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[PMID]: 28941455 [Au] Autor: Muronetz VI; Melnikova AK; Seferbekova ZN; Barinova KV; Schmalhausen EV [Ad] Endereço: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119234, Russia. vimuronets@belozersky.msu.ru. [Ti] Título: Glycation, Glycolysis, and Neurodegenerative Diseases: Is There Any Connection? [So] Source: Biochemistry (Mosc);82(8):874-886, 2017 Aug. [Is] ISSN: 1608-3040 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: This review considers the interrelation between different types of protein glycation, glycolysis, and the development of amyloid neurodegenerative diseases. The primary focus is on the role of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in changing the concentration of carbonyl compounds - first and foremost, glyceraldehyde-3-phosphate and methylglyoxal. It has been suggested that various modifications of the enzyme - from the oxidation of the sulfhydryl groups of the active site to glycation with sugars - can lead to its inactivation, which causes a direct increase in glyceraldehyde-3-phosphate concentration and an indirect increase in the content of other aldehydes. This "primary inactivation" of glyceraldehyde-3-phosphate dehydrogenase promotes its glycation with aldehydes, including its own substrate, and a further irreversible decrease in its activity. Such a cycle can lead to numerous consequences - from the induction of apoptosis, which is activated by modified forms of the enzyme, to glycation of amyloidogenic proteins by glycolytic aldehydes. Of particular importance during the inhibition of glyceraldehyde-3-phosphate dehydrogenase is an increase in the content of the glycating compound methylglyoxal, which is much more active than reducing sugars (glucose, fructose, and others). In addition, methylglyoxal is formed by two pathways - in the cascade of reactions during glycation and from glycolytic aldehydes. The ability of methylglyoxal to glycate proteins makes it the main participant in this protein modification. We consider the effect of glycation on the pathological transformation of amyloidogenic proteins and peptides - ß-amyloid peptide, α-synuclein, and prions. Our primary focus is on the glycation of monomeric forms of these proteins with methylglyoxal, although most works are dedicated to the analysis of the presence of "advanced glycation end products" in the already formed aggregates and fibrils of amyloid proteins. In our opinion, the modification of aggregates and fibrils is secondary in nature and does not play an important role in the development of neurodegenerative diseases. The glycation of amyloid proteins with carbonyl compounds can be one of the triggers of their transformation into toxic forms. The possible role of glycation of amyloidogenic proteins in the prevention of their modification by ubiquitin and the SUMO proteins due to a disruption of their degradation is separately considered. [Mh] Termos MeSH primário: Doenças Neurodegenerativas/patologia [Mh] Termos MeSH secundário: Aldeídos/química Proteínas Amiloidogênicas/metabolismo Produtos Finais de Glicação Avançada/análise Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/metabolismo Glicólise Glicosilação Seres Humanos Doenças Neurodegenerativas/metabolismo Processamento de Proteína Pós-Traducional alfa-Sinucleína/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Aldehydes); 0 (Amyloidogenic Proteins); 0 (Glycation End Products, Advanced); 0 (SNCA protein, human); 0 (alpha-Synuclein); EC 1.2.1.9 (Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)) [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: 170925 [St] Status: MEDLINE [do] DOI: 10.1134/S0006297917080028

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[PMID]: 28804110 [Au] Autor: Ito K; Inui Y; Kizawa T; Kimura Y; Kato T [Ad] Endereço: Department of Radiology, National Center for Geriatrics and Gerontology. [Ti] Título: Current and future prospects of nuclear medicine in dementia. [So] Source: Rinsho Shinkeigaku;57(9):479-484, 2017 09 30. [Is] ISSN: 1882-0654 [Cp] País de publicação: Japan [La] Idioma: jpn [Ab] Resumo: In clinical diagnostic imaging of Alzheimer's disease (AD), MRI and nuclear medicine studies such as cerebral blood flow SPECT are positioned as biomarkers expressing pathological conditions. With understanding its usefulness and limitations, it is important to conduct appropriate application and to utilize the correct evaluation of the result in clinical practice. Although FDG-PET and amyloid PET are still not covered for dementia by health insurance, they are extremely useful for differential diagnosis as well as early diagnosis of AD. As image biomarkers, they may have complementary implications. In addition, tau PET under development not only realizes more accurate evaluation of AD but also is expected to be applied in dementia other than AD. In the future, image biomarkers are indispensable for patient selection (early diagnosis) in mild cognitive impairment (MCI) or earlier stages and for judging the therapeutic effect of interventions in cases when early intervention for AD. [Mh] Termos MeSH primário: Doença de Alzheimer/diagnóstico por imagem Encéfalo/diagnóstico por imagem Demência/diagnóstico por imagem Medicina Nuclear/tendências [Mh] Termos MeSH secundário: Proteínas Amiloidogênicas/metabolismo Encéfalo/metabolismo Diagnóstico Diferencial Diagnóstico Precoce Fluordesoxiglucose F18 Seres Humanos Tomografia por Emissão de Pósitrons/métodos Tomografia por Emissão de Pósitrons/tendências Compostos Radiofarmacêuticos Tomografia Computadorizada de Emissão de Fóton Único Proteínas tau/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Amyloidogenic Proteins); 0 (Radiopharmaceuticals); 0 (tau Proteins); 0Z5B2CJX4D (Fluorodeoxyglucose F18) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170815 [St] Status: MEDLINE [do] DOI: 10.5692/clinicalneurol.cn-001016

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[PMID]: 28738073 [Au] Autor: Tashiro M; Iwata A; Yamauchi M; Shimizu K; Okada A; Ishiguro N; Inoshima Y [Ad] Endereço: Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan. [Ti] Título: The N-terminal region of serum amyloid A3 protein activates NF-κB and up-regulates MUC2 mucin mRNA expression in mouse colonic epithelial cells. [So] Source: PLoS One;12(7):e0181796, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Serum amyloid A (SAA) is the major acute-phase protein and a precursor of amyloid A (AA) in AA amyloidosis in humans and animals. SAA isoforms have been identified in a wide variety of animals, such as SAA1, SAA2, SAA3, and SAA4 in mouse. Although the biological functions of SAA isoforms are not completely understood, recent studies have suggested that SAA3 plays a role in host defense. Expression of SAA3 is increased on the mouse colon surface in the presence of microbiota in vivo, and it increases mRNA expression of mucin 2 (MUC2) in murine colonic epithelial cells in vitro, which constitutes a protective mucus barrier in the intestinal tract. In this study, to identify responsible regions in SAA3 for MUC2 expression, recombinant murine SAA1 (rSAA1), rSAA3, and rSAA1/3, a chimera protein constructed with mature SAA1 (amino acids 1-36) and SAA3 (amino acids 37-103), and vice versa for rSAA3/1, were added to murine colonic epithelial CMT-93 cells, and the mRNA expressions of MUC2 and cytokines were measured. Inhibition assays with NF-κB inhibitor or TLR4/MD2 inhibitor were also performed. Up-regulation of MUC2 mRNA expression was strongly stimulated by rSAA3 and rSAA3/1, but not by rSAA1 or rSAA1/3. Moreover, NF-κB and TLR4/MD2 inhibitors suppressed the increase of MUC2 mRNA expression. These results suggest that the major responsible region for MUC2 expression exists in amino acids 1-36 of SAA3, and that up-regulations of MUC2 expression by SAA3 and SAA3/1 are involved with activation of NF-κB via the TLR4/MD2 complex. [Mh] Termos MeSH primário: Colo/metabolismo Células Epiteliais/metabolismo Mucina-2/genética NF-kappa B/genética RNA Mensageiro/genética Proteína Amiloide A Sérica/genética Regulação para Cima/genética [Mh] Termos MeSH secundário: Proteínas Amiloidogênicas/genética Proteínas Amiloidogênicas/metabolismo Amiloidose/genética Amiloidose/metabolismo Animais Sequência de Bases Linhagem Celular Citocinas/genética Citocinas/metabolismo Camundongos Mucina-2/metabolismo NF-kappa B/metabolismo Alinhamento de Sequência Proteína Amiloide A Sérica/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amyloidogenic Proteins); 0 (Cytokines); 0 (Muc2 protein, mouse); 0 (Mucin-2); 0 (NF-kappa B); 0 (RNA, Messenger); 0 (Serum Amyloid A Protein) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170921 [Lr] Data última revisão: 170921 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170725 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0181796

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[PMID]: 28646497 [Au] Autor: Hayward S; Milner-White EJ [Ad] Endereço: D'Arcy Thompson Centre for Computational Biology, School of Computing Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom. [Ti] Título: Geometrical principles of homomeric ß-barrels and ß-helices: Application to modeling amyloid protofilaments. [So] Source: Proteins;85(10):1866-1881, 2017 Oct. [Is] ISSN: 1097-0134 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Examples of homomeric ß-helices and ß-barrels have recently emerged. Here we generalize the theory for the shear number in ß-barrels to encompass ß-helices and homomeric structures. We introduce the concept of the "ß-strip," the set of parallel or antiparallel neighboring strands, from which the whole helix can be generated giving it n-fold rotational symmetry. In this context, the shear number is interpreted as the sum around the helix of the fixed register shift between neighboring identical ß-strips. Using this approach, we have derived relationships between helical width, pitch, angle between strand direction and helical axis, mass per length, register shift, and number of strands. The validity and unifying power of the method is demonstrated with known structures including α-hemolysin, T4 phage spike, cylindrin, and the HET-s(218-289) prion. From reported dimensions measured by X-ray fiber diffraction on amyloid fibrils, the relationships can be used to predict the register shift and the number of strands within amyloid protofilaments. This was used to construct models of transthyretin and Alzheimer ß(40) amyloid protofilaments that comprise a single strip of in-register ß-strands folded into a "ß-strip helix." Results suggest both stabilization of an individual ß-strip helix and growth by addition of further ß-strip helices can involve the same pair of sequence segments associating with ß-sheet hydrogen bonding at the same register shift. This process would be aided by a repeat sequence. Hence, understanding how the register shift (as the distance between repeat sequences) relates to helical dimensions will be useful for nanotube design. [Mh] Termos MeSH primário: Peptídeos beta-Amiloides/química Amiloide/química Proteínas Amiloidogênicas/química Estrutura Secundária de Proteína [Mh] Termos MeSH secundário: Sequência de Aminoácidos Amiloide/genética Peptídeos beta-Amiloides/genética Proteínas Amiloidogênicas/genética Seres Humanos Ligações de Hidrogênio Conformação Proteica em alfa-Hélice/genética Dobramento de Proteína [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amyloid); 0 (Amyloid beta-Peptides); 0 (Amyloidogenic Proteins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171016 [Lr] Data última revisão: 171016 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170625 [St] Status: MEDLINE [do] DOI: 10.1002/prot.25341

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[PMID]: 28641562 [Au] Autor: Dutta M; Chutia R; Mattaparthi VSK [Ad] Endereço: Molecular Modelling & Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur-784 028, Assam. India. [Ti] Título: Structural Characterization of Amyloid ß17-42 Dimer by Potential of Mean Force Analysis: Insights from Molecular Dynamics Simulations. [So] Source: Protein Pept Lett;24(7):650-660, 2017. [Is] ISSN: 1875-5305 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: BACKGROUND: Recent experiments with Amyloid ß1-42 peptide have indicated that the initial dimerization of Aß1-42 monomers to form amyloid dimers stand out as a key event in the generation of toxic oligomers. However, the structural characterization of Aß1-42 dimer at the atomistic level and the dimerization mechanism by which Aß1-42 peptides co-aggregate still remains not clear. OBJECTIVE: In the present study, the process of Aß17-42 peptide dimerization which is known to play an important role in the plaque formation in Alzheimer's disease was evaluated in terms of potential of mean force. METHODS: The Aß17-42 dimer was constructed using PatchDock server. We have used molecular dynamics (MD) simulation with the umbrella sampling methodology to compute the Potential of Mean Force for the dimerization of Aß17-42. The global minima structure at the minimum distance of separation was isolated from the calculated free energy profile and the interactions involved in the formation of the dimer structure were examined. Protein-protein interfaces and the residueresidue interactions vital for generation of the dimer complexes were also evaluated. RESULTS: The simulation results elucidated the interaction between the monomeric units to be governed primarily by the hydrophobic and hydrogen bonds. The resultant Aß17-42 dimer was found to have an increased ß-strands propensity at the hydrophobic regions encompassing the CHC region. Furthermore, specific hydrophobic residues were found to play a vital role in the formation of the dimer complex. CONCLUSION: From the results we may therefore conclude hydrophobic region encompassing the CHC region to be crucial in dimerization process. The findings from this study provide detailed information for the complex process of early events of Aß aggregation. [Mh] Termos MeSH primário: Doença de Alzheimer/genética Peptídeos beta-Amiloides/química Proteínas Amiloidogênicas/química Fragmentos de Peptídeos/química [Mh] Termos MeSH secundário: Doença de Alzheimer/patologia Peptídeos beta-Amiloides/genética Proteínas Amiloidogênicas/genética Seres Humanos Interações Hidrofóbicas e Hidrofílicas Simulação de Dinâmica Molecular Fragmentos de Peptídeos/genética Multimerização Proteica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amyloid beta-Peptides); 0 (Amyloidogenic Proteins); 0 (Peptide Fragments) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171024 [Lr] Data última revisão: 171024 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170624 [St] Status: MEDLINE [do] DOI: 10.2174/0929866524666170621095702

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[PMID]: 28634774 [Au] Autor: Rosú SA; Toledo L; Urbano BF; Sanchez SA; Calabrese GC; Tricerri MA [Ad] Endereço: Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET, La Plata, Buenos Aires, Argentina. [Ti] Título: Learning from Synthetic Models of Extracellular Matrix; Differential Binding of Wild Type and Amyloidogenic Human Apolipoprotein A-I to Hydrogels Formed from Molecules Having Charges Similar to Those Found in Natural GAGs. [So] Source: Protein J;36(4):374-383, 2017 Aug. [Is] ISSN: 1875-8355 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Among other components of the extracellular matrix (ECM), glycoproteins and glycosaminoglycans (GAGs) have been strongly associated to the retention or misfolding of different proteins inducing the formation of deposits in amyloid diseases. The composition of these molecules is highly diverse and a key issue seems to be the equilibrium between physiological and pathological events. In order to have a model in which the composition of the matrix could be finely controlled, we designed and synthesized crosslinked hydrophilic polymers, the so-called hydrogels varying the amounts of negative charges and hydroxyl groups that are prevalent in GAGs. We checked and compared by fluorescence techniques the binding of human apolipoprotein A-I and a natural mutant involved in amyloidosis to the hydrogel scaffolds. Our results indicate that both proteins are highly retained as long as the negative charge increases, and in addition it was shown that the mutant is more retained than the Wt, indicating that the retention of specific proteins in the ECM could be part of the pathogenicity. These results show the importance of the use of these polymers as a model to get deep insight into the studies of proteins within macromolecules. [Mh] Termos MeSH primário: Proteínas Amiloidogênicas/química Apolipoproteína A-I/química Materiais Biomiméticos/química Hidrogéis/química Metacrilatos/química Polímeros/química Ácidos Sulfônicos/química [Mh] Termos MeSH secundário: Proteínas Amiloidogênicas/genética Apolipoproteína A-I/genética Sítios de Ligação Matriz Extracelular/química Glicosaminoglicanos/química Seres Humanos Interações Hidrofóbicas e Hidrofílicas Mutação Ligação Proteica Eletricidade Estática [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (APOA1 protein, human); 0 (Amyloidogenic Proteins); 0 (Apolipoprotein A-I); 0 (Glycosaminoglycans); 0 (Hydrogels); 0 (Methacrylates); 0 (Polymers); 0 (Sulfonic Acids); 6E1I4IV47V (hydroxyethyl methacrylate); ZSL2FB6GXN (styrenesulfonic acid polymer) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170728 [Lr] Data última revisão: 170728 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170622 [St] Status: MEDLINE [do] DOI: 10.1007/s10930-017-9728-8

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[PMID]: 28634213 [Au] Autor: Olivera-Perez HM; Lam L; Dang J; Jiang W; Rodriguez F; Rigali E; Weitzman S; Porter V; Rubbi L; Morselli M; Pellegrini M; Fiala M [Ad] Endereço: Department of Cell, Molecular, and Developmental Biology, UCLA Life Sciences, University of California, Los Angeles, Los Angeles, California, USA. [Ti] Título: Omega-3 fatty acids increase the unfolded protein response and improve amyloid-ß phagocytosis by macrophages of patients with mild cognitive impairment. [So] Source: FASEB J;31(10):4359-4369, 2017 Oct. [Is] ISSN: 1530-6860 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Macrophages (MÏ•s) of patients with Alzheimer's disease and mild cognitive impairment (MCI) are defective in amyloid-ß (Aß) phagocytosis and have low resistance to apoptosis by Aß. Omega-3 fatty acids (ω-3s) and and the ω-3 mediator, resolvin D1, increase Aß phagocytosis by MÏ•s of patients with MCI. We have investigated the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress by MÏ•s in a longitudinal study of fish-derived, ω-3-supplemented patients with MCI. Patients in the apolipoprotein E (ApoE)e3/e3 subgroup over time exhibited an increase of protein kinase RNA-like ER kinase (PERK) expression, Aß phagocytosis, intermediate M1-M2 MÏ• type, and a Mini-Mental State Examination (MMSE) rate of change of +1.8 points per year, whereas patients in the ApoEe3/e4 subgroup showed individually divergent results with an MMSE rate of change of -3.2 points per year. treatment of MÏ•s by fish-derived ω-3 emulsion increased Aß phagocytosis, PERK expression, and UPR RNA signature, and decreased ER stress signature. Augmented genes in the UPR signature included chaperones, lectins, foldases, and N-linked glycosylation enzymes. In summary, fish-derived ω-3s increase cytoprotective genes and decrease proapoptotic genes, improve immune clearance of Aß, and are associated with an improved MMSE rate of change in ApoEe3/e3 ApoEe3/e4 patients.-Olivera-Perez, H. M., Lam, L., Dang, J., Jiang, W., Rodriguez, F., Rigali, E., Weitzman, S., Porter, V., Rubbi, L., Morselli, M., Pellegrini, M., Fiala, M. Omega-3 fatty acids increase the unfolded protein response and improve amyloid-ß phagocytosis by macrophages of patients with mild cognitive impairment. [Mh] Termos MeSH primário: Peptídeos beta-Amiloides/metabolismo Disfunção Cognitiva/metabolismo Estresse do Retículo Endoplasmático/efeitos dos fármacos Ácidos Graxos Ômega-3/farmacologia Macrófagos/efeitos dos fármacos Fragmentos de Peptídeos/metabolismo Fagocitose/efeitos dos fármacos [Mh] Termos MeSH secundário: Doença de Alzheimer/genética Doença de Alzheimer/metabolismo Proteínas Amiloidogênicas/metabolismo Apoptose/efeitos dos fármacos Apoptose/fisiologia Ácidos Graxos Ômega-3/metabolismo Seres Humanos Macrófagos/metabolismo Desdobramento de Proteína [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amyloid beta-Peptides); 0 (Amyloidogenic Proteins); 0 (Fatty Acids, Omega-3); 0 (Peptide Fragments); 0 (amyloid beta-protein (1-42)) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171019 [Lr] Data última revisão: 171019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170622 [St] Status: MEDLINE [do] DOI: 10.1096/fj.201700290R

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[PMID]: 28521710 [Au] Autor: Makowska J [Ad] Endereço: Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk. Poland. [Ti] Título: Physicochemical and Structural Studies on Shaping of ß-hairpin in Proteins as a First Stage of Amyloid Formation. [So] Source: Curr Protein Pept Sci;18(12):1244-1253, 2017. [Is] ISSN: 1875-5550 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: The aggregation of proteins or their digested fragments through ß-sheet structures has a great significance because it leads to neurodegenerative diseases, which are a problem of the aging societies of the developed countries. Short peptides are typically used as models to study the formation of specific structures. However, while the formation of α-helical structure was investigated thoroughly, until recently, there have been much fewer studies on the formation of ß-structure. In this review, recent experimental and theoretical studies of ß-hairpin-forming peptides, both model alaninebased systems, and those based on the fragments of real proteins, are summarized with regard to the role of hydrophobic, local, and Coulombic interactions. It is demonstrated that the presence of charged residues can induce a bent structure not only owing to the formation of salt bridges if oppositely- charged residues present at the ends of a sequence but also through shielding the hydrophobic interior by like-charged residues at the end of the sequence. [Mh] Termos MeSH primário: Aminoácidos/química Amiloide/química Proteínas Amiloidogênicas/química Proteínas de Bactérias/química [Mh] Termos MeSH secundário: Equilíbrio Ácido-Base Sequência de Aminoácidos Amiloide/síntese química Interações Hidrofóbicas e Hidrofílicas Simulação de Dinâmica Molecular Conformação Proteica em alfa-Hélice Conformação Proteica em Folha beta Dobramento de Proteína Eletricidade Estática Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Amino Acids); 0 (Amyloid); 0 (Amyloidogenic Proteins); 0 (Bacterial Proteins); 0 (IgG Fc-binding protein, Streptococcus) [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: 170520 [St] Status: MEDLINE [do] DOI: 10.2174/1389203718666170516111601

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[PMID]: 28489421 [Au] Autor: Sontag EM; Samant RS; Frydman J [Ad] Endereço: Department of Biology, Stanford University, Stanford, California 94305; email: emsontag@stanford.edu , rsamant@stanford.edu , jfrydman@stanford.edu. [Ti] Título: Mechanisms and Functions of Spatial Protein Quality Control. [So] Source: Annu Rev Biochem;86:97-122, 2017 Jun 20. [Is] ISSN: 1545-4509 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A healthy proteome is essential for cell survival. Protein misfolding is linked to a rapidly expanding list of human diseases, ranging from neurodegenerative diseases to aging and cancer. Many of these diseases are characterized by the accumulation of misfolded proteins in intra- and extracellular inclusions, such as amyloid plaques. The clear link between protein misfolding and disease highlights the need to better understand the elaborate machinery that manages proteome homeostasis, or proteostasis, in the cell. Proteostasis depends on a network of molecular chaperones and clearance pathways involved in the recognition, refolding, and/or clearance of aberrant proteins. Recent studies reveal that an integral part of the cellular management of misfolded proteins is their spatial sequestration into several defined compartments. Here, we review the properties, function, and formation of these compartments. Spatial sequestration plays a central role in protein quality control and cellular fitness and represents a critical link to the pathogenesis of protein aggregation-linked diseases. [Mh] Termos MeSH primário: Envelhecimento/metabolismo Chaperonas Moleculares/metabolismo Doenças Neurodegenerativas/metabolismo Agregação Patológica de Proteínas/metabolismo Deficiências na Proteostase/metabolismo [Mh] Termos MeSH secundário: Envelhecimento/genética Envelhecimento/patologia Proteínas Amiloidogênicas/química Proteínas Amiloidogênicas/genética Proteínas Amiloidogênicas/metabolismo Compartimento Celular Regulação da Expressão Gênica Seres Humanos Chaperonas Moleculares/genética Doenças Neurodegenerativas/genética Doenças Neurodegenerativas/patologia Proteínas Priônicas/química Proteínas Priônicas/genética Proteínas Priônicas/metabolismo Agregação Patológica de Proteínas/genética Agregação Patológica de Proteínas/patologia Biossíntese de Proteínas Conformação Proteica Dobramento de Proteína Redobramento de Proteína Proteólise Deficiências na Proteostase/genética Deficiências na Proteostase/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Amyloidogenic Proteins); 0 (Molecular Chaperones); 0 (Prion Proteins) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170704 [Lr] Data última revisão: 170704 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170511 [St] Status: MEDLINE [do] DOI: 10.1146/annurev-biochem-060815-014616

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[PMID]: 28442538 [Au] Autor: Paouri E; Tzara O; Kartalou GI; Zenelak S; Georgopoulos S [Ad] Endereço: Laboratory of Cellular Neurobiology, Center of Basic Research, Biomedical Research Foundation, Academy of Athens, 11527, Athens, Greece. [Ti] Título: Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice. [So] Source: J Neurosci;37(20):5155-5171, 2017 May 17. [Is] ISSN: 1529-2401 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the CNS can provide potential therapeutic targets. TNF-α is a proinflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases, such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-α therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear. To investigate the role of peripheral TNF-α as a mediator of RA in the pathogenesis of AD, we generated double-transgenic 5XFAD/Tg197 AD/TNF mice that develop amyloid deposits and inflammatory arthritis induced by human TNF-α (huTNF-α) expression. We found that 5XFAD/Tg197 mice display decreased amyloid deposition, compromised neuronal integrity, and robust brain inflammation characterized by extensive gliosis and elevated blood-derived immune cell populations, including phagocytic macrophages and microglia. To evaluate the contribution of peripheral huTNF-α in the observed brain phenotype, we treated 5XFAD/Tg197 mice systemically with infliximab, an anti-huTNF-α antibody that does not penetrate the blood-brain barrier and prevents arthritis. Peripheral inhibition of huTNF-α increases amyloid deposition, rescues neuronal impairment, and suppresses gliosis and recruitment of blood-derived immune cells, without affecting brain huTNF-α levels. Our data report, for the first time, a distinctive role for peripheral TNF-α in the modulation of the amyloid phenotype in mice by regulating blood-derived and local brain inflammatory cell populations involved in ß-amyloid clearance. Mounting evidence supports the active involvement of systemic inflammation, in addition to local brain inflammation, in Alzheimer's disease (AD) progression. TNF-α is a pluripotent cytokine that has been independently involved in the pathogenesis of systemic inflammatory rheumatoid arthritis (RA) and AD. Here we first demonstrate that manipulation of peripheral TNF-α in the context of arthritis modulates the amyloid phenotype by regulating immune cell trafficking in the mouse brain. Our study suggests that additionally to its local actions in the AD brain, TNF-α can also indirectly modulate amyloid pathology as a regulator of peripheral inflammation. Our findings may have significant implications in the treatment of RA patients with anti-TNF-α drugs and in the potential use of TNF-targeted therapies for AD. [Mh] Termos MeSH primário: Doença de Alzheimer/imunologia Proteínas Amiloidogênicas/imunologia Artrite Reumatoide/imunologia Encéfalo/imunologia Macrófagos/imunologia Neuroglia/imunologia Fator de Necrose Tumoral alfa/imunologia [Mh] Termos MeSH secundário: Doença de Alzheimer/complicações Doença de Alzheimer/patologia Animais Artrite Reumatoide/complicações Artrite Reumatoide/patologia Encéfalo/patologia Citocinas/imunologia Feminino Fatores Imunológicos/imunologia Camundongos Camundongos Endogâmicos C57BL Camundongos Transgênicos Neuroglia/patologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amyloidogenic Proteins); 0 (Cytokines); 0 (Immunologic Factors); 0 (Tumor Necrosis Factor-alpha) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170818 [Lr] Data última revisão: 170818 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170427 [St] Status: MEDLINE [do] DOI: 10.1523/JNEUROSCI.2484-16.2017

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