility to a variety of diseases in offspring. In this study, we aimed to investigate the effect of PNE on cartilage development and osteoarthritis susceptibility in female offspring rats. Wistar rats were orally gavaged with nicotine on days 9-20 of pregnancy. The articular cartilage was obtained at gestational day (GD) 20 and postnatal week (PW) 24, respectively. Further, the effect of nicotine on chondrogenic differentiation was explored by the chondrogenic differentiation model in human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs). The PNE group showed significantly shallower Safranin O staining and lower Collagen 2a1 content of articular cartilage in female offspring rats. Further, we found that PNE activated pyroptosis in the articular cartilage at GD20 and PW24. In vitro experiments revealed that nicotine inhibited chondrogenic differentiation and activated pyroptosis. After interfering with nod-like receptors3 (NLRP3) expression by SiRNA, it was found that pyroptosis mediated the chondrogenic differentiation inhibition of WJ-MSCs induced by nicotine. In addition, we found that α7-nAChR antagonist α-BTX reversed nicotine-induced NLRP3 and P300 high expression. And, P300 SiRNA reversed the increase of NLRP3 mRNA expression and histone acetylation level in its promoter region induced by nicotine. In conclusion, PNE caused chondrodysplasia and poor articular cartilage quality in female offspring rats. PNE increased the histone acetylation level of NLRP3 promoter region by α7-nAChR/P300, which resulting in the high expression of NLRP3. Further, NLRP3 mediated the inhibition of chondrogenic differentiation by activating pyroptosis.
Assuntos
Cartilagem Articular , Células-Tronco Mesenquimais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nicotina , Efeitos Tardios da Exposição Pré-Natal , Piroptose , Ratos Wistar , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Nicotina/farmacologia , Nicotina/toxicidade , Feminino , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gravidez , Piroptose/efeitos dos fármacos , Ratos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Condrogênese/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Humanos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/citologiaRESUMO
Social controllability, or the ability to exert control during social interactions, is crucial for optimal decision-making. Inability to do so might contribute to maladaptive behaviors such as smoking, which often takes place in social settings. Here, we examined social controllability in nicotine-dependent humans as they performed an fMRI task where they could influence the offers made by simulated partners. Computational modeling revealed that smokers under-estimated the influence of their actions and self-reported a reduced sense of control, compared to non-smokers. These findings were replicated in a large independent sample of participants recruited online. Neurally, smokers showed reduced tracking of forward projected choice values in the ventromedial prefrontal cortex, and impaired computation of social prediction errors in the midbrain. These results demonstrate that smokers were less accurate in estimating their personal influence when the social environment calls for control, providing a neurocomputational account for the social cognitive deficits in this population. Pre-registrations: OSF Registries|How interoceptive state interacts with value-based decision-making in addiction (fMRI study). OSF Registries|COVID-19: social cognition, mental health, and social distancing (online study).
Assuntos
Imageamento por Ressonância Magnética , Tabagismo , Humanos , Masculino , Feminino , Adulto , Tabagismo/fisiopatologia , Tabagismo/psicologia , Tomada de Decisões , COVID-19/psicologia , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Pessoa de Meia-Idade , Adulto Jovem , Interação Social , Cognição Social , Nicotina/efeitos adversos , Nicotina/farmacologiaRESUMO
The use of traditional nicotine delivery products such as tobacco has long been linked to detrimental health effects. However, little work to date has focused on the emerging market of aerosolized nicotine delivery known as electronic nicotine delivery systems (ENDS) or electronic cigarettes, and their potential for new effects on human health. Challenges studying these devices include heterogeneity in the formulation of the common components of most available ENDS, including nicotine and a carrier (commonly composed of propylene glycol and vegetable glycerin, or PG/VG). In the present study, we report on experiments interrogating the effects of major identified components in e-cigarettes. Specifically, the potential concomitant effects of nicotine and common carrier ingredients in commercial "vape" products are explored in vitro to inform the potential health effects on the craniofacial skeleton through novel vectors as compared to traditional tobacco products. MC3T3-E1 murine pre-osteoblast cells were cultured in vitro with clinically relevant liquid concentrations of nicotine, propylene glycol (PG), vegetable glycerin (VG), Nicotine+PG/VG, and the vape liquid of a commercial product (Juul). Cells were treated acutely for 24 h and RNA-Seq was utilized to determine segregating alteration in mRNA signaling. Influential gene targets identified with sparse partial least squares discriminant analysis (sPLS-DA) implemented in mixOmics were assessed using the PANTHER Classification system for molecular functions, biological processes, cellular components, and pathways of effect. Additional endpoint functional analyses were used to confirm cell cycle changes. The initial excitatory concentration (EC50) studied defined a target concentration of carrier PG/VG liquid that altered the cell cycle of the calvarial cells. Initial sPLS-DA analysis demonstrated the segregation of nicotine and non-nicotine exposures utilized in our in vitro modeling. Pathway analysis suggests a strong influence of nicotine exposures on cellular processes including metabolic processes and response to stimuli including autophagic flux. Further interrogation of the individual treatment conditions demonstrated segregation by treatment modality (Control, Nicotine, Carrier (PG+VG), Nicotine+PG/VG) along three dimensions best characterized by: latent variable 1 (PLSDA-1) showing strong segregation based on nicotine influence on cellular processes associated with cellular adhesion to collagen, osteoblast differentiation, and calcium binding and metabolism; latent variable 2 (PLSDA-2) showing strong segregation of influence based on PG+VG and Control influence on cell migration, survival, and cycle regulation; and latent variable 3 (PLSDA-3) showing strong segregation based on Nicotine and Control exposure influence on cell activity and growth and developmental processes. Further, gene co-expression network analysis implicates targets of the major pathway genes associated with bone growth and development, particularly craniofacial (FGF, Notch, TGFß, WNT) and analysis of active subnetwork pathways found these additionally overrepresented in the Juul exposure relative to Nicotine+PG/VG. Finally, experimentation confirmed alterations in cell count, and increased evidence of cell stress (markers of autophagy), but no alteration in apoptosis. These data suggest concomitant treatment with Nicotine+PG/VG drives alterations in pre-osteoblast cell cycle signaling, specifically transcriptomic targets related to cell cycle and potentially cell stress. Although we suspected cell stress and well as cytotoxic effects of Nicotine+PG/VG, no great influence on apoptotic factors was observed. Further RNA-Seq analysis allowed for the direct interrogation of molecular targets of major pathways involved in bone and craniofacial development, each demonstrating segregation (altered signaling) due to e-cigarette-type exposure. These data have implications directed toward ENDS formulation as synergistic effects of Nicotine+PG/VG are evidenced here. Thus, future research will continue to interrogate how varied formulation of Nicotine+PG/VG affects overall cell functions in multiple vital systems.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Nicotina , Osteoblastos , Animais , Camundongos , Nicotina/farmacologia , Osteoblastos/metabolismo , Osteoblastos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Propilenoglicol , Linhagem CelularRESUMO
As the population ages, the prevalence of atherosclerosis (AS), a significant cause of cardiovascular disease (CVD), continues to increase. Apoptosis is an independent risk factor for atherosclerosis. Macrophages are the primary immune cell group in AS lesions, and their apoptosis plays a crucial role in the occurrence and development of AS. There is a common mechanism of action for circular RNAs (circRNAs) that involves the sponging of microRNAs (miRNAs) by binding to the miRNA response element (MRE), thereby increasing the transcription of their target messenger RNAs (mRNAs). Most diseases are profoundly reliant on circRNAs. However, the underlying mechanism of circRNAs in apoptosis is yet to be elucidated. All differentially expressed genes (DEGs) and their expression levels were analysed by whole-transcriptome sequencing of samples from the control and nicotine groups of THP-1 macrophages. GO and KEGG analyses revealed that nicotine affects macrophage physiological processes and related pathways. GSEA focused on gene sets to better understand the potential pathways and biological functions of all mRNAs. A competitive endogenous RNA (ceRNA) regulatory network was constructed and validated through molecular biology experiments. The Notch signalling pathway was activated in nicotine-treated macrophages, and the expression of DLL4 in this pathway was increased. Circ_0006476 is involved in apoptosis via miR-3074-5p/DLL4, regulating pathogenic processes related to the Notch signalling pathway. The better we understand the pathways involved in macrophage apoptosis, the more likely we are to find other novel therapeutic targets that can help treat, prevent, and reduce the mortality associated with AS.
Assuntos
Apoptose , Macrófagos , MicroRNAs , RNA Circular , Receptores Notch , Transdução de Sinais , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Apoptose/genética , Macrófagos/metabolismo , Receptores Notch/metabolismo , Receptores Notch/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Células THP-1 , Regulação da Expressão Gênica , Nicotina/farmacologiaRESUMO
Previous work from our laboratory showed that cotinine, a nicotine metabolite, reverses three nicotine-induced behavioral effects in freshwater planarians: motility decrease, seizure-like movements, and withdrawal-like behaviors. The present work explored whether cotinine, a nicotine metabolite, antagonized the nicotine-induced effects on planarian motility in a concentration-dependent manner. We found that nicotine decreased planarian motility at nicotine concentrations above 60 µM but increased planarian velocity at concentrations equal to or below 50 µM, in agreement with previous data. Cotinine did not affect planarian motility at a concentration range between 250 and 2750 µM. Furthermore, we found that cotinine alleviated the 100 µM nicotine-induced motility decrease in a concentration-dependent manner and reversed the low nicotine concentration motility increase, albeit in a concentration-independent manner. The apparent concentration-dependent alleviation of >60 µM nicotine-induced motility decrease by cotinine suggests an orthosteric relationship between nicotine and cotinine. On the other hand, the evident concentration-independent cotinine alleviation of the increase in motility induced by 50 µM nicotine suggests an allosteric relationship. Our data is consistent with the existing literature about the relationship between nicotine and cotinine in various models, reinforcing the case for the usefulness of the planarian model in pharmacological studies.
Assuntos
Cotinina , Nicotina , Planárias , Animais , Nicotina/farmacologia , Planárias/efeitos dos fármacos , Planárias/fisiologia , Cotinina/farmacologia , Relação Dose-Resposta a Droga , Movimento/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Agonistas Nicotínicos/farmacologiaRESUMO
Nicotine, the primary constituent of tobacco, is one of the important factors that induce the occurrence of hepatocellular carcinoma (HCC). The ß2-adrenergic receptor (ß2-AR) is implicated in the growth and advancement of tumors. However, the role of ß2-AR and its mediated cascades in nicotine-induced HCC remains unclear. This present study aims to observe the effects of nicotine on the proliferation, migration, and invasion of immortalized human liver epithelial (THLE-2) cells, as well as to explore the underlying mechanisms of action. The results of cell counting kit-8 (CCK-8) assay showed that 0.3125⯵M nicotine had the ability to promote the proliferation of THLE-2 cells with a significant time-dependent manner. Therefore, THLE-2 cells were mainly selected for chronic treatment with 0.3125⯵M nicotine in the later stage to cause transformation. After 30 passages of THLE-2 cells with 0.3125⯵M nicotine treatment, chronic exposure to nicotine significantly enhanced the proliferation, metastasis, and invasion of cells. Besides, it also upregulated the intracellular levels of ß2-AR, phosphoinositide 3-kinase (PI3K), AKT, matrix metalloproteinase-2 (MMP-2) and Cyclin D1, as well as downregulated the expression of p53. More importantly, the ß2-AR/PI3K/AKT pathway was found to mediate the expression of MMP-2, Cyclin D1, and p53 in THLE-2 cells, playing a crucial role in their proliferation, migration, and invasion after continuous exposure to nicotine. Simply put, it demonstrated the role of ß2-AR/PI3K/AKT pathway in the transformation of THLE-2 cells induced by nicotine. This study could provide valuable insights into the relationship between nicotine and HCC. Additionally, it lays the groundwork for investigating potential anticancer treatments for liver cancer linked to tobacco consumption.
Assuntos
Movimento Celular , Proliferação de Células , Nicotina , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores Adrenérgicos beta 2 , Transdução de Sinais , Nicotina/toxicidade , Nicotina/farmacologia , Humanos , Proliferação de Células/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Movimento Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Linhagem Celular , Invasividade Neoplásica , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/induzido quimicamente , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologiaRESUMO
BACKGROUND: Although zebrafish are increasingly utilized in biomedicine for CNS disease modelling and drug discovery, this generates big data necessitating objective, precise and reproducible analyses. The artificial intelligence (AI) applications have empowered automated image recognition and video-tracking to ensure more efficient behavioral testing. NEW METHOD: Capitalizing on several AI tools that most recently became available, here we present a novel open-access AI-driven platform to analyze tracks of adult zebrafish collected from in vivo neuropharmacological experiments. For this, we trained the AI system to distinguish zebrafish behavioral patterns following systemic treatment with several well-studied psychoactive drugs - nicotine, caffeine and ethanol. RESULTS: Experiment 1 showed the ability of the AI system to distinguish nicotine and caffeine with 75â¯% and ethanol with 88â¯% probability and high (81â¯%) accuracy following a post-training exposure to these drugs. Experiment 2 further validated our system with additional, previously unexposed compounds (cholinergic arecoline and varenicline, and serotonergic fluoxetine), used as positive and negative controls, respectively. COMPARISON WITH EXISTING METHODS: The present study introduces a novel open-access AI-driven approach to analyze locomotor activity of adult zebrafish. CONCLUSIONS: Taken together, these findings support the value of custom-made AI tools for unlocking full potential of zebrafish CNS drug research by monitoring, processing and interpreting the results of in vivo experiments.
Assuntos
Inteligência Artificial , Cafeína , Descoberta de Drogas , Etanol , Nicotina , Peixe-Zebra , Animais , Nicotina/farmacologia , Descoberta de Drogas/métodos , Cafeína/farmacologia , Etanol/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Fármacos do Sistema Nervoso Central/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologiaRESUMO
Nutrition and resilience are linked, though it is not yet clear how diet confers stress resistance or the breadth of stressors that it can protect against. We have previously shown that transiently restricting an essential amino acid can protect Drosophila melanogaster against nicotine poisoning. Here, we sought to characterize the nature of this dietary-mediated protection and determine whether it was sex, amino acid and/or nicotine specific. When we compared between sexes, we found that isoleucine deprivation increases female, but not male, nicotine resistance. Surprisingly, we found that this protection afforded to females was not replicated by dietary protein restriction and was instead specific to individual amino acid restriction. To understand whether these beneficial effects of diet were specific to nicotine or were generalizable across stressors, we pre-treated flies with amino acid restriction diets and exposed them to other types of stress. We found that some of the diets that protected against nicotine also protected against oxidative and starvation stress, and improved survival following cold shock. Interestingly, we found that a diet lacking isoleucine was the only diet to protect against all these stressors. These data point to isoleucine as a critical determinant of robustness in the face of environmental challenges.
Assuntos
Drosophila melanogaster , Nicotina , Estresse Fisiológico , Animais , Drosophila melanogaster/efeitos dos fármacos , Feminino , Masculino , Nicotina/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Isoleucina/farmacologiaRESUMO
Nicotine intake is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in rodents and humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n = 88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to enhanced physiological arousal to learned threats and overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.
Assuntos
Tonsila do Cerebelo , Medo , Hipocampo , Imageamento por Ressonância Magnética , Nicotina , Núcleo Accumbens , Humanos , Nicotina/farmacologia , Nicotina/efeitos adversos , Nicotina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/diagnóstico por imagem , Masculino , Hipocampo/efeitos dos fármacos , Medo/efeitos dos fármacos , Adulto , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/diagnóstico por imagem , Feminino , Adulto Jovem , Método Duplo-Cego , Discriminação Psicológica/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Agonistas Nicotínicos/efeitos adversos , Agonistas Nicotínicos/administração & dosagem , Extinção Psicológica/efeitos dos fármacosRESUMO
INTRODUCTION: Smoking poses a risk to flap viability, with nicotine being a major contributor to the formation of free radicals. Allopurinol, known for its antioxidant properties, has been shown to enhance tissue survival in ischemic conditions by reducing the production of reactive oxygen species (ROS). This study aims to assess the impact of allopurinol on the viability and success of skin flaps in Wistar rats exposed to nicotine. METHODS: This study examined skin flap survival in nicotine-exposed rats treated with allopurinol. Twenty-eight rats were separated into two groups. During 1 month of nicotine exposure, the treatment group received systemic allopurinol 7 days before and 2 days after the flap procedure, while the control group received no allopurinol. Pro-angiogenic factors, proinflammatory factors, anti-inflammatory factors, and oxidative markers were assessed on the 7th day after the flap procedure using enzyme-linked immunosorbent assay method. Macroscopic flap viability was evaluated on the 7th day using Image J photos. RESULTS: As an oxidative marker, malondialdehyde levels were significantly lower in rats given allopurinol than in controls (P < 0.001). The levels of interleukin 6 and tumor necrosis factor α, as markers of inflammatory factors, were significantly lower in the group of rats given allopurinol compared to controls (P < 0.001). The level of angiogenesis in rats given allopurinol, measured by vascular endothelial growth factor levels, was also higher in the treatment group compared to controls (P < 0.001). Macroscopically, the percentage of distal flap necrosis in Wistar rats given allopurinol was lower and statistically significant compared to controls (P < 0.001). CONCLUSIONS: Xanthine oxidoreductase is part of a group of enzymes involved in reactions that produce ROS. Allopurinol, as an effective inhibitor of the xanthine oxidase enzyme, can reduce oxidative stress by decreasing the formation of ROS. This reduction in oxidative stress mitigates the risk of ischemic-reperfusion injury effects and significantly increases the viability of Wistar rat flaps exposed to nicotine.
Assuntos
Alopurinol , Interleucina-6 , Malondialdeído , Nicotina , Retalhos Cirúrgicos , Fator de Necrose Tumoral alfa , Fator A de Crescimento do Endotélio Vascular , Animais , Masculino , Ratos , Alopurinol/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Nicotina/administração & dosagem , Nicotina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Retalhos Cirúrgicos/irrigação sanguínea , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Prolonged exposure to different occupational or environmental toxicants triggered oxidative stress and inflammatory reactions mediated lung damage. This study was designed to explore the influence and protective impact of flavone on lung injury in rats intoxicated with nicotine (NIC) and exposed to radiation (IR). Forty rats were divided into four groups; group I control, group II flavone; rats were administered with flavone (25 mg/kg/day), group III NIC + IR; rats were injected intraperitoneally with NIC (1 mg/kg/day) and exposed to γ-IR (3.5 Gy once/week for 2 weeks) while group IV NIC + IR + flavone; rats were injected with NIC, exposed to IR and administered with flavone. Redox status parameters and histopathological changes in lung tissue were evaluated. Nuclear factor-kappa B (NF-κB), forkhead box O-class1 (FoxO1) and nucleotide-binding domain- (NOD-) like receptor pyrin domain-containing-3 (NLRP3) gene expression were measured in lung tissues. Moreover, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and phosphatidylinositol three kinase (PI3K) were measured using ELISA kits. Our data demonstrates, for the first time, that flavone protects the lung from NIC/IR-associated cytotoxicity, by attenuating the disrupted redox status and aggravating the antioxidant defence mechanism via activation of the PI3K/Nrf2. Moreover, flavone alleviates pulmonary inflammation by inhibiting the inflammatory signaling pathway FOXO1/NF-κB/NLRP3- Inflammasome. Collectively, the obtained results exhibited a notable efficiency of flavone in alleviating lung injury induced by NIC and IR via modulating PI3K/Nrf2 and FoxO1/NLRP3 Inflammasome.
Assuntos
Flavonas , Inflamassomos , Lesão Pulmonar , Nicotina , Animais , Masculino , Ratos , Flavonas/farmacologia , Proteína Forkhead Box O1 , Raios gama , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Nicotina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
The present study aimed to assess the potential effect of vitamin B12 (Vit B12) on cognition impairment caused by nicotine (Nic) cessation in adolescent male rats. Adolescent male rats were categorized into two main groups as vehicle (normal saline, intraperitoneally), and Nic group in which received Nic (2â¯mg/kg) from 21 to 42 days of ages and then the Nic group were divided into three groups as withdrawal (the animals returned to regular diet without treatment), second and third groups received bupropion (20â¯mg/kg), and Vit B12 at three different doses including 0.5,1, and 1.5â¯mg/kg by oral gavage as treatments to attenuate Nic withdrawal symptoms. The last group including normal animals received the highest doses of Vit B12 just in the Nic abstinence period to compare the effect of that with vehicle. In MWM, Vit B12and bupropion increased the time spent in the target quadrant that is strongly associated with spatial memory as well as the more time spent with the NORT. Vit B12 and bupropion modulated both oxidant/antioxidant and inflammatory/anti-inflammatory balance, alongside inhibitory effect on AChE, and GFAP. However, BDNF and amyloid-B showed insignificant difference as compared to Vit B12 and bupropion. Considering the present results and similar related studies, Vit B12 can be introduced as a strong anti-oxidant, and anti-inflammatory agent by which probably improved memory impairment caused by Nic addiction accompanied by withdrawal. Further, other mechanisms including activity reduction of AChE, and GFAP should be considered; however, it needs further investigation and larger-scale evidences.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Proteína Glial Fibrilar Ácida , Transtornos da Memória , Nicotina , Síndrome de Abstinência a Substâncias , Vitamina B 12 , Animais , Masculino , Ratos , Acetilcolinesterase/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Bupropiona/farmacologia , Bupropiona/administração & dosagem , Suplementos Nutricionais , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/induzido quimicamente , Nicotina/farmacologia , Nicotina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Vitamina B 12/farmacologia , Vitamina B 12/administração & dosagemRESUMO
Increased blood-brain barrier (BBB) permeability can lead to cerebral vasogenic edema and hemorrhagic transformation (HT) after reperfusion with tissue plasminogen activator (tPA), the only United States Food and Drug Administration (FDA)-approved treatment for acute ischemia stroke (AIS). The therapeutic benefits of tPA after AIS are partially outweighed by a more than a six-fold increase in the risk of symptomatic intracerebral hemorrhage. Therefore, strategies to protect the integrity of BBB are urgently needed to reduce HT and vasogenic edema after tPA thrombolysis or endovascular thrombectomy. Interestingly, an NIH study showed that smokers treated with tPA had a significantly lower prevalence of brain hemorrhage than nonsmokers, suggesting that cigarette smoking may protect patients treated with tPA from the side effects of cerebral hemorrhage. Importantly, we recently showed that treatment with nicotine reduces AIS-induced BBB damage and that modulating α7nAChR by modulation could reduce ischemia/reperfusion-induced BBB damage, suggesting that α7nAChR could be a potential target to reduce BBB after AIS. In this review, we first provide an overview of stroke and the impact of α7nAChR activation on BBB damage. Next, we discuss the features and mechanism of BBB destruction after AIS. We then discuss the effect of nicotine effect on BBB integrity as well as the mechanism underlying those effects. Finally, we discuss the side effects and potential strategies for modulating α7nAChR to reduce AIS-induced BBB damage.
Assuntos
Autofagia , Barreira Hematoencefálica , AVC Isquêmico , Receptor Nicotínico de Acetilcolina alfa7 , Humanos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Animais , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , Autofagia/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Nicotina/farmacologiaRESUMO
BACKGROUND The effects of cigarette smoking on the health of active smokers and passive smokers have long been known, in contrast to the effects of alternative forms of nicotine intake that are gaining popularity. The aim of the study was to assess the effects of smoking traditional cigarettes and alternative forms of nicotine intake on the functional state of the respiratory system of smokers and non-smokers. MATERIAL AND METHODS Study participants (n=60) were divided into 3 groups: non-smokers (control group), cigarette smokers, and nicotine alternative users. Respiratory function testing (spirometry), forced oscillation technique, and measurement of respiratory muscle strength (PImax, PEmax) were performed. All of the above respiratory function tests were performed in accordance with European Respiratory Society and American Thoracic Society recommendations. RESULTS Smokers and those using alternative forms of nicotine intake had significantly higher values, including resistance at 5 Hz% and 11 Hz%, among others. CONCLUSIONS Smokers and users of alternative forms of nicotine are characterized by reduced flow through the small bronchioles, as evidenced by a reduction in maximal expiratory flow at 25% of vital capacity. Smokers and users of alternative forms of nicotine have higher resistance values at the height of small and medium bronchioles. Assessment method of technical forced oscillation parameters is simple to perform to detect early airway changes and is an important element in the early diagnosis of changes in smokers. The correlation analysis showed a significant correlation between age of smoking initiation/use of alternative forms of nicotine and changes in mid bronchial resistance.
Assuntos
Testes de Função Respiratória , Fumar , Produtos do Tabaco , Humanos , Masculino , Adulto , Feminino , Testes de Função Respiratória/métodos , Fumar/efeitos adversos , Nicotina/efeitos adversos , Nicotina/farmacologia , Pessoa de Meia-Idade , Fumantes , Espirometria/métodosRESUMO
Adolescence is characterized by a critical period of maturation and growth, during which regions of the brain are vulnerable to long-lasting cognitive disturbances. Adolescent exposure to nicotine can lead to deleterious neurological and psychological outcomes. Moreover, the nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain. CHRNA2 encodes for the α2 subunit of nicotinic acetylcholine receptors associated with CA1 oriens lacunosum moleculare GABAergic interneurons and is associated with learning and memory. Previously, we found that adolescent male hypersensitive CHRNA2L9'S/L9' mice had impairments in learning and memory during a pre-exposure-dependent contextual fear conditioning task that could be rescued by low-dose nicotine exposure. In this study, we assessed learning and memory in female adolescent hypersensitive CHRNA2L9'S/L9' mice exposed to saline or a subthreshold dose of nicotine using a hippocampus-dependent task of pre-exposure-dependent contextual fear conditioning. We found that nicotine-treated wild-type female mice had significantly greater improvements in learning and memory than both saline-treated wild-type mice and nicotine-treated CHRNA2L9'S/L9' female mice. Thus, hyperexcitability of CHRNA2 in female adolescent mice ablated the nicotine-mediated potentiation of learning and memory seen in wild-types. Our results indicate that nicotine exposure during adolescence mediates sexually dimorphic patterns of learning and memory, with wild-type female adolescents being more susceptible to the effects of sub-threshold nicotine exposure. To understand the mechanism underlying sexually dimorphic behavior between hyperexcitable CHRNA2 mice, it is critical that further research be conducted.
Assuntos
Medo , Hipocampo , Memória , Nicotina , Receptores Nicotínicos , Animais , Receptores Nicotínicos/metabolismo , Nicotina/farmacologia , Feminino , Camundongos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Medo/efeitos dos fármacos , Medo/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Agonistas Nicotínicos/farmacologia , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Camundongos Endogâmicos C57BLRESUMO
Given the pivotal role of neuronal populations in various biological processes, assessing their collective output is crucial for understanding the nervous system's complex functions. Building on our prior development of a spiral scanning mechanism for the rapid acquisition of Raman spectra from single cells and incorporating machine learning for label-free evaluation of cell states, we investigated whether the Paint Raman Express Spectroscopy System (PRESS) can assess neuronal activities. We tested this hypothesis by examining the chemical responses of glutamatergic neurons as individual neurons and autonomic neuron ganglia as neuronal populations derived from human-induced pluripotent stem cells. The PRESS successfully acquired Raman spectra from both individual neurons and ganglia within a few seconds, achieving a signal-to-noise ratio sufficient for detailed analysis. To evaluate the ligand responsiveness of the induced neurons and ganglia, the Raman spectra were subjected to principal component and partial least squares discriminant analyses. The PRESS detected neuronal activity in response to glutamate and nicotine, which were absent in the absence of calcium. Additionally, the PRESS induced dose-dependent neuronal activity changes. These findings underscore the capability of the PRESS to assess individual neuronal activity and elucidate neuronal population dynamics and pharmacological responses, heralding new opportunities for drug discovery and regenerative medicine advancement.