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Pesquisa : D08.811.277.656.300.032 [Categoria DeCS]
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[PMID]:29254295
[Au] Autor:Walkiewicz K; Nowakowska-Zajdel E; Strzelczyk J; Dziegielewska-Gesiak S; Muc-Wierzgon M
[Ad] Endereço:Department of Internal Medicine, School of Public Health in Bytom, Medical University of Silesia, Katowice, Poland.
[Ti] Título:Serum levels of ADAM10, ADAM12, ADAM17 AND ADAM28 in colorectal cancer patients.
[So] Source:J Biol Regul Homeost Agents;31(4):929-934, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:Colorectal cancer is the third most common cancer in the world. Our study analyzed the potential significance of serum levels of selected adamalysines (ADAM10, ADAM12, ADAM17, ADAM28) in colorectal cancer patients. The study was performed on a group of 85 colorectal cancer patients (48 men, 37 women). Serum protein concentrations were measured by ELISA. The ADAMs serum level changes were analyzed according to selected clinical parameters (BMI, sex, age, clinical stage of disease). The following ranges of concentration of analyzed proteins were obtained: ADAM10 min=1.7, max=321.8 [ng/ml]; ADAM12 min=0.6, max=26.7 [ng/ml]; ADAM17 min=0.4, max=9.8 [ng/ml]; ADAM28 min=17.1, max=1545.8 [ng/ml]. In addition, it was stated that there is a relationship between the serum level of ADAM28 and the degree of the clinical stage (p less than 0.04). The obtained results could be the starting point for further research into the role of adamalysines in the development of colorectal cancer, as well as the potential predictive and prognostic value of these proteins.
[Mh] Termos MeSH primário: Proteínas ADAM/genética
Adenocarcinoma/genética
Biomarcadores Tumorais/genética
Colo/metabolismo
Neoplasias Colorretais/genética
Regulação Neoplásica da Expressão Gênica
[Mh] Termos MeSH secundário: Proteínas ADAM/sangue
Proteína ADAM10/sangue
Proteína ADAM10/genética
Proteína ADAM12/sangue
Proteína ADAM12/genética
Proteína ADAM17/sangue
Proteína ADAM17/genética
Adenocarcinoma/sangue
Adenocarcinoma/diagnóstico
Adenocarcinoma/patologia
Adulto
Fatores Etários
Idoso
Idoso de 80 Anos ou mais
Secretases da Proteína Precursora do Amiloide/sangue
Secretases da Proteína Precursora do Amiloide/genética
Biomarcadores Tumorais/sangue
Índice de Massa Corporal
Colo/patologia
Neoplasias Colorretais/sangue
Neoplasias Colorretais/diagnóstico
Neoplasias Colorretais/patologia
Feminino
Seres Humanos
Masculino
Proteínas de Membrana/sangue
Proteínas de Membrana/genética
Meia-Idade
Estadiamento de Neoplasias
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Membrane Proteins); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.- (ADAM Proteins); EC 3.4.24.- (ADAM12 Protein); EC 3.4.24.- (ADAM12 protein, human); EC 3.4.24.- (ADAM28 protein, human); EC 3.4.24.81 (ADAM10 Protein); EC 3.4.24.81 (ADAM10 protein, human); EC 3.4.24.86 (ADAM17 Protein); EC 3.4.24.86 (ADAM17 protein, human)
[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:171220
[St] Status:MEDLINE


  2 / 5690 MEDLINE  
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[PMID]:29249626
[Au] Autor:Sekioka R; Honjo E; Honda S; Fuji H; Akashiba H; Mitani Y; Yamasaki S
[Ad] Endereço:Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ryuichi.sekioka@astellas.com.
[Ti] Título:Discovery of novel scaffolds for γ-secretase modulators without an arylimidazole moiety.
[So] Source:Bioorg Med Chem;26(2):435-442, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-ß 42 (Aß42) and may therefore be useful in the management of Alzheimer's disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aß42 (IC = 7.1 µM) without changing total production of Aß. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aß42 (IC = 0.39 µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores
Descoberta de Drogas
Compostos Heterocíclicos/farmacologia
Imidazóis/farmacologia
Piridinas/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Secretases da Proteína Precursora do Amiloide/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/biossíntese
Animais
Linhagem Celular Tumoral
Citocromo P-450 CYP3A/metabolismo
Relação Dose-Resposta a Droga
Compostos Heterocíclicos/administração & dosagem
Compostos Heterocíclicos/química
Seres Humanos
Imidazóis/administração & dosagem
Imidazóis/química
Injeções Intraperitoneais
Masculino
Camundongos
Camundongos Endogâmicos
Microssomos Hepáticos/química
Microssomos Hepáticos/metabolismo
Modelos Moleculares
Estrutura Molecular
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/biossíntese
Piridinas/administração & dosagem
Piridinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Heterocyclic Compounds); 0 (Imidazoles); 0 (Peptide Fragments); 0 (Pyridines); 0 (amyloid beta-protein (1-42)); 0 (imidazopyridine); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.14.14.1 (cytochrome P450 3A4, mouse); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE


  3 / 5690 MEDLINE  
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[PMID]:27770745
[Au] Autor:Kocak A; Erol I; Yildiz M; Can H
[Ad] Endereço:Department of Chemistry, Gebze Technical University, 41400, Gebze, Kocaeli, Turkey. Electronic address: kocak@gtu.edu.tr.
[Ti] Título:Computational insights into the protonation states of catalytic dyad in BACE1-acyl guanidine based inhibitor complex.
[So] Source:J Mol Graph Model;70:226-235, 2016 11.
[Is] ISSN:1873-4243
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Developing small compound based drugs targeting the ß-secretase (BACE) enzyme is one of the most promising strategies in treatment of the Alzheimer's disease. As the enzyme shows the activity based on the acid-base reaction at a very narrow pH range, the protonation state of aspartic acids with the residue number 32 and 228 (Asp32 and Asp228), which forms the active site dyad, along with the protonation state of the ligand (substrate or inhibitor) play very critical role in interactions between the ligand and enzyme. Thus, understanding the nature of the protonation state of both enzyme's active site dyad and ligand is crucial for drug design in Alzheimer's disease field. Here we have investigated the protonation state of the Asp32 and Asp228 residues in the presence of a highly potent beta secretase inhibitor, containing acyl guanidine warhead that have recently been devised but not extensively studied. Our Quantum Mechanical, Molecular Dynamics and Docking studies on all the possible protonation states have suggested that the dyad residues are in di-deprotonated states in the presence of protonated inhibitor.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores
Secretases da Proteína Precursora do Amiloide/química
Biocatálise
Guanidina/farmacologia
Modelos Moleculares
Inibidores de Proteases/química
Inibidores de Proteases/farmacologia
Prótons
[Mh] Termos MeSH secundário: Acilação
Guanidina/química
Ligações de Hidrogênio
Ligantes
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Teoria Quântica
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Protease Inhibitors); 0 (Protons); EC 3.4.- (Amyloid Precursor Protein Secretases); JU58VJ6Y3B (Guanidine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE


  4 / 5690 MEDLINE  
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[PMID]:29253571
[Au] Autor:Nasrin A; Hassan M; Ye P
[Ad] Endereço:Faculty of Dentistry, The University of Sydney, Sydney, Australia.
[Ti] Título:Inhibition of Notch signaling pathway using γ-secretase inhibitor delivered by a low dose of Triton-X100 in cultured oral cancer cells.
[So] Source:Biochem Biophys Res Commun;495(3):2118-2124, 2018 01 15.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:How to effectively delivering therapeutic agents, including γ-secretase inhibitors (GSIs), into live cells, remains a significant challenge. This study assessed the effect of Notch signaling inhibition by examining levels of the Notch1 intracellular domain (N1ICD) in cultured oral cancer cells analyzed with random stitched images (2D) and 3D visualizations using confocal microscopy and quantitative gene analysis. Substantially, we have developed a novel method to assist the delivery of γ-secretase inhibitor, DAPT, into live cells in the presence of an effective minimum concentration of Triton-X100 (0.001%) without damaging cell activity and membrane integrity assessed with cell proliferation assays. The images obtained in this study showed that DAPT alone could not block the γ-secretase inhibitor despite inhibiting cell growth. Further analysis of quantitative gene expressions of Notch signaling canonical pathway to verify the effectiveness of the novel method for delivering inhibitor into live cells, displayed deregulation of Notch1, Delta-like ligand 1 (DLL1) and hairy and enhancer of split 1 (Hes1). Our data suggest that Notch1/Hes1 signaling pathway is deactivated using DAPT with a low dose of Triton-X100 in this cancer cells. And the finding also suggests that Notch1 could be engaged by DLL1 to promote differentiation in oral cancer cells. Using this approach, we demonstrate that Triton-X100 is a promising and effective permeabilization agent to deliver γ-secretase inhibitor DAPT into live oral epithelial cells. This strategy has the potential to implicate in the treatment of cancer diseases.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores
Dipeptídeos/administração & dosagem
Neoplasias Bucais/tratamento farmacológico
Neoplasias Bucais/metabolismo
Octoxinol/administração & dosagem
Receptor Notch1/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antineoplásicos/administração & dosagem
Antineoplásicos/química
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Dipeptídeos/farmacologia
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Emulsões/química
Seres Humanos
Neoplasias Bucais/patologia
Octoxinol/química
Octoxinol/farmacologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Dipeptides); 0 (Emulsions); 0 (N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester); 0 (NOTCH1 protein, human); 0 (Receptor, Notch1); 9002-93-1 (Octoxynol); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE


  5 / 5690 MEDLINE  
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[PMID]:28930532
[Au] Autor:Ahmad Rather M; Justin Thenmozhi A; Manivasagam T; Dhivya Bharathi M; Essa MM; Guillemin GJ
[Ad] Endereço:Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu 608002, India.
[Ti] Título:Neuroprotective role of Asiatic acid in aluminium chloride induced rat model of Alzheimer's disease.
[So] Source:Front Biosci (Schol Ed);10:262-275, 2018 01 01.
[Is] ISSN:1945-0524
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Alzheimer's disease (AD) is the most common form of dementia, characterized by memory loss, cognitive impairment and personality disorders accompanied by diffuse structural abnormalities in the brain of elderly people. The current investigation explored the neuroprotective potential of asiatic acid (AA), a natural triterpene of on aluminium chloride (AlCl ) induced rat model of AD. Oral administration of AlCl (100 mg/kg b.w.) for 42 days significantly elevated the levels of Al, activity of acetyl cholinesterase and expressions of amyloid precursor protein, amyloid beta , beta and gamma secretases, glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, interleukins -1ß, 6, 4, 2, tumor necrosis factor alpha, inducible nitric oxide synthase, nuclear factor- k beta and cyclooxygenase-2 in the hippocampus and cortex  compared to the control group. Our observations suggested that AA treatment mitigated AlCl induced AD associated pathologies, which might be due to its multiple pharmacological actions. Further studies are necessary in order to explore the link between AlCl -mediated oxidative stress and associated apoptosis to establish its neuroprotective role in AD.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Fármacos Neuroprotetores/farmacologia
Triterpenos Pentacíclicos/farmacologia
[Mh] Termos MeSH secundário: Compostos de Alumínio
Doença de Alzheimer/induzido quimicamente
Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Amiloide/metabolismo
Secretases da Proteína Precursora do Amiloide/metabolismo
Peptídeos beta-Amiloides/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Animais
Apoptose/efeitos dos fármacos
Cloretos
Modelos Animais de Doenças
Masculino
Estresse Oxidativo/efeitos dos fármacos
Distribuição Aleatória
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aluminum Compounds); 0 (Amyloid); 0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Chlorides); 0 (Neuroprotective Agents); 0 (Pentacyclic Triterpenes); 3CYT62D3GA (aluminum chloride); 9PA5A687X5 (asiatic acid); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE


  6 / 5690 MEDLINE  
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[PMID]:29300757
[Au] Autor:Han S; Kim D; Shivakumar M; Lee YJ; Garg T; Miller JE; Kim JH; Kim D; Lee Y
[Ad] Endereço:Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
[Ti] Título:The effects of alternative splicing on miRNA binding sites in bladder cancer.
[So] Source:PLoS One;13(1):e0190708, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eukaryotic organisms have developed a variety of mechanisms to regulate translation post-transcriptionally, including but not limited to the use of miRNA silencing in many species. One method of post-transcriptional regulation is through miRNAs that bind to the 3' UTRs to regulate mRNA abundance and influence protein expression. Therefore, the diversity of mRNA 3' UTRs mediating miRNA binding sites influence miRNA-mediated regulation. Alternative polyadenylation, by shortening mRNA isoforms, increases the diversity of 3' UTRs; moreover, short mRNA isoforms elude miRNA-medicated repression. Because no current prediction methods for putative miRNA target sites consider whether or not 1) splicing-informed miRNA binding sites and/or 2) the use of 3' UTRs provide higher resolution or functionality, we sought to identify not only the genome-wide impact of using exons in mRNA 3' UTRs but also their functional connection to miRNA regulation and clinical outcomes in cancer. With a genome-wide expression of mRNA and miRNA quantified by 395 bladder cancer cases from The Cancer Genome Atlas (TCGA), we 1) demonstrate the diversity of 3' UTRs affecting miRNA efficiency and 2) identify a set of genes clinically associated with mRNA expression in bladder cancer. Knowledge of 3' UTR diversity will not only be a useful addition to current miRNA target prediction algorithms but also enhance the clinical utility of mRNA isoforms in the expression of mRNA in cancer. Thus, variability among cancer patient's variability in molecular signatures based on these exon usage events in 3' UTR along with miRNAs in bladder cancer may lead to better prognostic/treatment strategies for improved precision medicine.
[Mh] Termos MeSH primário: Processamento Alternativo
Sítios de Ligação
Carcinoma/metabolismo
MicroRNAs/metabolismo
Neoplasias da Bexiga Urinária/metabolismo
[Mh] Termos MeSH secundário: Secretases da Proteína Precursora do Amiloide/genética
Secretases da Proteína Precursora do Amiloide/metabolismo
Ácido Aspártico Endopeptidases/genética
Ácido Aspártico Endopeptidases/metabolismo
Carcinoma/genética
Carcinoma/patologia
Seres Humanos
Estimativa de Kaplan-Meier
Modelos Lineares
Estadiamento de Neoplasias
Poliadenilação
RNA Mensageiro/metabolismo
Neoplasias da Bexiga Urinária/genética
Neoplasias da Bexiga Urinária/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (MicroRNAs); 0 (RNA, Messenger); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.46 (BACE1 protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180105
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190708


  7 / 5690 MEDLINE  
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[PMID]:29224781
[Au] Autor:Seegar TCM; Killingsworth LB; Saha N; Meyer PA; Patra D; Zimmerman B; Janes PW; Rubinstein E; Nikolov DB; Skiniotis G; Kruse AC; Blacklow SC
[Ad] Endereço:Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10.
[So] Source:Cell;171(7):1638-1648.e7, 2017 Dec 14.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer's precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.
[Mh] Termos MeSH primário: Proteína ADAM10/química
Secretases da Proteína Precursora do Amiloide/química
Proteínas de Membrana/química
Proteólise
[Mh] Termos MeSH secundário: Proteína ADAM10/metabolismo
Secretases da Proteína Precursora do Amiloide/metabolismo
Cristalografia por Raios X
Seres Humanos
Proteínas de Membrana/metabolismo
Modelos Moleculares
Receptores Notch/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Proteins); 0 (Receptors, Notch); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.81 (ADAM10 Protein); EC 3.4.24.81 (ADAM10 protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180120
[Lr] Data última revisão:
180120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:29262358
[Au] Autor:Lee JY; Feng Z; Xie XQ; Bahar I
[Ad] Endereço:Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; NIH Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania.
[Ti] Título:Allosteric Modulation of Intact γ-Secretase Structural Dynamics.
[So] Source:Biophys J;113(12):2634-2649, 2017 Dec 19.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As a protease complex involved in the cleavage of amyloid precursor proteins that lead to the formation of amyloid ß fibrils implicated in Alzheimer's disease, γ-secretase is an important target for developing therapeutics against Alzheimer's disease. γ-secretase is composed of four subunits: nicastrin (NCT) in the extracellular (EC) domain, presenilin-1 (PS1), anterior pharynx defective 1, and presenilin enhancer 2 in the transmembrane (TM) domain. NCT and PS1 play important roles in binding amyloid ß precursor proteins and modulating PS1 catalytic activity. Yet, the molecular mechanisms of coupling between substrate/modulator binding and catalytic activity remain to be elucidated. Recent determination of intact human γ-secretase cryo-electron microscopy structure has opened the way for a detailed investigation of the structural dynamics of this complex. Our analysis, based on a membrane-coupled anisotropic network model, reveals two types of NCT motions, bending and twisting, with respect to PS1. These underlie the fluctuations between the "open" and "closed" states of the lid-like NCT with respect to a hydrophilic loop 1 (HL1) on PS1, thus allowing or blocking access of the substrate peptide (EC portion) to HL1 and to the neighboring helix TM2. In addition to this alternating access mechanism, fluctuations in the volume of the PS1 central cavity facilitate the exposure of the catalytic site for substrate cleavage. Druggability simulations show that γ-secretase presents several hot spots for either orthosteric or allosteric inhibition of catalytic activity, consistent with experimental data. In particular, a hinge region at the interface between the EC and TM domains, near the interlobe groove of NCT, emerges as an allo-targeting site that would impact the coupling between HL1/TM2 and the catalytic pocket, opening, to our knowledge, new avenues for structure-based design of novel allosteric modulators of γ-secretase protease activity.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/química
Secretases da Proteína Precursora do Amiloide/metabolismo
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Regulação Alostérica
Domínio Catalítico
Bicamadas Lipídicas/metabolismo
Glicoproteínas de Membrana/metabolismo
Modelos Moleculares
Presenilina-1/metabolismo
Estrutura Quaternária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipid Bilayers); 0 (Membrane Glycoproteins); 0 (Presenilin-1); 0 (nicastrin protein); 8L70Q75FXE (Adenosine Triphosphate); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


  9 / 5690 MEDLINE  
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[PMID]:29176823
[Au] Autor:Dursun E; Gezen-Ak D
[Ad] Endereço:Brain and Neurodegenerative Disorders Research Laboratory, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey.
[Ti] Título:Vitamin D receptor is present on the neuronal plasma membrane and is co-localized with amyloid precursor protein, ADAM10 or Nicastrin.
[So] Source:PLoS One;12(11):e0188605, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our recent study indicated that vitamin D and its receptors are important parts of the amyloid processing pathway in neurons. Yet the role of vitamin D receptor (VDR) in amyloid pathogenesis is complex and all regulations over the production of amyloid beta cannot be explained solely with the transcriptional regulatory properties of VDR. Given that we hypothesized that VDR might exist on the neuronal plasma membrane in close proximity with amyloid precursor protein (APP) and secretase complexes. The present study primarily focused on the localization of VDR in neurons and its interaction with amyloid pathology-related proteins. The localization of VDR on neuronal membranes and its co-localization with target proteins were investigated with cell surface staining followed by immunofluorescence labelling. The FpClass was used for protein-protein interaction prediction. Our results demonstrated the localization of VDR on the neuronal plasma membrane and the co-localization of VDR and APP or ADAM10 or Nicastrin and limited co-localization of VDR and PS1. E-cadherin interaction with APP or the γ-secretase complex may involve NOTCH1, NUMB, or FHL2, according to FpClass. This suggested complex might also include VDR, which greatly contributes to Ca+2 hemostasis with its ligand vitamin D. Consequently, we suggested that VDR might be a member of this complex also with its own non-genomic action and that it can regulate the APP processing pathway in this way in neurons.
[Mh] Termos MeSH primário: Proteína ADAM10/metabolismo
Secretases da Proteína Precursora do Amiloide/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Membrana Celular/metabolismo
Glicoproteínas de Membrana/metabolismo
Neurônios/metabolismo
Receptores de Calcitriol/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Mapeamento de Interação de Proteínas
Transporte Proteico
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Membrane Glycoproteins); 0 (Receptors, Calcitriol); 0 (nicastrin protein); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.81 (ADAM10 Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188605


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[PMID]:28465241
[Au] Autor:Kizuka Y; Kitazume S; Taniguchi N
[Ad] Endereço:Disease Glycomics Team, Systems Glycobiology Research Group, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: y.kizuka@riken.jp.
[Ti] Título:N-glycan and Alzheimer's disease.
[So] Source:Biochim Biophys Acta;1861(10):2447-2454, 2017 10.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Alzheimer's disease (AD) is a major form of dementia. Many evidence-based clinical trials have been performed, but no effective treatment has yet been developed. This suggests that our understanding of AD patho-mechanisms is still insufficient. In particular, the pathological roles of posttranslational modifications including glycosylation have remained poorly understood, but recent advances in glycobiology technology have gradually revealed that sugar modifications of AD-related molecules are profoundly involved in the onset and progression of this disease. SCOPE OF REVIEW: We summarize the roles of N-glycans in AD pathogenesis and progression, particularly focusing on key AD-related molecules, including amyloid precursor protein (APP), α-, ß-, and γ-secretases, and tau. MAJOR CONCLUSIONS: Biochemical, genetic and pharmacological studies have gradually revealed how N-glycans regulate AD development and progression through functional modulation of the key glycoproteins. These findings suggest that further glycobiology approaches in AD research will reveal novel glycan-based drug targets and early biomarkers of AD. However, N-glycan structures of these molecules in physiological and disease conditions and their precise functions are still largely unclear. Deeper glycobiology studies will be needed to reveal how AD pathology is regulated by glycosylation. GENERAL SIGNIFICANCE: It is now known that N-glycans play significant roles in AD development. However, specific pathological functions of particular glycan epitopes on each AD-related glycoprotein are still poorly understood. Future glycobiology studies with more sensitive glycoproteomic techniques and a wider variety of chemical glycosylation inhibitors could contribute to the development of novel glycan-based AD therapeutics. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.
[Mh] Termos MeSH primário: Doença de Alzheimer/metabolismo
Secretases da Proteína Precursora do Amiloide/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Polissacarídeos/metabolismo
Processamento de Proteína Pós-Traducional
Proteínas tau/metabolismo
[Mh] Termos MeSH secundário: Doença de Alzheimer/genética
Doença de Alzheimer/patologia
Secretases da Proteína Precursora do Amiloide/genética
Precursor de Proteína beta-Amiloide/genética
Sequência de Carboidratos
Glicosilação
Seres Humanos
Glicoproteínas de Membrana/genética
Glicoproteínas de Membrana/metabolismo
Neprilisina/genética
Neprilisina/metabolismo
Polissacarídeos/química
Proteólise
Receptores Imunológicos/genética
Receptores Imunológicos/metabolismo
Transdução de Sinais
Proteínas tau/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (APP protein, human); 0 (Amyloid beta-Protein Precursor); 0 (MAPT protein, human); 0 (Membrane Glycoproteins); 0 (Polysaccharides); 0 (Receptors, Immunologic); 0 (TREM2 protein, human); 0 (tau Proteins); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.11 (Neprilysin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171130
[Lr] Data última revisão:
171130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE



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