| Title : Genistein: A Dual Inhibitor of Both Amyloid beta and Human Islet Amylin Peptides - Ren_2018_ACS.Chem.Neurosci_9_1215 |
| Author(s) : Ren B , Liu Y , Zhang Y , Cai Y , Gong X , Chang Y , Xu L , Zheng J |
| Ref : ACS Chem Neurosci , 9 :1215 , 2018 |
| Abstract : Abnormal misfolding and aggregation of amyloid peptides into amyloid fibrils are common and critical pathological events in many neurodegenerative diseases. Most inhibitors or drugs have been developed to prevent amyloid aggregation of a specific peptide, showing sequence-dependent inhibition mechanisms. It is more challenging to develop or discover inhibitors capable of preventing the aggregation of two or more different amyloid peptides. Genistein, a major phytoestrogen in soybean, has been widely used as an anti-inflammation and cerebrovascular drug due to its antioxidation and antiacetylcholinesterase effects. Herein, we examine the inhibitory effects of genistein on the aggregation of amyloid-beta (Abeta, associated with Alzheimer's disease) and human islet amylin (hIAPP, associated with type 2 diabetes) and Abeta- and hIAPP-induced neurotoxicity using a combination of experimental and computational approaches. Collective experimental results from thioflavin T (ThT), atomic force microscopy (AFM), and circular dichroism (CD) demonstrate that genistein shows strong inhibition ability to prevent the conformational transition of both Abeta and hIAPP monomers to beta-sheet structures, thus reducing final amyloid fibrillization from Abeta and hIAPP monomer aggregation by 40-63%. Further 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and large unilamellar vesicle (LUV) assays show that genistein helps to increase cell viability, decrease cell apoptosis, and reduce cell membrane leakage, where the cell protection effect of genistein is likely correlated with its reduced membrane leakage. Comparative molecular dynamics (MD) simulations reveal that genistein prefers to bind the beta-sheet groove, a common structural motif of amyloid fibrils, of both Abeta and hIAPP oligomers to interfere with their self-aggregation. This work for the first time demonstrates genistein as a dual inhibitor of Abeta and hIAPP aggregation. Further structural optimization and refinement of genistein may generate a series of effective sequence-independent inhibitors against the aggregation and toxicity of different amyloid peptides. |
| ESTHER : Ren_2018_ACS.Chem.Neurosci_9_1215 |
| PubMedSearch : Ren_2018_ACS.Chem.Neurosci_9_1215 |
| PubMedID: 29432676 |
Ren B, Liu Y, Zhang Y, Cai Y, Gong X, Chang Y, Xu L, Zheng J (2018)
Genistein: A Dual Inhibitor of Both Amyloid beta and Human Islet Amylin Peptides
ACS Chem Neurosci
9 :1215
Ren B, Liu Y, Zhang Y, Cai Y, Gong X, Chang Y, Xu L, Zheng J (2018)
ACS Chem Neurosci
9 :1215