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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


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[PMID]:29286727
[Au] Autor:Segota I; Franck C
[Ad] Endereço:Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca 14853, USA.
[Ti] Título:Extracellular Processing of Molecular Gradients by Eukaryotic Cells Can Improve Gradient Detection Accuracy.
[So] Source:Phys Rev Lett;119(24):248101, 2017 Dec 15.
[Is] ISSN:1079-7114
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eukaryotic cells sense molecular gradients by measuring spatial concentration variation through the difference in the number of occupied receptors to which molecules can bind. They also secrete enzymes that degrade these molecules, and it is presently not well understood how this affects the local gradient perceived by cells. Numerical and analytical results show that these enzymes can substantially increase the signal-to-noise ratio of the receptor difference and allow cells to respond to a much broader range of molecular concentrations and gradients than they would without these enzymes.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
Células Eucarióticas/metabolismo
Modelos Biológicos
Diester Fosfórico Hidrolases/metabolismo
[Mh] Termos MeSH secundário: Ácido Aspártico Endopeptidases/metabolismo
Quimiotaxia
Dictyostelium/enzimologia
Dictyostelium/metabolismo
Difusão
Células Eucarióticas/citologia
Células Eucarióticas/enzimologia
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Saccharomyces cerevisiae Proteins); E0399OZS9N (Cyclic AMP); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.- (BAR1 protein, S cerevisiae)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE
[do] DOI:10.1103/PhysRevLett.119.248101


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[PMID]:29266433
[Au] Autor:Rekhi B; Deodhar KK; Menon S; Maheshwari A; Bajpai J; Ghosh J; Shylasree ST; Gupta S
[Ad] Endereço:Department of Surgical Pathology, Tata Memorial Hospital, Parel, Mumbai, India.
[Ti] Título:Napsin A and WT 1 are useful immunohistochemical markers for differentiating clear cell carcinoma ovary from high-grade serous carcinoma.
[So] Source:APMIS;126(1):45-55, 2018 Jan.
[Is] ISSN:1600-0463
[Cp] País de publicação:Denmark
[La] Idioma:eng
[Ab] Resumo:Clear cell carcinoma (CCC) of the ovary is an uncommon, but an aggressive epithelial ovarian cancer (EOC), which has overlapping histopathologic features with other ovarian tumours. Lately, Napsin A has been identified as its useful diagnostic immunohistochemical (IHC) marker. Fifty-eight prospectively diagnosed ovarian CCCs, 53 high-grade serous carcinomas (HGSCs), 16 endometrioid adenocarcinomas (EMACs), six mixed carcinomas, containing components of CCC and EMAC, seven metastatic mucinous adenocarcinomas and six ovarian yolk sac tumours (YSTs) were tested for Napsin A immunostaining. Fifty ovarian CCCs, 50 HGSCs, seven ovarian EMACs and five mixed carcinomas were tested for WT1 immunostaining. Napsin A was positively expressed in all 58 (100%) CCCs; was focally positive in 1 of 6 YSTs; in 1/16 EMACs and in six cases of mixed carcinomas, while it was negative in all 53 HGSCs and in seven metastatic mucinous adenocarcinomas. Other IHC markers expressed in cases of CCC ovary were CK7 (31/31) (100%), WT1 (0/50), p53 (20/26, 'wild type'), ER (4/31, focal) (12.9%), PAX8 (14/14) (100%), glypican-3 (4/10, focal) (44.4%), p16INK4 (5/5, focal) and CK20 (0/5). Various IHC markers expressed in HGSCs were WT1 (48/50) (96%), p53 (31/31, mostly 'mutation type'), CK7 (9/9) (100%) ER (13/16, variable) (81.2%) and PAX8 (14/14) (100%). IHC markers expressed in EMACs were ER (15/16) (93.7%), CK7 (2/2) (100%) and WT1 (0/7). IHC markers expressed in mixed carcinomas were CK7 (2/2) (100%), WT1 (0/2), focal Napsin A (6/6) and focal ER (5/6). The sensitivity and specificity of Napsin A for the diagnosis of CCC ovary was 100% and 90.9%, respectively. The sensitivity and specificity of WT1 for diagnosis of HGSC ovary was found to be 96% and 100%, respectively. Napsin A and WT1 are highly sensitive and specific IHC markers for diagnosing ovarian CCCs and HGSCs, respectively, and in differentiating these tumours from their mimics. Napsin A is useful in identification of component of CCC in certain EMACs.
[Mh] Termos MeSH primário: Adenocarcinoma de Células Claras/diagnóstico
Ácido Aspártico Endopeptidases/análise
Cistadenocarcinoma Seroso/diagnóstico
Neoplasias Epiteliais e Glandulares/diagnóstico
Neoplasias Ovarianas/diagnóstico
Proteínas WT1/análise
[Mh] Termos MeSH secundário: Adenocarcinoma de Células Claras/patologia
Adulto
Idoso
Biomarcadores Tumorais
Cistadenocarcinoma Seroso/patologia
Diagnóstico Diferencial
Seres Humanos
Imuno-Histoquímica
Meia-Idade
Neoplasias Epiteliais e Glandulares/patologia
Neoplasias Ovarianas/patologia
Estudos Prospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (WT1 Proteins); 0 (WT1 protein, human); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.- (NAPSA protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE
[do] DOI:10.1111/apm.12784


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[PMID]:29074752
[Au] Autor:Boddey JA
[Ad] Endereço:The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. boddey@wehi.edu.au.
[Ti] Título:Plasmepsins on the antimalarial hit list.
[So] Source:Science;358(6362):445-446, 2017 10 27.
[Is] ISSN:1095-9203
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Antimaláricos
Ácido Aspártico Endopeptidases
[Mh] Termos MeSH secundário: Seres Humanos
Plasmodium falciparum
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Antimalarials); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.38 (plasmepsin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171028
[St] Status:MEDLINE
[do] DOI:10.1126/science.aaq0002


  5 / 6362 MEDLINE  
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[PMID]:28931241
[Au] Autor:Agrawal S; Moser KA; Morton L; Cummings MP; Parihar A; Dwivedi A; Shetty AC; Drabek EF; Jacob CG; Henrich PP; Parobek CM; Jongsakul K; Huy R; Spring MD; Lanteri CA; Chaorattanakawee S; Lon C; Fukuda MM; Saunders DL; Fidock DA; Lin JT; Juliano JJ; Plowe CV; Silva JC; Takala-Harrison S
[Ad] Endereço:Division of Malaria Research, Institute for Global Health.
[Ti] Título:Association of a Novel Mutation in the Plasmodium falciparum Chloroquine Resistance Transporter With Decreased Piperaquine Sensitivity.
[So] Source:J Infect Dis;216(4):468-476, 2017 Aug 15.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Amplified copy number in the plasmepsin II/III genes within Plasmodium falciparum has been associated with decreased sensitivity to piperaquine. To examine this association and test whether additional loci might also contribute, we performed a genome-wide association study of ex vivo P. falciparum susceptibility to piperaquine. Methods: Plasmodium falciparum DNA from 183 samples collected primarily from Cambodia was genotyped at 33716 genome-wide single nucleotide polymorphisms (SNPs). Linear mixed models and random forests were used to estimate associations between parasite genotypes and piperaquine susceptibility. Candidate polymorphisms were evaluated for their association with dihydroartemisinin-piperaquine treatment outcomes in an independent dataset. Results: Single nucleotide polymorphisms on multiple chromosomes were associated with piperaquine 90% inhibitory concentrations (IC90) in a genome-wide analysis. Fine-mapping of genomic regions implicated in genome-wide analyses identified multiple SNPs in linkage disequilibrium with each other that were significantly associated with piperaquine IC90, including a novel mutation within the gene encoding the P. falciparum chloroquine resistance transporter, PfCRT. This mutation (F145I) was associated with dihydroartemisinin-piperaquine treatment failure after adjusting for the presence of amplified plasmepsin II/III, which was also associated with decreased piperaquine sensitivity. Conclusions: Our data suggest that, in addition to plasmepsin II/III copy number, other loci, including pfcrt, may also be involved in piperaquine resistance.
[Mh] Termos MeSH primário: Resistência a Medicamentos/genética
Proteínas de Membrana Transportadoras/genética
Plasmodium falciparum/genética
Proteínas de Protozoários/genética
Quinolinas/farmacologia
[Mh] Termos MeSH secundário: Artemisininas/farmacologia
Ácido Aspártico Endopeptidases/genética
Ácido Aspártico Endopeptidases/metabolismo
Camboja
Variações do Número de Cópias de DNA
DNA de Protozoário/genética
Loci Gênicos
Estudo de Associação Genômica Ampla
Técnicas de Genotipagem
Seres Humanos
Concentração Inibidora 50
Desequilíbrio de Ligação
Proteínas de Membrana Transportadoras/metabolismo
Mutação
Plasmodium falciparum/efeitos dos fármacos
Polimorfismo de Nucleotídeo Único
Modelos de Riscos Proporcionais
Proteínas de Protozoários/metabolismo
Sensibilidade e Especificidade
Falha de Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Artemisinins); 0 (DNA, Protozoan); 0 (Membrane Transport Proteins); 0 (PfCRT protein, Plasmodium falciparum); 0 (Protozoan Proteins); 0 (Quinolines); 6A9O50735X (dihydroartemisinin); A0HV2Q956Y (piperaquine); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.39 (plasmepsin II)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jix334


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[PMID]:28872858
[Au] Autor:Huang J; Sun B; Yao Y; Liu J
[Ad] Endereço:School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology , 13 Hangkong Road, Wuhan, Hubei 430030, P.R. China.
[Ti] Título:Fast and Reliable Thermodynamic Approach for Determining the Protonation State of the Asp Dyad.
[So] Source:J Chem Inf Model;57(9):2273-2280, 2017 Sep 25.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The protonation state of the asp dyad is significantly important in revealing enzymatic mechanisms and developing drugs. However, it is hard to determine by calculating free energy changes between possible protonation states, because the free energy changes due to protein conformational flexibility are usually much larger than those originating from different locations of protons. Sophisticated and computationally expensive methods such as free energy perturbation, thermodynamic integration (TI), and quantum mechanics/molecular mechanics are therefore usually used for this purpose. In the present study, we have developed a simple thermodynamic approach to effectively eliminating the free energy changes arising from protein conformational flexibility and estimating the free energy changes only originated from the locations of protons, which provides a fast and reliable method for determining the protonation state of asp dyads. The test of this approach on a total of 15 asp dyad systems, including BACE-1 and HIV-1 protease, shows that the predictions from this approach are all consistent with experiments or with the computationally expensive TI calculations. It is clear that our thermodynamic approach could be used to rapidly and reliably determine the protonation state of the asp dyad.
[Mh] Termos MeSH primário: Ácido Aspártico Endopeptidases/química
Ácido Aspártico
Protease de HIV/química
Prótons
Teoria Quântica
[Mh] Termos MeSH secundário: Ácido Aspártico Endopeptidases/metabolismo
Protease de HIV/metabolismo
Conformação Proteica
Termodinâmica
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protons); 30KYC7MIAI (Aspartic Acid); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.- (HIV Protease)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00207


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[PMID]:28867212
[Au] Autor:Du X; Huo X; Yang Y; Hu Z; Botchway BOA; Jiang Y; Fang M
[Ad] Endereço:Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China.
[Ti] Título:miR-124 downregulates BACE 1 and alters autophagy in APP/PS1 transgenic mice.
[So] Source:Toxicol Lett;280:195-205, 2017 Oct 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:One role of BACE 1 (Beta-site amyloid precursor protein cleaving enzyme 1) is to cleave the sequential amyloid precursor protein (APP) into ß-Amyloid (Aß), the accumulation of which is an important participant in the formation of the amyloid plaques and neurofibrillary tangles of Alzheimer's disease (AD). Our previous study showed BACE 1, the potential functional downstream target of miR-124, to be connected to cell death in AD cell models. Recent studies have shown that autophagy is altered in AD, however, as to whether miR-124 is involved in this alteration is not clear. In this study, 7-month-old APP/PS1 transgenic mice were transfected with miR-124 lentiviral vectors, injected bilaterally into the dentate gyrus (DG) of mice hippocampi. Following 7 days of recovery, both behavior and biochemical pathology tests were implemented. The results demonstrated learning ability improvement and specific AD pathology alleviation. Meanwhile there was down-regulation of Bcl-2 to Bax ratio expression, increase in Beclin-1 and decreases in expression of LC3II, Atg5 and p62/SQSTMl. In view of this, we hypothesis that miR-124 conducts its neuroprotective effect through BACE 1 by regulation of autophagic pathways.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Ácido Aspártico Endopeptidases/metabolismo
Regulação da Expressão Gênica/fisiologia
MicroRNAs/metabolismo
Presenilina-1/metabolismo
[Mh] Termos MeSH secundário: Secretases da Proteína Precursora do Amiloide/genética
Precursor de Proteína beta-Amiloide/genética
Animais
Ácido Aspártico Endopeptidases/genética
Comportamento Animal
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
MicroRNAs/genética
MicroRNAs/farmacologia
Presenilina-1/genética
Proteínas tau/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (MicroRNAs); 0 (Mirn124 microRNA, mouse); 0 (Presenilin-1); 0 (tau Proteins); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.46 (Bace1 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:28855330
[Au] Autor:Choi GE; Lee SJ; Lee HJ; Ko SH; Chae CW; Han HJ
[Ad] Endereço:Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Research Center, Seoul National University, Seoul 08826, Korea, and.
[Ti] Título:Membrane-Associated Effects of Glucocorticoid on BACE1 Upregulation and Aß Generation: Involvement of Lipid Raft-Mediated CREB Activation.
[So] Source:J Neurosci;37(35):8459-8476, 2017 Aug 30.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucocorticoid has been widely accepted to induce Alzheimer's disease, but the nongenomic effect of glucocorticoid on amyloid ß (Aß) generation has yet to be studied. Here, we investigated the effect of the nongenomic pathway induced by glucocorticoid on amyloid precursor protein processing enzymes as well as Aß production using male ICR mice and human neuroblastoma SK-N-MC cells. Mice groups exposed to restraint stress or intracerebroventricular injection of Aß showed impaired cognition, decreased intracellular glucocorticoid receptor (GR) level, but elevated level of membrane GR (mGR). In this respect, we identified the mGR-dependent pathway evoked by glucocorticoid using impermeable cortisol conjugated to BSA (cortisol-BSA) on SK-N-MC cells. Cortisol-BSA augmented the expression of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), the level of C-terminal fragment ß of amyloid precursor protein (C99) and Aß production, which were maintained even after blocking intracellular GR. We also found that cortisol-BSA enhanced the interaction between mGR and Gαs, which colocalized in the lipid raft. The subsequently activated CREB by cortisol-BSA bound to the CRE site of the BACE1 promoter increasing its expression, which was downregulated by inhibiting CBP. Consistently, blocking CBP attenuated cognitive impairment and Aß production induced by corticosterone treatment or intracerebroventricular injection of Aß more efficiently than inhibiting intracellular GR in mice. In conclusion, glucocorticoid couples mGR with Gαs and triggers cAMP-PKA-CREB axis dependent on the lipid raft to stimulate BACE1 upregulation and Aß generation. Patients with Alzheimer's disease (AD) have been growing sharply and stress is considered as the major environment factor of AD. Glucocorticoid is the primarily responsive factor to stress and is widely known to induce AD. However, most AD patients usually have impaired genomic pathway of glucocorticoid due to intracellular glucocorticoid receptor deficiency. In this respect, the genomic mechanism of glucocorticoid faces difficulties in explaining the consistent amyloid ß (Aß) production. Therefore, it is necessary to investigate the novel pathway of glucocorticoid on Aß generation to find a more selective therapeutic approach to AD patients. In this study, we revealed the importance of nongenomic pathway induced by glucocorticoid where membrane glucocorticoid receptor plays an important role in Aß formation.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/metabolismo
Peptídeos beta-Amiloides/biossíntese
Ácido Aspártico Endopeptidases/metabolismo
Glucocorticoides/metabolismo
Microdomínios da Membrana/metabolismo
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos ICR
Transdução de Sinais/fisiologia
Regulação para Cima/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Glucocorticoids); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.46 (Bace1 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0074-17.2017


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[PMID]:28820612
[Au] Autor:Moriishi K
[Ad] Endereço:a Department of Microbiology, Graduate School of Medical Science , University of Yamanashi , Yamanashi , Japan.
[Ti] Título:The potential of signal peptide peptidase as a therapeutic target for hepatitis C.
[So] Source:Expert Opin Ther Targets;21(9):827-836, 2017 Sep.
[Is] ISSN:1744-7631
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Chronic infection with hepatitis C virus (HCV) causes liver steatosis, cirrhosis, metabolic syndrome with inflammation, and eventually leads to hepatocellular carcinoma. HCV core protein is a well-known capsid protein and pathogenic factor related to lipid accumulation, type 2 diabetes mellitus, and carcinogenesis. Cleavage of the C-terminal transmembrane region by signal peptide peptidase (SPP) is required for maturation of the core protein. Areas covered: Herein, this review details the general aspects of the structure, lifecycle, pathogenesis, and maturation of the HCV core protein, the function of SPP, and clinically available direct-acting antivirals (DAAs). SPP is classified into a group of GXGD-type intramembrane proteases including presenilin-1, which is a component of γ-secretase complex. Several SPP inhibitors were previously identified from γ-secretase inhibitors, but have not yet been improved based on specificity to SPP. Finally, the author discusses the potential of SPP inhibitors for hepatitis C therapy. Expert opinion: Currently available DAAs therapies are limited because of different viral genotypes and underlying conditions in each patient. DAA-resistant viruses have also been reported. Development of SPP-selective inhibitors may improve current HCV therapies by decreasing in the emergence of DAA-resistant viruses irrespective of viral genotype.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Ácido Aspártico Endopeptidases/metabolismo
Hepatite C Crônica/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Desenho de Drogas
Farmacorresistência Viral
Genótipo
Hepacivirus/genética
Hepatite C Crônica/enzimologia
Hepatite C Crônica/virologia
Seres Humanos
Terapia de Alvo Molecular
Proteínas do Core Viral/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Viral Core Proteins); 0 (nucleocapsid protein, Hepatitis C virus); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.- (signal peptide peptidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170904
[Lr] Data última revisão:
170904
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE
[do] DOI:10.1080/14728222.2017.1369959


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[PMID]:28817311
[Au] Autor:Moussa CE
[Ad] Endereço:a Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program , Georgetown University Medical Center , Washington , DC , USA.
[Ti] Título:Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer's disease.
[So] Source:Expert Opin Investig Drugs;26(10):1131-1136, 2017 Oct.
[Is] ISSN:1744-7658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-ß peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aß accumulation and halt AD onset and progression. Areas covered: This review discusses clinical developments of BACE1 inhibitors and focuses on what is learned about these inhibitors as a potential treatment. Expert opinion: BACE1 inhibition as a therapeutic strategy to improve cognition in AD has been challening. Brain-penetrant BACE1 inhibitors have been developed and clinical trials are underway, both safety and efficacy are questionable. Several clinical trials suggest that BACE1 inhibition and other immunotherapies to reduce brain Aß are insufficient to improve cognition in AD. This may be due to the emphasis on the amyloid hypothesis despite big failures. We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Aß alone and pay more attention to simultaneous clearance of tau and Aß.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores
Ácido Aspártico Endopeptidases/antagonistas & inibidores
Inibidores Enzimáticos/uso terapêutico
[Mh] Termos MeSH secundário: Doença de Alzheimer/enzimologia
Secretases da Proteína Precursora do Amiloide/genética
Peptídeos beta-Amiloides/metabolismo
Precursor de Proteína beta-Amiloide/metabolismo
Animais
Ácido Aspártico Endopeptidases/genética
Progressão da Doença
Desenho de Drogas
Drogas em Investigação/farmacologia
Drogas em Investigação/uso terapêutico
Inibidores Enzimáticos/farmacologia
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Drugs, Investigational); 0 (Enzyme Inhibitors); 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:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1080/13543784.2017.1369527



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