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1.
Cell Host Microbe ; 27(1): 25-40.e6, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31866426

RESUMO

Although a link between the gut microbiota and alcohol-related liver diseases (ALDs) has previously been suggested, the causative effects of specific taxa and their functions have not been fully investigated to date. Here, we analyze the gut microbiota of 410 fecal samples from 212 Korean twins by using the Alcohol Use Disorders Identification Test (AUDIT) scales to adjust for host genetics. This analysis revealed a strong association between low AUDIT scores and the abundance of the butyrate-producing genus Roseburia. When Roseburia spp. are administered to ALD murine models, both hepatic steatosis and inflammation significantly improve regardless of bacterial viability. Specifically, the flagellin of R. intestinalis, possibly through Toll-like receptor 5 (TLR5) recognition, recovers gut barrier integrity through upregulation of the tight junction protein Occludin and helps to restore the gut microbiota through elevated expression of IL-22 and REG3γ. Our study demonstrates that Roseburia spp. improve the gut ecosystem and prevent leaky gut, leading to ameliorated ALDs.


Assuntos
Clostridiales/metabolismo , Fígado Gorduroso Alcoólico/terapia , Microbioma Gastrointestinal , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Clostridiales/isolamento & purificação , Disbiose/microbiologia , Fígado Gorduroso Alcoólico/metabolismo , Fezes/microbiologia , Feminino , Flagelina/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Ocludina/metabolismo
2.
In Vivo ; 33(1): 145-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30587615

RESUMO

BACKGROUND/AIM: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) has been increasing. But there is no proper management based on age stratification in elderly patients. Therefore, we evaluated the clinical characteristics and outcomes of elderly HCC patients more than 75 years old in South Korea. PATIENTS AND METHODS: Five hundred and fifty elderly patients with HCC were enrolled and divided into the oldest-old (age ≥85 years), middle-old (age between 80 and 85 years), and young-old groups (age between 75 and 80 years). RESULTS: Fifty-one, 153, and 346 patients were included in the oldest-old (mean age: 87 years), middle-old (mean age: 82 years), and young-old groups (mean age: 77 years), respectively. There was a significantly lower rate of alcohol-related and hepatitis B virus-related diseases in the oldest-old group than in the other groups, whereas there was no significant difference in other characteristics. With increasing age, conservative treatment was predominantly performed. Transarterial chemoembolization was the main modality of active treatment in all groups. In multivariate analysis, the performance score, model for end-stage liver disease score, modified Union for International Cancer Control staging, Barcelona Clinic Liver Cancer staging, presence of portal vein tumor thrombosis, ruptured HCC, and active treatment were risk factors of overall survival. CONCLUSION: When the therapeutic approach is used in elderly patients with HCC, the patient's performance status, liver function, and stage of cancer should be considered, and its use should not be restricted to those of advanced age.


Assuntos
Transtornos Relacionados ao Uso de Álcool/epidemiologia , Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Transtornos Relacionados ao Uso de Álcool/patologia , Transtornos Relacionados ao Uso de Álcool/terapia , Transtornos Relacionados ao Uso de Álcool/virologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Quimioembolização Terapêutica , Feminino , Vírus da Hepatite B/patogenicidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virologia , Masculino , Estadiamento de Neoplasias , República da Coreia , Fatores de Risco , Resultado do Tratamento
3.
ACS Chem Neurosci ; 9(7): 1616-1624, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29708326

RESUMO

Ethanol is a principle ingredient of alcoholic beverages with potential neurotoxicity and genotoxicity, and the ethanol-associated oxidative DNA damage in the central nervous system is well documented. Natural source compounds may offer new options to protect the brain against ethanol-induced genotoxicity. Veratrum maackii Regel is a toxic rangeland plant linked to teratogenicity which is also used in traditional Chinese medicine as "Lilu" and is reported to contain a family of compounds called stilbenes that can have positive biological activity. In this study, nine stilbenes were isolated from the aerial parts of V. maackii Regel, and their structures were identified as cis-mulberroside A (1), resveratrol-4,3'- O-ß-d-diglucopyranoside (2), mulberroside A (3), gentifolin K (4), resveratrol-3,5- O-ß-d-diglucopyranoside (5), oxyresveratrol- 4'- O-ß-d-glucopyranoside (6), oxyresveratrol-3- O-ß-d-glucopyranoside (7), oxyresveratrol (8), and resveratrol (9) using ESI-MS and NMR techniques. The total concentration of extracted compounds 2-9 was 2.04 mg/g, suggesting that V. maackii Regel is a novel viable source of these compounds. In an in vivo comet assay, compounds 1-9 were observed to decrease DNA damage in mouse cerebellum and cerebral cortex caused by acute ethanol administration. Histological observation also revealed decreased brain injury in mice administered with compounds 1-9 after acute ethanol administration. The protective effects of compound 6 were associated with increasing T-SOD and GSH-PX activities and a decrease in NO and MDA concentrations. These findings suggest that these compounds are potent inhibitors of ethanol-induced brain injury possibly via the inhibition of oxidative stress and may be valuable leads for future therapeutic development.


Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Etanol/efeitos adversos , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Veratrum , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Masculino , Camundongos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fototerapia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Distribuição Aleatória , Estilbenos/química , Estilbenos/isolamento & purificação
4.
Transl Psychiatry ; 7(11): 1265, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29187748

RESUMO

Depending on the traumatic event, a significant fraction of trauma survivors subsequently develop PTSD. The additional variability in PTSD risk is expected to arise from genetic susceptibility. Unfortunately, several genome-wide association studies (GWAS) have failed to identify a consistent genetic marker for PTSD. The heritability of intermediate phenotypes such as regional brain volumes is often 80% or higher. We conducted a GWAS of subcortical brain volumes in a sample of recent military veteran trauma survivors (n = 157), grouped into PTSD (n = 66) and non-PTSD controls (n = 91). Covariates included PTSD diagnosis, sex, intracranial volume, ancestry, childhood trauma, SNP×PTSD diagnosis, and SNP×childhood trauma. We identified several genetic markers in high linkage disequilibrium (LD) with rs9373240 (p = 2.0 × 10-7, FDR q = 0.0375) that were associated with caudate volume. We also observed a significant interaction between rs9373240 and childhood trauma (p-values = 0.0007-0.002), whereby increased trauma exposure produced a stronger association between SNPs and increased caudate volume. We identified several SNPs in high LD with rs34043524, which is downstream of the TRAM1L1 gene that were associated with right lateral ventricular volume (p = 1.73 × 10-7; FDR q = 0.032) and were also associated with lifetime alcohol abuse or dependence (p = 2.49 × 10-7; FDR q = 0.0375). Finally, we identified several SNPs in high LD with rs13140180 (p = 2.58 × 10-7; FDR q = .0016), an intergenic region on chromosome 4, and several SNPs in the TMPRSS15 associated with right nucleus accumbens volume (p = 2.58 × 10-7; FDR q = 0.017). Both TRAM1L1 and TMPRSS15 have been previously implicated in neuronal function. Key results survived genome-wide multiple-testing correction in our sample. Leveraging neuroimaging phenotypes may offer a shortcut, relative to clinical phenotypes, in mapping the genetic architecture and neurobiological pathways of PTSD.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância , Transtornos Relacionados ao Uso de Álcool/genética , Transtornos Relacionados ao Uso de Álcool/patologia , Núcleo Caudado/patologia , Estudo de Associação Genômica Ampla/métodos , Ventrículos Laterais/patologia , Núcleo Accumbens/patologia , Trauma Psicológico/genética , Trauma Psicológico/patologia , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/patologia , Veteranos , Adulto , Transtornos Relacionados ao Uso de Álcool/diagnóstico por imagem , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Trauma Psicológico/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem
5.
Handb Clin Neurol ; 145: 175-180, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28987168

RESUMO

Alcohol abuse and dependence are serious medical and economic problems in Western countries. Brain changes encountered in alcoholism are manifold and encompass brain atrophy, selective neuronal loss, astroglial, and microglial changes. Alcohol-related disorders are complex multifactorial disorders where the interaction of multiple genes and environment plays an important role in the pathogenesis.


Assuntos
Transtornos Relacionados ao Uso de Álcool , Encefalopatias/etiologia , Encefalopatias/patologia , Encéfalo/patologia , Transtornos Relacionados ao Uso de Álcool/complicações , Transtornos Relacionados ao Uso de Álcool/patologia , Humanos
6.
Brain Res ; 1676: 83-90, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28912059

RESUMO

Excessive ethanol (EtOH) intake, especially to prenatal exposure, can significantly affect cognitive function and cause permanent learning and memory injures in children. As a result, how to protect children from EtOH neurotoxicity has gained increasing attention in recent years. Piracetam (Pir) is a nootropic drug derived from c-aminobutyric acid and can manage cognition impairments in multiple neurological disorders. Studies have shown that Pir can exert therapeutic effects on EtOH-induced memory impairments, but the underlying mechanism is still unknown. In this study, we found that Pir inhibited ethanol-induced memory deficit by mediating multiple pathways. Treatment with EtOH could cause cognitive deficit in juvenile rats, and triggered the alteration of synaptic plasticity. Administration with Pir significantly increased long-term potentiation and protected hippocampus neurons from EtOH neurotoxicity. Pir intervention ameliorated EtOH-induced cell apoptosis and inhibited the activation of Caspase-3 in vitro, suggesting that Pir protected neurons by anti-apoptotic effects. Pir could decrease the expression of LC3-II and Beclin-1 induced by EtOH, and increase the phosphorylation of mTOR and reduce the phosphorylation of Akt, which suggested that the protective effect of Pir was involved in regulation of autophagic process and mTOR/Akt pathways. In conclusion, we speculate that Pir reduces EtOH-induced neuronal damage by regulation of apoptotic action and autophagic action, and our research offers preclinical evidence for the application of Pir in ethanol toxicity.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Piracetam/farmacologia , Transtornos Relacionados ao Uso de Álcool/patologia , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos
7.
eNeuro ; 4(4)2017.
Artigo em Inglês | MEDLINE | ID: mdl-28785727

RESUMO

Pain is often described as a "biopsychosocial" process, yet social influences on pain and underlying neural mechanisms are only now receiving significant experimental attention. Expression of pain by one individual can be communicated to nearby individuals by auditory, visual, and olfactory cues. Conversely, the perception of another's pain can lead to physiological and behavioral changes in the observer, which can include induction of hyperalgesia in "bystanders" exposed to "primary" conspecifics in which hyperalgesia has been induced directly. The current studies were designed to investigate the neural mechanisms responsible for the social transfer of hyperalgesia in bystander mice housed and tested with primary mice in which hyperalgesia was induced using withdrawal (WD) from voluntary alcohol consumption. Male C57BL/6J mice undergoing WD from a two-bottle choice voluntary alcohol-drinking procedure served as the primary mice. Mice housed in the same room served as bystanders. Naïve, water-drinking controls were housed in a separate room. Immunohistochemical mapping identified significantly enhanced Fos immunoreactivity (Fos-ir) in the anterior cingulate cortex (ACC) and insula (INS) of bystander mice compared to naïve controls, and in the dorsal medial hypothalamus (DMH) of primary mice. Chemogenetic inactivation of the ACC but not primary somatosensory cortex reversed the expression of hyperalgesia in both primary and bystander mice. These studies point to an overlapping neural substrate for expression of socially transferred hyperalgesia and that expressed during alcohol WD.


Assuntos
Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Giro do Cíngulo/fisiopatologia , Hiperalgesia/fisiopatologia , Comportamento Social , Síndrome de Abstinência a Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/patologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Modelos Animais de Doenças , Giro do Cíngulo/patologia , Hiperalgesia/patologia , Hiperalgesia/psicologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Síndrome de Abstinência a Substâncias/psicologia
8.
Neuropharmacology ; 125: 376-385, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28807677

RESUMO

It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro-inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels. Further, along with Pde4b, there was a robust activation of astrocytes and microglia accompanied by significant increases in the inflammatory cytokines (Tnfα, Il-1ß, Mcp-1 and Il-17) and the generalized inflammatory marker Cox-2. At the cellular level, alcohol and inflammatory mediators, particularly LPS, Tnfα and Hmgb1 significantly activated microglial cells (Iba-1 expression) and selectively induced Pde4b expression with a minimal to no change in Pde4a and d isoforms. In comparison, the alcohol-induced decrease in brain cAMP levels was completely inhibited in WT mice treated with the Pde4 specific pharmacologic inhibitor rolipram and in Pde4b-/- mice. Moreover, all the observed markers of alcohol-induced brain inflammation were markedly attenuated. Importantly, glial cell activation induced by systemic endotoxemia (LPS administration) was also markedly decreased in Pde4b-/- mice. Taken together, these findings strongly support the notion that Pde4b plays a critical role in coordinating alcohol-induced, peripheral endotoxemia mediated neuro-inflammation and could serve as a significant therapeutic target.


Assuntos
Transtornos Relacionados ao Uso de Álcool/enzimologia , Transtornos Relacionados ao Uso de Álcool/imunologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inflamação/enzimologia , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/enzimologia , Astrócitos/imunologia , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/imunologia , Encéfalo/patologia , Células Cultivadas , Depressores do Sistema Nervoso Central/administração & dosagem , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/enzimologia , Microglia/imunologia , Microglia/patologia , Inibidores da Fosfodiesterase 4/farmacologia , RNA Mensageiro/metabolismo , Rolipram/farmacologia
9.
Neuroscience ; 340: 530-541, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-27871891

RESUMO

Nonsynaptic mechanism changes, particularly the enhancement of NKCC1 expression in the dentate gyrus (DG) after 4weeks of ethanol consumption, motivate the present work, in which rats were submitted to a period of chronic consumption (12weeks). Four groups of six animals (6-week-old male Wistar rats) were formed, including the control (C), ethanol 1 (E1), ethanol 2 (E2) and ethanol 3 (E3) groups. The rats in the E1, E2 and E3 groups were treated daily with a 30% v/v solution of ethanol, administered via oral gavage (1.0, 2.0 and 3.0g/kg, respectively). Nonsynaptic epileptiform activities (NEA) were induced by means of the zero-Ca2+ and high-K+ model using hippocampal slices and were recorded in the DG. The presence of NKCC1, KCC2, α1-Na+/K+-ATPase and GFAP immunoreactivity was analyzed. The results demonstrate that alcohol consumption changes NEA, and these changes are more prominent at the lower dosage. An increase in the DC shifts associated with epileptiform discharges was present with the low dose. This increase was correlated with the increment of NKCC1 expression. Confocal microscopy images indicate the NKCC1 increase was pronounced in the initial axonal segment of granule cells. The blockage of these cotransporters during NEA induction with bumetanide suppressed the DC shift increase and diminished all parameters of NEA that were quantified for all groups treated with ethanol. Therefore, the increase in NKCC1 expression and the effective activity of this cotransporter, which were observed in the treated groups, suggest that drugs that act for block NKCC1 represent promising strategies for diminishing the effects of alcohol damage on the brain.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Epilepsia/metabolismo , Hipocampo/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Simportadores/metabolismo , Transtornos Relacionados ao Uso de Álcool/complicações , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Bumetanida/farmacologia , Depressores do Sistema Nervoso Central/toxicidade , Relação Dose-Resposta a Droga , Epilepsia/etiologia , Epilepsia/patologia , Etanol/toxicidade , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Ratos Wistar , Receptores de GABA-A/metabolismo , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Técnicas de Cultura de Tecidos
10.
Alcohol Clin Exp Res ; 40(8): 1633-40, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27388583

RESUMO

BACKGROUND: Epigenetic factors, including DNA methylation, play an important role in the etiology of alcohol use disorders (AUDs). Noncandidate-based methylome-wide studies leveraging multiple tissue types are needed in order to identify a set of CpG targets that reliably differentiate AUD patients from controls and strongly correlate across brain tissue and more commonly collected tissue types (e.g., buccal cells). METHODS: Postmortem precuneus brain tissue samples were collected from 49 alcohol-dependent (AD) cases and 47 controls (sample I), and DNA was extracted from precuneus and putamen brain tissue and buccal cells in 24 postmortem subjects (sample II). Methylation levels were analyzed at over 450,000 CpG sites in both samples. CpGs that demonstrated significant methylation differences between cases and controls were advanced for further analysis with the goal of identifying CpGs that also demonstrated consistent methylation correlations across tissue type. RESULTS: In the primary analysis, 244 hypomethylated and 188 hypermethylated CpGs met a priori criteria for both significant methylation differences between cases and controls as well as significant correlation across brain and buccal cell tissue types, employing stringent Bonferroni p-value correction. Many of these CpGs were involved in gene networks related to lipid metabolism, immune response, inflammatory response/disease, and gastro-intestinal disease. CONCLUSIONS: More than 400 CpGs demonstrated differences in methylation between AD cases and controls and showed significant correlation across tissue types. Several genes and pathways (e.g., inflammation and immune functioning) that have been previously associated with AUD were identified in the current analyses.


Assuntos
Transtornos Relacionados ao Uso de Álcool/genética , Transtornos Relacionados ao Uso de Álcool/patologia , Encéfalo/patologia , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Adulto , Ilhas de CpG/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Alcohol ; 52: 33-39, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27139235

RESUMO

The New South Wales Brain Tissue Resource Centre (NSWBTRC) at the University of Sydney (Australia) is an established human brain bank providing tissue to the neuroscience research community for investigations on alcohol-related brain damage and major psychiatric illnesses such as schizophrenia. The NSWBTRC relies on wide community engagement to encourage those with and without neuropsychiatric illness to consent to donation through its allied research programs. The subsequent provision of high-quality samples relies on standardized operational protocols, associated clinical data, quality control measures, integrated information systems, robust infrastructure, and governance. These processes are continually augmented to complement the changes in internal and external governance as well as the complexity and diversity of advanced investigation techniques. This report provides an overview of the dynamic process of brain banking and discusses the challenges of meeting the future needs of researchers, including synchronicity with other disease-focus collections.


Assuntos
Transtornos Relacionados ao Uso de Álcool/patologia , Pesquisa Biomédica/métodos , Encéfalo/patologia , Transtornos Mentais/patologia , Bancos de Tecidos , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Pesquisa Biomédica/normas , Dissecação/métodos , Dissecação/normas , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , New South Wales/epidemiologia , Inquéritos e Questionários , Bancos de Tecidos/normas , Adulto Jovem
12.
Brain Res Bull ; 125: 53-78, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27093941

RESUMO

Ethanol-induced behavioral sensitization (EBS) was first described in 1980, approximately 10 years after the phenomenon was described for psychostimulants. Ethanol acts on γ-aminobutyric acid (GABA) and glutamate receptors as an allosteric agonist and antagonist, respectively, but it also affects many other molecular targets. The multiplicity of factors involved in the behavioral and neurochemical effects of ethanol and the ensuing complexity may explain much of the apparent disparate results, found across different labs, regarding ethanol-induced behavioral sensitization. Although the mesocorticolimbic dopamine system plays an important role in EBS, we provide evidence of the involvement of other neurotransmitter systems, mainly the glutamatergic, GABAergic, and opioidergic systems. This review also analyses the neural underpinnings (e.g., induction of cellular transcription factors such as cyclic adenosine monophosphate response element binding protein and growth factors, such as the brain-derived neurotrophic factor) and other factors that influence the phenomenon, including age, sex, dose, and protocols of drug administration. One of the reasons that make EBS an attractive phenomenon is the assumption, firmly based on empirical evidence, that EBS and addiction-related processes have common molecular and neural basis. Therefore, EBS has been used as a model of addiction processes. We discuss the association between different measures of ethanol-induced reward and EBS. Parallels between the pharmacological basis of EBS and acute motor effects of ethanol are also discussed.


Assuntos
Transtornos Relacionados ao Uso de Álcool/patologia , Encéfalo , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Transtornos Relacionados ao Uso de Álcool/história , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , História do Século XX , Humanos , Recompensa
13.
Drug Alcohol Depend ; 162: 124-9, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27038675

RESUMO

BACKGROUND: Alcohol abuse impacts innate and adaptive immunity and predisposes to infections. However, prevalence and correlations of cellular immune alterations in large case series is underreported. We aimed to analyze quantitative alterations of T-lymphocyte subpopulations in patients with alcohol use disorder (AUD). METHODS: cross-sectional study in patients admitted for detoxification between January 1, 2002 and December 31, 2012. Socio-demographic and alcohol use characteristics and blood samples for biochemistry, hematology and immune phenotype was obtained at admission. RESULTS: 238 patients (79.8%M) were eligible; age at admission was 43 years (interquartile range [IQR]: 38-51 years), the amount of alcohol consumption was 180 g/day (IQR: 120-200 g/day) and median duration of AUD was 18 years (IQR: 9-25 years). Compared to healthy individuals, 50% of patients had significantly fewer double-negative (DN) T-lymphocytes (<34 × 10(9)/L) and 23% had more double-positive (DP) T-cells (>52 × 10(9)/L). In addition, 24% of patients had high number of CD8(+) cells (>735 × 10(9)/L) and 13% had low CD4(+) cell counts (<600 × 10(9)/L). In multivariable analysis, age, sex, serum albumin, and current cocaine use were predictors of T-cell subpopulation alterations. Women were three-times (OR=3.5, 95%CI:1.3-9.5) more likely to present with higher DP T-lymphocytes than men. CONCLUSIONS: Quantitative alterations of T-cell subpopulations are frequent in patients seeking treatment of AUD. Assessment of cellular immunity in this population may help to identify those at increased risk of immune alterations.


Assuntos
Transtornos Relacionados ao Uso de Álcool/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Adulto , Consumo de Bebidas Alcoólicas/imunologia , Consumo de Bebidas Alcoólicas/patologia , Transtornos Relacionados ao Uso de Álcool/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais
14.
Neuropharmacology ; 107: 58-67, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26921770

RESUMO

There has been increasing interest in the rostromedial tegmental nucleus (RMTg), given its potential regulatory role in many aversion-related behaviors. The RMTg contains mostly GABAergic neurons, sends a dense inhibitory projection to dopamine neurons in the midbrain, and is rich with µ-opioid receptors (MOR). Like most addictive drugs, ethanol has both aversive and rewarding properties. However, the cellular mechanisms underlying the effects of ethanol, particularly the aversive effect that limits its intake are not well understood. Recent studies have linked aversion with synaptic inhibition of dopamine neurons in the ventral tegmental area. To determine a potential role that the RMTg plays in the effect of ethanol, in this study, we employed a neurotoxin, dermorphin-saporin (DS), to lesion RMTg neurons prior to assessing ethanol-related behaviors. Rats were infused with DS bilaterally into the RMTg. This manipulation substantially increased the intake and preference for ethanol but not sucrose. It also reduced the number of neurons with MOR and glutamic acid decarboxylase 67 immunoreactivity within the RMTg. These changes did not occur after intra-RMTg infusion of blank saporin or vehicle. Importantly, intra-RMTg DS infusion significantly enhanced expression of conditioned place preference induced by ethanol (2 g/kg, i.p.), and slowed the extinction process. These results suggest that MOR-expressing GABAergic neurons in the RMTg contribute significantly to the regulation of ethanol consumption and related behaviors.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Neurônios GABAérgicos/metabolismo , Receptores Opioides mu/metabolismo , Tegmento Mesencefálico/metabolismo , Consumo de Bebidas Alcoólicas/patologia , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , /fisiologia , Modelos Animais de Doenças , Etanol/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Glutamato Descarboxilase/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Peptídeos Opioides , Distribuição Aleatória , Ratos Sprague-Dawley , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Autoadministração , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Tegmento Mesencefálico/efeitos dos fármacos , Tegmento Mesencefálico/patologia
15.
Morfologiia ; 150(4): 20-3, 2016.
Artigo em Russo | MEDLINE | ID: mdl-30136817

RESUMO

Analysis of cytoarchitectonics of the basolateral nucleus (BLN) of the brain amygdala was performed in cresyl violetstained frontal paraffin sections of the brain in 10 alcoholpreferring (AP) and 10 alcohol-nonpreferring (ANP) rats (with an equal number of male and female animals in each group). The presence of large and small neurons was detected in BLN. Most of the large neurons in AP rats had the character of chromoneutral and moderately chromophilic cells, while in ANP rats these cells were moderately chromophobic. Application of Golgi method demonstrated that the equivalents of large neurons were long-axonal densely branched pyramid-like neurons, and those of small-sized neurons ­ short-axonal neurons. The determination of the ratio of large and smallsized neurons showed that in AP rats the proportion of latter was 12.3±0.6%, while in the ANP rats it was significantly greater ­ 19.70±0.23%. These results help to explain the previously obtained data on larger specific area of BLN in amygdala of ANP rats by the presence of greater number of interneurons than in AP rats.


Assuntos
Transtornos Relacionados ao Uso de Álcool , Complexo Nuclear Basolateral da Amígdala , Células Piramidais , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/patologia , Feminino , Masculino , Células Piramidais/metabolismo , Células Piramidais/patologia , Ratos
16.
Neuropsychobiology ; 74(3): 131-138, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28441648

RESUMO

OBJECTIVE: Natriuretic peptides participate in the collection of metabolic effects during alcohol withdrawal. Having witnessed modulation of other natriuretic peptides in alcohol-dependent patients during alcohol withdrawal, we were interested in the relation of brain natriuretic peptide (BNP) methylation with protein expression and craving in this longitudinal study. METHODS: Ninety-nine male patients were compared to 101 healthy controls concerning epigenetic regulation and protein expression during detoxification treatment. RESULTS: With BNP expression being GATA4 dependent, we observed a correlation of GATA4 binding site methylation and protein expression. BNP serum levels and Obsessive Compulsive Drinking Scale scores are significantly decreased during withdrawal. Focusing on the two CpGs that are between GATA transcription factor binding sites, statistical analysis revealed a reversely proportional methylation pattern, significantly increasing with ongoing detoxification and thereby supporting the observed serum level changes. CONCLUSION: Without the functional knowledge about regulation of BNP expression via the GATA transcription factor, it would have been easy to take the mean results of the global CpG data and propose a direct relationship between methylation and expression. Thus, these findings are a voice for functionally and mechanistically approved results. There was no causal relationship between protein expression levels and epigenetic changes. Further research is needed which includes protein expression and other approaches.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/patologia , Fator de Transcrição GATA4/genética , Peptídeo Natriurético Encefálico/metabolismo , Adolescente , Adulto , Transtornos Relacionados ao Uso de Álcool/genética , Sítios de Ligação/genética , Fissura/fisiologia , Citosina/análogos & derivados , Citosina/metabolismo , Metilação de DNA , Epigênese Genética , Feminino , Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
17.
Alcohol ; 49(7): 639-46, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26537482

RESUMO

Long-term heavy alcohol consumption has traditionally been associated with impaired cognitive abilities, such as deficits in abstract reasoning, problem solving, verbal fluency, memory, attention, and visuospatial processing. The present study aimed at exploring these neuropsychological deficits in alcohol-use disorders (AUD) in an Indian population using the Postgraduate Institute Battery of Brain Dysfunction (PGIBBD) and their possible correlation with alterations in T2 relaxation times (T2-RT), using whole-brain voxel-based relaxometry (VBR) and conventional region of interest (ROI) approach. Multi-echo T2 mapping sequence was performed on 25 subjects with AUD and 25 healthy controls matched for age, education, and socioeconomic status. Whole-brain T2-RT measurements were conducted using VBR and conventional ROI approach. The study was carried out on a 3T whole-body MR scanner. Post processing for VBR and ROI analysis was performed using SPM 8 software and vendor-provided software, respectively. A PGIBBD test battery was conducted on all subjects to assess their cognitive abilities, and the results were reported as raw scores. VBR and ROI results revealed that AUD subjects showed prolonged T2-RTs in cerebellum bilaterally, parahippocampal gyrus bilaterally, right anterior cingulate cortex, left superior temporal gyrus, left middle frontal gyrus, and left calcarine gyrus. A significant correlation was also observed between the neuropsychological test raw scores and alterations in T2-RT in AUD subjects. Our results are consistent with previous studies suggesting tissue disruption or gliosis or demyelination as a possible reason for prolonged T2-RTs. This damage to brain tissue, which is evident as prolonged T2-RT, could possibly be associated with impaired cognitive abilities noticeable in AUD subjects.


Assuntos
Transtornos Relacionados ao Uso de Álcool/patologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Alcoolismo/patologia , Alcoolismo/psicologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Adulto , Encéfalo/patologia , Mapeamento Encefálico , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/psicologia , Feminino , Gliose/patologia , Gliose/psicologia , Humanos , Processamento de Imagem Assistida por Computador , Índia , Testes de Inteligência , Imagem por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto Jovem
18.
BMC Neurosci ; 16: 55, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26341662

RESUMO

BACKGROUND: There is currently a lack of reliable, minimally invasive biomarkers that could predict the extent of alcoholism-induced CNS damage. Developing such biomarkers may prove useful in reducing the prevalence of alcohol use disorders (AUDs). Extracellular microRNAs (miRNAs) can be informative molecular indicators of changes in neuronal gene expression. In this study, we performed a global analysis of extracellular miRNAs to identify robust biomarkers of early CNS damage in humans diagnosed with DSM-IV AUDs. We recruited a relatively young set of 20 AUD subjects and 10 age-matched controls. They were subjected to comprehensive medical, neuropsychological and neuroimaging tests, followed by comparison of miRNA levels found in peripheral blood serum. Employing a conservative strategy to identify candidate biomarkers, miRNAs were quantified using two independent high-throughput methods: microarray and next-generation RNA-sequencing. This improved our capacity to discover and validate relevant miRNAs. RESULTS: Our results identified several miRNAs with significant and reproducible expression changes in AUD subjects versus controls. Moreover, several significant associations between candidate miRNA biomarkers and various medical, neuropsychological and neuroimaging parameters were identified using Pearson correlation and unbiased hierarchical clustering analyses. Some of the top candidate biomarkers identified, such as mir-92b and mir-96 have established roles in neural development. Cross-species validation of miRNA expression was performed using two different in vivo rat drinking models and two different in vitro mouse neural stem cell exposure models. A systems level analysis revealed a remarkable degree of convergence in the top changes seen in all of these data sets, specifically identifying cell death, cell proliferation and cell cycle processes as most consistently affected. Though not necessarily the same molecules, the affected miRNAs within these pathways clearly influence common genes, such as p53 and TNF, which stand out as potential keystone molecules. Lastly, we also examined the potential tissue origins of these biomarkers by quantifying their levels in 15 different tissue types and show that several are highly-enriched in the brain. CONCLUSIONS: Collectively, our results suggest that serum miRNA expression changes can directly relate to alterations in CNS structure and function, and may do so through effects on highly specific cellular pathways.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/patologia , Encéfalo/metabolismo , Encéfalo/patologia , MicroRNAs/sangue , Adulto , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Morte Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/efeitos adversos , Modelos Animais de Doenças , Etanol/administração & dosagem , Etanol/efeitos adversos , Estudos de Viabilidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imageamento Tridimensional , Imagem por Ressonância Magnética , Masculino , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Testes Neuropsicológicos , Ratos Long-Evans
19.
Psicol. conduct ; 23(2): 325-343, mayo-ago. 2015. tab
Artigo em Espanhol | IBECS | ID: ibc-151100

RESUMO

Este estudio tuvo como objetivo evaluar la autoeficacia de consumidores de heroína y alcohol que están en tratamiento para su adicción, a partir de los modelos teóricos propuestos por Bandura y Annis. Participaron 162 pacientes ambulatorios, asignados a uno de los tres grupos de tratamiento: con metadona, libre de drogas y para el consumo de alcohol. Los sujetos fueron evaluados con la "Escala de autoeficacia" (Sherer et al., 1982), el "Cuestionario de confianza situacional" (IDTS; Annis y Martin, 1985) y la "Entrevista de investigación acerca del comportamiento adictivo" (EICA; López-Torrecillas, 1996). Los grupos con metadona y libre de drogas obtuvieron puntuaciones más altas en autoeficacia (general y total) que el grupo de alcohol y el grupo con metadona obtuvo puntuaciones más bajas en confianza situacional que el grupo libre de drogas y el grupo de alcohol, obteniendo este último las puntuaciones más altas. Los resultados parecen indicar que los modelos hacen referencia a aspectos diferentes de la autoeficacia. Serán necesarias más investigaciones para analizar la naturaleza de esta diferencia


The aim of this study was to examine the self-efficacy of outpatient drug heroin and alcohol abusers in treatment for their addiction, using the theoretical models proposed by Bandura and Annis. The sample consisted of 162 participants, who were assigned to one of three treatment groups: methadone, drug-free and alcohol. The Self-Efficacy Scale (Sherer et al., 1982), the Inventory of Drug-Taking Situation (IDTS; Annis & Martin, 1985) and the Interview for Research on Addictive Behavior (EICA; López-Torrecillas, 1996) were used to assess them. Methadone and the drug-free groups had higher scores of selfefficacy (general and total score) than the alcohol group. Methadone group showed lower scores in situational confidence that free drug and the alcohol groups, the latter showing highest scores. The results suggest that the models refer to different aspects of self-efficacy. More research is necessary to analyze the nature of this difference


Assuntos
Humanos , Masculino , Feminino , Autoeficácia , Confiança/psicologia , Metadona/administração & dosagem , Metadona/farmacologia , Metadona/uso terapêutico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Usuários de Drogas/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Consumo de Bebidas Alcoólicas/terapia , Transtornos Relacionados ao Uso de Álcool/patologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Transtornos Relacionados ao Uso de Álcool/terapia , Transtornos Psicóticos/terapia , Psicopatologia/instrumentação , Psicopatologia/métodos , Psicopatologia/tendências
20.
J Prev Med Public Health ; 48(3): 142-50, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26081651

RESUMO

OBJECTIVES: The purpose of this study was to investigate the association between suicidal behavior and patterns of alcohol consumption in Korean adults. METHODS: This study was based on data provided by the Korea National Health and Nutritional Examination Survey from 2007 to 2011. A total of 42 347 subjects were included in the study, of whom 19 292 were male and 23 055 were female. Logistic regression analysis was performed to assess the association between patterns of alcohol consumption and suicidal behavior. RESULTS: Among the study subjects, 1426 males (11.3%) and 3599 females (21.2%) had experienced suicidal ideation, and 106 males (0.8%) and 190 females (1.1%) had attempted suicide during the previous 12 months. Alcohol Use Disorders Identification Test (AUDIT) scores were found to be associated with suicidal ideation in males and associated with both suicidal ideation and suicide attempts in females. Alcoholic blackouts were associated with suicidal ideation and suicide attempts in males, and were also associated with suicidal ideation in females. CONCLUSIONS: In this study, we found that certain patterns of alcohol consumption were associated with suicidal behaviors. In particular, only alcoholic blackouts and categorized AUDIT scores were found to be associated with suicidal behavior in males. We therefore suggest that further research is needed to examine this relationship prospectively and in other settings.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Tentativa de Suicídio/psicologia , Adulto , Idoso , Transtornos Relacionados ao Uso de Álcool/patologia , Grupo com Ancestrais do Continente Asiático , Demografia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , República da Coreia , Fatores Sexuais , Ideação Suicida , Tentativa de Suicídio/estatística & dados numéricos
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