Silibinin inhibits the toxic aggregation of human islet amyloid polypeptide

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 02/2012; 419(3):495-9. DOI: 10.1016/j.bbrc.2012.02.042
Source: PubMed


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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    • "Samples for TEM assay were prepared as we previously described62. Incubated solution was applied onto a 300-mesh formvar-carbon coated copper grid and sit for 5 min. "
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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.
    Full-text · Article · Jul 2014 · Scientific Reports
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    • "As a matter of fact, silibinin has the ability to inhibit the amyloid structure formation of various model or pathogenic proteins in vitro, including Aβ1-42[38] human islet amyloid polypeptide [39], and human insulin and albumin [40]. This may be suggestive of a generic anti-amyloidogenic effect for this compound, as it has been suggested/observed for various other aromatic/polyphenolic molecules [41,42]. "
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    ABSTRACT: The deposition of amyloid peptides is associated with Alzheimer's disease (AD). These amyloid peptides are derived from the amyloid protein precursor (APP). Silymarin, a standardized extract of milk thistle, which is currently used in liver diseases, may be effective in the inhibition of amyloid formation. However, its effect has not been assessed on APP expression. In this study, first, the effect of silymarin was examined on the passive avoidance learning in a rat model of AD. This model was induced by the intracerebroventricular injection of Abeta peptide (Abeta1-42) in Wistar rats. Rats were treated with 70 and 140 mg/kgof the extract, once a day, for 4 weeks. Memory function that was evaluated in a shuttle-cage test, showed improvement upon administration of this extract. Brain amyloid plaques had also decreased upon administration of the extract. Furthermore, APP gene expression was compared in treated and untreated groups. The result showed that silymarin was able to suppress APP expression. Our results are in accordance with the in vitro tests concerning the positive antiamyloidogenic property of the main component of silymarin, namely silibinin. We suggest that the beneficial effect of sylimarin in the AD model is related to its capacity to disaggregate amyloid plaques and to suppress APP expression. Considering the limited side effects of silymarin, this compound could be of use in AD therapy.
    Full-text · Article · Jan 2014 · DARU-JOURNAL OF FACULTY OF PHARMACY
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    • "In accordance with the similarity calculation results, Silibinin is a flavonolignan extracted from milk thistle seeds, which showed antiviral efficacy, anti-inflammatory activity, anticancer effects, protection against experimental ischemic stroke, and inhibition of Aβ peptide aggregation with unclear mechanisms [54–60]. Presently, there are no reports on signs of severe toxicity induced by Silibinin, but transient hyperbilirubinemia and mild sensation of heat with infusion were found as the most relevant drug-associated side effects [61, 62]. "
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    ABSTRACT: As the major issue to limit the use of drugs, drug safety leads to the attrition or failure in clinical trials of drugs. Therefore, it would be more efficient to minimize therapeutic risks if it could be predicted before large-scale clinical trials. Here, we integrated a network topology analysis with cheminformatics measurements on drug information from the DrugBank database to detect the discrepancies between approved drugs and withdrawn drugs and give drug safety indications. Thus, 47 approved drugs were unfolded with higher similarity measurements to withdrawn ones by the same target and confirmed to be already withdrawn or discontinued in certain countries or regions in subsequent investigations. Accordingly, with the 2D chemical fingerprint similarity calculation as a medium, the method was applied to predict pharmacovigilance for natural products from an in-house traditional Chinese medicine (TCM) database. Among them, Silibinin was highlighted for the high similarity to the withdrawn drug Plicamycin although it was regarded as a promising drug candidate with a lower toxicity in existing reports. In summary, the network approach integrated with cheminformatics could provide drug safety indications effectively, especially for compounds with unknown targets or mechanisms like natural products. It would be helpful for drug safety surveillance in all phases of drug development.
    Full-text · Article · Apr 2013 · Evidence-based Complementary and Alternative Medicine
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