Molecular Mechanism of the Inhibition and Remodeling of Human Islet Amyloid Polypeptide (hIAPP1–37) Oligomer by Resveratrol from Molecular Dynamics Simulation

2014 ◽  
Vol 119 (1) ◽  
pp. 15-24 ◽  
Author(s):  
Qianqian Wang ◽  
Lulu Ning ◽  
Yuzhen Niu ◽  
Huanxiang Liu ◽  
Xiaojun Yao
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Molecular Mechanism ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Dynamics Simulation ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and protects pancreatic β-cells from human islet amyloid polypeptide/amylin-induced cytotoxicity

2019 ◽  
Vol 476 (5) ◽  
pp. 889-907 ◽  
Author(s):  
Richa Dubey ◽  
Ketaki Patil ◽  
Sarath C. Dantu ◽  
Devika M. Sardesai ◽  
Parnika Bhatia ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Dynamics Simulation ◽  
Major Constituent ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Abstract The human islet amyloid polypeptide (hIAPP) or amylin is the major constituent of amyloidogenic aggregates found in pancreatic islets of type 2 diabetic patients that have been associated with β-cell dysfunction and/or death associated with type 2 diabetes mellitus (T2DM). Therefore, developing and/or identifying inhibitors of hIAPP aggregation pathway and/or compound that can mediate disaggregation of preformed aggregates holds promise as a medical intervention for T2DM management. In the current study, the anti-amyloidogenic potential of Azadirachtin (AZD)—a secondary metabolite isolated from traditional medicinal plant Neem (Azadirachta indica)—was investigated by using a combination of biophysical and cellular assays. Our results indicate that AZD supplementation not only inhibits hIAPP aggregation but also disaggregates pre-existing hIAPP fibrils by forming amorphous aggregates that are non-toxic to pancreatic β-cells. Furthermore, AZD supplementation in pancreatic β-cells (INS-1E) resulted in inhibition of oxidative stress; along with restoration of the DNA damage, lipid peroxidation and the associated membrane damage, endoplasmic reticulum stress and mitochondrial membrane potential. AZD treatment also restored glucose-stimulated insulin secretion from pancreatic islets exposed to hIAPP. All-atom molecular dynamics simulation studies on full-length hIAPP pentamer with AZD suggested that AZD interacted with four possible binding sites in the amyloidogenic region of hIAPP. In summary, our results suggest AZD to be a promising candidate for combating T2DM and related amyloidogenic disorders.

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.

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