Silibinin inhibits the toxic aggregation of human islet amyloid polypeptide.
ABSTRACT In type 2 diabetes mellitus (T2DM), misfolded human islet amyloid polypeptide (hIAPP) forms amyloid deposits in pancreatic islets. These amyloid deposits contribute to the dysfunction of β-cells and the loss of β-cell mass in T2DM patients. Inhibition of hIAPP fibrillization has been regarded as a potential therapeutic approach for T2DM. Silibinin, a major active flavonoid extracted from herb milk thistle (Silybum marianum), has been used for centuries to treat diabetes in Asia and Europe with unclear mechanisms. In this study, we tested whether silibinin has any effect on the amyloidogenicity of hIAPP. Our results provide first evidence that silibinin inhibits hIAPP fibrillization via suppressing the toxic oligomerization of hIAPP and enhances the viability of pancreatic β-cells, therefore silibinin may serve as a potential therapeutic agent for T2DM.
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ABSTRACT: Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases and metabolic diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis diseases. Polyphenols have been extensively studied as a class of amyloid inhibitors, with several polyphenols under clinical trials as anti-neurodegenerative drugs. As oxidative intermediates of natural polyphenols, quinones widely exist in medicinal plants or food. In this study, we used insulin as an amyloid model to test the anti-amyloid effects of four simple quinones and four natural anthraquinone derivatives from rhubarb, a traditional herbal medicine used for treating Alzheimer's disease. Our results demonstrated that all eight quinones show inhibitory effects to different extent on insulin oligomerization, especially for 1,4-benzoquinone and 1,4-naphthoquinone. Significantly attenuated oligomerization, reduced amount of amyloid fibrils and reduced hemolysis levels were found after quinones treatments, indicating quinones may inhibit insulin from forming toxic oligomeric species. The results suggest a potential action of native anthraquinone derivatives in preventing protein misfolding diseases, the quinone skeleton may thus be further explored for designing effective anti-amyloidosis compounds.Scientific reports. 01/2014; 4:5648.
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ABSTRACT: Amylin or islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone secreted from the pancreatic islets into the blood circulation and is cleared by peptidases in the kidney. IAPP aggregates are strongly associated with β-cell degeneration in type 2 diabetes, as demonstrated by the fact that more than 95% of patients exhibit IAPP amyloid upon autopsy. Recently, it has been reported that metal ions such as copper(II) and zinc(II) are implicated in the aggregation of IAPP as well as able to modulate the proteolytic activity of IAPP degrading enzymes. For this reason, in this work, the role of the latter metal ions in the degradation of IAPP by insulin-degrading enzyme (IDE) has been investigated by a chromatographic and mass spectrometric combined method. The latter experimental approach allowed not only to assess the overall metal ion inhibition of the human and murine IAPP degradation by IDE but also to have information on copper- and zinc-induced changes in IAPP aggregation. In addition, IDE cleavage site preferences in the presence of metal ions are rationalized as metal ion-induced changes in substrate accessibility. Copyright © 2014 John Wiley & Sons, Ltd.Biological Mass Spectrometry 04/2014; 49(4). · 2.71 Impact Factor
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ABSTRACT: Human islet amyloid polypeptide (hIAPP) fibril is the major constituent of amyloid deposits in pancreatic islets of type 2 diabetes. Misfolding and hIAPP fibril formation are thought to be important in the pathogenesis of diabetes. Studies have showed that selenium-containing phycocyanin (Se-PC) inhibited the fibrillation of hIAPP to form nanoscale particles, which is mainly by interfering with the combination between hIAPP. Small nanoscale oligomers tended to grow into larger nanoparticles and the size of nanoparticles increased with the incubation time. By interfering with the fibrillation of hIAPP and altering the structure, Se-PC alleviated hIAPP-induced cell apoptosis. Meantime, generation of ROS produced during the fibrillation process was inhibited, which was proposed to be the main factor for the hIAPP-cytotoxicity in beta cells. Taken together, Se-PC inhibited hIAPP fibrillation, thus suppressed the formation of ROS to show protective effect on hIAPP mediated cell apoptosis. Our studies provide useful information for our understanding of the interaction mechanisms of Se-PC on hIAPP structure and protective mechanisms on hIAPP cytotoxicity, presenting useful candidate for anti-diabetes drug development.Biomaterials 07/2014; · 8.31 Impact Factor