Modeling the Interface between Islet Amyloid Polypeptide and Insulin-Based Aggregation Inhibitors: Correlation to Aggregation Kinetics and Membrane Damage

2012 ◽  
Vol 52 (5) ◽  
pp. 1298-1307 ◽  
Author(s):  
Hector Figueroa ◽  
Durgaprasad Peddi ◽  
Joshua M. Osborne ◽  
Brenan M. Wilson ◽  
Ranadheer Reddy Pesaru ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Aggregation Kinetics ◽  
Islet Amyloid ◽  
Aggregation Inhibitors

scholarly journals Regulation of divalent metal ions to the aggregation and membrane damage of human islet amyloid polypeptide oligomers

RSC Advances ◽  
2021 ◽  
Vol 11 (21) ◽  
pp. 12815-12825
Author(s):  
Yajie Wang ◽  
Feihong Meng ◽  
Tong Lu ◽  
Chunyun Wang ◽  
Fei Li
Keyword(s):  
Metal Ions ◽  
Metal Binding ◽  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Divalent Metal ◽  
Human Islet ◽  
Divalent Metal Ions ◽  
Islet Amyloid ◽  
Induced Membrane ◽  
Human Islet Amyloid Polypeptide

Their is a counteraction between a decrease in the disruptive ability of metal-associated oligomer species and an increase in the quantity of oligomers promoted by the metal binding in the activity of hIAPP induced membrane damage.

The effects of a series of carbon dots on fibrillation and cytotoxicity of human islet amyloid polypeptide

2016 ◽  
Vol 4 (28) ◽  
pp. 4913-4921 ◽  
Author(s):  
Li Wang ◽  
Shoujun Zhu ◽  
Tong Lu ◽  
Guangji Zhang ◽  
Jia Xu ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Aggregation Kinetics ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Carbon dots can change hIAPP aggregation kinetics and have a potential to reduce the cytotoxicity of the polypeptide.

Impaired Processing of Human Pro-Islet Amyloid Polypeptide Is Not a Causative Factor for Fibril Formation or Membrane Damage in Vitro

Biochemistry ◽  
2009 ◽  
Vol 48 (46) ◽  
pp. 10918-10925 ◽  
Author(s):  
Lucie Khemtémourian ◽  
Gemma Lahoz Casarramona ◽  
Dennis P. L. Suylen ◽  
Tilman M. Hackeng ◽  
Johannes D. Meeldijk ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Causative Factor ◽  
Fibril Formation ◽  
Islet Amyloid

scholarly journals Inhibition of islet amyloid polypeptide aggregation and associated cytotoxicity by nonsteroidal anti-inflammatory drugs

2016 ◽  
Vol 94 (1) ◽  
pp. 35-48 ◽  
Author(s):  
Jessica S. Fortin ◽  
Marie-Odile Benoit-Biancamano
Keyword(s):  
Circular Dichroism ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Deposition ◽  
Molar Ratio ◽  
Helical Structures ◽  
Islet Amyloid ◽  
Aggregation Inhibitors ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Circular Dichroïsm

Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute an important pharmacotherapeutic class that, over the past decade, have expanded in application to a panoply of medical conditions. They have been tested for neurodegenerative diseases such as Alzheimer’s to reduce inflammation and also in the attempt to abrogate amyloid deposition. However, the use of NSAIDs as aggregation inhibitors has not been extensively studied in pancreatic amyloid deposition. Pancreatic amyloidosis involves the misfolding of islet amyloid polypeptide (IAPP) and contributes to the progression of type-2 diabetes in humans and felines. To ascertain their antiamyloidogenic activity, several NSAIDs were tested using fluorometric thioflavin-T assays, circular dichroism, photo-induced cross-linking assays, and cell culture. Celecoxib, diclofenac, indomethacin, meloxicam, niflumic acid, nimesulide, phenylbutazone, piroxicam, sulindac, and tenoxicam reduced fibrillization at a molar ratio of 1:10. The circular dichroism spectra of diclofenac, piroxicam, and sulindac showed characteristic spectral signatures found in predominantly α-helical structures. The oligomerization of human IAPP was abrogated with diclofenac and sulindac at a molar ratio of 1:5. The cytotoxic effects of pre-incubated human IAPP on cultured INS-1 cells were noticeably reduced in the presence of diclofenac, meloxicam, phenylbutazone, sulindac, and tenoxicam at a molar ratio of 1:10. Our results demonstrate that NSAIDs can provide chemical scaffolds to generate new and promising antiamyloidogenic agents that can be used alone or as a coadjuvant therapy.

scholarly journals Recent Insights in Islet Amyloid Polypeptide-Induced Membrane Disruption and Its Role inβ-Cell Death in Type 2 Diabetes Mellitus

2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Lucie Khemtémourian ◽  
J. Antoinette Killian ◽  
Jo W. M. Höppener ◽  
Maarten F. M. Engel
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cell Death ◽  
Type 2 Diabetes Mellitus ◽  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Islet Amyloid ◽  
Induced Membrane ◽  
Pancreatic Islets Of Langerhans

The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing isletβ-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-inducedβ-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption ofβ-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer’s disease, Parkinson’s disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation toβ-cell death in DM2.

scholarly journals Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

2008 ◽  
Vol 105 (16) ◽  
pp. 6033-6038 ◽  
Author(s):  
M. F. M. Engel ◽  
L. Khemtemourian ◽  
C. C. Kleijer ◽  
H. J. D. Meeldijk ◽  
J. Jacobs ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals Molecular Structure, Membrane Interactions, and Toxicity of the Islet Amyloid Polypeptide in Type 2 Diabetes Mellitus

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Lucie Caillon ◽  
Anais R. F. Hoffmann ◽  
Alexandra Botz ◽  
Lucie Khemtemourian
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Formation ◽  
Membrane Interactions ◽  
Islet Amyloid ◽  
Amyloid Deposits

Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Mature hIAPP, a 37-aa peptide, is natively unfolded in its monomeric state but forms islet amyloid in T2DM. In common with other misfolded and aggregated proteins, amyloid formation involves aggregation of monomers of hIAPP into oligomers, fibrils, and ultimately mature amyloid deposits. hIAPP is coproduced and stored with insulin by the pancreatic isletβ-cells and is released in response to the stimuli that lead to insulin secretion. Accumulating evidence suggests that hIAPP amyloid deposits that accompany T2DM are not just an insignificant phenomenon derived from the disease progression but that hIAPP aggregation induces processes that impair the functionality and the viability ofβ-cells. In this review, we particularly focus on hIAPP structure, hIAPP aggregation, and hIAPP-membrane interactions. We will also discuss recent findings on the mechanism of hIAPP-membrane damage and on hIAPP-induced cell death. Finally, the development of successful antiamyloidogenic agents that prevent hIAPP fibril formation will be examined.

Myricetin protects pancreatic β-cells from human islet amyloid polypeptide (hIAPP) induced cytotoxicity and restores islet function

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Richa Dubey ◽  
Shruti H. Kulkarni ◽  
Sarath Chandra Dantu ◽  
Rajlaxmi Panigrahi ◽  
Devika M. Sardesai ◽  
...  
Keyword(s):  
Stress Reduction ◽  
Self Assembly ◽  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Dynamics Simulation ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

AbstractThe aberrant misfolding and self-assembly of human islet amyloid polypeptide (hIAPP)–a hormone that is co-secreted with insulin from pancreatic β-cells–into toxic oligomers, protofibrils and fibrils has been observed in type 2 diabetes mellitus (T2DM). The formation of these insoluble aggregates has been linked with the death and dysfunction of β-cells. Therefore, hIAPP aggregation has been identified as a therapeutic target for T2DM management. Several natural products are now being investigated for their potential to inhibit hIAPP aggregation and/or disaggregate preformed aggregates. In this study, we attempt to identify the anti-amyloidogenic potential of Myricetin (MYR)- a polyphenolic flavanoid, commonly found in fruits (like Syzygium cumini). Our results from biophysical studies indicated that MYR supplementation inhibits hIAPP aggregation and disaggregates preformed fibrils into non-toxic species. This protection was accompanied by inhibition of oxidative stress, reduction in lipid peroxidation and the associated membrane damage and restoration of mitochondrial membrane potential in INS-1E cells. MYR supplementation also reversed the loss of functionality in hIAPP exposed pancreatic islets via restoration of glucose-stimulated insulin secretion. Molecular dynamics simulation studies suggested that MYR molecules interact with the hIAPP pentameric fibril model at the amyloidogenic core region and thus prevents aggregation and distort the fibrils.

Low pH Acts as Inhibitor of Membrane Damage Induced by Human Islet Amyloid Polypeptide

2011 ◽  
Vol 133 (39) ◽  
pp. 15598-15604 ◽  
Author(s):  
Lucie Khemtémourian ◽  
Elena Doménech ◽  
Jacques P. F. Doux ◽  
Martijn C. Koorengevel ◽  
J. Antoinette Killian
Keyword(s):  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Low Ph ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide
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