文献类型：期刊文献

英文题名：Sappanwood-derived polyphenolic antidote of amyloidal toxins achieved detoxification via inhibition/reversion of amyloidal fibrillation

作者：Xuan, Qize[1];Zhou, JinFeng[1];Jiang, Feng[2];Zhang, Wei[1];Wei, Anqi[1];Zhang, Wenxue[1];Zhang, Qi[1];Shen, Hao[2];Li, Hui[3];Chen, Chao[1,3];Wang, Ping[4]

机构：[1]East China Univ Sci & Technol, Biomed Nanotechnol Ctr, Shanghai Collaborat Innovat Ctr Biomfg Technol, Sch Biotechnol,State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Orthopaed, Shanghai 200233, Peoples R China;[3]Shanghai Univ, Inst Environm Pollut & Hlth, Sch Environm & Chem Engn, Shanghai 200444, Peoples R China;[4]Univ Minnesota, Dept Bioprod & Biosyst Engn, St Paul, MN 55108 USA

年份：2022

卷号：214

起止页码：446

外文期刊名：INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

收录：;EI(收录号：20242616399328);WOS:【SCI-EXPANDED(收录号:WOS:000851009300006)】；

基金：This work was sponsored by the National Natural Science Foundation of China (Nos. 21908059 and 21636003), the China Postdoctoral Science Foundation (No. 2019M651419), Shanghai Sailing Program (No. 19YF1410900), the Natural Science Foundation of Shanghai (22ZR1415400), the Fundamental Research Funds for the Central Universities (No. 22221818014), the Shanghai Post-doctoral Excellence Program (No. 2018011), the Foundation of State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Sciences (Grant No: GZKF202031), and the Open Funding Project of the State Key Laboratory of Bioreactor Engineering. We also thank the support from Zhang Jiangshu Excellent Doctoral Program and the Research Centre of Analysis and Test of East China University of Science and Technology for the help with the TEM and AFM characterization of peptide assemblies.

语种：英文

外文关键词：Phenol -soluble modulins?3; Brazilin; Amyloidal fibrillation; Cytotoxicity; Antidote

摘要：The formidable virulence of methicillin-resistant staphylococcus aureus (MRSA) have thrown great challenges to biomedicine, which mainly derives from their autocrine phenol-soluble modulins (PSMs) toxins, especially the most toxic member termed phenol-soluble modulins alpha 3 (PSM alpha 3). PSM alpha 3 cytotoxicity is attributed to its amyloidal fibrillation and subsequent formation of cross-alpha sheet fibrils. Inspired by the multiple biological activity of Sappanwood, herein, we adopted brazilin, a natural polyphenolic compound originated from Caesalpinia sappan, as a potential antidote of PSM alpha 3 toxins, and attempted to prove that the regulation of PSM alpha 3 fibrillation was an effective alexipharmic way for MRSA infections. In vitro results revealed that brazilin suppressed PSM alpha 3 fibrillation and disassembled preformed amyloidal fibrils in a dose-dependent manner, in which molar ratio (brazilin: PSM alpha 3) of efficient inhibition and disassembly were both 1:1. These desired regulations dominated by brazilin benefited from its bonding to core fibrils-forming residues of PSM alpha 3 monomers urged by hydrogen bonding and pi-pi stacking, and such binding modes facilitated brazilin-mediated inhibition or disruption of interactions between neighboring PSM alpha 3 monomers. In this context, these inhibited and disassembled PSM alpha 3 assemblies could not easily insert into cell membrane and subsequent penetration, and thus alleviating the membrane disruption, cytoplasmic leakage, and reactive oxygen species (ROS) generation in normal cells. As such, brazilin dramatically decreased the cytotoxicity borne by toxic PSM alpha 3 fibrils. In addition, in vivo experiments affirmed that brazilin relieved the toxicity of PSM alpha 3 toxins and thus promoted the skin wound healing of mice. This study provides a new antidote of PSM alpha 3 toxins, and also confirms the feasibility of the assembly-regulation strategy in development of antidotes against supramolecular fibrillation-dependent toxins.