Heterotropic Modulation of Amylin Fibrillation by Small Molecules: Implications for Formulative Designs

Sinézia, Celimar; Lima, L.M.T.R.

doi:10.1007/s10930-019-09877-w

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…The peptide incubated alone forms amyloid aggregates which over time evolve toward the formation of fibrils coexisting with electron-dense amyloid aggregates (Figure 5A-C). Similar results were obtained by other authors [73][74][75]. The TEM images obtained in the presence of Ca 2+ show that the morphology of the aggregates changes drastically, passing from a fibrillar morphology and amyloid aggregates at 10 µM of Ca 2+ to an approximately spherical morphology and with small, low electron-dense aggregates at 100 µM of Ca 2+ after 72 h of incubation (Figure 5D-N).…”

Section: Discussionsupporting

confidence: 90%

The Effect of Calcium Ions on hIAPP Channel Activity: Possible Implications in T2DM

Meleleo,

Cibelli,

Valenzano

et al. 2023

Membranes

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The calcium ion (Ca2+) has been linked to type 2 diabetes mellitus (T2DM), although the role of Ca2+ in this disorder is the subject of intense investigation. Serum Ca2+ dyshomeostasis is associated with the development of insulin resistance, reduced insulin sensitivity, and impaired glucose tolerance. However, the molecular mechanisms involving Ca2+ ions in pancreatic β-cell loss and subsequently in T2DM remain poorly understood. Implicated in the decline in β-cell functions are aggregates of human islet amyloid polypeptide (hIAPP), a small peptide secreted by β-cells that shows a strong tendency to self-aggregate into β-sheet-rich aggregates that evolve toward the formation of amyloid deposits and mature fibrils. The soluble oligomers of hIAPP can permeabilize the cell membrane by interacting with bilayer lipids. Our study aimed to evaluate the effect of Ca2+ on the ability of the peptide to incorporate and form ion channels in zwitterionic planar lipid membranes (PLMs) composed of palmitoyl-oleoyl-phosphatidylcholine (POPC) and on the aggregation process of hIAPP molecules in solution. Our results may help to clarify the link between Ca2+ ions, hIAPP peptide, and consequently the pathophysiology of T2DM.

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Section: Discussionsupporting

confidence: 90%

The Effect of Calcium Ions on hIAPP Channel Activity: Possible Implications in T2DM

Meleleo,

Cibelli,

Valenzano

et al. 2023

Membranes

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“…Previous studies indicated that the existence of buffer ions shows significant influences on the initial adsorption of peptide molecules to lipid surface and their further interactions with the membrane. , In addition, the aggregation of hIAPP is very sensitive to the properties of the solvents. ,− In order to minimize the salt effect, we did not use buffer solution to control the solution pH value in this study. The experiments at pH 6.2 were performed in ultrapure deionized (DI) water (purified by a Milli-Q reference system), which is slightly deviated from pH 7 due to atmospheric CO 2 adsorption.…”

Section: Methodsmentioning

confidence: 99%

Acidic Environment Significantly Alters Aggregation Pathway of Human Islet Amyloid Polypeptide at Negative Lipid Membrane

et al. 2020

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The misfolding and aggregation of human islet amyloid polypeptide (hIAPP) at cell membrane has a close relationship with the development of type 2 diabetes (T2DM). This aggregation process is susceptible to various physiologically related factors, and systematic studies on condition-mediated hIAPP aggregation are therefore essential for a thorough understanding of the pathology of T2DM. In this study, we combined surface-sensitive amide I and amide II spectral signals from the protein backbone, generated simultaneously in a highly sensitive femtosecond broad-band sum frequency generation vibrational spectroscopy system, to examine the effect of environmental pH on the dynamical structural changes of hIAPP at membrane surface in situ and in real time. Such a combination can directly discriminate the formation of β-hairpin-like monomer and oligomer/fibril at the membrane surface. It is evident that, in an acidic milieu, hIAPP slows down its conformational evolution and alters its aggregation pathway, leading to the formation of off-pathway oligomers. When matured hIAPP aggregates are exposed to basic subphase, partial conversion from β-sheet oligomers into ordered β-sheet fibrillar structures is observed. When exposed to acidic environment, however, hIAPP fibrils partially converse into more loosely patterned β-sheet oligomeric structures.

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“…Folding and aggregation of the C-terminal domains (amino acids 20–29 and 30–37) are most likely driven by hydrophobic interactions, and it has been reported previously that the rate of aggregation at low pH increases drastically in the presence of salt [ 60 , 61 ]. Our results align with those findings, as amylin aggregation was observed when diluted into high salt buffers ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Oxidant-modified amylin fibrils and aggregates alter the inflammatory profile of multiple myeloid cell types, but are non-toxic to islet β cells

Clemen,

Fuentes-Lemus,

Bekeschus

et al. 2023

Redox Biology

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Heterotropic Modulation of Amylin Fibrillation by Small Molecules: Implications for Formulative Designs

Cited by 7 publications

References 51 publications

The Effect of Calcium Ions on hIAPP Channel Activity: Possible Implications in T2DM

The Effect of Calcium Ions on hIAPP Channel Activity: Possible Implications in T2DM

Acidic Environment Significantly Alters Aggregation Pathway of Human Islet Amyloid Polypeptide at Negative Lipid Membrane

Oxidant-modified amylin fibrils and aggregates alter the inflammatory profile of multiple myeloid cell types, but are non-toxic to islet β cells

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