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1.
Anal Chem ; 96(18): 7022-7029, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38669590

RESUMEN

The utility of two novel laser-based methods, laser ablation electrospray ionization (LAESI) and laser desorption ionization (LDI) from silicon nanopost array (NAPA), is explored via local analysis and mass spectrometry imaging (MSI) of hard tissues (tooth and hair) for the detection and mapping of organic components. Complex mass spectra are recorded in local analysis mode from tooth dentin and scalp hair samples. Nicotine and its metabolites (cotinine, hydroxycotinine, norcotinine, and nicotine) are detected by LAESI-MS in the teeth of rats exposed to tobacco smoke. The intensities of the detected metabolite peaks are proportional to the degree of exposure. Incorporating ion mobility separation in the LAESI-MS analysis of scalp hair enables the detection of cotinine in smoker hair along with other common molecular species, including endogenous steroid hormones and some lipids. Single hair strands are imaged by MALDI-MSI and NAPA-LDI-MSI to explore longitudinal variations in the level of small molecules. Comparing spectra integrated from NAPA-LDI-MSI and MALDI-MSI images reveals that the two techniques provide complementary information. There were 105 and 82 sample-related peaks for MALDI and NAPA, respectively, with an overlap of only 16 peaks, indicating a high degree of complementarity. Enhanced molecular coverage and spatial resolution offered by LAESI-MS and NAPA-LDI-MSI can reveal the distributions of known and potential biomarkers in hard tissues, facilitating exposome research.


Asunto(s)
Cabello , Rayos Láser , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Xenobióticos , Animales , Cabello/química , Ratas , Xenobióticos/análisis , Xenobióticos/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Diente/química , Diente/metabolismo , Nicotina/análisis , Nicotina/metabolismo , Masculino
2.
Cells ; 13(6)2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38534318

RESUMEN

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by resting tremor, bradykinesia, rigidity, and postural instability that also includes non-motor symptoms such as mood dysregulation. Dopamine (DA) is the primary neurotransmitter involved in this disease, but cholinergic imbalance has also been implicated. Current intervention in PD is focused on replenishing central DA, which provides remarkable temporary symptomatic relief but does not address neuronal loss and the progression of the disease. It has been well established that neuronal nicotinic cholinergic receptors (nAChRs) can regulate DA release and that nicotine itself may have neuroprotective effects. Recent studies identified nAChRs in nonneuronal cell types, including glial cells, where they may regulate inflammatory responses. Given the crucial role of neuroinflammation in dopaminergic degeneration and the involvement of microglia and astrocytes in this response, glial nAChRs may provide a novel therapeutic target in the prevention and/or treatment of PD. In this review, following a brief discussion of PD, we focus on the role of glial cells and, specifically, their nAChRs in PD pathology and/or treatment.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Receptores Nicotínicos , Humanos , Enfermedad de Parkinson/metabolismo , Receptores Nicotínicos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Nicotina/metabolismo , Dopamina/metabolismo , Astrocitos/metabolismo
3.
Exp Brain Res ; 242(4): 971-986, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38430248

RESUMEN

The gradual nature of age-related neurodegeneration causes Parkinson's disease (PD) and impairs movement, memory, intellectual ability, and social interaction. One of the most prevalent neurodegenerative conditions affecting the central nervous system (CNS) among the elderly is PD. PD affects both motor and cognitive functions. Degeneration of dopaminergic (DA) neurons and buildup of the protein α-synuclein (α-Syn) in the substantia nigra pars compacta (SNpc) are two major causes of this disorder. Both UPS and ALS systems serve to eliminate α-Syn. Autophagy and UPS deficits, shortened life duration, and lipofuscin buildup accelerate PD. This sickness has no cure. Innovative therapies are halting PD progression. Bioactive phytochemicals may provide older individuals with a natural substitute to help delay the onset of neurodegenerative illnesses. This study examines whether nicotine helps transgenic C. elegans PD models. According to numerous studies, nicotine enhances synaptic plasticity and dopaminergic neuronal survival. Upgrades UPS pathways, increases autophagy, and decreases oxidative stress and mitochondrial dysfunction. At 100, 150, and 200 µM nicotine levels, worms showed reduced α-Syn aggregation, repaired DA neurotoxicity after 6-OHDA intoxication, increased lifetime, and reduced lipofuscin accumulation. Furthermore, nicotine triggered autophagy and UPS. We revealed nicotine's potential as a UPS and autophagy activator to prevent PD and other neurodegenerative diseases.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Animales , Humanos , Anciano , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Nicotina/farmacología , Nicotina/metabolismo , Caenorhabditis elegans/metabolismo , Lipofuscina/metabolismo , Lipofuscina/farmacología , alfa-Sinucleína/metabolismo , alfa-Sinucleína/farmacología , Enfermedades Neurodegenerativas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Autofagia
4.
Pediatrics ; 153(4)2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38463008

RESUMEN

BACKGROUND: Despite the increasing prevalence of vaping e-cigarettes among adolescents, there remains a lack of population-level assessments regarding the objective measurement of nicotine exposure. METHODS: This study analyzed a nationally representative sample of adolescents aged 13 to 17 years from Wave 5 of the Population Assessment of Tobacco and Health Study conducted between 2018 and 2019. Urinary nicotine metabolites, including cotinine and trans-3'-hydroxycotinine (3-HC), were assessed among exclusive nonnicotine e-cigarette users (n = 56), exclusive nicotine e-cigarette users (n = 200), and nonusers (n = 1059). We further examined nicotine exposure by past 30-day vaping frequency (ie, occasional [1-5 days], intermittent [6-19 days], and frequent [20+ days]) and flavor types among nicotine e-cigarette users. Multivariable linear regressions tested pairwise group effects, and biomarkers were normalized by the log transformation. RESULTS: Compared with nonusers, both nonnicotine and nicotine e-cigarette users exhibited higher levels of cotinine and 3-HC. Nicotine e-cigarette users had mean cotinine concentrations (61.3; 95% confidence interval, 23.8-158.0, ng/mg creatinine) approximately 146 times higher (P < .0001) than nonusers (0.4; 0.3-0.5), whereas nonnicotine users (4.9; 1.0-23.2) exhibited cotinine concentrations ∼12 times higher (P = .02). Among nicotine e-cigarette users, the levels of cotinine and 3-HC increased by vaping frequency, with cotinine increasing from 10.1 (2.5-40.1) among occasional users to 73.6 (31.8-170.6) among intermittent users and 949.1 (482.5-1866.9) among frequent users. Nicotine exposure was not significantly different by flavor type. CONCLUSIONS: E-cigarette use poses health-related risks resulting from nicotine exposure among adolescents. Comprehensive regulations of e-cigarette products and marketing, vaping prevention, cessation, and public policies are needed to prevent youth from developing nicotine addiction.


Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Productos de Tabaco , Vapeo , Humanos , Adolescente , Nicotina/metabolismo , Cotinina/orina , Vapeo/epidemiología , Vapeo/orina , Biomarcadores/orina
5.
Ecotoxicol Environ Saf ; 273: 116079, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38377778

RESUMEN

Nicotine, an addictive component of cigarettes, causes cognitive defects, particularly when exposure occurs early in life. However, the exact mechanism through which nicotine causes toxicity and alters synaptic plasticity is still not fully understood. The aim of the current study is to examine how non-coding developmental regulatory RNA impacts the hippocampus of mice offspring whose mothers were exposed to nicotine. Female C57BL/6J mice were given nicotine water from one week before pregnancy until end of lactation. Hippocampal tissue from offspring at 20 days post-birth was used for LncRNA and mRNA microarray analysis. Differential expression of LncRNAs and mRNAs associated with neuronal development were screened and validated, and the CeRNA pathway mediating neuronal synaptic plasticity GM13530/miR-7119-3p/mef2c was predicted using LncBase Predicted v.2. Using protein immunoblotting, Golgi staining and behavioral tests, our findings revealed that nicotine exposure in offspring mice increased hippocampal NMDAR receptor, activated receptor-dependent calcium channels, enhanced the formation of NMDAR/nNOS/PSD95 ternary complexes, increased NO synthesis, mediated p38 activation, induced neuronal excitability toxicity. Furthermore, an epigenetic CeRNA regulatory mechanism was identified, which suppresses Mef2c-mediated synaptic plasticity and leads to modifications in the learning and social behavior of the offspring during adolescence. This study uncovers the way in which maternal nicotine exposure results in neurotoxicity in offspring.


Asunto(s)
Nicotina , Efectos Tardíos de la Exposición Prenatal , Embarazo , Humanos , Ratones , Animales , Femenino , Nicotina/toxicidad , Nicotina/metabolismo , ARN Endógeno Competitivo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratones Endogámicos C57BL , Exposición Materna/efectos adversos , Hipocampo/metabolismo
6.
CNS Neurosci Ther ; 30(2): e14627, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38353058

RESUMEN

BACKGROUND: Systemic inflammation in which lipopolysaccharide (LPS) is released into circulation can cause cognitive dysfunction and we have previously shown that LPS impaired working memory (WM) which refers to the ability to guide incoming behavior by retrieving recently acquired information. However, the mechanism is not very clear, and currently, there is no approved strategy to improve inflammation-induced WM deficit. Notably, epidemiological studies have demonstrated a lower occurrence rate of inflammatory-related diseases in smoking patients, suggesting that inflammation-induced WM impairment may be improved by nicotine treatment. Here, our object is to investigate the effect and potential mechanisms of acute and chronic nicotine treatment on LPS-produced WM deficiency. METHODS: Delayed alternation T-maze task (DAT) was applied for evaluating WM which includes both the short-term information storage and the ability to correct errors in adult male mice. Immunofluorescence staining and immunoblotting were used for assessing the levels and distribution of CREB-regulated transcription coactivator 1 (CRTC1) and hyperpolarization-activated cation channels 2 (HCN2) in the medial prefrontal cortex (mPFC) and hippocampus. Quantitative PCR and ELISA were employed for analyzing the mRNA and protein levels of TNF-α and IL-1ß. RESULTS: Our results revealed that administration of LPS (i.p.) at a dose of 0.5 mg/kg significantly produced WM impairment in the DAT task accompanied by an increase in IL-1ß and TNF-α expression in the mPFC. Moreover, intra-mPFC infusion of IL-1Ra, an IL-1 antagonist, markedly alleviated LPS-induced WM deficiency. More important, chronic (2 weeks) but not acute nicotine (0.2 mg/kg, subcutaneous) treatment significantly alleviated LPS-induced WM deficiency by upregulating CRTC1 and HCN2. Of note, intra-mPFC infusion of HCN blocker ZD7288 produced significant WM deficiency. CONCLUSIONS: In summary, in this study, we show that chronic nicotine treatment ameliorates acute inflammation-induced working memory deficiency by increasing CRTC1 and HCN2 in adult male mice.


Asunto(s)
Memoria a Corto Plazo , Nicotina , Humanos , Ratones , Masculino , Animales , Memoria a Corto Plazo/fisiología , Nicotina/farmacología , Nicotina/uso terapéutico , Nicotina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Lipopolisacáridos/toxicidad , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Hipocampo/metabolismo , Factores de Transcripción/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Canales de Potasio/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo
7.
Placenta ; 147: 42-51, 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38308901

RESUMEN

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


Asunto(s)
Nicotina , Nacimiento Prematuro , Recién Nacido , Femenino , Humanos , Ratas , Animales , Nicotina/farmacología , Nicotina/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Sirtuina 1/metabolismo , NAD/metabolismo , NAD/farmacología , Movimiento Celular , Nacimiento Prematuro/metabolismo , Trofoblastos/metabolismo , Macrófagos/metabolismo , Inflamación/metabolismo
8.
Appl Environ Microbiol ; 90(3): e0225523, 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38415602

RESUMEN

Flavoprotein monooxygenases catalyze reactions, including hydroxylation and epoxidation, involved in the catabolism, detoxification, and biosynthesis of natural substrates and industrial contaminants. Among them, the 6-hydroxy-3-succinoyl-pyridine (HSP) monooxygenase (HspB) from Pseudomonas putida S16 facilitates the hydroxylation and C-C bond cleavage of the pyridine ring in nicotine. However, the mechanism for biodegradation remains elusive. Here, we refined the crystal structure of HspB and elucidated the detailed mechanism behind the oxidative hydroxylation and C-C cleavage processes. Leveraging structural information about domains for binding the cofactor flavin adenine dinucleotide (FAD) and HSP substrate, we used molecular dynamics simulations and quantum/molecular mechanics calculations to demonstrate that the transfer of an oxygen atom from the reactive FAD peroxide species (C4a-hydroperoxyflavin) to the C3 atom in the HSP substrate constitutes a rate-limiting step, with a calculated reaction barrier of about 20 kcal/mol. Subsequently, the hydrogen atom was rebounded to the FAD cofactor, forming C4a-hydroxyflavin. The residue Cys218 then catalyzed the subsequent hydrolytic process of C-C cleavage. Our findings contribute to a deeper understanding of the versatile functions of flavoproteins in the natural transformation of pyridine and HspB in nicotine degradation.IMPORTANCEPseudomonas putida S16 plays a pivotal role in degrading nicotine, a toxic pyridine derivative that poses significant environmental challenges. This study highlights a key enzyme, HspB (6-hydroxy-3-succinoyl-pyridine monooxygenase), in breaking down nicotine through the pyrrolidine pathway. Utilizing dioxygen and a flavin adenine dinucleotide cofactor, HspB hydroxylates and cleaves the substrate's side chain. Structural analysis of the refined HspB crystal structure, combined with state-of-the-art computations, reveals its distinctive mechanism. The crucial function of Cys218 was never discovered in its homologous enzymes. Our findings not only deepen our understanding of bacterial nicotine degradation but also open avenues for applications in both environmental cleanup and pharmaceutical development.


Asunto(s)
Oxigenasas de Función Mixta , Nicotina , Succinatos , Oxigenasas de Función Mixta/metabolismo , Nicotina/metabolismo , Flavina-Adenina Dinucleótido/metabolismo , Flavoproteínas/metabolismo , Hidroxilación , Piridinas/metabolismo
9.
Neuropharmacology ; 247: 109846, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38211698

RESUMEN

Tobacco smoking remains a leading cause of preventable death in the United States, with approximately a 5% success rate for smokers attempting to quit. High relapse rates have been linked to several genetic factors, indicating that the mechanistic relationship between genes and drugs of abuse is a valuable avenue for the development of novel smoking cessation therapies. For example, various single nucleotide polymorphisms (SNPs) in the gene for neuregulin 3 (NRG3) and its cognate receptor, the receptor tyrosine-protein kinase erbB-4 (ERBB4), have been linked to nicotine addiction. Our lab has previously shown that ERBB4 plays a role in anxiety-like behavior during nicotine withdrawal (WD); however, the neuronal mechanisms and circuit-specific effects of NRG3-ERBB4 signaling during nicotine and WD are unknown. The present study utilizes genetic, biochemical, and functional approaches to examine the anxiety-related behavioral and functional role of NRG3-ERBB4 signaling, specifically in the ventral hippocampus (VH) of male and female mice. We report that 24hWD from nicotine is associated with altered synaptic expression of VH NRG3 and ERBB4, and genetic disruption of VH ErbB4 leads to an elimination of anxiety-like behaviors induced during 24hWD. Moreover, we observed attenuation of GABAergic transmission as well as alterations in Ca2+-dependent network activity in the ventral CA1 area of VH ErbB4 knock-down mice during 24hWD. Our findings further highlight contributions of the NRG3-ERBB4 signaling pathway to anxiety-related behaviors seen during nicotine WD.


Asunto(s)
Nicotina , Síndrome de Abstinencia a Sustancias , Masculino , Femenino , Ratones , Animales , Nicotina/farmacología , Nicotina/metabolismo , Neurregulinas/genética , Neurregulinas/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Hipocampo/metabolismo , Transducción de Señal , Receptor ErbB-4/genética , Receptor ErbB-4/metabolismo
10.
Sci China Life Sci ; 67(5): 854-864, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38265598

RESUMEN

Tobacco smoking is a prevalent and detrimental habit practiced worldwide, increasing the risk of various diseases, including chronic obstructive pulmonary disease (COPD), cardiovascular disease, liver disease, and cancer. Although previous research has explored the detrimental health effects of tobacco smoking, recent studies suggest that gut microbiota dysbiosis may play a critical role in these outcomes. Numerous tobacco smoke components, such as nicotine, are found in the gastrointestinal tract and interact with gut microbiota, leading to lasting impacts on host health and diseases. This review delves into the ways tobacco smoking and its various constituents influence gut microbiota composition and functionality. We also summarize recent advancements in understanding how tobacco smoking-induced gut microbiota dysbiosis affects host health. Furthermore, this review introduces a novel perspective on how changes in gut microbiota following smoking cessation may contribute to withdrawal syndrome and the degree of health improvements in smokers.


Asunto(s)
Disbiosis , Microbioma Gastrointestinal , Fumar Tabaco , Humanos , Fumar Tabaco/efectos adversos , Disbiosis/microbiología , Nicotina/efectos adversos , Nicotina/metabolismo , Animales , Tracto Gastrointestinal/microbiología , Cese del Hábito de Fumar , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Enfermedad Pulmonar Obstructiva Crónica/etiología
11.
Drug Des Devel Ther ; 18: 71-80, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38229917

RESUMEN

Introduction: Nicotine is a major component of cigarette smoke with various detrimental cardiovascular effects, including increased oxidative stress in the heart. Agonism of α2-adrenergic receptors (ARs), such as with dexmedetomidine, has been documented to exert cardioprotective effects against oxidative stress and related apoptosis and necroptosis. α2-ARs are membrane-residing G protein-coupled receptors (GPCRs) that primarily activate Gi/o proteins. They are also subjected to GPCR-kinase (GRK)-2-dependent desensitization, which entails phosphorylation of the agonist-activated receptor by GRK2 to induce its decoupling from G proteins, thus terminating α2AR-mediated G protein signaling. Objective: In the present study, we sought to examine the effects of nicotine on α2AR signaling and effects in H9c2 cardiomyocytes exposed to H2O2 to induce oxidative cellular damage. Methods and Results: As expected, treatment of H9c2 cardiomyocytes with H2O2 significantly decreased cell viability and increased oxidative stress, as assessed by reactive oxygen species (ROS)-associated fluorescence levels (DCF assay) and superoxide dismutase activity. Both H2O2 effects were partly rescued by α2AR activation with brimonidine in control cardiomyocytes but not in cells pretreated with nicotine for 24 hours, in which brimonidine was unable to reduce H2O2-induced cell death and oxidative stress. This was due to severe α2AR desensitization, manifested as very low Gi protein activation by brimonidine, and accompanied by GRK2 upregulation in nicotine-treated cardiomyocytes. Finally, pharmacological inhibition of adenylyl cyclase (AC) blocked H2O2-dependent oxidative damage in nicotine-pretreated H9c2 cardiomyocytes, indicating that α2AR activation protects against oxidative injury via its classic coupling to Gai-mediated AC inhibition. Discussion/Conclusions: Nicotine can negate the cardioprotective effects of α2AR agonists against oxidative injury, which may have important implications for patients treated with this class of drugs that are chronic tobacco smokers.


Asunto(s)
Miocitos Cardíacos , Nicotina , Humanos , Nicotina/farmacología , Nicotina/metabolismo , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Estrés Oxidativo , Apoptosis , Tartrato de Brimonidina/metabolismo , Tartrato de Brimonidina/farmacología
12.
Pestic Biochem Physiol ; 198: 105743, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38225086

RESUMEN

The alkaloid, nicotine, produced by tobacco and other Solanaceae as an anti-herbivore defence chemical is one of the most toxic natural insecticides in nature. However, some insects, such as the whitefly species, Trialeurodes vaporariorum and Bemisia tabaci show strong tolerance to this allelochemical and can utilise tobacco as a host. Here, we used biological, molecular and functional approaches to investigate the role of cytochrome P450 enzymes in nicotine tolerance in T. vaporariorum and B. tabaci. Insecticide bioassays revealed that feeding on tobacco resulted in strong induced tolerance to nicotine in both species. Transcriptome profiling of both species reared on tobacco and bean hosts revealed profound differences in the transcriptional response these host plants. Interrogation of the expression of P450 genes in the host-adapted lines revealed that P450 genes belonging to the CYP6DP subfamily are strongly upregulated in lines reared on tobacco. Functional characterisation of these P450s revealed that CYP6DP1 and CYP6DP2 of T. vaporariorum and CYP6DP3 of B. tabaci confer resistance to nicotine in vivo. These three genes, in addition to the B. tabaci P450 CYP6DP5, were also found to confer resistance to the neonicotinoid imidacloprid. Our data provide new insight into the molecular basis of nicotine resistance in insects and illustrates how divergence in the evolution of P450 genes in this subfamily in whiteflies may have impacted the extent to which different species can tolerate a potent natural insecticide.


Asunto(s)
Hemípteros , Insecticidas , Animales , Nicotina/farmacología , Nicotina/metabolismo , Insecticidas/farmacología , Insecticidas/metabolismo , Resistencia a los Insecticidas/genética , Neonicotinoides/farmacología , Neonicotinoides/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Nicotiana/genética , Hemípteros/metabolismo , Nitrocompuestos/farmacología , Nitrocompuestos/metabolismo
13.
Drug Metab Dispos ; 52(3): 171-179, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38195520

RESUMEN

Coumarin 7'-hydroxylase activity, a specific marker of CYP2A5 activity, and the protein level were measured in liver microsomes of male mice after chronic exposure to e-cigarettes (e-cigs) (2.4% nicotine). After exposure for 240 minutes per day for 5 days, the activity and the protein level in preproenkephalin (ppENK)-heterozygous [ppENK (+/-)] mice were significantly elevated (P <0.05) compared with the untreated control. This elevation was not due to deletion of the ppENK gene because the activity did not differ among untreated ppENK (+/-), ppENK (-/-), and wild-type ppENK (+/+) controls. Hence, the elevation can reasonably be attributed to nicotine exposure. The production of reactive oxygen species (ROS) upon incubation of the hepatic microsomes of these mice with cotinine was higher in microsomes from the e-cig-treated mice compared with the untreated controls (P < 0.01). Liquid chromatography mass spectrometry assay showed three oxidation products of cotinine, viz trans 3'-hydroxycotinine (3'-HC), 5'-hydroxycotinine (5'-HC), and cotinine N-oxide (CNO) in the plasma of these mice. The result identifies these three oxidation reactions as the source of the observed ROS and also shows that, in nicotine-treated mice, the appropriate "nicotine metabolite ratio" is (3'-HC + 5'-HC + CNO)/cotinine. The results suggest intriguing possibilities that 1) this metabolite ratio may correlate with plasma nicotine clearance and hence impact nicotine's psychoactive effects and 2) chronic e-cig treatment causes ROS-induced oxidative stress, which may play a major role in the regulation of CYP2A5 expression. Our present results clearly show that both the activity and the protein level of CYP2A5 are elevated by repeated exposure to nicotine. SIGNIFICANCE STATEMENT: Nicotine, the psychoactive ingredient of tobacco, is eliminated as the oxidation products of cotinine in reactions catalyzed by the enzymes CYP2A5 in mice and CYP2A6 in humans. This study shows that repeated exposure to e-cigarettes elevates the level of CYP2A5 and the formation of reactive oxygen species. The results suggest an intriguing possibility that CYP2A5 may be upregulated by chronic nicotine exposure due to oxidative stress caused by the oxidation of cotinine in this preclinical model of human smokers.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Sistemas Electrónicos de Liberación de Nicotina , Masculino , Humanos , Animales , Ratones , Cotinina/metabolismo , Nicotina/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Microsomas Hepáticos/metabolismo , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2A6/metabolismo
14.
Am J Physiol Lung Cell Mol Physiol ; 326(2): L149-L163, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38084408

RESUMEN

With continued smoking of tobacco products and expanded use of nicotine delivery devices worldwide, understanding the impact of smoking and vaping on respiratory health remains a major global unmet need. Although multiple studies have shown a strong association between smoking and asthma, there is a relative paucity of mechanistic understanding of how elements in cigarette smoke impact the airway. Recognizing that nicotine is a major component in both smoking and vaping products, it is critical to understand the mechanisms by which nicotine impacts airways and promotes lung diseases such as asthma. There is now increasing evidence that α7 nicotinic acetylcholine receptors (α7nAChRs) are critical players in nicotine effects on airways, but the mechanisms by which α7nAChR influences different airway cell types have not been widely explored. In this review, we highlight and integrate the current state of knowledge regarding nicotine and α7nAChR in the context of asthma and identify potential approaches to alleviate the impact of smoking and vaping on the lungs.


Asunto(s)
Asma , Receptores Nicotínicos , Trastornos Respiratorios , Humanos , Receptores Nicotínicos/metabolismo , Nicotina/efectos adversos , Nicotina/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Pulmón/metabolismo , Asma/metabolismo , Trastornos Respiratorios/metabolismo , Productos de Tabaco
15.
Clin Pharmacol Ther ; 115(1): 80-85, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37787039

RESUMEN

Rates of cigarette smoking in people with HIV (PWH) are two to three times higher than in people without HIV. Nicotine is metabolized by CYP2A6 and the nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is a measure of nicotine clearance. Higher NMR has been observed in PWH and is associated with lower quit rates. Efavirenz, a mainstay antiretroviral therapy (ART) globally, partially upregulates its own metabolism through CYP2A6. We hypothesized that efavirenz also upregulates nicotine metabolism by CYP2A6, resulting in a higher NMR, and switching to non-efavirenz ART would decrease the NMR, potentially leading to improved quit rates. We compared the NMR during and after efavirenz use among PWH in a longitudinal, multisite cohort. Eligibility criteria included: (i) active cigarette smoking, (ii) ART switched from efavirenz-based to non-efavirenz-based regimen, (iii) plasma available at pre- and post-ART switch, and (iv) viral suppression during study period. Plasma cotinine and 3-hydroxycotinine were measured by liquid chromatography-tandem mass spectrometry. T-tests compared the NMR on and off efavirenz. Samples were collected between 2010 and 2019 in 72 PWH. The mean NMR difference after switching to a non-efavirenz-based regimen was -0.24 (SD: 0.37, P < 0.001); 44 PWH had at least a 0.1 decrease in NMR. Effect modification by race was present; Black PWH had a larger mean decrease. Our findings suggest that previously observed higher NMR among PWH may be due to direct pharmacologic effects of ART. Assessing the effect of ART on the NMR suggests that avoiding nicotine metabolism inducers could potentially increase quit rates.


Asunto(s)
Fumar Cigarrillos , Infecciones por VIH , Humanos , Nicotina/metabolismo , Cotinina , Infecciones por VIH/tratamiento farmacológico
16.
J Allergy Clin Immunol ; 153(1): 320-329.e8, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37678576

RESUMEN

BACKGROUND: Electronic cigarette (e-cigarette) use continues to rise despite concerns of long-term effects, especially the risk of developing lung diseases such as chronic obstructive pulmonary disease. Neutrophils are central to the pathogenesis of chronic obstructive pulmonary disease, with changes in phenotype and function implicated in tissue damage. OBJECTIVE: We sought to measure the impact of direct exposure to nicotine-containing and nicotine-free e-cigarette vapor on human neutrophil function and phenotype. METHODS: Neutrophils were isolated from the whole blood of self-reported nonsmoking, nonvaping healthy volunteers. Neutrophils were exposed to 40 puffs of e-cigarette vapor generated from e-cigarette devices using flavorless e-cigarette liquids with and without nicotine before functions, deformability, and phenotype were assessed. RESULTS: Neutrophil surface marker expression was altered, with CD62L and CXCR2 expression significantly reduced in neutrophils treated with e-cigarette vapor containing nicotine. Neutrophil migration to IL-8, phagocytosis of Escherichia coli and Staphylococcus aureus pHrodo bioparticles, oxidative burst response, and phorbol 12-myristate 13-acetate-stimulated neutrophil extracellular trap formation were all significantly reduced by e-cigarette vapor treatments, independent of nicotine content. E-cigarette vapor induced increased levels of baseline polymerized filamentous actin levels in the cytoplasm, compared with untreated controls. CONCLUSIONS: The significant reduction in effector neutrophil functions after exposure to high-power e-cigarette devices, even in the absence of nicotine, is associated with excessive filamentous actin polymerization. This highlights the potentially damaging impact of vaping on respiratory health and reinforces the urgency of research to uncover the long-term health implications of e-cigarettes.


Asunto(s)
Cigarrillo Electrónico a Vapor , Sistemas Electrónicos de Liberación de Nicotina , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Neutrófilos , Cigarrillo Electrónico a Vapor/metabolismo , Cigarrillo Electrónico a Vapor/farmacología , Nicotina/efectos adversos , Nicotina/metabolismo , Actinas/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo
17.
Nicotine Tob Res ; 26(4): 474-483, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-37535700

RESUMEN

INTRODUCTION: Electronic cigarettes (E-cigs) are in a controversial state. Although E-cig aerosol generally contains fewer harmful substances than smoke from burned traditional cigarettes, aerosol along with other compounds of the E-cigs may also affect lung functions and promote the development of lung-related diseases. We investigated the effects of E-cig on the pulmonary functions of male C57BL/6 mice and reveal the potential underlying mechanisms. METHODS: A total of 60 male C57BL/6 mice were randomly divided into four groups. They were exposed to fresh-air, traditional cigarette smoke, E-cig vapor with 12 mg/mL of nicotine, and E-cig with no nicotine for 8 weeks. Lung functions were evaluated by using quantitative analysis of the whole body plethysmograph, FlexiVent system, lung tissue histological and morphometric analysis, and RT-PCR analysis of mRNA expression of inflammation-related genes. In addition, the effects of nicotine and acrolein on the survival rate and DNA damage were investigated using cultured human alveolar basal epithelial cells. RESULTS: Exposure to E-cig vapor led to significant changes in lung functions and structures including the rupture of the alveolar cavity and enlarged alveolar space. The pathological changes were also accompanied by increased expression of interleukin-6 and tumor necrosis factor-α. CONCLUSIONS: The findings of the present study indicate that the safety of E-cig should be further evaluated. IMPLICATIONS: Some people currently believe that using nicotine-free E-cigs is a safe way to smoke. However, our research shows that E-cigs can cause lung damage regardless of whether they contain nicotine.


Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Productos de Tabaco , Ratones , Animales , Masculino , Humanos , Nicotina/efectos adversos , Nicotina/metabolismo , Ratones Endogámicos C57BL , Pulmón , Aerosoles/farmacología
18.
Naunyn Schmiedebergs Arch Pharmacol ; 397(2): 1105-1114, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37606756

RESUMEN

Dexpanthenol (DEX), a subtype of vitamin B5, plays an important role in anabolic reactions, cellular energy and regeneration in the body. Nicotine has been shown to induce kidney damage through the mechanisms of oxidative stress and apoptosis. The purpose of this study was to investigate the potential protective effects of DEX against nicotine-induced kidney damage through modulation of the AKT/Nrf2/HO-1 signaling pathway. Male rats were intraperitoneally administered with 0.5 mg/kg/day nicotine and/or 500 mg/kg/day DEX for 8 weeks. Following administration, renal function tests were conducted on serum samples, and histopathological examinations and analysis of oxidative stress markers and antioxidant enzymes were performed on tissue samples. Protein levels of Akt, Nrf-2, HO-1, Bcl-xL, and Caspase-9 were also evaluated. Nicotine administration resulted in decreased protein levels of p-Akt, Nrf-2, HO-1, and Bcl-xL and increased Caspase-9 protein levels. In addition, nicotine administration caused an increase in MDA, TOS, and OSI levels and a decrease in GSH, GSH-Px, GST, CAT, SOD, and TAS levels. Additionally, BUN and Creatinine levels increased after nicotine administration. DEX administration positively regulated these parameters and brought them closer to control levels. Nicotine-induced kidney injury caused apoptosis and oxidative stress through Caspase-9 activation. DEX effectively prevented nicotine-induced kidney damage by increasing intracellular antioxidant levels and regulating apoptosis through Bcl-xL activation. These findings suggest that DEX has potential as a protective agent against nicotine-induced kidney damage.


Asunto(s)
Antioxidantes , Ácido Pantoténico/análogos & derivados , Proteínas Proto-Oncogénicas c-akt , Masculino , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Caspasa 9/metabolismo , Caspasa 9/farmacología , Nicotina/toxicidad , Nicotina/metabolismo , Estrés Oxidativo , Apoptosis , Riñón
19.
Plant Physiol Biochem ; 206: 108234, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38056040

RESUMEN

Nicotine conversion is the process by which nornicotine is synthesized from nicotine. The capacity of a plant to carry out this process is represented by the nicotine conversion rate (NCR), which is defined as the percentage of nornicotine content out of the total nicotine + nornicotine content. Nicotine conversion in tobacco is mediated by CYP82E4. Although there are cultivar-specific differences in NCR, these do not correspond to differences in the CYP82E4 promoter or gene body sequences, and little is known about the underlying regulatory mechanism. Here, we found that histone H3 Lysine 27 trimethylation (H3K27me3) was involved in CYP82E4 expression, functioning as a transcriptional repressor. Compared to a high-NCR near-isogenic line, a low-NCR cultivar showed increased levels of the repressive histone modification markers H3K27me3 and H3K9me3 at CYP82E4. Comparison of histone markers between several cultivars with varying NCRs showed that H3K27me3 and H3K9me3 levels were significantly associated with cultivar-specific differences in NCR. Treatment with the H3K27me3 demethylase inhibitor GSK-J4 increased total H3K27me3 levels and enriched H3K27me3 at the CYP82E4 locus; the increased levels of H3K27me3 further inhibited CYP82E4 expression. Knocking out E(z), an indispensable gene for H3K27me3 formation, decreased H3K27me3 levels at CYP82E4, leading to a more than three-fold increase in CYP82E4 expression. Changes in CYP82E4 expression during leaf senescence and chilling stress were also strongly correlated with H3K27me3 levels. These findings reveal a strong correlation between CYP82E4 expression and histone modifications, and demonstrate an instance of histone-mediated alkaloid regulation for the first time.


Asunto(s)
Nicotiana , Nicotina , Nicotina/metabolismo , Nicotiana/genética , Histonas/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Hojas de la Planta/metabolismo
20.
CNS Neurosci Ther ; 30(4): e14508, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-37864452

RESUMEN

AIMS: Exposure to crystalline silica (CS) in occupational settings induces chronic inflammation in the respiratory system and, potentially, the brain. Some workers are frequently concurrently exposed to both CS and nicotine. Here, we explored the impact of nicotine on CS-induced neuroinflammation in the mouse hippocampus. METHODS: In this study, we established double-exposed models of CS and nicotine in C57BL/6 mice. To assess depression-like behavior, experiments were conducted at 3, 6, and 9 weeks. Serum inflammatory factors were analyzed by ELISA. Hippocampus was collected for RNA sequencing analysis and examining the gene expression patterns linked to inflammation and cell death. Microglia and astrocyte activation and hippocampal neuronal death were assessed using immunohistochemistry and immunofluorescence staining. Western blotting was used to analyze the NF-κB expression level. RESULTS: Mice exposed to CS for 3 weeks showed signs of depression. This was accompanied by elevated IL-6 in blood, destruction of the blood-brain barrier, and activation of astrocytes caused by an increased NF-κB expression in the CA1 area of the hippocampus. The elevated levels of astrocyte-derived Lcn2 and upregulated genes related to inflammation led to higher neuronal mortality. Moreover, nicotine mitigated the NF-κB expression, astrocyte activation, and neuronal death, thereby ameliorating the associated symptoms. CONCLUSION: Silica exposure induces neuroinflammation and neuronal death in the mouse hippocampal CA1 region and depressive behavior. However, nicotine inhibits CS-induced neuroinflammation and neuronal apoptosis, alleviating depressive-like behaviors in mice.


Asunto(s)
FN-kappa B , Nicotina , Ratones , Animales , FN-kappa B/metabolismo , Nicotina/farmacología , Nicotina/metabolismo , Astrocitos/metabolismo , Enfermedades Neuroinflamatorias , Ratones Endogámicos C57BL , Hipocampo/metabolismo , Región CA1 Hipocampal/metabolismo , Inflamación/metabolismo , Apoptosis , Microglía/metabolismo
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