Modulation of the Activity of the Insulin-Degrading Enzyme by Aβ Peptides.

The insulin-degrading enzyme (IDE) is an evolutionarily conserved protease implicated in the degradation of insulin and amyloidogenic peptides. Most of the biochemical and biophysical characterization of IDE's catalytic activity has been conducted using solutions containing a single substrate, i.e.

Exchange Broadening Underlies the Enhancement of IDE-Dependent Degradation of Insulin by Anionic Membranes.

Insulin-degrading enzyme (IDE) is an evolutionarily conserved ubiquitous zinc metalloprotease implicated in the efficient degradation of insulin monomer. However, IDE also degrades monomers of amyloidogenic peptides associated with disease, complicating the development of IDE inhibitors. In this work, we investigated the effects of the lipid composition of membranes on the IDE-dependent degradation of insulin.

Is the whole greater than the sum of its parts? The implementation and outcomes of a whole blood program in Ecuador.

Background: Hemorrhagic shock is a major cause of mortality in low-income and middle-income countries (LMICs). Many institutions in LMICs lack the resources to adequately prescribe balanced resuscitation. This study aims to describe the implementation of a whole blood (WB) program in Latin America and to discuss the outcomes of the patients who received WB.

Differential Effects of Polyphenols on Insulin Proteolysis by the Insulin-Degrading Enzyme.

The insulin-degrading enzyme (IDE) possesses a strong ability to degrade insulin and Aβ42 that has been linked to the neurodegeneration in Alzheimer's disease (AD). Given this, an attractive IDE-centric strategy for the development of therapeutics for AD is to boost IDE's activity for the clearance of Aβ42 without offsetting insulin proteostasis. Recently, we showed that resveratrol enhances IDE's activity toward Aβ42.

Helix Dipole and Membrane Electrostatics Delineate Conformational Transitions in the Self-Assembly of Amyloidogenic Peptides.

The self-assembly of amyloidogenic peptides on membrane surfaces is associated with the death of neurons and β-cells in Alzheimer's disease and type 2 diabetes, respectively. The early events of self-assembly are not known, but there is increasing evidence for the importance of the α-helix. To test the hypothesis that electrostatic interactions involving the helix dipole play a key role in membrane-mediated peptide self-assembly, we studied IAPP[11-25(S20G)-NH] (RLANFLVHSGNNFGA-NH), which under certain conditions self-assembles to form β-sheet assemblies through an α-helix-containing intermediate.

Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies.

The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer's disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aβ and tau.

Resveratrol Sustains Insulin-Degrading Enzyme Activity toward Aβ42.

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is the sixth leading cause of death in the United States. We hypothesize that the impaired clearance of Aβ42 from the brain is partly responsible for the onset of sporadic AD. In this work, we evaluated the activity of insulin-degrading enzyme (IDE) toward Aβ42 in the presence of resveratrol, a polyphenol found in red wine and grape juice.

Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme.

Insulin-degrading enzyme (IDE) is a zinc metalloprotease that selectively degrades biologically important substrates associated with type 2 diabetes and Alzheimer's disease (AD). As such, IDE is an attractive target for therapeutic innovations. A major requirement is an understanding of how other molecules present in cells regulate the activity of the enzyme toward insulin, IDE's most important physiologically relevant substrate.

The Longest Amyloid-β Precursor Protein Intracellular Domain Produced with Aβ42 Forms β-Sheet-Containing Monomers That Self-Assemble and Are Proteolyzed by Insulin-Degrading Enzyme.

Alzheimer's disease (AD) is the most common neurodegenerative disease resulting in dementia. It is characterized pathologically by extracellular amyloid plaques composed mainly of deposited Aβ42 and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Recent clinical trials targeting Aβ have failed, suggesting that other polypeptides produced from the amyloid-β precursor protein (APP) may be involved in AD.

Mechanistic Studies of the Inhibition of Insulin Fibril Formation by Rosmarinic Acid.

The self-assembly of insulin to form amyloid fibrils has been widely studied because it is a significant problem in the medical management of diabetes and is an important model system for the investigation of amyloid formation and its inhibition. A few inhibitors of insulin fibrillation have been identified with potencies that could be higher. Knowledge of how these work at the molecular level is not known but important for the development of more potent inhibitors.

A versatile platform for adding functional properties to amyloid fibrils.

Herein we report the design, synthesis, and testing of prototype members of a family of amyloid-binding molecular tools that can manipulate the fibrils by giving them various new functional properties. Potential applications include manipulating disease-relevant fibrils, developing novel functional nanomaterials, and studying the molecular details of fibril structures.

Binding Modes of Thioflavin T on the Surface of Amyloid Fibrils Studied by NMR.

The mechanism for the interaction of thioflavin T (ThT) with amyloid fibrils at the molecular level is not known. Here, we used (1) H NMR spectroscopy to determine the binding mode of ThT on the surface of fibrils from lysozyme and insulin. Relayed rotating-frame Overhauser enhancements in ThT were observed, indicating that the orientation of ThT is orthogonal to the fibril surface.

Optimized bio-inspired stiffening design for an engine nacelle.

Structural efficiency is a common engineering goal in which an ideal solution provides a structure with optimized performance at minimized weight, with consideration of material mechanical properties, structural geometry, and manufacturability. This study aims to address this goal in developing high performance lightweight, stiff mechanical components by creating an optimized design from a biologically-inspired template. The approach is implemented on the optimization of rib stiffeners along an aircraft engine nacelle.

K114 (trans, trans)-bromo-2,5-bis(4-hydroxystyryl)benzene is an efficient detector of cationic amyloid fibrils.

Cationic amyloid fibrils found in human semen enhance the transmission of the human immunodeficiency virus (HIV) and thus, are named semen-derived enhancer of virus infection (SEVI). The mechanism for the enhancement of transmission is not completely understood but it has been proposed that SEVI neutralizes the repulsion that exists between the negatively charged viral envelope and host cell membrane. Consistent with this view, here we show that the fluorescence of cationic thioflavin T (ThT) in the presence of SEVI is weak, and thus ThT is not an efficient detector of SEVI.

Conformational analysis of thioflavin T bound to the surface of amyloid fibrils.

The interaction of small molecules with the surface of amyloid assemblies is important for the detection and inhibition of amyloid formation. Thioflavin T (ThT), a small molecular rotor, has been used for the detection of amyloid fibrils for over half a century. The basis for detection is simple in that in the presence of fibrils the fluorescence of ThT is dramatically enhanced.

Kinetic profile of amyloid formation in the presence of an aromatic inhibitor by nuclear magnetic resonance.

The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are potential inhibitors of β-sheet formation.

Curcumin modulates the self-assembly of the islet amyloid polypeptide by disassembling α-helix.

Understanding how small molecules affect amyloid formation is of major biomedical and pharmaceutical importance due to the association of amyloid with incurable diseases including Alzheimer's, Parkinson's, and type II diabetes. Using solution state (1)H NMR, we demonstrate that curcumin, a planar biphenolic compound found in the Indian spice turmeric, delays the self-assembly of islet amyloid polypeptide to NMR-invisible assemblies. Accompanying circular dichroism studies show that curcumin disassembles α-helix in maturing assemblies of IAPP.

Helix-dipole effects in peptide self-assembly to amyloid.

The formation of amyloid fibrils is associated with incurable diseases including Alzheimer's, Parkinson's, and type 2 diabetes. Important mechanistic details of the self-assembly are unknown partly because of the absence of a clear structural characterization of intermediates. There is experimental evidence, however, for α-helical intermediates that has come primarily from circular dichroism spectroscopy.

Treatment of malignant, non-resectable, epithelial origin esophageal tumours with the humanized anti-epidermal growth factor antibody nimotuzumab combined with radiation therapy and chemotherapy.

Background: Over-expression of epidermal growth factor receptor in esophageal cancer is associated with poor prognosis. The present study was conducted to evaluate safety and preliminary efficacy of nimotuzumab, a humanized anti-EGFR antibody in combination with radiation and chemotherapy in advanced esophageal tumours.

Patients And Methods: A Phase II clinical trial was conducted, where patients received cisplatin, 5-fluorouracil, and radiotherapy, either alone or combined with six weekly infusions of nimotuzumab at the dose of 200 mg.

Mechanistic studies of peptide self-assembly: transient α-helices to stable β-sheets.

The pathologic self-assembly of proteins is associated with typically late-onset disorders such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. Important mechanistic details of the self-assembly are unknown, but there is increasing evidence supporting the role of transient α-helices in the early events. Islet amyloid polypeptide (IAPP) is a 37-residue polypeptide that self-assembles into aggregates that are toxic to the insulin-producing β cells.

Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease.

In recent years, small protein oligomers have been implicated in the aetiology of a number of important amyloid diseases, such as type 2 diabetes, Parkinson's disease and Alzheimer's disease. As a consequence, research efforts are being directed away from traditional targets, such as amyloid plaques, and towards characterization of early oligomer states. Here we present a new analysis method, ion mobility coupled with mass spectrometry, for this challenging problem, which allows determination of in vitro oligomer distributions and the qualitative structure of each of the aggregates.

Amyloid beta-protein: experiment and theory on the 21-30 fragment.

The structure of the 21-30 fragment of the amyloid beta-protein (Abeta) was investigated by ion mobility mass spectrometry and replica exchange dynamics simulations. Mutations associated with familial Alzheimer's disease (E22G, E22Q, E22K, and D23N) of Abeta(21-30) were also studied, in order to understand any structural changes that might occur with these substitutions. The structure of the WT peptide shows a bend and a perpendicular turn in the backbone which is maintained by a network of D23 hydrogen bonding.

Effects of familial Alzheimer's disease mutations on the folding nucleation of the amyloid beta-protein.

The effect of single amino acid substitutions associated with the Italian (E22K), Arctic (E22G), Dutch (E22Q) and Iowa (D23N) familial forms of Alzheimer's disease and cerebral amyloid angiopathy on the structure of the 21-30 fragment of the Alzheimer amyloid beta-protein (Abeta) is investigated by replica-exchange molecular dynamics simulations. The 21-30 segment has been shown in our earlier work to adopt a bend structure in solution that may serve as the folding nucleation site for Abeta. Our simulations reveal that the 24-28 bend motif is retained in all E22 mutants, suggesting that mutations involving residue E22 may not affect the structure of the folding nucleation site of Abeta.

Familial Alzheimer's disease mutations alter the stability of the amyloid beta-protein monomer folding nucleus.

Amyloid beta-protein (Abeta) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate the oligomerization pathway, we studied Abeta monomer folding and identified a decapeptide segment of Abeta, (21)Ala-(22)Glu-(23)Asp-(24)Val-(25)Gly-(26)Ser-(27)Asn-(28)Lys-(29)Gly-(30)Ala, within which turn formation appears to nucleate monomer folding. The turn is stabilized by hydrophobic interactions between Val-24 and Lys-28 and by long-range electrostatic interactions between Lys-28 and either Glu-22 or Asp-23.