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  1 / 2179 MEDLINE  
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[PMID]:28465284
[Au] Autor:Qian J; Thomas AP; Schroeder AM; Rakshit K; Colwell CS; Matveyenko AV
[Ad] Endereço:Departments of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.
[Ti] Título:Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus.
[So] Source:Am J Physiol Endocrinol Metab;313(2):E213-E221, 2017 08 01.
[Is] ISSN:1522-1555
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on ) behavioral circadian rhythms, ) photic entrainment of circadian activity, ) SCN and peripheral tissue molecular clock function, and ) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.
[Mh] Termos MeSH primário: Comportamento Animal/fisiologia
Ritmo Circadiano/genética
Diabetes Mellitus Tipo 2
[Mh] Termos MeSH secundário: Animais
Diabetes Mellitus Experimental/genética
Diabetes Mellitus Experimental/metabolismo
Diabetes Mellitus Experimental/patologia
Diabetes Mellitus Experimental/fisiopatologia
Diabetes Mellitus Tipo 2/genética
Diabetes Mellitus Tipo 2/metabolismo
Diabetes Mellitus Tipo 2/patologia
Diabetes Mellitus Tipo 2/fisiopatologia
Modelos Animais de Doenças
Progressão da Doença
Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
Luz
Masculino
Proteínas Circadianas Period/metabolismo
Ratos
Ratos Sprague-Dawley
Ratos Transgênicos
Núcleo Supraquiasmático/metabolismo
Núcleo Supraquiasmático/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 0 (Period Circadian Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1152/ajpendo.00406.2016


  2 / 2179 MEDLINE  
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[PMID]:29251925
[Au] Autor:Seal M; Dey SG
[Ad] Endereço:Department of Inorganic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700032, India.
[Ti] Título:Active-Site Environment of Copper-Bound Human Amylin Relevant to Type 2 Diabetes.
[So] Source:Inorg Chem;57(1):129-138, 2018 Jan 02.
[Is] ISSN:1520-510X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Type 2 diabetes mellitus (T2Dm) is characterized by reduced ß cell mass and amyloid deposits of human islet amyloid polypeptide (hIAPP) or amylin, a 37 amino acid containing peptide around pancreatic ß cells. The interaction of copper (Cu) with amylin and its mutants has been studied in detail using absorption, circular dichroism, electron paramagnetic resonance spectroscopy, and cyclic voltammetry. Cu binds amylin in a 1:1 ratio, and the binding domain lies within the first 19 amino acid residues of the peptide. Depending on the pH of the medium, Cu-amylin shows the formation of five pH-dependent components (component IV at pH 4.0, component III at pH 5.0, component II at pH 6.0, component I at pH 8.0, and another higher pH component above pH 9.0). The terminal amine, His18, and amidates are established as key residues in the peptide that coordinate the Cu center. The physiologically relevant components I and II can generate H O , which can possibly account for the enhanced toxicity of amylin in the presence of Cu, causing damage of the ß cells of the pancreas via oxidative stress.
[Mh] Termos MeSH primário: Cobre/química
Diabetes Mellitus Tipo 2/metabolismo
Polipeptídeo Amiloide das Ilhotas Pancreáticas/química
[Mh] Termos MeSH secundário: Domínio Catalítico
Cobre/metabolismo
Seres Humanos
Peróxido de Hidrogênio/metabolismo
Peróxido de Hidrogênio/farmacologia
Concentração de Íons de Hidrogênio
Células Secretoras de Insulina/efeitos dos fármacos
Células Secretoras de Insulina/metabolismo
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
Estresse Oxidativo/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 789U1901C5 (Copper); BBX060AN9V (Hydrogen Peroxide)
[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:171219
[St] Status:MEDLINE
[do] DOI:10.1021/acs.inorgchem.7b02266


  3 / 2179 MEDLINE  
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[PMID]:28920428
[Au] Autor:Sivanesam K; Andersen NH
[Ad] Endereço:Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
[Ti] Título:Inhibition of Human Amylin Amyloidogenesis by Human Amylin-Fragment Peptides: Exploring the Effects of Serine Residues and Oligomerization upon Inhibitory Potency.
[So] Source:Biochemistry;56(40):5373-5379, 2017 Oct 10.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To date, fragments from within the amyloidogenic-patch region of human amylin (hAM) have been shown to aggregate independently of the full-length peptide. In this study, we show that under certain conditions, both oligomers of NFGAILSS and the monomeric form are capable of inhibiting the aggregation of the full-length hAM sequence. The inhibition, rather than aggregate seeding, observed with the soluble portion of aged NFGAILSS solutions was particularly striking occurring at far substoichiometric levels. Apparently, the oligomer form of this fragment is responsible for inhibiting the transition from random coil to ß-sheet or serves as a disaggregator of hAM ß-oligomers. Sequential deletion of the serine residues from NFGAILSS results in a decrease of inhibition, indicating that these residues are important to the activity of this fragment. We, like others, observed instances of α-helix-like CD spectra prior to ß-sheet formation as part of the amyloidogenesis pathway. The partially aggregated sample and the fragments studied display spectroscopic diagnostics, suggesting that they slow down the conversion of full-length hAM monomers to cytotoxic oligomers.
[Mh] Termos MeSH primário: Polipeptídeo Amiloide das Ilhotas Pancreáticas/química
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/farmacologia
Multimerização Proteica/efeitos dos fármacos
Serina
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Seres Humanos
Modelos Moleculares
Agregados Proteicos
Estrutura Quaternária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 0 (Peptide Fragments); 0 (Protein Aggregates); 452VLY9402 (Serine)
[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:170919
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00739


  4 / 2179 MEDLINE  
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[PMID]:28892816
[Au] Autor:Chamberlain JJ; Kalyani RR; Leal S; Rhinehart AS; Shubrook JH; Skolnik N; Herman WH
[Ad] Endereço:From St. Mark's Hospital and St. Mark's Diabetes Center, Salt Lake City, Utah; Johns Hopkins University, Baltimore, Maryland; SinfoníaRx, Tucson, Arizona; Glytec, Marco Island, Florida; Touro University College of Osteopathic Medicine, Vallejo, California; Abington Memorial Hospital, Jenkintown, Pen
[Ti] Título:Treatment of Type 1 Diabetes: Synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes.
[So] Source:Ann Intern Med;167(7):493-498, 2017 Oct 03.
[Is] ISSN:1539-3704
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Description: The American Diabetes Association (ADA) annually updates Standards of Medical Care in Diabetes to provide clinicians, patients, researchers, payers, and other interested parties with evidence-based recommendations for the diagnosis and management of patients with diabetes. Methods: For the 2017 Standards of Care, the ADA Professional Practice Committee did MEDLINE searches from 1 January 2016 to November 2016 to add, clarify, or revise recommendations on the basis of new evidence. The committee rated the recommendations as A, B, or C, depending on the quality of evidence, or E for expert consensus or clinical experience. The Standards of Care were reviewed and approved by the Executive Committee of the ADA Board of Directors, which includes health care professionals, scientists, and laypersons. Feedback from the larger clinical community informed revisions. Recommendation: This synopsis focuses on recommendations from the 2017 Standards of Care about monitoring and pharmacologic approaches to glycemic management for type 1 diabetes.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 1/tratamento farmacológico
Hipoglicemiantes/uso terapêutico
[Mh] Termos MeSH secundário: Glicemia/análise
Automonitorização da Glicemia
Diabetes Mellitus Tipo 1/sangue
Hemoglobina A Glicada/análise
Seres Humanos
Hipoglicemia/induzido quimicamente
Hipoglicemia/classificação
Hipoglicemiantes/efeitos adversos
Hipoglicemiantes/farmacocinética
Insulina/efeitos adversos
Insulina/farmacocinética
Insulina/uso terapêutico
Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico
Liraglutida/uso terapêutico
Metformina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; PRACTICE GUIDELINE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Glycated Hemoglobin A); 0 (Hypoglycemic Agents); 0 (Insulin); 0 (Islet Amyloid Polypeptide); 839I73S42A (Liraglutide); 9100L32L2N (Metformin); D3FM8FA78T (pramlintide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.7326/M17-1259


  5 / 2179 MEDLINE  
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[PMID]:28829122
[Au] Autor:Wu L; Velander P; Liu D; Xu B
[Ad] Endereço:Department of Biochemistry, ‡Center for Drug Discovery, §Translational Obesity Research Center, ∥School of Neuroscience, and ⊥Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute & State University , Blacksburg, Virginia 24061, United States.
[Ti] Título:Olive Component Oleuropein Promotes ß-Cell Insulin Secretion and Protects ß-Cells from Amylin Amyloid-Induced Cytotoxicity.
[So] Source:Biochemistry;56(38):5035-5039, 2017 Sep 26.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Oleuropein, a natural product derived from olive leaves, has reported anti-diabetic functions. However, detailed molecular mechanisms for how it affects ß-cell functions remain poorly understood. Here, we present evidence that oleuropein promotes glucose-stimulated insulin secretion (GSIS) in ß-cells. The effect is dose-dependent and stimulates the ERK/MAPK signaling pathway. We further demonstrated that oleuropein inhibits the cytotoxicity induced by amylin amyloids, a hallmark feature of type 2 diabetes. We demonstrated that these dual functions are structure-specific: we identified the 3-hydroxytyrosol moiety of oleuropein as the main functional entity responsible for amyloid inhibition, but the novel GSIS function requires the entire structure scaffold of the molecule.
[Mh] Termos MeSH primário: Células Secretoras de Insulina/efeitos dos fármacos
Insulina/secreção
Iridoides/química
Iridoides/farmacologia
Polipeptídeo Amiloide das Ilhotas Pancreáticas/toxicidade
[Mh] Termos MeSH secundário: Amiloide/metabolismo
Animais
Linhagem Celular
Relação Dose-Resposta a Droga
Flavonoides/farmacologia
Células Secretoras de Insulina/metabolismo
Células Secretoras de Insulina/secreção
Iridoides/administração & dosagem
Microscopia Eletrônica de Transmissão
Olea/química
Proteínas Quinases/metabolismo
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one); 0 (Amyloid); 0 (Flavonoids); 0 (Insulin); 0 (Iridoids); 0 (Islet Amyloid Polypeptide); 2O4553545L (oleuropein); EC 2.7.- (Protein Kinases)
[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:170823
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00199


  6 / 2179 MEDLINE  
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[PMID]:28787568
[Au] Autor:Wu J; Zhao J; Yang Z; Li H; Gao Z
[Ad] Endereço:School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology , Wuhan 430074, People's Republic of China.
[Ti] Título:Strong Inhibitory Effect of Heme on hIAPP Fibrillation.
[So] Source:Chem Res Toxicol;30(9):1711-1719, 2017 Sep 18.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The deposition of human islet amyloid polypeptide (hIAPP) within ß-cells is implicated in the etiology of type 2 diabetes mellitus (T2Dm). It was reported that heme could bind to hIAPP. We speculate that binding may affect the aggregation of hIAPP. In this study, UV-vis spectroscopy was used to detect the interaction pattern between the heme and hIAPP. ThT and Bis-ANS fluorescence assay, circular dichroism spectroscopy, gel electrophoresis assay, and transmission electron microscopy were employed to study the effect of heme on the aggregation of hIAPP. We found that heme dramatically inhibited hIAPP aggregation, even partially dismantled hIAPP aggregates by preventing its conformational changes. Moreover, a similar inhibitory effect was also observed on mutant hIAPP. In the compared group, the inhibitory effects of protoporphyrin on hIAPP and its mutants aggregation were weaker. Similarly, its effect on the dismantlement of the aggregates was also weaker. On the basis of these results, we revealed that the heme iron center was not required for the inhibitory effect on hIAPP but affected the binding affinity of heme to hIAPP. Besides Arg11 and His18, other hydrophobic residues of hIAPP may also play important roles in heme binding. Our results may help to develop an in-depth understanding of the interaction between heme and hIAPP, which would be helpful in designing new therapeutic strategies against T2Dm.
[Mh] Termos MeSH primário: Heme/química
Polipeptídeo Amiloide das Ilhotas Pancreáticas/química
[Mh] Termos MeSH secundário: Dicroísmo Circular
Eletroforese em Gel de Campo Pulsado
Heme/metabolismo
Seres Humanos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
Microscopia Eletrônica de Transmissão
Ligação Proteica
Protoporfirinas/química
Espectrometria de Fluorescência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 0 (Protoporphyrins); 42VZT0U6YR (Heme); C2K325S808 (protoporphyrin IX)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.7b00170


  7 / 2179 MEDLINE  
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[PMID]:28786287
[Au] Autor:Christensen M; Skeby KK; Schiøtt B
[Ad] Endereço:Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University , DK-8000 Aarhus, Denmark.
[Ti] Título:Identification of Key Interactions in the Initial Self-Assembly of Amylin in a Membrane Environment.
[So] Source:Biochemistry;56(36):4884-4894, 2017 Sep 12.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Islet amyloid polypeptide, also known as amylin, forms aggregates that reduce the amount of insulin-producing cells in patients with type II diabetes mellitus. Much remains unknown about the process of aggregation and cytotoxicity, but it is known that certain cell membrane components can alter the rate of aggregation. Using atomistic molecular dynamics simulations combined with the highly mobile membrane mimetic model incorporating enhanced sampling of lipid diffusion, we investigate interaction of amylin peptides with the membrane components as well as the self-assembly of amylin. Consistent with experimental evidence, we find that an initial membrane-bound α-helical state folds into stable ß-sheet structures upon self-assembly. Our results suggest the following mechanism for the initial phase of amylin self-assembly. The peptides move around on the membrane with the positively charged N-terminus interacting with the negatively charged lipid headgroups. When the peptides start to interact, they partly unfold and break some of the contacts with the membrane. The initial interactions between the peptides are dominated by aromatic and hydrophobic interactions. Oligomers are formed showing both intra- and interpeptide ß-sheets, initially with interactions mainly in the C-terminal domain of the peptides. Decreasing the pH to 5.5 is known to inhibit amyloid formation. At low pH, His18 is protonated, adding a fourth positive charge at the peptide. With His18 protonated, no oligomerization is observed in the simulations. The additional charge gives a strong midpoint anchoring of the peptides to negatively charged membrane components, and the peptides experience additional interpeptide repulsion, thereby preventing interactions.
[Mh] Termos MeSH primário: Polipeptídeo Amiloide das Ilhotas Pancreáticas/química
[Mh] Termos MeSH secundário: Membrana Celular
Simulação por Computador
Modelos Químicos
Modelos Moleculares
Conformação Proteica
Multimerização Proteica
Subunidades Proteicas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 0 (Protein Subunits)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00344


  8 / 2179 MEDLINE  
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[PMID]:28768713
[Au] Autor:Petrou AL; Terzidaki A
[Ad] Endereço:Laboratory of Inorganic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece athpetrou@chem.uoa.gr.
[Ti] Título:A meta-analysis and review examining a possible role for oxidative stress and singlet oxygen in diverse diseases.
[So] Source:Biochem J;474(16):2713-2731, 2017 Aug 02.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:From kinetic data (k, T) we calculated the thermodynamic parameters for various processes (nucleation, elongation, fibrillization, etc.) of proteinaceous diseases that are related to the ß-amyloid protein (Alzheimer's), to tau protein (Alzheimer's, Pick's), to α-synuclein (Parkinson's), prion, amylin (type II diabetes), and to α-crystallin (cataract). Our calculations led to ΔG values that vary in the range 92.8-127 kJ mol at 310 K. A value of ∼10-30 kJ mol is the activation energy for the diffusion of reactants, depending on the reaction and the medium. The energy needed for the excitation of O from the ground to the first excited state ( Δ , singlet oxygen) is equal to 92 kJ mol So, the ΔG is equal to the energy needed for the excitation of ground state oxygen to the singlet oxygen ( Δ first excited) state. The similarity of the ΔG values is an indication that a common mechanism in the above disorders may be taking place. We attribute this common mechanism to the (same) role of the oxidative stress and specifically of singlet oxygen, ( Δ ), to the above-mentioned processes: excitation of ground state oxygen to the singlet oxygen, Δ , state (92 kJ mol ), and reaction of the empty π* orbital with high electron density regions of biomolecules (∼10-30 kJ mol for their diffusion). The ΔG for cases of heat-induced cell killing (cancer) lie also in the above range at 310 K. The present paper is a review and meta-analysis of literature data referring to neurodegenerative and other disorders.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/metabolismo
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
alfa-Cristalinas/metabolismo
alfa-Sinucleína/química
Proteínas tau/metabolismo
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Peptídeos beta-Amiloides/química
Catarata/metabolismo
Catarata/patologia
Diabetes Mellitus Tipo 2/metabolismo
Diabetes Mellitus Tipo 2/patologia
Metabolismo Energético
Seres Humanos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/química
Estresse Oxidativo
Oxigênio/química
Oxigênio/metabolismo
Doença de Parkinson/metabolismo
Doença de Parkinson/patologia
Oxigênio Singlete
Termodinâmica
alfa-Cristalinas/química
alfa-Sinucleína/metabolismo
Proteínas tau/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Islet Amyloid Polypeptide); 0 (alpha-Crystallins); 0 (alpha-Synuclein); 0 (tau Proteins); 17778-80-2 (Singlet Oxygen); S88TT14065 (Oxygen)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20161058


  9 / 2179 MEDLINE  
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[PMID]:28765400
[Au] Autor:Mukherjee A; Morales-Scheihing D; Salvadores N; Moreno-Gonzalez I; Gonzalez C; Taylor-Presse K; Mendez N; Shahnawaz M; Gaber AO; Sabek OM; Fraga DW; Soto C
[Ad] Endereço:Mitchell Center for Alzheimer's Disease, Department of Neurology, John P. and Kathrine G. McGovern Medical School, University of Texas Medical School at Houston, Houston, TX.
[Ti] Título:Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism.
[So] Source:J Exp Med;214(9):2591-2610, 2017 Sep 04.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although a large proportion of patients with type 2 diabetes (T2D) accumulate misfolded aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas. Islet homogenates immunodepleted with anti-IAPP-specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposition, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on ß cell number and mass. Finally, induction of IAPP deposition and diabetic abnormalities were also induced in vivo by administration of IAPP aggregates prepared in vitro using pure, synthetic IAPP. Our findings suggest that some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/metabolismo
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
Ilhotas Pancreáticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Diabetes Mellitus Tipo 2/etiologia
Diabetes Mellitus Tipo 2/patologia
Feminino
Seres Humanos
Ilhotas Pancreáticas/patologia
Masculino
Camundongos
Camundongos Transgênicos
Príons/metabolismo
Agregados Proteicos
Deficiências na Proteostase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 0 (Prions); 0 (Protein Aggregates)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20161134


  10 / 2179 MEDLINE  
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[PMID]:28696548
[Au] Autor:Ly H; Verma N; Wu F; Liu M; Saatman KE; Nelson PT; Slevin JT; Goldstein LB; Biessels GJ; Despa F
[Ad] Endereço:Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY.
[Ti] Título:Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.
[So] Source:Ann Neurol;82(2):208-222, 2017 Aug.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins. METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo. RESULTS: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. INTERPRETATION: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222.
[Mh] Termos MeSH primário: Encéfalo/patologia
Diabetes Mellitus Tipo 2/patologia
Polipeptídeo Amiloide das Ilhotas Pancreáticas/efeitos adversos
Leucoencefalopatias/induzido quimicamente
Leucoencefalopatias/patologia
Microvasos/metabolismo
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Animais
Apolipoproteína E4/administração & dosagem
Apolipoproteína E4/efeitos adversos
Encéfalo/irrigação sanguínea
Encéfalo/efeitos dos fármacos
Células Cultivadas
Diabetes Mellitus Tipo 2/sangue
Diabetes Mellitus Tipo 2/complicações
Sinergismo Farmacológico
Endotélio/metabolismo
Técnicas de Inativação de Genes
Seres Humanos
Hemorragias Intracranianas/induzido quimicamente
Polipeptídeo Amiloide das Ilhotas Pancreáticas/sangue
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
Leucoencefalopatias/sangue
Leucoencefalopatias/complicações
Imagem por Ressonância Magnética
Aprendizagem em Labirinto/efeitos dos fármacos
Destreza Motora/efeitos dos fármacos
Neuroimagem
Pâncreas/metabolismo
Ratos
Ratos Mutantes
Junções Íntimas/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoprotein E4); 0 (Islet Amyloid Polypeptide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1002/ana.24992



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