Study On Inhibitors For Toxicity Amyloid Formation Of Human Islet Amyloid Polypeptide

Protein misfolding which can induce amyloid deposition is a characteristic component in more than twenty human diseases, including Alzheimer’s disease, Parkinson’s disease and type2diabetes (T2DM), which also known as amyloidogenic diseases. Proteins that induce amyloidogenic diseases are defined as amyloidogenic protein, such as beta amyloid (Aβ) in Alzheimer’s disease, a-synuclein in Parkinson’s disease and human islet amyloid polypeptide (hIAPP) in T2DM.hIAPP is the major component of islet amyloid in pancreatic in patients with T2DM. hIAPP has a strong abilitity to form amyloid aggregation, thus it is one of the most strongest natural amyloidogeinc proteins. In physiological conditions, hIAPP, together with insulin and glucagon, prelongs gastric emptying, suppress eating more food and regulates blood glucose. However, for conditions in T2DM the amyloid deposits formed by islet amyloid polypeptide in islet induce P-cell apoptosis and impair pancreas function by causing oxidative stress, ER stress and damages to mitochondria. Thus, amyloid deposits formed by hIAPP are regarded as one of the pathologies for T2DM.Recently, increasing research has been focused on developing inhibitors of amyloid formation, not only because of their obvious therapeutic potential, but also because they are useful tools for aggregation mechanistic studies. There has been excessive study on inhibitors of the Alzheimer beta amyloid peptide (Aβ), and some of these inhibitors are now in phase II or III clinical, including Epigallocatechin gallate (EGCG) and PTB2. However, less focus has been noticed in developing IAPP amyloid inhibitors. In this dissertation, small molecule inhibitors from natural compounds or traditional chinese medicines were investigated.Epidemiological studies have shown that there is less risk of diabetes of the people who has a long-term coffee drinking. In this paper, caffeic acid (CA) and chlorogenic acid (CGA), the two main composition of coffee have been showed a ignificantly ability of suppression on the toxic oligomerization of hIAPP, prelonging the secondary structure transition during the fibrilization of hIAPP. Further photo-crosslinking based on oligomerisation result suggested CA and CGA significantly interrupting toxic oligomerization of hIAPP.Silibinin, a major component of water-extracted derived from silybum marianum, is usually applied to therapy for diabetes patients in Asia and Europe with unknown mechanisms. Previous data have shown benefit effect of silibinin in cancer and diabetes prevention, and now it has been widely utilize in medicine, food and other health care products. In this paper, we results declared that silibinin retards the fiberil formation of hIAPP by decreasing the formation of hIAPP oligomer and increas the viability of pancreatic β-cells.Salvianolic acid B (Sa1B) is one of the most water-extracted component of salvia miltiorrhiza, which is one of the most commonly used of traditional Chinese medicines and is major composition of Chinese herbal compound for treating diabetes. SalB has several properties including anti-oxidation and inhibiting oxidative stress. Results have clearly demonstrated that SalB notably suppression the formation of hIAPP amyloid and degradation hIAPP mature fibrils. Furthermore, PICUP and MTT assyas indicate that SalB significantly decreases hIAPP induced cytotoxicity.Summary, we focus on the common active elements in traditional Chinese medicine and daily food which have polyphenolic structure, to explore their properties on hIAPP fibrilization. Our data not only provides better understanding of the mechanism of amyloid formation, but also provide evidence for anti-diabetes drugs that target anti-hIAPP toxicity aggregation, given different understanding into the development of functioning beneficial approaches for a widespread kind of protein mis misfolding diseases.