Biochimica et Biophysica Acta (BBA) - Biomembranes, Год журнала: 2023, Номер 1865(6), С. 184161 - 184161
Опубликована: Апрель 28, 2023
Язык: Английский
Nature Communications, Год журнала: 2022, Номер 13(1)
Опубликована: Фев. 24, 2022
Human islet amyloid polypeptide (hIAPP) self-assembles into fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism assembly wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that aggregation both peptides involves primary nucleation, secondary nucleation elongation. also report discovery two structurally distinct small-molecule modulators assembly, one delaying wt hIAPP, but not S20G; while other enhances rate variants at substoichiometric concentrations. Investigation inhibition mechanism(s) using kinetics, native mass spectrometry, fluorescence titration, SPR NMR revealed inhibitor retards elongation, by binding peptide monomers. By contrast, accelerator predominantly interacts with species formed lag phase. These compounds represent useful tools may serve as promising starting-points for development therapeutics T2D.
Язык: Английский
Процитировано
48
Diabetology & Metabolic Syndrome, Год журнала: 2023, Номер 15(1)
Опубликована: Май 13, 2023
Abstract Human Islet amyloid polypeptide (hIAPP) from pancreatic β cells in the islet of Langerhans has different physiological functions including inhibiting release insulin and glucagon. Type 2 diabetes mellitus (T2DM) is an endocrine disorder due to relative insufficiency resistance (IR) associated with increased circulating hIAPP. Remarkably, hIAPP structural similarity beta (Aβ) can engage pathogenesis T2DM Alzheimer’s disease (AD). Therefore, present review aimed elucidate how acts as a link between AD. IR, aging low cell mass increase expression which binds membrane leading aberrant Ca 2+ activation proteolytic enzymes series events causing loss cells. Peripheral plays major role AD, high level AD risk patients. However, there no hard evidence for brain-derived Nevertheless, oxidative stress, mitochondrial dysfunction, chaperon-mediated autophagy, heparan sulfate proteoglycan (HSPG), immune response, zinc homeostasis could be possible mechanisms induction aggregation risk. In conclusion, increasing levels patients predispose them development progression Dipeptidyl peptidase 4 (DPP4) inhibitors glucagon-like peptide-1 (GLP-1) agonists attenuate by deposition hIAP.
Язык: Английский
Процитировано
39
Coordination Chemistry Reviews, Год журнала: 2022, Номер 478, С. 214978 - 214978
Опубликована: Дек. 16, 2022
Язык: Английский
Процитировано
32
Advanced Science, Год журнала: 2024, Номер 11(21)
Опубликована: Март 19, 2024
Developing time-sustained drug delivery systems is a main goal in innovative medicines. Inspired by the architecture of secretory granules from mammalian endocrine system it has generated non-toxic microscale amyloid materials through coordination between divalent metals and poly-histidine stretches. Like their natural counterparts that keep functionalities assembled protein, those synthetic structures release biologically active proteins during slow self-disintegration process occurring vitro upon vivo administration. Being these formed single pure protein species therefore, chemically homogenous, they act as highly promising systems. Despite enormous clinical potential, nature clustering quality released have been so far neglected issues. By using diverse polypeptide protein-only oligomeric nanoscale versions convenient models, conformational rearrangement stabilization building blocks transit granules, being material structurally distinguishable original source proved here. This fact indicates dynamic amyloids arrangers rather than plain, inert protein-recruiting/protein-releasing granular depots.
Язык: Английский
Процитировано
7
Macromolecular Bioscience, Год журнала: 2023, Номер 23(7)
Опубликована: Апрель 24, 2023
Lipoic acid (LA) and dihydrolipoic (DHLA) are well established antioxidants to scavenge reactive oxygen species (ROS). However, they carboxylates with ≈4.7 pKa making them negatively charged at physiological pH (7.4) reducing their passive diffusion through cell membranes. LA is known be capable of protein fibrillation. Incorporation especially DHLA in polymer side chains scarce. Herein, the first examples anti-amyloidogenic effect incorporated into side-chain a block copolymer water-soluble poly(polyethylene glycol methyl ether methacrylate) (PPEGMA) segment presented. The resultant polymers show improved ROS scavenging activity ability reduce insulin fibrillation compared free DHLA. Furthermore, also disintegrating preformed firbrils. Interestingly, dihydro-lipoate moieties showed 93% radical 91% anti-fibrillating efficacies for confirmed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay Thioflavin T (ThT) dye binding study, respectively. Further, antioxidant increase viability against fibrillar aggregates that may involved etiology several diseases. Overall, this work reveals polymer-based therapeutic agents can serve as powerful modulation strategy developing novel drugs future amyloid-related disorders.
Язык: Английский
Процитировано
15
Small Methods, Год журнала: 2024, Номер unknown
Опубликована: Апрель 21, 2024
Abstract Prion‐like protein aggregation is characteristic of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. This process involves the formation aggregates ranging from small potentially neurotoxic oligomers to highly structured self‐propagating amyloid fibrils. Various approaches are used study aggregation, but they do not always provide continuous information on polymorphic, transient, heterogeneous species formed. review provides an updated state‐of‐the‐art approach detection characterization a wide range using nanopore technology. For each type nanopore, biological, solid‐state polymer, nanopipette, discuss main achievements for well significant contributions understanding diagnostics.
Язык: Английский
Процитировано
6
Journal of Pharmaceutical Analysis, Год журнала: 2022, Номер 12(4), С. 556 - 569
Опубликована: Апрель 7, 2022
Type 2 diabetes mellitus (T2DM) and other metabolic disorders are often silent go unnoticed in patients because of the lack suitable prognostic diagnostic markers. The current therapeutic regimens available for managing T2DM do not reverse diabetes; instead, they delay progression diabetes. Their efficacy (in principle) may be significantly improved if implemented at earlier stages. misfolding aggregation human islet amyloid polypeptide (hIAPP) or amylin has been associated with a gradual decrease pancreatic β-cell function mass T2DM. Hence, hIAPP recognized as target This review summarizes hIAPP's role mediating dysfunction apoptosis β-cells via induction endoplasmic reticulum stress, oxidative mitochondrial dysfunction, inflammatory cytokine secretion, autophagy blockade, etc. Furthermore, it explores possibility using intermediates pathway potential drug targets management. Finally, effects common antidiabetic molecules repurposed drugs; mimetics peptides; small organic natural compounds; nanoparticles, nanobodies, quantum dots; metals metal complexes; chaperones that have demonstrated to inhibit and/or can, therefore, further developed discussed.
Язык: Английский
Процитировано
21
Molecules, Год журнала: 2022, Номер 27(3), С. 1021 - 1021
Опубликована: Фев. 2, 2022
Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, pancreatic hormone linked β-cells demise diabetics. The unifying mechanism by proteins, including hIAPP, aggregate kill cells still matter of debate. pathology type-2 diabetes mellitus (T2DM) characterized extracellular intracellular accumulation hIAPP species, islets, eventually leading loss β-cell mass. This review focuses on molecular, biochemical cell-biology studies exploring mechanisms synthesis, trafficking degradation the pancreas. In addition turnover, dynamics IAPP–membrane interactions; aggregation toxicity vitro situ; regulatory role diabetic factors, such as lipids cholesterol, these processes also discussed.
Язык: Английский
Процитировано
19
Scientific Reports, Год журнала: 2023, Номер 13(1)
Опубликована: Март 15, 2023
Abstract Metal homeostasis is tightly regulated in cells and organisms, its disturbance frequently observed some diseases such as neurodegenerative metabolic disorders. Previous studies suggest that zinc iron are necessary for the normal functions of pancreatic β cells. However, distribution elements conditions pathophysiological significance dysregulated islet diabetic have remained unclear. In this study, to investigate dynamics islets a mouse model expressing human amyloid polypeptide (hIAPP): hIAPP transgenic (hIAPP-Tg) mice, we performed imaging analysis using synchrotron scanning X-ray fluorescence microscopy quantitative inductively coupled plasma mass spectrometry. We found islets, significantly decreased early stage diabetes, while gradually concurrently with increase blood glucose levels hIAPP-Tg mice. Notably, when and/or were dysregulation glucose-stimulated mitochondrial respiration was observed. Our findings may contribute clarifying roles under conditions.
Язык: Английский
Процитировано
9
Natural Product Communications, Год журнала: 2025, Номер 20(2)
Опубликована: Фев. 1, 2025
Objectives Amyloid fibrils are misfolded proteins that self-assemble to form insoluble, elongated, β-sheet structures. These linked with the progression of neurodegenerative diseases like Alzheimer's Disease and metabolic disorders such as Type II diabetes. A range molecules have shown ability impede formation these fibrils, often by acting on monomeric oligomeric forms protein. Our work focuses inhibitory effect curcumin, gallic acid mangiferin amyloid fibrils. Materials methods Bovine insulin was used a model system for lowering pH at 60 °C, several different small were test inhibition. Samples analyzed using Atomic Force Microscopy (AFM) in liquid environment, well Congo Red Thioflavin T assays. Results We been able observe significant inhibition fibril formed from compounds beginning stages morphology Mangiferin, acid, curcumin all slow down formation, though 5 days started solution. After 7 days, solutions containing or still show no strong evidence structured Conclusion Gallic effects system, being somewhat less effective than other two. The AFM technique image performed an environment more closely resembles vivo conditions air dried samples.
Язык: Английский
Процитировано
0