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[PMID]:27771175
[Au] Autor:Chang C; Gau SS; Huang WS; Shiue CY; Yeh CB
[Ad] Endereço:Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
[Ti] Título:Abnormal serotonin transporter availability in the brains of adults with conduct disorder.
[So] Source:J Formos Med Assoc;116(6):469-475, 2017 Jun.
[Is] ISSN:0929-6646
[Cp] País de publicação:Singapore
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/PURPOSE: The aims of the current study were to determine whether patients with conduct disorder (CD) showed an abnormal availability of serotonin reuptake transporter (SERT), and if their hyperkinetic symptoms, impulsivity, and quality of life were correlated with the availability of SERT. METHODS: We recruited 14 drug-naïve patients with CD and eight age-matched healthy controls (HCs). The adult attention-deficit/hyperactivity disorder (ADHD) self-report scale (ASRS), Barrett impulsivity scale (BIS), and the World Health Organization quality of life-brief version (WHOQOL-BREF) scale were administered. Positron emission tomography (PET) of the brain with 4-[ F]-ADAM was arranged for SERT imaging. RESULTS: SERT availability was significantly reduced in the striatum and midbrain of patients with CD. Quality of life and inattention symptoms were also significantly correlated with the availability of SERT in the prefrontal cortex. CONCLUSION: The study suggested that a reduction in the availability of SERT might be associated with CD and could potentially predict poor quality of life or symptoms of inattention for these patients. The implications of our results might be limited to individuals with CD; a future study with a larger sample to validate our preliminary results is warranted.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Transtorno da Conduta/metabolismo
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
[Mh] Termos MeSH secundário: Adulto
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo
Encéfalo/diagnóstico por imagem
Estudos de Casos e Controles
Seres Humanos
Masculino
Tomografia por Emissão de Pósitrons
Qualidade de Vida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SLC6A4 protein, human); 0 (Serotonin Plasma Membrane Transport Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:29412172
[Au] Autor:Hull JD; Lyon RA
[Ad] Endereço:Procter & Gamble, Greater London Innovation Centre, Egham, Surrey TW20 9NW, UK.
[Ti] Título:In vitro pharmacology of ambroxol: Potential serotonergic sites of action.
[So] Source:Life Sci;197:67-72, 2018 Mar 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Ambroxol is a muco-active agent with multiple, clinically relevant effects in the airway. Despite its widespread use and well documented clinical efficacy, there are few data on its mechanism of action and receptor pharmacology beyond sodium channel blockade and inhibition of guanylate cyclase. Accordingly, in vitro studies were conducted to determine its overall receptor pharmacology and possible sites of action. MATERIALS AND METHODS: In vitro radioligand binding/enzyme inhibition studies were conducted at 62 receptors, ion channels and enzymes using standard techniques. Additional in vitro studies were conducted to establish the potency of ambroxol at selected sites. KEY FINDINGS: These studies indicate that ambroxol has affinity for the 5-HT serotonin receptor, as well as affinity for the 5-HT serotonin transporter (SERT), with IC values of 17,600 nM and 19,500 nM respectively. In vitro functional studies in isolated guinea pig colon indicate that ambroxol is a 5-HT serotonin receptor antagonist with an IC value of 36,000 nM. SIGNIFICANCE: Together, these studies indicate that ambroxol may exert its beneficial properties via antagonism of the 5-HT serotonin receptor and/or inhibition of serotonin uptake (5-HT transport: SERT), in addition to its reported effects at the sodium channel and guanylate cyclase.
[Mh] Termos MeSH primário: Ambroxol
Receptores 5-HT3 de Serotonina/metabolismo
Antagonistas do Receptor 5-HT3 de Serotonina
[Mh] Termos MeSH secundário: Ambroxol/farmacocinética
Ambroxol/farmacologia
Animais
Linhagem Celular Tumoral
Cobaias
Seres Humanos
Camundongos
Proteínas de Ligação a RNA/metabolismo
Ratos
Antagonistas do Receptor 5-HT3 de Serotonina/farmacocinética
Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA-Binding Proteins); 0 (Receptors, Serotonin, 5-HT3); 0 (SERT protein, rat); 0 (SLC6A4 protein, human); 0 (Serotonin 5-HT3 Receptor Antagonists); 0 (Serotonin Plasma Membrane Transport Proteins); 0 (Slc6a4 protein, mouse); 200168S0CL (Ambroxol)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE


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[PMID]:29325311
[Ti] Título:[Effects of trimetazidine, a myocardial metabolism agent, on regulating 5-hydroxytrytamine system of rats with myocardial infarction and/or depression].
[So] Source:Zhonghua Nei Ke Za Zhi;57(1):48-53, 2018 Jan 01.
[Is] ISSN:0578-1426
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:5-Hydroxytrytamine (5-HT) system was reported to be associated with myocardial infarction (MI) and depression. The aim of the present study was to study the effect of trimetazidine on 5-HT in MI and/or depression rats. Ninety rats were divided into three groups: trimetazidine, sertraline and saline groups ( 30 in each group), and pretreated with trimetazidine, sertarline, or saline, respectively, by gavage once a day for 4 weeks. Thereafter, each group was further divided into three subgroups: MI subgroup, depression subgroup, and MI+ depression subgroup. Serum 5-HT, platelet 5-HT, 5-HT(2A) receptor (5-HT(2A)R), and serotonin transporter (SERT) were detected by enzyme linked immunosorbent assay. Similar to sertarline, comparing to saline, trimetazidine treatment increased serum 5-HT [(221±23) pg/ml vs. (176±11) pg/ml; (395±31) pg/ml vs. (195±5) pg/ml; (348±28) pg/ml vs. (183±10) pg/ml], platelet 5-HT [(305±22) pg/ml vs. (130±27) pg/ml; (252±18) pg/ml vs. (175±5) pg/ml; (241±26) pg/ml vs. (181±11) pg/ml], and platelet 5-HT(2A)R levels [(247±13) pg/ml vs. (197±12) pg/ml; (320±13) pg/ml vs. (193±18)pg/ml; (334±17) pg/ml vs. (206±15) pg/ml]), and lowered platelet SERT levels [(248±11) pg/ml vs. (323±36) pg/ml; (188±7) pg/ml vs. (278±20) pg/ml; (170±23) pg/ml vs. (282±22) pg/ml] in MI, depression and MI+ depression subgroups, respectively (all 0.05). When compared the effect of trimetazidine and sertarline treatment, serum 5-HT and platelet 5-HT(2A)R in MI group were significantly lower in trimetazidine than in sertraline group ( 0.05), while serum 5-HT and platelet 5-HT, 5-HT(2A)R in depression group rats were significantly higher in trimetazidine than in sertraline group ( 0.05).Interestingly, platelet 5-HT(2A)R in MI+ depression rats was much higher in trimetazidine than in sertraline group ( 0.05). Trimetazidine, a kind of myocardial metabolism agent, could play a role on the regulation of 5-HT, 5-HT(2A)R, and SERT levels in rats with MI and/or depression.
[Mh] Termos MeSH primário: Depressão/metabolismo
Infarto do Miocárdio/metabolismo
Receptor 5-HT2A de Serotonina/metabolismo
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
Trimetazidina/farmacologia
Vasodilatadores/farmacologia
[Mh] Termos MeSH secundário: Animais
Transtorno Depressivo
Ensaio de Imunoadsorção Enzimática
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, Serotonin, 5-HT2A); 0 (Serotonin Plasma Membrane Transport Proteins); 0 (Vasodilator Agents); N9A0A0R9S8 (Trimetazidine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0578-1426.2018.01.009


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[PMID]:27770470
[Au] Autor:Vanicek T; Kutzelnigg A; Philippe C; Sigurdardottir HL; James GM; Hahn A; Kranz GS; Höflich A; Kautzky A; Traub-Weidinger T; Hacker M; Wadsak W; Mitterhauser M; Kasper S; Lanzenberger R
[Ad] Endereço:Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
[Ti] Título:Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET.
[So] Source:Hum Brain Mapp;38(2):792-802, 2017 02.
[Is] ISSN:1097-0193
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP ) in patients with ADHD and to assess associations of SERT BP between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [ C]DASB. SERT BP maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R = 0.284, R = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem
Transtorno do Deficit de Atenção com Hiperatividade/metabolismo
Encéfalo/diagnóstico por imagem
Tomografia por Emissão de Pósitrons
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
[Mh] Termos MeSH secundário: Adulto
Encéfalo/metabolismo
Estudos de Casos e Controles
Feminino
Seres Humanos
Modelos Lineares
Masculino
Escalas de Graduação Psiquiátrica
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Serotonin Plasma Membrane Transport Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180217
[Lr] Data última revisão:
180217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1002/hbm.23418


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[PMID]:29304146
[Au] Autor:Fumagalli M; Provenzi L; De Carli P; Dessimone F; Sirgiovanni I; Giorda R; Cinnante C; Squarcina L; Pozzoli U; Triulzi F; Brambilla P; Borgatti R; Mosca F; Montirosso R
[Ad] Endereço:NICU, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
[Ti] Título:From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth.
[So] Source:PLoS One;13(1):e0190602, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain.
[Mh] Termos MeSH primário: Encéfalo/crescimento & desenvolvimento
Epigênese Genética
Recém-Nascido Prematuro
[Mh] Termos MeSH secundário: Desenvolvimento Infantil
Metilação de DNA
Emoções
Feminino
Seres Humanos
Lactente
Recém-Nascido
Masculino
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (SLC6A4 protein, human); 0 (Serotonin Plasma Membrane Transport Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190602


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[PMID]:29228944
[Au] Autor:Yang TY; Jang EY; Ryu Y; Lee GW; Lee EB; Chang S; Lee JH; Koo JS; Yang CH; Kim HY
[Ad] Endereço:College of Korean Medicine, Daegu Haany University, Daegu, 42158, South Korea.
[Ti] Título:Effect of acupuncture on Lipopolysaccharide-induced anxiety-like behavioral changes: involvement of serotonin system in dorsal Raphe nucleus.
[So] Source:BMC Complement Altern Med;17(1):528, 2017 Dec 11.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Acupuncture has been used as a common therapeutic tool in many disorders including anxiety and depression. Serotonin transporter (SERT) plays an important role in the pathology of anxiety and other mood disorders. The aim of this study was to evaluate the effects of acupuncture on lipopolysaccharide (LPS)-induced anxiety-like behaviors and SERT in the dorsal raphe nuclei (DRN). METHODS: Rats were given acupuncture at ST41 (Jiexi), LI11 (Quchi) or SI3 (Houxi) acupoint in LPS-treated rats. Anxiety-like behaviors of elevated plus maze (EPM) and open field test (OFT) were measured and expressions of SERT and/or c-Fos were also examined in the DRN using immunohistochemistry. RESULTS: The results showed that 1) acupuncture at ST41 acupoint, but neither LI11 nor SI3, significantly attenuated LPS-induced anxiety-like behaviors in EPM and OFT, 2) acupuncture at ST41 decreased SERT expression increased by LPS in the DRN. CONCLUSIONS: Our results suggest that acupuncture can ameliorate anxiety-like behaviors, possibly through regulation of SERT in the DRN.
[Mh] Termos MeSH primário: Terapia por Acupuntura
Ansiedade/terapia
Comportamento Animal/fisiologia
Núcleo Dorsal da Rafe/metabolismo
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
[Mh] Termos MeSH secundário: Animais
Ansiedade/induzido quimicamente
Modelos Animais de Doenças
Núcleo Dorsal da Rafe/química
Lipopolissacarídeos/efeitos adversos
Masculino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipopolysaccharides); 0 (Serotonin Plasma Membrane Transport Proteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171227
[Lr] Data última revisão:
171227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-2039-y


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[PMID]:28743254
[Au] Autor:Kalungi A; Seedat S; Hemmings SMJ; van der Merwe L; Joloba ML; Nanteza A; Nakassujja N; Birabwa H; Serwanga J; Kaleebu P; Kinyanda E
[Ad] Endereço:Department of Biotechnical and Diagnostic Sciences, College of Veterinary Medicine, Animal Resources and Biosafety (COVAB), Makerere University, Kampala, Uganda. allankalungi1@gmail.com.
[Ti] Título:Association between serotonin transporter gene polymorphisms and increased suicidal risk among HIV positive patients in Uganda.
[So] Source:BMC Genet;18(1):71, 2017 07 25.
[Is] ISSN:1471-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Persons living with HIV/AIDS (PLWHA) are at an increased risk of suicide. Increased suicidal risk is a predictor of future attempted and completed suicides and has been associated with poor quality of life and poor adherence with antiretroviral therapy. Clinical risk factors have low predictive value for suicide, hence the interest in potential neurobiological correlates and specific heritable markers of suicide vulnerability. The serotonin transporter gene has previously been implicated in the aetiology of increased suicidal risk in non-HIV infected study populations and its variations may provide a platform for identifying genetic risk for suicidality among PLWHA. The present cross-sectional study aimed at identifying two common genetic variants of the serotonin transporter gene and their association with increased suicidal risk among human immunodeficiency virus (HIV)-positive adults in Uganda. RESULTS: The prevalence of increased suicidal risk (defined as moderate to high risk suicidality on the suicidality module of the Mini Neuropsychiatric Interview (M.I.N.I) was 3.3% (95% CI, 2.0-5.3). The 5-HTTLPR was found to be associated with increased suicidal risk before Bonferroni correction (p-value = 0.0174). A protective effect on increased suicidal risk was found for the 5-HTTLPR/rs25531 S allele (p-value = 0.0046)- which directs reduced expression of the serotonin transporter gene (5-HTT). CONCLUSION: The S allele at the 5-HTTLPR/rs25531 locus is associated with increased suicidal risk among Ugandan PLWHA. Further studies are needed to validate this finding in Ugandan and other sub-Saharan samples.
[Mh] Termos MeSH primário: Infecções por HIV/complicações
Infecções por HIV/genética
Polimorfismo Genético
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Suicídio
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos Transversais
Feminino
Genótipo
Infecções por HIV/psicologia
HIV-1/isolamento & purificação
Seres Humanos
Masculino
Qualidade de Vida
Fatores de Risco
Suicídio/psicologia
Inquéritos e Questionários
Uganda
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (SLC6A4 protein, human); 0 (Serotonin Plasma Membrane Transport Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171221
[Lr] Data última revisão:
171221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1186/s12863-017-0538-y


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[PMID]:28969722
[Au] Autor:Schepers R; Markus CR
[Ad] Endereço:Department of Neuropsychology & Psychopharmacology, Faculty of Psychology and Neuroscience,University Maastricht,6229 ER Maastricht,The Netherlands.
[Ti] Título:The interaction between 5-HTTLPR genotype and ruminative thinking on BMI.
[So] Source:Br J Nutr;118(8):629-637, 2017 Oct.
[Is] ISSN:1475-2662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Negative affect or stress is often found to increase energy intake for high palatable energy-rich foods and hence weight gain. Reduced brain serotonin (5-HT) function is known to increase stress vulnerability and the risk for eating-related disturbances. A short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) is associated with a less efficient functioning brain serotonin system and therefore higher stress vulnerability. It has been suggested that this genotype may be directly linked to an increased risk for weight gain and/or obesity. However, a high amount of variability has been apparent in replicating such a direct gene on weight gain relationship. A most recent suggestion is that this gene by weight relationship might be moderated by an additional (cognitive) vulnerability factor involving repetitive negative thinking (rumination). Our objective was to investigate whether the S-allele of 5-HTTLPR contributes to weight gain particularly in high cognitive ruminating individuals. A total of 827 healthy young male and female college students (aged 21·3 (sd 3·0) years; BMI 16-41·7 kg/m2) were genotyped for the 5-HTTLPR polymorphism and assessed for rumination (Event Related Ruminative Index) and body weight. In line with the hypothesis, a hierarchical regression model showed that higher BMI scores were observed in specifically high ruminating S'-carriers (P=0·031, f²=0·022). These results suggest that cognitive rumination may be a critical moderator of the association between 5-HTTLPR and body mass.
[Mh] Termos MeSH primário: Índice de Massa Corporal
Polimorfismo Genético
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Estresse Psicológico/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Alelos
Transtornos de Ansiedade/genética
Transtornos de Ansiedade/psicologia
Ingestão de Alimentos/psicologia
Feminino
Frequência do Gene
Genótipo
Técnicas de Genotipagem
Seres Humanos
Masculino
Pessimismo
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
Inquéritos e Questionários
Ganho de Peso
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SLC6A4 protein, human); 0 (Serotonin Plasma Membrane Transport Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1017/S0007114517002562


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[PMID]:28842491
[Au] Autor:Bhat S; Hasenhuetl PS; Kasture A; El-Kasaby A; Baumann MH; Blough BE; Sucic S; Sandtner W; Freissmuth M
[Ad] Endereço:From the Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
[Ti] Título:Conformational state interactions provide clues to the pharmacochaperone potential of serotonin transporter partial substrates.
[So] Source:J Biol Chem;292(40):16773-16786, 2017 Oct 06.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Point mutations in SLC6 transporters cause misfolding, which can be remedied by pharmacochaperones. The serotonin transporter (SERT/SLC6A4) has a rich pharmacology including inhibitors, releasers (amphetamines, which promote the exchange mode), and more recently, discovered partial substrates. We hypothesized that partial substrates trapped the transporter in one or several states of the transport cycle. This conformational trapping may also be conducive to folding. We selected naphthylpropane-2-amines of the phenethylamine library (PAL) including the partial substrate PAL1045 and its congeners PAL287 and PAL1046. We analyzed their impact on the transport cycle of SERT by biochemical approaches and by electrophysiological recordings; substrate-induced peak currents and steady-state currents monitored the translocation of substrate and co-substrate Na across the lipid bilayer and the transport cycle, respectively. These experiments showed that PAL1045 and its congeners bound with different affinities (ranging from nm to µm) to various conformational intermediates of SERT during the transport cycle. Consistent with the working hypothesis, PAL1045 was the most efficacious compound in restoring surface expression and transport activity to the folding-deficient mutant SERT- PG -AA. These experiments provide a proof-of-principle for a rational search for pharmacochaperones, which may be useful to restore function to clinically relevant folding-deficient transporter mutants.
[Mh] Termos MeSH primário: Chaperonas Moleculares/química
Naftóis/química
Proteínas da Membrana Plasmática de Transporte de Serotonina/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Células HEK293
Seres Humanos
Transporte de Íons
Bicamadas Lipídicas/química
Chaperonas Moleculares/farmacologia
Mutação de Sentido Incorreto
Naftóis/farmacologia
Conformação Proteica
Dobramento de Proteína
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
Sódio/química
Sódio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipid Bilayers); 0 (Molecular Chaperones); 0 (Naphthols); 0 (SLC6A4 protein, human); 0 (Serotonin Plasma Membrane Transport Proteins); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.794081


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[PMID]:28716823
[Au] Autor:Mitchell C; McLanahan S; Schneper L; Garfinkel I; Brooks-Gunn J; Notterman D
[Ad] Endereço:University of Michigan, Ann Arbor, Michigan.
[Ti] Título:Father Loss and Child Telomere Length.
[So] Source:Pediatrics;140(2), 2017 Aug.
[Is] ISSN:1098-4275
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND OBJECTIVES: Father loss during childhood has negative health and behavioral consequences, but the biological consequences are unknown. Our goal was to examine how father loss (because of separation and/or divorce, death, or incarceration) is associated with cellular function as estimated by telomere length. METHODS: Data come from the 9-year follow-up of the Fragile Families and Child Wellbeing Study, a birth cohort study of children in 20 large American cities ( = 2420). Principal measures are as follows: salivary telomere length (sTL), mother reports of father loss, and polymorphisms in genes related to serotonergic and dopaminergic signaling. RESULTS: At 9 years of age, children with father loss have significantly shorter telomeres (14% reduction). Paternal death has the largest association (16%), followed by incarceration (10%), and separation and/or divorce (6%). Changes in income partially mediate these associations (95% mediation for separation and/or divorce, 30% for incarceration, and 25% for death). Effects are 40% greater for boys and 90% greater for children with the most reactive alleles of the serotonin transporter genes when compared with those with the least reactive alleles. No differences were found by age at father loss or a child's race/ethnicity. CONCLUSIONS: Father loss has a significant association with children's sTL, with the death of a father showing the largest effect. Income loss explains most of the association between child sTL and separation and/or divorce but much less of the association with incarceration or death. This underscores the important role of fathers in the care and development of children and supplements evidence of the strong negative effects of parental incarceration.
[Mh] Termos MeSH primário: Privação Paterna
Encurtamento do Telômero/genética
[Mh] Termos MeSH secundário: Adolescente
Fatores Etários
Alelos
Estudos de Casos e Controles
Criança
Pré-Escolar
Estudos de Coortes
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética
Feminino
Seguimentos
Seres Humanos
Renda
Lactente
Recém-Nascido
Masculino
Polimorfismo Genético/genética
Reação em Cadeia da Polimerase em Tempo Real
Distribuição Espacial da População
Fatores de Risco
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Transdução de Sinais/genética
Estatística como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dopamine Plasma Membrane Transport Proteins); 0 (Serotonin Plasma Membrane Transport Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171015
[Lr] Data última revisão:
171015
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE



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