Study On Effects Of Several Quinones And Derivates On Protein Amyloid Aggregation

Amyloid aggregation is a process that proteins misfold into β-sheet-rich oligomers and further form fibrils. Aggregated proteins lose their normal activities and cause cell dysfunction and toxicity. Studies suggested that oligomers and fibrils may induce cell apoptosis by several pathways such as membrane disruption, endoplasmic reticulum stress and oxidative stress. The toxic effect may cause various diseases, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and metabolic diseases like type2diabetes (T2DM). Proteins including α-synuclein (a-syn), P-amyloid1-42(Aβ42) and islet amyloid polypeptide (IAPP) have been used as models for studying amyloid aggregation.Inhibition of aggregation process has been generally accepted as an important prevention strategy for amyloid associated diseases. A great number of studies have focused on discovery of amyloid inhibitors which may contribute to the development of therapeutic drugs. Polyphenols have been extensively studied as a class of small molecular amyloid inhibitors, with several polyphenols under clinical trials as anti-neurodegenerative drugs. As oxidative intermediates of natural polyphenols, quinones widely exist in medicinal plants. For example, anthraquinone derivatives can be found in rhubarb, a traditional herbal medicine. Previous reports on natural quinones mainly focused on the mechanisms behind their anti-cancer or anti-bacterial activities. However, the exact effects and mechanisms on amyloid aggregation remain limited.Insulin is a hypoglycemic drug that widely used in the treatment of diabetes. Insulin does not belong to pathogenic proteins but insulin amyloidosis is commonly found in certain in vitro condition, which may influence the drug storage and clinical application. This protein has been applied as an amyloid model to investigate mechanism and inhibitors of amyloid aggregation. In the first part of this study, we used insulin as an amyloid model to test the anti-amyloid effects of four simple quinones (benzoquinone, naphthoquinone, anthraquinone and phenanthraquinone). We also investigated the inhibitory effects of four natural anthraquinone derivatives from rhubarb, in order to provide basis for the further application research of natural quinones. For the most effective compound, naphthoquinone, a-syn and Aβ342were further studied to investigate its broad-spectrum inhibition effect.To study the naphthoquinone derivatives, we further selected menadione sodium bisulfite (MSB) as the target compound. MSB belongs to vitamin K medicine, which may assist the formation of thrombin, alleviate vitamin deficiency and has analgesic effect. MSB is a member of the synthetic vitamin K3derivatives and also a naphthoquinone derivative. Compared with natural vitamin K1and K2, MSB has better solubility and internal absorption. Since naphthoquinone strongly inhibited amyloid aggregation in insulin model, we speculated that MSB may also affect aggregation process as an amyloid inhibitor, this possibility was further tested in amyloid models of a-syn and Aβ342. Inhibitory effect was also analyzed base on the experiments on transgenetic elegans.The results of the dissertation will provide possible active molecular bones for the development of amyloid inhibitors. It will also provide theoretical basis for the application of amyloid inhibitors as potential therapeutic drugs.