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Artykuły w czasopismach na temat "Amyloid Fibril Inhibition"
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Šneideris, Tomas, Lina Baranauskienė, Jonathan G. Cannon, Rasa Rutkienė, Rolandas Meškys i Vytautas Smirnovas. "Looking for a generic inhibitor of amyloid-like fibril formation among flavone derivatives". PeerJ 3 (24.09.2015): e1271. http://dx.doi.org/10.7717/peerj.1271.
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A range of diseases is associated with amyloid fibril formation. Despite different proteins being responsible for each disease, all of them share similar features including beta-sheet-rich secondary structure and fibril-like protein aggregates. A number of proteins can form amyloid-like fibrilsin vitro, resembling structural features of disease-related amyloids. Given these generic structural properties of amyloid and amyloid-like fibrils, generic inhibitors of fibril formation would be of interest for treatment of amyloid diseases. Recently, we identified five outstanding inhibitors of insulin amyloid-like fibril formation among the pool of 265 commercially available flavone derivatives. Here we report testing of these five compounds and of epi-gallocatechine-3-gallate (EGCG) on aggregation of alpha-synuclein and beta-amyloid. We used a Thioflavin T (ThT) fluorescence assay, relying on halftimes of aggregation as the measure of inhibition. This method avoids large numbers of false positive results. Our data indicate that four of the five flavones and EGCG inhibit alpha-synuclein aggregation in a concentration-dependent manner. However none of these derivatives were able to increase halftimes of aggregation of beta-amyloid.
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HOWLETT, David R., Amanda E. PERRY, Fiona GODFREY, Jane E. SWATTON, Kevin H. JENNINGS, Claus SPITZFADEN, Harry WADSWORTH, Stephen J. WOOD i Roger E. MARKWELL. "Inhibition of fibril formation in β-amyloid peptide by a novel series of benzofurans". Biochemical Journal 340, nr 1 (10.05.1999): 283–89. http://dx.doi.org/10.1042/bj3400283.
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A series of benzofuran derivatives have been identified as inhibitors of fibril formation in the β-amyloid peptide. The activity of these compounds has been assessed by a novel fibril-formation-specific immunoassay and for their effects on the production of a biologically active fibril product. The inhibition afforded by the compounds seems to be associated with their binding to β-amyloid, as identified by scintillation proximity binding assay. Binding assays and NMR studies also indicate that the inhibition is associated with self-aggregation of the compounds. There is a close correlation between the activity of the benzofurans as inhibitors of fibril formation and their ability to bind to β-amyloid. Non-benzofuran inhibitors of the fibril formation process do not seem to bind to the same site on the β-amyloid molecule as the benzofurans. Thus a specific recognition site might exist for benzofurans on β-amyloid, binding to which seems to interfere with the ability of the peptide to form fibrils.
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Saelices, Lorena, Kevin Chung, Ji H. Lee, Whitaker Cohn, Julian P. Whitelegge, Merrill D. Benson i David S. Eisenberg. "Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition". Proceedings of the National Academy of Sciences 115, nr 29 (28.06.2018): E6741—E6750. http://dx.doi.org/10.1073/pnas.1805131115.
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Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutantTTRgene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.
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Hasanbašić, Samra, Alma Jahić, Selma Berbić, Magda Tušek Žnidarič i Eva Žerovnik. "Inhibition of Protein Aggregation by Several Antioxidants". Oxidative Medicine and Cellular Longevity 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/8613209.
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Amyloid fibril formation is a shared property of all proteins; therefore, model proteins can be used to study this process. We measured protein aggregation of the model amyloid-forming protein stefin B in the presence and absence of several antioxidants. Amyloid fibril formation by stefin B was routinely induced at pH 5 and 10% TFE, at room temperature. The effects of antioxidants NAC, vitamin C, vitamin E, and the three polyphenols resveratrol, quercetin, and curcumin on the kinetics of fibril formation were followed using ThT fluorescence. Concomitantly, the morphology and amount of the aggregates and fibrils were checked by transmission electron microscopy (TEM). The concentration of the antioxidants was varied, and it was observed that different modes of action apply at low or high concentrations relative to the binding constant. In order to obtain more insight into the possible mode of binding, docking of NAC, vitamin C, and all three polyphenols was done to the monomeric form of stefin B.
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Selig, Emily E., Courtney O. Zlatic, Dezerae Cox, Yee-Foong Mok, Paul R. Gooley, Heath Ecroyd i Michael D. W. Griffin. "N- and C-terminal regions of αB-crystallin and Hsp27 mediate inhibition of amyloid nucleation, fibril binding, and fibril disaggregation". Journal of Biological Chemistry 295, nr 29 (16.05.2020): 9838–54. http://dx.doi.org/10.1074/jbc.ra120.012748.
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Small heat-shock proteins (sHSPs) are ubiquitously expressed molecular chaperones that inhibit amyloid fibril formation; however, their mechanisms of action remain poorly understood. sHSPs comprise a conserved α-crystallin domain flanked by variable N- and C-terminal regions. To investigate the functional contributions of these three regions, we compared the chaperone activities of various constructs of human αB-crystallin (HSPB5) and heat-shock 27-kDa protein (Hsp27, HSPB1) during amyloid formation by α-synuclein and apolipoprotein C-II. Using an array of approaches, including thioflavin T fluorescence assays and sedimentation analysis, we found that the N-terminal region of Hsp27 and the terminal regions of αB-crystallin are important for delaying amyloid fibril nucleation and for disaggregating mature apolipoprotein C-II fibrils. We further show that the terminal regions are required for stable fibril binding by both sHSPs and for mediating lateral fibril–fibril association, which sequesters preformed fibrils into large aggregates and is believed to have a cytoprotective function. We conclude that although the isolated α-crystallin domain retains some chaperone activity against amyloid formation, the flanking domains contribute additional and important chaperone activities, both in delaying amyloid formation and in mediating interactions of sHSPs with amyloid aggregates. Both these chaperone activities have significant implications for the pathogenesis and progression of diseases associated with amyloid deposition, such as Parkinson's and Alzheimer's diseases.
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Xun, Tianrong, Wenjuan Li, Jinquan Chen, Fei Yu, Wei Xu, Qian Wang, Ruizhe Yu i in. "ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection". Antimicrobial Agents and Chemotherapy 59, nr 9 (8.06.2015): 5123–34. http://dx.doi.org/10.1128/aac.00385-15.
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ABSTRACTSemen-derived enhancer of viral infection (SEVI) is composed of amyloid fibrils that can greatly enhance HIV-1 infectivity. By its cationic property, SEVI promotes viral sexual transmission by facilitating the attachment and internalization of HIV-1 to target cells. Therefore, semen-derived amyloid fibrils are potential targets for microbicide design. ADS-J1 is an anionic HIV-1 entry inhibitor. In this study, we explored an additional function of ADS-J1: inhibition of SEVI fibril formation and blockage of SEVI-mediated enhancement of viral infection. We found that ADS-J1 bound to an amyloidogenic peptide fragment (PAP248–286, comprising amino acids 248 to 286 of the enzyme prostatic acid phosphatase), thereby inhibiting peptide assembly into amyloid fibrils. In addition, ADS-J1 binds to mature amyloid fibrils and antagonizes fibril-mediated enhancement of viral infection. Unlike cellulose sulfate, a polyanion that failed in clinical trial to prevent HIV-1 sexual transmission, ADS-J1 shows no ability to facilitate fibril formation. More importantly, the combination of ADS-J1 with several antiretroviral drugs exhibited synergistic effects against HIV-1 infection in semen, with little cytotoxicity to vaginal epithelial cells. Our results suggest that ADS-J1 or a derivative may be incorporated into a combination microbicide for prevention of the sexual transmission of HIV-1.
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AITKEN, Jacqueline F., Kerry M. LOOMES, Barbara KONARKOWSKA i Garth J. S. COOPER. "Suppression by polycyclic compounds of the conversion of human amylin into insoluble amyloid". Biochemical Journal 374, nr 3 (15.09.2003): 779–84. http://dx.doi.org/10.1042/bj20030422.
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There is a significant correlation between the occurrence of pancreatic islet amyloid and β-cell failure in advanced type II diabetes mellitus. Islet amyloid is composed primarily of the fibrillar form of the pancreatic hormone, amylin. Using thioflavin-T fluorescence binding and radioprecipitation assays, we investigated whether or not a series of small tricyclic compounds, tetracycline or Congo Red could interfere with the conversion of synthetic human amylin into its insoluble amyloid form. Of the compounds investigated, incubation of human amylin with a 20-fold molar excess of either Congo Red or Acridine Orange resulted in significant inhibition in the rate of amyloid formation. With Congo Red, maximal inhibition effectively occurred at a 1:1 molar ratio or greater over human amylin, whereas inhibition by Acridine Orange was dose-dependent. A 20-fold molar excess of the compound tetracycline also decreased insoluble amyloid content after extended incubation periods of approx. 20 h. Amyloid fibril morphology in the presence of tetracycline, as measured by transmission electron microscopy, was characterized by short fragmented fibrils compared with the longer and denser appearance of fibrils formed by amylin alone. These findings show that polycyclic compounds can suppress the formation of amyloid by human amylin, providing support for an alternative approach to peptide-based strategies by which islet amyloid formation could be modulated.
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Okumura, Hisashi, i Satoru G. Itoh. "Molecular Dynamics Simulation Studies on the Aggregation of Amyloid-β Peptides and Their Disaggregation by Ultrasonic Wave and Infrared Laser Irradiation". Molecules 27, nr 8 (12.04.2022): 2483. http://dx.doi.org/10.3390/molecules27082483.
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Alzheimer’s disease is understood to be caused by amyloid fibrils and oligomers formed by aggregated amyloid-β (Aβ) peptides. This review article presents molecular dynamics (MD) simulation studies of Aβ peptides and Aβ fragments on their aggregation, aggregation inhibition, amyloid fibril conformations in equilibrium, and disruption of the amyloid fibril by ultrasonic wave and infrared laser irradiation. In the aggregation of Aβ, a β-hairpin structure promotes the formation of intermolecular β-sheet structures. Aβ peptides tend to exist at hydrophilic/hydrophobic interfaces and form more β-hairpin structures than in bulk water. These facts are the reasons why the aggregation is accelerated at the interface. We also explain how polyphenols, which are attracting attention as aggregation inhibitors of Aβ peptides, interact with Aβ. An MD simulation study of the Aβ amyloid fibrils in equilibrium is also presented: the Aβ amyloid fibril has a different structure at one end from that at the other end. The amyloid fibrils can be destroyed by ultrasonic wave and infrared laser irradiation. The molecular mechanisms of these amyloid fibril disruptions are also explained, particularly focusing on the function of water molecules. Finally, we discuss the prospects for developing treatments for Alzheimer’s disease using MD simulations.
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Bhasikuttan, Achikanath C., i Jyotirmayee Mohanty. "Detection, inhibition and disintegration of amyloid fibrils: the role of optical probes and macrocyclic receptors". Chemical Communications 53, nr 19 (2017): 2789–809. http://dx.doi.org/10.1039/c6cc08727b.
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This article provides a brief account of the recent reports on the early detection of amyloid fibril formation using fluorescent dyes and inhibition and disintegration of fibrils using macrocyclic receptors, which find applications in the treatment of fibril associated neurodegenerative diseases.
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Sandhya A, Gomathi Kanayiram, Kiruthika L i Aafreen Afroz S. "Nigella Sativa : A Potential Inhibitor for Insulin Fibril Formation". International Journal of Research in Pharmaceutical Sciences 11, nr 1 (23.01.2020): 765–74. http://dx.doi.org/10.26452/ijrps.v11i1.1891.
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The high order structure from proteins which are self-assembled are known as fibrils. They are collectively called as amyloid fibrils, which generally lead to neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, Type II diabetes. Insulin fibril aggregation is identified to be the major cause of neurodegenerative diseases. The effect of Nigella sativa extract is analyzed based on the fibril inhibition process. The formed fibrils is reduced with the concentration increase of Nigella sativa extract. Insulin fibril is found in Type II diabetes patients after repeated insulin injections subcutaneously. Insulin fibrils are formed in organisms or humans irrespective of their places like hips, shoulder, hands and abdomen. These are evident from the anti-aggregation assay. Thioflavin T (ThT) fluroscence and congo red (CR) assay confirms the inhibition of insulin fibril in the presence of Nigella sativa (NS) extract. Further, inhibition of fibril was confirmed by Scanning Electron Microscope (SEM), where no insulin fibrils was detected whose secondary conformational changes are studied using Fourier Transform Infrared spectroscopy (FT-IR). It is confirmed that insulin fibril inhibition depends on the various concentration of Nigella sativa. Based on the results obtained, it is demonstrated that Nigella sativa extract inhibits the fibril formation and it also provides a therapeutic strategy to prevent insulin fibril formation.
Rozprawy doktorskie na temat "Amyloid Fibril Inhibition"
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Young, Lydia Mary. "Defining the mechanism of small molecule inhibition of amyloid fibril formation using ion mobility spectrometry-mass spectrometry". Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/11887/.
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The study of protein/peptide folding, misfolding, structure, and interactions are vital to understanding complex biological problems. The work presented in this thesis describes the development and application of mass spectrometry -based techniques to investigate protein structure, aggregation and interference with aggregation, providing insights into the self-assembly and inhibition of several disease-related peptides. Mass spectrometry has evolved significantly over the past decade, its applications varying from small molecules to macromolecules. Travelling wave ion mobility spectrometry (TWIMS), when combined with mass spectrometry (MS), has the unique and unrivalled capability of separating molecular ions based on their collision cross-sectional area in addition to their mass-to-charge ratio, thus facilitating structural studies of co-populated protein conformations and structural isomers of protein complexes that cannot be separated by molecular weight alone. One biological system that has benefitted enormously from such advances is the study of in vitro amyloid formation. The ability of amyloidogenic protein/peptides to assemble into insoluble fibrils is the basis of a vast array of human disorders. Human islet amyloid polypeptide (hIAPP) is one such peptide able to readily assemble into amyloid fibrils in vitro at neutral pH, despite being intrinsically disordered. Identifying oligomeric states occupied between monomer and final fibrils creates an enormous challenge, given that few techniques are able to separate and characterise such lowly-populated and transient species. In addition to characterisation of fibril precursors, recent research has focussed on the identification of small molecule inhibitors of the amyloid cascade and understanding their mechanism of action is of great interest to this field. In the work presented here, the power of TWIMS-MS has been harnessed to achieve the separation and characterisation of oligomeric precursors of the type-2 diabetes-related peptide hIAPP along with IAPP mutants and peptides corresponding to its core sequence. In addition, the effects of small molecule inhibitors on oligomer population and fibril formation have been studied and described in detail. Further, an experimentally simple, in vitro MS-based screen has been developed and implemented that provides rapid and accurate analysis of protein aggregation and its inhibition. All of the results highlight the powers of MS to provide important insights into the mechanism of amyloid formation and demonstrate the potential of this approach for screening for novel inhibitors of disease-related amyloid assembly.
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Boehringer, Régis. "Synthèse chimique de protéines pour l'étude structurale et fonctionnelle de fibres amyloïdes". Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAF001/document.
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Les fibres amyloïdes sont souvent à l’origine de nombreuses maladies dégénératives telles que la maladie d’Alzheimer ou la maladie de Parkinson. La formation de ces plaques insolubles est due à une agrégation anormale de protéines. Les études structurales et biologiques des amyloïdes sont hautement complexes du fait de leur organisation sous forme de superstructures unidirectionnelles composées d’une infinité d’unités peptidiques ou protéiques, mais aussi à cause de leur hétérogénéité conformationnelle et polymorphique. Au cours de ces différents travaux de thèse en collaboration avec différents laboratoires d’analyses structurales, nous avons développé plusieurs outils de synthèse tant pour la formation de différents polymorphes de fibres amyloïdes que pour la formation d’espèces oligomériques de tailles conséquentes qui sont un challenge du point de vue synthétique et méthodologique mais aussi pour leur caractérisation. Ces différentes avancées permettront de mieux comprendre les mécanismes de formation de fibres amyloïdes et de préparer des échantillons homogènes pour les analyses structurales et biologiques. L’étude de modifications chimiques telles que la N-méthylation ou les polypeptides D est également un enjeu important pour l’élucidation des interactions protéine-protéine vis-à-vis des structures amyloïdogéniques et ainsi permettre l’élaboration de nouveaux composés inhibant la formation de plaques amyloïdesAmyloid fibrils are associated with many human disorders including Alzheimer’s or Parkinson’s diseases. The formation of insoluble plaques is the result of protein misfolding and aggregation due to abnormal conformational isomerization of the involved protein. The structural and biological studies of amyloids are highly complex. In this thesis, we report on the development of different synthetic methodologies for the preparation of distinct amyloid fibril polymorphs as homogeneous samples for structural and biological studies. We also synthesized covalently-tethered oligomers composed of nine copies of an amyloidogenic peptide segment, where we were able to control the self-assembly of the structure by insertion of N-methylated amino-acids and to obtain monomeric oligomers mimicking a cross section of an amyloid fibril. We also report on the chiral recognition of L-peptides and L-proteins towards corresponding D-enantiomers during amyloid formation. Moreover, we studied various N-methylated peptide analogues to suppress amyloid growth. Overall, the results obtained in this thesis pave the way towards rational design of peptide-based inhibitors and diagnostics against amyloid propagation
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Okada, Takuma. "Formation of toxic fibrils of Alzheimer's amyloid β-proteins mediated by GM1 ganglioside and its inhibition". 京都大学 (Kyoto University), 2008. http://hdl.handle.net/2433/137149.
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Lunven, Laurent. "Synthèse et évaluation d'aurones sur des modèles de fibres de tau". Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV007/document.
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La fibrillation anormale de la protéine tau est un phénomène présent dans de nombreuses maladies neurodégénératives, dont la maladie d’Alzheimer, et conduit à la formation de fibres amyloïdes appelées dégénérescences neurofibrillaires. L’utilisation de molécules organiques capables de marquer ces fibres ou d’inhiber leur formation revêt un intérêt à la fois diagnostic et thérapeutique dans la maladie d’Alzheimer. Une série d’aurones a été synthétisée et leur capacité à interagir et interférer avec le processus de fibrillation a été évaluée in vitro sur des modèles de fibres de tau développés ou optimisés lors de ce projet. Ce travail a permis de montrer que des aurones polyhydroxylées sont capables d’agir comme sonde et/ou comme inhibiteur du processus de fibrillation. Afin d’élargir les applications possibles des aurones, la ligation d’aurones avec des biomolécules ou encore leur radiomarquage a également été évaluéeThe fibrillation of the tau protein occurs in many neurodegenerative diseases, including Alzheimer’s disease, and leads to the formation of amyloid fibres called neurofibrillary tangles. Using organic molecules able to mark these fibres or inhibit their formation provides an interest both in diagnosis and therapy in Alzheimer’s disease. A series of aurones was synthesized and their ability to interfere with the fibrillation process was evaluated in vitro on models of tau fibres developed in this project. This work shows that polyhydroxylated aurones are able to act both as probes and as inhibitors of the fibrillation process. The ligation of these aurones with biomolecules or their radiolabelling has also been investigated
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How, Su-Chun, i 侯素君. "Inhibition of Amyloid Fibril Formation of Hen Egg White Lysozyme". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/zeu3kb.
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博士國立臺灣大學
化學工程學研究所
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Amyloid fibril formation serves as a key pathological feature of several different human degenerative diseases. Evidence suggests that mitigation/inhibition of amyloid fibril formation is considered a promising approach toward treating these diseases. However, as of now, there has been no effective small molecule available to cure amyloid diseases. The reasons why hen egg white lysozyme was used as the model protein in this research work are as follows: (1) hen egg white lysozyme is structurally homologous to human lysozyme, which is the protein associated with hereditary systemic amyloidosis, and (2) its fibrils were found to resemble the fibrillar species of human lysozyme. Investigation of amyloid fibril formation using hen egg white lysozyme can aid in a better understanding of the possible inhibition strategies for tackling amyloid aggregation. In our study, we used three kinds of small molecules including fast green FCF, methylene blue, and brilliant blue G. Both fast green FCF and brilliant blue G are triarylmethane dyes, fast green FCF is approved by the FDA as a food dye, while brilliant blue G has been shown to be safe with good blood–brain-barrier-permeability. Methylene blue, a compound belonging to the phenothiazinium family, has the potential to treat a variety of cancerous and non-cancerous diseases with low toxicity and minimal side effects. Furthermore, evidence demonstrates that methylene blue may be a promising molecules for the treatment of Alzheimer’s disease. Here, we examine the effects of fast green FCF, methylene blue and brilliant blue G on amyloid fibril formation derived from hen egg white lysozyme using a variety of spectroscopic techniques, such as intrinsic fluorescence, ANS fluorescence and ThT fluorescence assays, transmission electron microscopy, and circular dichroism spectroscopy. ThT fluorescence intensity results show that fast green FCF(25%) and brilliant blue G(32.8%) possess better inhibition efficacy than methylene blue (below 1:1.11,ThT intensity has no significant change). However, CD results reveal that fast green FCF and brilliant blue G affect hen egg white lysozyme differently. The addition of fast green FCF was observed to reduce the β-sheet secondary structure content associated with amyloid fibrillogenesis, which was not found in the case of brilliant blue G. Our results demonstrate that the addition of brilliant blue G is not able to suppress the amyloid fibril-forming propensity of lysozyme but only shorten the length of fibrillary species. Moreover, our SDS-PAGE results suggest that more native proteins are retained in the sample. In addition, our results further suggest that the observed inhibitory actions against amyloid fibril formation is mainly correlated with the interaction between the small molecules and protein hydrophobic sites. Given that both fast green FCF and brilliant blue G have sulfonate functional groups, the two molecules are able to electrostatically interact with the protein, thus further mitigating amyloid fibril formation. In addition, we surmise that the less negative charge and two additional methyl groups attached to the triphenylmethane structure might account for why the presence of brilliant blue G induces the formation of shorter fibrils, but can not suppress amyloid fibrillogenesis. Taken together, we conclude that small molecules’ inhibitory activity toward amyloid fibril formation is dependent upon the structure, size, and types of functional groups attached to them. We believe exploring the effects of small molecule on amyloid fibrillogenesis of lysozyme can contribute to the development of drugs for the treatment of amyloid diseases.
Streszczenia konferencji na temat "Amyloid Fibril Inhibition"
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Abioye, Raliat, i Chibuike Udenigwe. "Inhibition of islet amyloid polypeptide fibril formation by natural polyphenols". W Virtual 2021 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2021. http://dx.doi.org/10.21748/am21.601.
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Abioye, Raliat, Chibuike Udenigwe i Ogadimma Okagu. "Disaggregation of islet amyloid polypeptide fibrils as a potential anti-fibrillation mechanism of tetrapeptide TNGQ". W 2022 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2022. http://dx.doi.org/10.21748/szym9744.
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Islet amyloid polypeptide (IAPP) fibrillation has been commonly associated with the exacerbation of type 2 diabetes prognosis. Consequently, inhibition of IAPP fibrillation to minimize β-cell cytotoxicity is an important approach towards β-cell preservation and type 2 diabetes management. In this study, three tetrapeptides, TNGQ, MANT, and YMSV, were identified as potential IAPP fibrillation inhibitors. The potential anti-fibrillation mechanisms of these tetrapeptides were monitored using thioflavin T (ThT) fluorescence assay, circular dichroism (CD) spectroscopy, dynamic light scattering (DLS) and molecular docking. ThT fluorescence kinetics and microscopy, as well as transmission electron microscopy, showed that TNGQ was the most effective inhibitor based on the absence of normal IAPP fibrillar morphology and alluded to its IAPP fibrillar disaggregatory potential. CD spectroscopy showed that TNGQ maintained the α-helical conformation of monomeric IAPP, while DLS confirmed the presence of varying fibrillation species. Molecular docking showed that interactions between TNGQ and MANT and monomeric IAPP favoured hydrogen bonding and electrostatic interactions. Furthermore, TNGQ bound at the IAPP surface, unlike YMSV, which had the highest docking score but interact mainly through hydrophobic interactions in the IAPP core. These findings indicate the potential of TNGQ in the development of peptide-based anti-fibrillation and antidiabetic nutraceuticals.
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Soares, Izadora Fonseca Zaiden, João Nicoli Ferreira dos Santos i Lis Gomes Silva. "Dramatic cognitive improvement with acetylcholinesterase inhibitor in cerebral amyloid angiopathyrelated inflammation". W XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.578.
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Context: Cerebral amyloid angiopathy (CAA) is characterized by progressive deposition of amyloid-ß fibrils in the walls of small arterioles and capillaries of the leptomeninges and cerebral cortex. A rare subtype of CAA is CAA-related inflammation (CAA-RI), which exhibits marked perivascular or transmural inflammatory infiltration in brain tissue. The major clinical features of CAA-RI are rapidly progressive dementia, behavioral changes, headache, seizures, or stroke-like signs. Conclusive diagnosis requires histopathological confirmation, but validated clinicoradiological criteria for the diagnosis of probable CAA-RI have good sensitivity (82%) and specificity (97%). Treatment with high dose corticosteroids with or without other immunosuppressive therapy is recommended. We report a case of probable CAA-RI that did not respond to corticosteroid therapy but had a surprising improvement with acetylcholinesterase inhibitor. Case report: A 77-year-old illiterate woman presented with a history of subacute onset of seizures and behavioral changes. Her medical history was positive for a hearing loss due to a toxic exposure in childhood, and a cured breast cancer. The neurological examination showed attention impairment, disorientation, and incoherent speech. CSF showed a mildly elevated protein count. Brain MRI met criteria for probable CAA-RI. She had a poor response with high doses of corticosteroids, but after a trial with Donepezil she showed important cognitive and functional improvement. Conclusion: This result attracts attention to the importance of the cholinergic pathway in the etiology and pathological mechanisms of CAA. Randomized Controlled Trials would be required to confirm our hypothesis and to find new therapeutic options for CAA.