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[PMID]: 28465352 [Au] Autor: Zhang J; Johnson JL; He J; Napolitano G; Ramadass M; Rocca C; Kiosses WB; Bucci C; Xin Q; Gavathiotis E; Cuervo AM; Cherqui S; Catz SD [Ad] Endereço: From the Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037. [Ti] Título: Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A. [So] Source: J Biol Chem;292(25):10328-10346, 2017 06 23. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The lysosomal storage disease cystinosis, caused by cystinosin deficiency, is characterized by cell malfunction, tissue failure, and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. We also found mislocalization of the CMA lysosomal receptor LAMP2A and impaired substrate translocation into the lysosome caused by defective CMA in cystinosis. The impaired LAMP2A trafficking and localization were rescued either by the expression of wild-type cystinosin or by the disease-associated point mutant CTNS-K280R, which has no cystine transporter activity. Defective LAMP2A trafficking in cystinosis was found to associate with decreased expression of the small GTPase Rab11 and the Rab7 effector RILP. Defective Rab11 trafficking in cystinosis was rescued by treatment with small-molecule CMA activators. RILP expression was restored by up-regulation of the transcription factor EB (TFEB), which was down-regulated in cystinosis. Although LAMP2A expression is independent of TFEB, TFEB up-regulation corrected lysosome distribution and lysosomal LAMP2A localization in cells but not Rab11 defects. The up-regulation of Rab11, Rab7, or RILP, but not its truncated form RILP-C33, rescued LAMP2A-defective trafficking in cystinosis, whereas dominant-negative Rab11 or Rab7 impaired LAMP2A trafficking. Treatment of cystinotic cells with a CMA activator increased LAMP2A localization at the lysosome and increased cell survival. Altogether, we show that LAMP2A trafficking is regulated by cystinosin, Rab11, and RILP and that CMA up-regulation is a potential clinically relevant mechanism to increase cell survival in cystinosis. [Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo Sistemas de Transporte de Aminoácidos Neutros/metabolismo Cistinose/metabolismo Proteína 2 de Membrana Associada ao Lisossomo/metabolismo Lisossomos/metabolismo Proteínas rab de Ligação ao GTP/metabolismo [Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética Substituição de Aminoácidos Sistemas de Transporte de Aminoácidos Neutros/genética Animais Cistinose/genética Cistinose/patologia Ativadores de Enzimas/farmacologia Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos Regulação Enzimológica da Expressão Gênica/genética Proteína 2 de Membrana Associada ao Lisossomo/genética Lisossomos/genética Camundongos Camundongos Knockout Mutação Puntual Transporte Proteico/genética Proteínas rab de Ligação ao GTP/biossíntese Proteínas rab de Ligação ao GTP/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (Amino Acid Transport Systems, Neutral); 0 (Enzyme Activators); 0 (Lysosomal-Associated Membrane Protein 2); 0 (Rilp protein, mouse); 0 (cystinosin protein, mouse); 152989-05-4 (rab7 protein); EC 3.6.1.- (rab11 protein); EC 3.6.5.2 (rab GTP-Binding Proteins) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 180219 [Lr] Data última revisão: 180219 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170504 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M116.764076

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[PMID]: 28915252 [Au] Autor: Jando J; Camargo SMR; Herzog B; Verrey F [Ad] Endereço: Institute of Physiology, Zurich Center of Integrative Human Physiology and NCCR Kidney.CH, University of Zurich, Zurich, Switzerland. [Ti] Título: Expression and regulation of the neutral amino acid transporter B0AT1 in rat small intestine. [So] Source: PLoS One;12(9):e0184845, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Absorption of neutral amino acids across the luminal membrane of intestinal enterocytes is mediated by the broad neutral amino acid transporter B0AT1 (SLC6A19). Its intestinal expression depends on co-expression of the membrane-anchored peptidase angiotensin converting enzyme 2 (ACE2) and is additionally enhanced by aminopeptidase N (CD13). We investigated in this study the expression of B0AT1 and its auxiliary peptidases as well as its transport function along the rat small intestine. Additionally, we tested its possible short- and long-term regulation by dietary proteins and amino acids. We showed by immunofluorescence that B0AT1, ACE2 and CD13 co-localize on the luminal membrane of small intestinal villi and by Western blotting that their protein expression increases in distal direction. Furthermore, we observed an elevated transport activity of the neutral amino acid L-isoleucine during the nocturnal active phase compared to the inactive one. Gastric emptying was delayed by intragastric application of an amino acid cocktail but we observed no acute dietary regulation of B0AT1 protein expression and L-isoleucine transport. Investigation of the chronic dietary regulation of B0AT1, ACE2 and CD13 by different diets revealed an increased B0AT1 protein expression under amino acid-supplemented diet in the proximal section but not in the distal one and for ACE2 protein expression a reverse localization of the effect. Dietary regulation for CD13 protein expression was not as distinct as for the two other proteins. Ring uptake experiments showed a tendency for increased L-isoleucine uptake under amino acid-supplemented diet and in vivo L-isoleucine absorption was more efficient under high protein and amino acid-supplemented diet. Additionally, plasma levels of branched-chain amino acids were elevated under high protein and amino acid diet. Taken together, our experiments did not reveal an acute amino acid-induced regulation of B0AT1 but revealed a chronic dietary adaptation mainly restricted to the proximal segment of the small intestine. [Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/biossíntese Antígenos CD13/metabolismo Regulação da Expressão Gênica/efeitos dos fármacos Intestino Delgado/metabolismo Isoleucina/farmacologia Peptidil Dipeptidase A/metabolismo [Mh] Termos MeSH secundário: Animais Suplementos Nutricionais Masculino Ratos Ratos Wistar [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Neutral); 0 (SLC6A19 protein, rat); 04Y7590D77 (Isoleucine); EC 3.4.11.2 (CD13 Antigens); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170916 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0184845

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[PMID]: 28576941 [Au] Autor: Chandra R; Francis TC; Nam H; Riggs LM; Engeln M; Rudzinskas S; Konkalmatt P; Russo SJ; Turecki G; Iniguez SD; Lobo MK [Ad] Endereço: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201. [Ti] Título: Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility. [So] Source: J Neurosci;37(27):6527-6538, 2017 Jul 05. [Is] ISSN: 1529-2401 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is associated with depression susceptibility. However, no study examined Slc6a15 in the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous characterization of Slc6a15 as a striatal dopamine receptor 2 (D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in mediating susceptibility to stress in male mice. First, we showed that mRNA was reduced in NAc of mice susceptible to chronic social defeat stress (CSDS), a paradigm that produces behavioral and molecular adaptations that resemble clinical depression. Consistent with our preclinical data, we observed mRNA reduction in NAc of individuals with major depressive disorder (MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced susceptibility to a subthreshold social defeat stress (SSDS) as observed by reduced social interaction, while a reduction in social interaction following CSDS was not observed when Slc6a15 expression in D2-neurons was restored. Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15 protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs, using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15 in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons underlies stress susceptibility. Our study demonstrates a role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens (NAc) in depression and stress susceptibility. The reduction of Slc6a15 occurs selectively in the NAc D2-neurons. Genetic reduction of Slc6a15 induces susceptibility to a subthreshold stress, while genetic overexpression in D2-neurons prevents social avoidance after chronic social defeat stress. [Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/metabolismo Dominação-Subordinação Neurônios Dopaminérgicos/metabolismo Núcleo Accumbens/fisiopatologia Receptores de Dopamina D2/metabolismo Estresse Psicológico/fisiopatologia [Mh] Termos MeSH secundário: Animais Comportamento Animal Suscetibilidade a Doenças/fisiopatologia Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Transgênicos Comportamento Social [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Neutral); 0 (Receptors, Dopamine D2); 0 (Slc6a15 protein, mouse) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171003 [Lr] Data última revisão: 171003 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170604 [St] Status: MEDLINE [do] DOI: 10.1523/JNEUROSCI.3250-16.2017

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[PMID]: 28575418 [Au] Autor: Beukhof CM; van Doorn L; Visser TJ; Bins S; Visser WE; van Heerebeek R; van Kemenade FJ; de Rijke YB; de Herder WW; Chaker L; Mathijssen RH; Peeters RP [Ad] Endereço: Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands. [Ti] Título: Sorafenib-Induced Changes in Thyroid Hormone Levels in Patients Treated for Hepatocellular Carcinoma. [So] Source: J Clin Endocrinol Metab;102(8):2922-2929, 2017 Aug 01. [Is] ISSN: 1945-7197 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Context: The pathogenesis of tyrosine kinase inhibitor-induced thyroid hormone (TH) alterations are still a matter of debate. Objective: The objective of this study was to determine the effects of sorafenib on TH levels in patients with hepatocellular carcinoma (HCC) and to evaluate possible mechanisms. Design: We performed a prospective cohort study between 2009 and 2016. Setting: This study was conducted at a tertiary referral center. Patients: This study included 57 consecutive patients with HCC who were treated with sorafenib. Main Outcome Measure: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were measured every 6 weeks, and extensive thyroid function tests (TFTs) were measured before treatment (t0), after 6 weeks (t6), and at the end of therapy. The effect of sorafenib on TH transport by monocarboxylate transporter (MCT)8 or MCT10 was tested in transfected COS1 cells. Results: Four patients (7%) developed thyroiditis. Among the other patients, 30% had elevation of TSH or FT4 above the normal range. Overall, between t0 and t6, mean TSH increased from 1.28 to 1.57 mU/L (P < 0.001) and mean FT4 from 18.4 to 21.2 pmol/L (P < 0.001). Simultaneously, the serum triiodothyronine (T3)/reverse triiodothyronine ratio and the (T3/thyroxine) ×100 ratio decreased. Sorafenib decreased cellular T3 uptake by MCT8 and to a lesser extent by MCT10. Conclusions: These in vivo data suggest that sorafenib affects TFTs on multiple levels. Our in vitro experiments suggest a possible role of sorafenib-induced inhibition of T3 transport into the cell by MCT8 and MCT10. [Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico Carcinoma Hepatocelular/tratamento farmacológico Neoplasias Hepáticas/tratamento farmacológico Niacinamida/análogos & derivados Compostos de Fenilureia/uso terapêutico Tireotropina/metabolismo Tiroxina/metabolismo Tri-Iodotironina/metabolismo [Mh] Termos MeSH secundário: Idoso Sistemas de Transporte de Aminoácidos Neutros/efeitos dos fármacos Sistemas de Transporte de Aminoácidos Neutros/metabolismo Animais Antineoplásicos/farmacologia Células COS Carcinoma Hepatocelular/patologia Cercopithecus aethiops Estudos de Coortes Feminino Seres Humanos Técnicas In Vitro Neoplasias Hepáticas/patologia Masculino Meia-Idade Transportadores de Ácidos Monocarboxílicos/efeitos dos fármacos Transportadores de Ácidos Monocarboxílicos/metabolismo Niacinamida/farmacologia Niacinamida/uso terapêutico Compostos de Fenilureia/farmacologia Estudos Prospectivos Tri-Iodotironina/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Neutral); 0 (Antineoplastic Agents); 0 (Monocarboxylic Acid Transporters); 0 (Phenylurea Compounds); 0 (SLC16A10 protein, human); 0 (SLC16A2 protein, human); 06LU7C9H1V (Triiodothyronine); 25X51I8RD4 (Niacinamide); 9002-71-5 (Thyrotropin); 9ZOQ3TZI87 (sorafenib); Q51BO43MG4 (Thyroxine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170920 [Lr] Data última revisão: 170920 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170603 [St] Status: MEDLINE [do] DOI: 10.1210/jc.2016-4025

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[PMID]: 28555782 [Au] Autor: Gassner C; Brönnimann C; Merki Y; Mattle-Greminger MP; Sigurdardottir S; Meyer E; Engström C; O'Sullivan JD; Jung HH; Frey BM [Ad] Endereço: Department of Molecular Diagnostics & Research (MOC), Swiss Red Cross (SRC), Zürich-Schlieren, Switzerland. [Ti] Título: Stepwise partitioning of Xp21: a profiling method for XK deletions causative of the McLeod syndrome. [So] Source: Transfusion;57(9):2125-2135, 2017 Sep. [Is] ISSN: 1537-2995 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: McLeod syndrome (MLS) is hematologically defined by the absence of the red blood cell (RBC) antigen Kx on the transmembrane RBC protein, XK, representing a highly specific diagnostic marker. Direct molecular assessment of XK therefore represents a desirable diagnostic tool. Whereas pathogenic point mutations may be simply identified, partial and complete deletions of XK on Xp21.1, eventually covering adjacent genes and causing multifaceted "continuous gene syndromes," are difficult to localize. STUDY DESIGN AND METHODS: Three different McLeod patient samples were tested using 16 initial positional polymerase chain reaction (PCR) procedures distributed over an approximately 2.8-Mbp Xp-chromosomal region, ranging telomeric from MAGEB16 to OTC, centromeric of XK. The molecular breakpoint of one sample with an apparent large Xp deletion was iteratively narrowed down by stepwise positioning further PCR procedures and sequenced. Two mutant XK genes, one previously published and serving as a positive control, were also sequenced. RESULTS: We confirmed the positive control as previously published and listed as XK*N.20 by the International Society of Blood Transfusion (ISBT). The other XK showed a novel four-nucleotide deletion in Exon 1, 195-198delCCGC (newly listed as XK*N.39 by the ISBT). The third sample had an approximately 151-kbp X-chromosomal deletion, reaching from Exon 2 of LANCL3, across XK to Exon 3 of CYBB (newly listed as XK*N.01.016 by the ISBT). Carrier status of the patients' sister was diagnosed using a diagnostic "gap-PCR." CONCLUSIONS: The stepwise partitioning of Xp21.1 is pragmatic and cost-efficient in comparison to other diagnostic techniques such as "massive parallel sequencing" given the rarity of MLS. All males with suspected MLS should be considered for molecular XK profiling. [Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/genética Cromossomos Humanos X/genética Neuroacantocitose/genética [Mh] Termos MeSH secundário: Deleção de Genes Seres Humanos Masculino Reação em Cadeia da Polimerase Deleção de Sequência [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Neutral); 0 (XK protein, human) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171027 [Lr] Data última revisão: 171027 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170531 [St] Status: MEDLINE [do] DOI: 10.1111/trf.14172

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[PMID]: 28382174 [Au] Autor: Jiang Y; Cao Y; Wang Y; Li W; Liu X; Lv Y; Li X; Mi J [Ad] Endereço: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine; Institute of Cancer Stem Cell, Dalian Medical University. [Ti] Título: Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis. [So] Source: Theranostics;7(4):1036-1046, 2017. [Is] ISSN: 1838-7640 [Cp] País de publicação: Australia [La] Idioma: eng [Ab] Resumo: Cysteine is an essential amino acid for infants, aged people as well as patients with metabolic disorders. Although the thiol group of cysteine side chain is active in oxidative reactions, the role of cysteine in cancer remains largely unknown. Here, we report that the expression level of the solute carrier family 3, member 1 (SLC3A1), the cysteine carrier, tightly correlated with clinical stages and patients' survival. Elevated SLC3A1 expression accelerated the cysteine uptake and the accumulation of reductive glutathione (GSH), leading to reduced reactive oxygen species (ROS). ROS increased the stability and activity of PP2Ac, resulting in decreased AKT activity. Hence, SLC3A1 activated the AKT signaling through inhibiting PP2A phosphatase activity. Consistently, overexpression of SLC3A1 enhanced tumorigenesis of breast cancer cells, whereas blocking SLC3A1 either with specific siRNA or SLC3A1 specific inhibitor sulfasalazine suppressed tumor growth and also abolished dietary NAC-promoted tumor growth. Collectively, our data demonstrate that SLC3A1 promotes cysteine uptake and determines cellular response to antioxidant N-acetylcysteine, suggesting SLC3A1 is a potential therapeutic target for breast cancer. [Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Básicos/metabolismo Sistemas de Transporte de Aminoácidos Neutros/metabolismo Neoplasias da Mama/fisiopatologia Carcinogênese Cisteína/metabolismo [Mh] Termos MeSH secundário: Sistemas de Transporte de Aminoácidos Básicos/genética Sistemas de Transporte de Aminoácidos Neutros/genética Animais Neoplasias da Mama/patologia Linhagem Celular Tumoral Modelos Animais de Doenças Perfilação da Expressão Gênica Células HEK293 Xenoenxertos Seres Humanos Camundongos Endogâmicos BALB C Camundongos Nus Análise de Sobrevida [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Basic); 0 (Amino Acid Transport Systems, Neutral); 0 (SLC3A1 protein, human); K848JZ4886 (Cysteine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171023 [Lr] Data última revisão: 171023 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170407 [St] Status: MEDLINE [do] DOI: 10.7150/thno.18005

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[PMID]: 28320136 [Au] Autor: Zheng J; Yang X; Zhao Q; Tian S; Huang H; Chen Y; Xu Y [Ad] Endereço: Department of Neurology, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan Province 610041, PR China. [Ti] Título: Association between gene polymorphism and depression in Parkinson's disease: A case-control study. [So] Source: J Neurol Sci;375:231-234, 2017 Apr 15. [Is] ISSN: 1878-5883 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: OBJECTIVE: To investigate possible associations of Parkinson's disease (PD) with polymorphism in depression-related genes and in the alpha-synuclein (SNCA) gene. METHODS: A consecutive series of patients with PD were divided into those with depression and those without it. Patients (330) were genotyped at four single-nucleotide polymorphisms (SNPs) in four genes previously associated with depression, as well as four SNPs in the PD-associated SNCA gene. RESULTS: Of 330 patients, 125 (37.9%) had depression and 205 (62.1%) did not. Univariate analysis revealed significant differences between the two groups in minor allele frequency at the SNP rs1545843 in the SLC6A15 gene (p<0.05), as well as in frequencies of genotypes and minor alleles at rs78162420 in the TPH2 gene (all p<0.05). Logistic regression identified the following risk factors for depression among patients with PD: Hoehn and Yahr stage>2 (OR 1.759, 95%CI 1.035-2.989, p=0.037), AA genotype at rs1545843 (OR 1.866, 95%CI 1.017-3.426, p=0.044), and AC genotype at rs78162420 (OR 5.036, 95%CI 1.451-17.484, p=0.011). CONCLUSIONS: Among patients with PD, depression is associated with polymorphism at rs78162420 and rs1545843, both previously linked with depression. Our results may help clarify the pathogenesis of depression in PD. [Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/genética Depressão/genética Predisposição Genética para Doença/genética Proteínas do Tecido Nervoso/genética Doença de Parkinson/genética Polimorfismo de Nucleotídeo Único/genética Triptofano Hidroxilase/genética [Mh] Termos MeSH secundário: Idoso Grupo com Ancestrais do Continente Asiático Fatores de Transcrição de Zíper de Leucina Básica/genética Estudos de Casos e Controles Depressão/etiologia Feminino Frequência do Gene Estudos de Associação Genética Genótipo Seres Humanos Modelos Logísticos Masculino Meia-Idade Doença de Parkinson/complicações alfa-Sinucleína/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Neutral); 0 (Basic-Leucine Zipper Transcription Factors); 0 (Nerve Tissue Proteins); 0 (SLC6A15 protein, human); 0 (TEF protein, human); 0 (alpha-Synuclein); EC 1.14.16.4 (TPH2 protein, human); EC 1.14.16.4 (Tryptophan Hydroxylase) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170705 [Lr] Data última revisão: 170705 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170322 [St] Status: MEDLINE

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[PMID]: 28272791 [Au] Autor: Todd AC; Marx MC; Hulme SR; Bröer S; Billups B [Ad] Endereço: Eccles Institute of Neuroscience, The John Curtin School of Medical Research, The Australian National University, 131 Garran Road, Canberra, ACT 2601, Australia. [Ti] Título: SNAT3-mediated glutamine transport in perisynaptic astrocytes in situ is regulated by intracellular sodium. [So] Source: Glia;65(6):900-916, 2017 Jun. [Is] ISSN: 1098-1136 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The release of glutamine from astrocytes adjacent to synapses in the central nervous system is thought to play a vital role in the mechanism of glutamate recycling and is therefore important for maintaining excitatory neurotransmission. Here we investigate the nature of astrocytic membrane transport of glutamine in rat brainstem slices, using electrophysiological recording and fluorescent imaging of pH and Nai+. Glutamine application to perisynaptic astrocytes induced a membrane current, caused by activation of system A (SA) family transporters. A significant electroneutral component was also observed, which was mediated by the system N (SN) family transporters. This response was stimulated by glutamine (K of 1.57 mM), histidine, and asparagine, but not by leucine or serine, indicating activation of the SNAT3 isoform of SN. We hypothesized that increasing the [Na ] would alter the SNAT3 transporter equilibrium, thereby stimulating glutamine release. In support of this hypothesis, we show that SNAT3 transport can be driven by changing cation concentration and that manipulations to raise [Na ] (activation of excitatory amino acid transporters (EAATs), SA transporters or AMPA receptors) all directly influence SNAT3 transport rate. A kinetic model of glutamine fluxes is presented, which shows that EAAT activation causes the release of glutamine, driven mainly by the increased [Na ] . These data demonstrate that SNAT3 is functionally active in perisynaptic astrocytes in situ. As a result, astrocytic Nai+ signaling, as would be stimulated by neighboring synaptic activity, has the capacity to stimulate astrocytic glutamine release to support glutamate recycling. [Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/metabolismo Astrócitos/metabolismo Glutamina/metabolismo Espaço Intracelular/metabolismo Sódio/metabolismo Sinapses/metabolismo [Mh] Termos MeSH secundário: Sistema A de Transporte de Aminoácidos/metabolismo Animais Astrócitos/efeitos dos fármacos Tronco Encefálico/efeitos dos fármacos Tronco Encefálico/metabolismo Cátions Monovalentes/metabolismo Feminino Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo Concentração de Íons de Hidrogênio Espaço Intracelular/efeitos dos fármacos Cinética Lítio/metabolismo Masculino Modelos Neurológicos Ratos Wistar Receptores de AMPA/metabolismo Sinapses/efeitos dos fármacos Técnicas de Cultura de Tecidos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport System A); 0 (Amino Acid Transport Systems, Neutral); 0 (Cations, Monovalent); 0 (Glutamate Plasma Membrane Transport Proteins); 0 (Receptors, AMPA); 0 (system N protein 1); 0RH81L854J (Glutamine); 9FN79X2M3F (Lithium); 9NEZ333N27 (Sodium) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170502 [Lr] Data última revisão: 170502 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170309 [St] Status: MEDLINE [do] DOI: 10.1002/glia.23133

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[PMID]: 28176326 [Au] Autor: Cheng Q; Shah N; Bröer A; Fairweather S; Jiang Y; Schmoll D; Corry B; Bröer S [Ad] Endereço: Research School of Biology, The Australian National University, Canberra, Australia. [Ti] Título: Identification of novel inhibitors of the amino acid transporter B AT1 (SLC6A19), a potential target to induce protein restriction and to treat type 2 diabetes. [So] Source: Br J Pharmacol;174(6):468-482, 2017 Mar. [Is] ISSN: 1476-5381 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND AND PURPOSE: The neutral amino acid transporter B AT1 (SLC6A19) has recently been identified as a possible target to treat type 2 diabetes and related disorders. B AT1 mediates the Na -dependent uptake of all neutral amino acids. For surface expression and catalytic activity, B AT1 requires coexpression of collectrin (TMEM27). In this study, we established tools to identify and evaluate novel inhibitors of B AT1. EXPERIMENTAL APPROACH: A CHO-based cell line was generated, stably expressing collectrin and B AT1. Using this cell line, a high-throughput screening assay was developed, which uses a fluorescent dye to detect depolarisation of the cell membrane during amino acid uptake via B AT1. In parallel to these functional assays, we ran a computational compound screen using AutoDock4 and a homology model of B AT1 based on the high-resolution structure of the highly homologous Drosophila dopamine transporter. KEY RESULTS: We characterized a series of novel inhibitors of the B AT1 transporter. Benztropine was identified as a competitive inhibitor of the transporter showing an IC of 44 ± 9 µM. The compound was selective with regard to related transporters and blocked neutral amino acid uptake in inverted sections of mouse intestine. CONCLUSION AND IMPLICATIONS: The tools established in this study can be widely used to identify new transport inhibitors. Using these tools, we were able to identify compounds that can be used to study epithelial transport, to induce protein restriction, or be developed further through medicinal chemistry. [Mh] Termos MeSH primário: Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores Benzotropina/farmacologia Diabetes Mellitus Tipo 2/tratamento farmacológico [Mh] Termos MeSH secundário: Sistemas de Transporte de Aminoácidos/química Sistemas de Transporte de Aminoácidos/metabolismo Sistemas de Transporte de Aminoácidos Neutros/metabolismo Animais Benzotropina/química Células CHO Cricetulus Diabetes Mellitus Tipo 2/metabolismo Relação Dose-Resposta a Droga Drosophila Feminino Ensaios de Triagem em Larga Escala Masculino Camundongos Camundongos Endogâmicos C57BL Simulação de Acoplamento Molecular Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems); 0 (Amino Acid Transport Systems, Neutral); 0 (SLC6A19 protein, mouse); 1NHL2J4X8K (Benztropine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171020 [Lr] Data última revisão: 171020 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170209 [St] Status: MEDLINE [do] DOI: 10.1111/bph.13711

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MEDLINE

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[PMID]: 28165480 [Au] Autor: Zee T; Bose N; Zee J; Beck JN; Yang S; Parihar J; Yang M; Damodar S; Hall D; O'Leary MN; Ramanathan A; Gerona RR; Killilea DW; Chi T; Tischfield J; Sahota A; Kahn A; Stoller ML; Kapahi P [Ad] Endereço: Department of Urology, University of California, San Francisco, San Francisco, California, USA. [Ti] Título: α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria. [So] Source: Nat Med;23(3):288-290, 2017 Mar. [Is] ISSN: 1546-170X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cystinuria is an incompletely dominant disorder characterized by defective urinary cystine reabsorption that results in the formation of cystine-based urinary stones. Current treatment options are limited in their effectiveness at preventing stone recurrence and are often poorly tolerated. We report that the nutritional supplement α-lipoic acid inhibits cystine stone formation in the Slc3a1 mouse model of cystinuria by increasing the solubility of urinary cystine. These findings identify a novel therapeutic strategy for the clinical treatment of cystinuria. [Mh] Termos MeSH primário: Cistina/efeitos dos fármacos Cistinúria/metabolismo Rim/efeitos dos fármacos Ácido Tióctico/farmacologia Urolitíase/metabolismo [Mh] Termos MeSH secundário: Sistemas de Transporte de Aminoácidos Básicos/genética Sistemas de Transporte de Aminoácidos Neutros/genética Animais Cistina/metabolismo Modelos Animais de Doenças Rim/diagnóstico por imagem Rim/metabolismo Camundongos Camundongos Knockout Solubilidade/efeitos dos fármacos Urolitíase/diagnóstico por imagem Microtomografia por Raio-X [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amino Acid Transport Systems, Basic); 0 (Amino Acid Transport Systems, Neutral); 0 (Slc3a1 protein, mouse); 48TCX9A1VT (Cystine); 73Y7P0K73Y (Thioctic Acid) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171027 [Lr] Data última revisão: 171027 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170207 [St] Status: MEDLINE [do] DOI: 10.1038/nm.4280

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