RESUMO
Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR-dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.
Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Idoso , Animais , Neoplasias dos Ductos Biliares/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fibrose/metabolismo , Xenoenxertos , Humanos , Queratina-19/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/fisiologiaRESUMO
UNLABELLED: Secretin stimulates ductal secretion by interacting with secretin receptor (SR) activating cyclic adenosine 3',5'-monophosphate/cystic fibrosis transmembrane conductance regulator/chloride bicarbonate anion exchanger 2 (cAMPâCFTRâCl(-) /HCO 3- AE2) signaling that is elevated by biliary hyperplasia. Cholangiocytes secrete several neuroendocrine factors regulating biliary functions by autocrine mechanisms. Melatonin inhibits biliary growth and secretin-stimulated choleresis in cholestatic bile-duct-ligated (BDL) rats by interaction with melatonin type 1 (MT1) receptor through down-regulation of cAMP-dependent signaling. No data exist regarding the role of melatonin synthesized locally by cholangiocytes in the autocrine regulation of biliary growth and function. In this study, we evaluated the (1) expression of arylalkylamine N-acetyltransferase (AANAT; the rate-limiting enzyme for melatonin synthesis from serotonin) in cholangiocytes and (2) effect of local modulation of biliary AANAT expression on the autocrine proliferative/secretory responses of cholangiocytes. In the liver, cholangiocytes (and, to a lesser extent, BDL hepatocytes) expressed AANAT. AANAT expression and melatonin secretion (1) increased in BDL, compared to normal rats and BDL rats treated with melatonin, and (2) decreased in normal and BDL rats treated with AANAT Vivo-Morpholino, compared to controls. The decrease in AANAT expression, and subsequent lower melatonin secretion by cholangiocytes, was associated with increased biliary proliferation and increased SR, CFTR, and Cl(-) /HCO 3- AE2 expression. Overexpression of AANAT in cholangiocyte cell lines decreased the basal proliferative rate and expression of SR, CFTR, and Cl(-) /HCO 3- AE2 and ablated secretin-stimulated biliary secretion in these cells. CONCLUSION: Local modulation of melatonin synthesis may be important for management of the balance between biliary proliferation/damage that is typical of cholangiopathies. (HEPATOLOGY 2013).
Assuntos
Arilalquilamina N-Acetiltransferase/metabolismo , Comunicação Autócrina/fisiologia , Ductos Biliares Intra-Hepáticos/citologia , Ductos Biliares Intra-Hepáticos/enzimologia , Colestase/metabolismo , Colestase/patologia , Animais , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antiporters/genética , Antiporters/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Arilalquilamina N-Acetiltransferase/genética , Comunicação Autócrina/efeitos dos fármacos , Ductos Biliares Intra-Hepáticos/efeitos dos fármacos , Linhagem Celular Transformada , Proliferação de Células , Técnicas de Silenciamento de Genes , Masculino , Melatonina/sangue , Melatonina/farmacologia , Camundongos , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Proteínas SLC4ARESUMO
Cigarette smoking contributes to the development of cancer, and pathogenesis of other diseases. Many chemicals have been identified in cigarettes that have potent biological properties. Nicotine is especially known for its role in addiction and plays a role in other physiological effects of smoking and tobacco use. Recent studies have provided compelling evidence that, in addition to promoting cancer, nicotine also plays a pathogenic role in systems, such as the lung, kidney, heart, and liver. In many organ systems, nicotine modulates fibrosis by altering the functions of fibroblasts. Understanding the processes modulated by nicotine holds therapeutic potential and may guide future clinical and research decisions. This review discusses the role of nicotine in the general fibrogenic process that governs fibrosis and fibrosis-related diseases, focusing on the cellular mechanisms that have implications in multiple organ systems. Potential research directions for the management of nicotine-induced fibrosis, and potential clinical considerations with regard to nicotine-replacement therapy (NRT) are presented.
Assuntos
Células Epiteliais/efeitos dos fármacos , Estimulantes Ganglionares/intoxicação , Nicotina/intoxicação , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose/induzido quimicamente , Fibrose/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias/induzido quimicamente , Neoplasias/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVE: To understand the geopolitics of the supply of fentanyl and heroin. RESULTS: In our practice, the percent of fentanyl positive drug tests increased from years 2016 to 2022, but heroin positive drug tests decreased by 80% in the same period. CONCLUSION: Fentanyl has replaced heroin as a street drug for opioid dependent drug users.
Assuntos
Overdose de Drogas , Dependência de Heroína , Humanos , Heroína/uso terapêutico , Fentanila , Analgésicos OpioidesRESUMO
Parkinson's disease (PD) may be misdiagnosed due to the clinical overlap between PD and atypical parkinsonism. The utility of α-Synuclein (αSyn) Seed Amplification Assay (SAA) as a diagnostic indicator for PD has been reported in numerous studies, but never when administered as a validated clinical laboratory test. This study compares results from αSyn-SAA validation testing performed using well-characterized cohorts from two biorepositories to better understand the accuracy of PD clinical diagnosis. Blinded cerebrospinal fluid (CSF) specimens from a repository that included cohorts of subjects clinically diagnosed as PD or healthy controls, both with confirmatory dopamine transporter single-photon emission computed tomography (DAT SPECT) imaging, and blinded CSF specimens from a repository that included cohorts of subjects clinically diagnosed as PD or healthy controls based on clinical diagnosis alone, were tested as part of the validation studies for the diagnostic αSyn-SAA test (SYNTap® Biomarker Test). Measured αSyn-SAA test accuracy was 83.9% using clinical diagnosis as comparator, and 93.6% using clinical diagnosis with confirmatory DAT- SPECT imaging as comparator. The statistically significant discordance between accuracy determinations using specimens classified using different diagnostic inclusion criteria indicates that there is some symbiosis between dopamine-weighted imaging and αSyn-SAA results, both of which are associated with higher accuracy compared with the clinical diagnosis alone.
Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , DopaminaRESUMO
The bile duct system of the liver is lined by epithelial cells (i.e., cholangiocytes) that respond to a large number of neuroendocrine factors through alterations in their proliferative activities and the subsequent modification of the microenvironment. As such, activation of biliary proliferation compensates for the loss of cholangiocytes due to apoptosis and slows the progression of toxic injury and cholestasis. Over the course of the last three decades, much progress has been made in identifying the factors that trigger the biliary epithelium to remodel and grow. Because a large number of autocrine factors have recently been identified as relevant clinical targets, a compiled review of their contributions and function in cholestatic liver diseases would be beneficial. In this context, it is important to define the specific processes triggered by autocrine factors that promote cholangiocytes to proliferate, activate neighboring cells, and ultimately lead to extracellular matrix deposition. In this review, we discuss the role of each of the known autocrine factors with particular emphasis on proliferation and fibrogenesis. Because many of these molecules interact with one another throughout the progression of liver fibrosis, a model speculating their involvement in the progression of cholestatic liver disease is also presented.
Assuntos
Comunicação Autócrina/fisiologia , Ductos Biliares/citologia , Sistema Biliar/patologia , Células Epiteliais/citologia , Animais , Ductos Biliares/fisiologia , Proliferação de Células/efeitos dos fármacos , Endotelinas/fisiologia , Células Epiteliais/patologia , Estrogênios/fisiologia , Humanos , Integrinas/fisiologia , Cirrose Hepática/patologia , Neuropeptídeos/fisiologia , Hormônios Peptídicos/fisiologia , Fator de Crescimento Derivado de Plaquetas/fisiologia , Sistema Renina-Angiotensina/fisiologia , Fator de Crescimento Transformador beta/fisiologiaRESUMO
IMPORTANCE: Cell-free DNA (cfDNA) testing is increasingly used in the treatment of patients with advanced prostate cancer. Clonal hematopoiesis of indeterminate potential (CHIP) can interfere with cfDNA testing and cause incorrect interpretation of results. There is an urgent need to better understand this problem following recent US Food and Drug Administration approval of poly(ADP) ribose polymerase inhibitors (PARPi) for metastatic prostate cancer based on variants in DNA repair genes that can be affected by CHIP. OBJECTIVE: To determine the prevalence of clinically relevant CHIP interference in prostate cancer cfDNA testing. DESIGN, SETTING, AND PARTICIPANTS: We report a case series of 69 patients with advanced prostate cancer (metastatic disease or with rising PSA following localized therapy) who had cfDNA variant testing with a large panel cancer next generation sequencing assay (UW-OncoPlexCT). To determine the source of variants in plasma, we tested paired cfDNA and whole blood control samples. The study was carried out in an academic medical center system reference laboratory. MAIN OUTCOMES AND MEASURES: Prevalence and gene spectrum of CHIP interference in patients with prostate cancer undergoing cfDNA testing. RESULTS: We detected CHIP variants at 2% or more variant fraction in cfDNA from 13 of 69 men with prostate cancer (19%; 95% CI, 10%-30%). Seven men (10%; 95% CI, 4%-20%) had CHIP variants in DNA repair genes used to determine PARPi candidacy, including ATM (n = 5), BRCA2 (n = 1), and CHEK2 (n = 1). Overall, CHIP variants accounted for almost half of the somatic DNA repair gene variants detected. Participant CHIP variants were exponentially correlated with older age (R2 = 0.82). CHIP interference variants could be distinguished from prostate cancer variants using a paired whole-blood control. CONCLUSIONS AND RELEVANCE: In this case series, approximately 10% of men with advanced prostate cancer had CHIP interference in plasma cfDNA in DNA repair genes that are used for eligibility of PARPi therapy, most frequently in ATM. Clinical cfDNA testing should include a paired whole-blood control to exclude CHIP variants and avoid misdiagnosis.
Assuntos
Ácidos Nucleicos Livres , Neoplasias da Próstata , Ácidos Nucleicos Livres/genética , Hematopoiese Clonal , Reparo do DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genéticaRESUMO
BACKGROUND: Specimen turnaround time (TAT) is an important metric for laboratory safety and quality. Various methods to improve TAT have seen success using process improvement initiatives. However, there are limited data on barcoding, pneumatic receiving proximity to modular preanalytics, 1 vs 2 measuring cells, and upgrading to Cobas 8000. The example describes the complete execution of a process improvement initiative to improve TAT within these areas over a 20-month period. The study aimed to improve specimen timeliness by decreasing the TAT for preanalytic and analytic specimen processing through a systematic process improvement initiative and to empower staff to "own" their scientific method. METHODS: The primary outcome TAT was reported from a prospective quality initiative beginning January 2017 for 2 analytes: troponin and potassium. TATs for albumins from the complete metabolic panels were added to the study design retrospectively during team rounds. Mean TAT was defined as time from arrival to verified times. Process improvement tools within the study design were borrowed from Lean management. RESULTS: After implementation of the process improvement initiative, the number of steps medical laboratory assistants and technologists performed per specimen decreased from 8 to 5. Mean TATs decreased for all analytes. Preimplementation to postimplementation comparisons from 2017 to 2018 decreased for all 3 analytes and within 2017. The number of troponin specimens verified within 60 min improved from 70% in January 2017 to 95% in August 2018, with an improvement from 64% in January 2017 to 87% in August 2018 during peak hours. CONCLUSIONS: A systematic process improvement initiative whereby employees "own" the scientific process within specimen preanalytic and analytic testing phases can significantly improve metrics for laboratory quality and safety.
Assuntos
Química Analítica , Eficiência Organizacional , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/normas , Melhoria de Qualidade , Jornada de Trabalho em Turnos , Biomarcadores , Testes Diagnósticos de Rotina , Implementação de Plano de Saúde , Humanos , Laboratórios Hospitalares , Fatores de Tempo , Fluxo de TrabalhoRESUMO
CONTEXT.: Northwell Health Laboratories were established in 1997, serving the Northwell Health system. In 2008, the health system considered minority entry into a joint venture with a commercial laboratory. Based on arguments made by Northwell laboratory leadership, the decision was made to retain full ownership of the laboratory. OBJECTIVE.: To evaluate the 10-year outcomes of the 2008 decision and assess the value of a fully integrated laboratory service line for a regional health network. DESIGN.: Ten-year outcomes were analyzed including financial, volume, and value-based activities. RESULTS.: First, a fully integrated laboratory service line was created, with unified medical and managerial leadership. Second, Core Laboratory volumes and revenues grew at annualized rates of 4.5% and 16.0%, respectively. Third, hospital-based laboratory costs were held either constant, or grew in accordance with strategic clinical programs. Fourth, laboratory services were able to provide leadership in innovative system clinical programming and value-based payment programs. Fifth, the laboratories became a regional asset, forming a joint venture affiliation with New York City Health + Hospitals, and supporting distressed hospitals in Brooklyn, New York. Lastly, Northwell Health Laboratories have become a reputational asset through leadership in 2 consortia: The Compass Group and Project Santa Fe. CONCLUSIONS.: The 10-year outcomes have exceeded projections made in 2008, validating the decision to retain the laboratories as a wholly owned system asset. The laboratories are now well positioned for leading innovation in patient care and for helping to drive a favorable posture for the health system under new payment models for health care.
Assuntos
Atenção à Saúde/organização & administração , Laboratórios Hospitalares/organização & administração , Tomada de Decisões Gerenciais , Atenção à Saúde/economia , Humanos , Laboratórios Hospitalares/economiaRESUMO
It is well documented in the scientific literature that ozone-oxygen mixtures inactivate microorganisms including bacteria, fungi and viruses (Hoff, J.C., 1986. Inactivation of microbial agents by chemical disinfectants. EPA 600 S2-86 067. Office of Water, U.S. Environmental Protection Agency, Washington, DC; Khadre, M.A., Yousef, A.E., Kim, J.-G., 2001. Microbiological aspects of ozone applications in food: a review. J. Food Sci. 66, 1242-1252). In the current study, delivery and absorption of precisely known concentrations of ozone (in liquid media) were used to inactivate virus infectivity. An ozone-oxygen delivery system capable of monitoring and recording ozone concentrations in real time was used to inactivate a series of enveloped and non-enveloped viruses including herpes simplex virus type-1 (HHV-1, strain McIntyre), vesicular stomatitis Indiana virus (VSIV), vaccinia virus (VACV, strain Elstree), adenovirus type-2 (HAdV-2), and the PR8 strain of influenza A virus (FLUAVA/PR/8/34/H1N1; FLUAV). The results of the study showed that ozone exposure reduced viral infectivity by lipid peroxidation and subsequent lipid envelope and protein shell damage. These data suggest that a wide range of virus types can be inactivated in an environment of known ozone exposure.
Assuntos
Desinfetantes/farmacologia , Ozônio/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Vírion/efeitos dos fármacos , Inativação de Vírus , Adenoviridae/efeitos dos fármacos , Adenoviridae/ultraestrutura , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/ultraestrutura , Microscopia Eletrônica de Transmissão , Simplexvirus/efeitos dos fármacos , Simplexvirus/ultraestrutura , Vaccinia virus/efeitos dos fármacos , Vaccinia virus/ultraestrutura , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Vírus da Estomatite Vesicular Indiana/ultraestrutura , Ensaio de Placa Viral , Vírion/ultraestruturaRESUMO
Acute kidney injury, especially early-stage disease, is a common hospital comorbidity requiring timely recognition and treatment. We investigated the effect of daily laboratory alerting of patients at risk for acute kidney injury as measured by documented International Classification of Diseases diagnoses. A quasi-experimental study was conducted at 8 New York hospitals between January 1, 2014, and June 30, 2017. Education of clinical documentation improvement specialists, physicians, and nurses was conducted from July 1, 2014, to December 31, 2014, prior to initiating daily hospital-wide laboratory acute kidney injury alerting on January 1, 2015. Incidence based on documented International Classification of Diseases diagnosis of acute kidney injury and acute tubular necrosis during the intervention periods (3 periods of 6 months each: January 1 to June 30 of 2015, 2016, and 2017) were compared to one preintervention period (January 1, 2014, to June 30, 2014). The sample consisted of 269 607 adult hospital discharges, among which there were 39 071 episodes based on laboratory estimates and 27 660 episodes of documented International Classification of Diseases diagnoses of acute kidney injury or acute tubular necrosis. Documented incidence improved significantly from the 2014 preintervention period (5.70%; 95% confidence interval: 5.52%-5.88%) to intervention periods in 2015 (9.89%; 95% confidence interval, 9.66%-10.12%; risk ratio = 1.73, P < .001), 2016 (12.76%; 95% confidence interval, 12.51%-13.01%; risk ratio = 2.24, P < .001), and 2017 (12.49%; 95% confidence interval, 12.24%-12.74%; risk ratio = 2.19, P < .001). A multifactorial intervention comprising daily laboratory alerting and education of physicians, nurses, and clinical documentation improvement specialists led to increased recognition and clinical documentation of acute kidney injury.
RESUMO
The liver has a nervous system containing both afferent and efferent neurons that are involved in a number of processes. The afferent arm includes the sensation of lipids, glucose, and metabolites (after eating and drinking) and triggers the nervous system to make appropriate physiological changes. The efferent arm is essential for metabolic regulation, modulation of fibrosis and biliary function and the control of a number of other processes. Experimental models have helped us to establish how: (i) the liver is innervated by the autonomic nervous system; and (ii) the cell types that are involved in these processes. Thus, the liver acts as both a sensor and effector that is influenced by neurological signals and ablation. Understanding these processes hold significant implications in disease processes such as diabetes and obesity, which are influenced by appetite and hormonal signals.
Assuntos
Fígado/inervação , Animais , Humanos , Fígado/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso , Neurônios Aferentes/fisiologia , Neurônios Eferentes/fisiologiaRESUMO
Melatonin exerts a multitude of physiological functions including the regulation of the sleep cycle and circadian rhythm. Although the synthesis of melatonin in the pineal gland is regulated by changes in the light/dark cycle, the release of melatonin in the gastrointestinal tract is related to food consumption. Melatonin regulates antioxidative processes and it improves T-helper cell response by stimulating the production of specific cytokines. Melatonin is directly involved in preventing tumor initiation, promotion, and progression in a variety of cancers of the gastrointestinal tract including colorectal cancer, cholangiocarcinoma, hepatocarcinoma, and pancreatic carcinoma. This paper is a review of the literature regarding melatonin in the gastrointestinal tract and as a potential therapy for gastrointestinal cancers.
RESUMO
Secretin is secreted by S cells in the small intestine and affects the function of a number of organ systems. Secretin receptors (SR) are expressed in the basolateral domain of several cell types. In addition to regulating the secretion of a number of epithelia (e.g., in the pancreas and biliary epithelium in the liver), secretin exerts trophic effects in several cell types. In this article, we will provide a comprehensive review on the multiple roles of secretin and SR signaling in the regulation of epithelial functions in various organ systems with particular emphasis in the liver. We will discuss the role of secretin and its receptor in health and biliary disease pathogenesis. Finally, we propose future areas of research for the further evaluation of the secretin/secretin receptor axis in liver pathophysiology.
RESUMO
BACKGROUND: Epidemiological studies have indicated smoking to be a risk factor for the progression of liver diseases. Nicotine is the chief addictive substance in cigarette smoke and has powerful biological properties throughout the body. Nicotine has been implicated in a number of disease processes, including increased cell proliferation and fibrosis in several organ systems. AIMS: The aim of this study was to evaluate the effects of chronic administration of nicotine on biliary proliferation and fibrosis in normal rats. METHODS: In vivo, rats were treated with nicotine by osmotic minipumps for two weeks. Proliferation, α7-nicotinic receptor and profibrotic expression were evaluated in liver tissue, cholangiocytes and a polarized cholangiocyte cell line (normal rat intrahepatic cholangiocyte). Nicotine-dependent activation of the Ca(2+)/IP3/ERK 1/2 intracellular signalling pathway was also evaluated in normal rat intrahepatic cholangiocyte. RESULTS: Cholangiocytes express α7-nicotinic receptor. Chronic administration of nicotine to normal rats stimulated biliary proliferation and profibrotic gene and protein expression such as alpha-smooth muscle actin and fibronectin 1. Activation of α7-nicotinic receptor stimulated Ca(2+)/ERK1/2-dependent cholangiocyte proliferation. CONCLUSION: Chronic exposure to nicotine contributes to biliary fibrosis by activation of cholangiocyte proliferation and expression of profibrotic genes. Modulation of α7-nicotinic receptor signalling axis may be useful for the management of biliary proliferation and fibrosis during cholangiopathies.
Assuntos
Ductos Biliares/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Fígado/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , RNA Mensageiro/análise , Actinas/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Animais , Ductos Biliares/citologia , Ductos Biliares/metabolismo , Colágeno/efeitos dos fármacos , Colágeno/genética , Colágeno/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Fibronectinas/efeitos dos fármacos , Fibronectinas/genética , Fibronectinas/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
Long-term smoking is major risk factor for a variety of cancers, including those of the gastrointestinal (GI) tract. Historically, nicotine and its derivatives are well known for their role in addiction, and have more recently been documented for their carcinogenic role in a number of human cancers. The cellular and molecular pathways activated by nicotine mimic physiological and environmental carcinogenesis in cancers throughout the GI tract potentiating cancer growth and/or inducing the formation of cancer on their own. Thus, it is important to unlock the carcinogenic mechanisms induced by nicotine in these systems, and underscore nicotine's potential as an environmental hazard. This review outlines the specific pathways demonstrated to mediate nicotine's carcinogenic mechanism in the GI tract. The abundance of cell and animal evidence calls for increased epidemiologic and case-control evaluation of nicotine's role in cancer.