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      Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy

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          A new Keap1–Nrf2 protein–protein interaction (PPI) inhibitor ZJ01 was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. ZJ01 could in vitro trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, ZJ01 suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in H9c2 cardiac cells. Moreover, in an in vivo mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, ZJ01 demonstrated a cytoprotective effect, upregulated Nrf2 protein nuclear accumulation, and remarkably suppressed the abovementioned cytokine levels in cardiomyocytes. The results presented herein provided a novel chemotype for the development of direct Keap1–Nrf2 PPI inhibitors and suggested that compound ZJ01 is a promising drug lead for septic cardiomyopathy treatment.

          ZJ01 was identified as a new Keap1–Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by in vitro and in vivo experiments.


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          H++: a server for estimating pKas and adding missing hydrogens to macromolecules

          The structure and function of macromolecules depend critically on the ionization (protonation) states of their acidic and basic groups. A number of existing practical methods predict protonation equilibrium pK constants of macromolecules based upon their atomic resolution Protein Data Bank (PDB) structures; the calculations are often performed within the framework of the continuum electrostatics model. Unfortunately, these methodologies are complex, involve multiple steps and require considerable investment of effort. Our web server provides access to a tool that automates this process, allowing both experts and novices to quickly obtain estimates of pKs as well as other related characteristics of biomolecules such as isoelectric points, titration curves and energies of protonation microstates. Protons are added to the input structure according to the calculated ionization states of its titratable groups at the user-specified pH; the output is in the PQR (PDB + charges + radii) format. In addition, corresponding coordinate and topology files are generated in the format supported by the molecular modeling package AMBER. The server is intended for a broad community of biochemists, molecular modelers, structural biologists and drug designers; it can also be used as an educational tool in biochemistry courses.
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            Inflammation in myocardial diseases.

            Inflammatory processes underlie a broad spectrum of conditions that injure the heart muscle and cause both structural and functional deficits. In this article, we address current knowledge regarding 4 common forms of myocardial inflammation: myocardial ischemia and reperfusion, sepsis, viral myocarditis, and immune rejection. Each of these pathological states has its own unique features in pathogenesis and disease evolution, but all reflect inflammatory mechanisms that are partially shared. From the point of injury to the mobilization of innate and adaptive immune responses and inflammatory amplification, the cellular and soluble mediators and mechanisms examined in this review will be discussed with a view that both beneficial and adverse consequences arise in these human conditions.
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              Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.

              Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification. Copyright © 2013 Elsevier Ltd. All rights reserved.

                Author and article information

                J Enzyme Inhib Med Chem
                J Enzyme Inhib Med Chem
                Journal of Enzyme Inhibition and Medicinal Chemistry
                Taylor & Francis
                25 April 2018
                : 33
                : 1
                : 833-841
                [a ] School of Biological Science and Technology, University of Jinan , Jinan, China;
                [b ] School of Pharmacy, Second Military Medical University , Shanghai, China;
                [c ] Faculty of Ceilandia, University of Brasília , Brasilia, Brazil;
                [d ] Institute of Biological Sciences, University of Brasília , Brasilia, Brazil
                Author notes

                These authors contributed equally to this work.

                Supplemental data for this article can be accessed here .

                CONTACT Ning Meng mls_mengn@ 123456ujn.edu.cn ;
                Hua Zhang bio_zhangh@ 123456ujn.edu.cn School of Biological Science and Technology, University of Jinan , Jinan, China
                © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 9, Words: 6060
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 21672082
                Award ID: 31671214
                Funded by: Shandong Key Development Project
                Award ID: 2016GSF201209
                Funded by: Young Taishan Scholars Program
                Award ID: tsqn20161037
                Funded by: Shandong Talents Team Cultivation Plan of University Preponderant Discipline
                Award ID: 10027
                Funded by: Fund of Shandong Province Natural Science Foundation 10.13039/501100007129
                Award ID: ZR2017BH038
                Funded by: Scientific Research fund of University of Jinan
                Award ID: XKY1609
                Award ID: 160100202
                Funded by: Shanghai “ChenGuang” Project
                Award ID: 16CG42
                Funded by: Shanghai Municipal Commission of Health and Family Planning 10.13039/501100008410
                Award ID: 2017YQ052
                Funded by: Brazilian Government Agencies FAP/DF 10.13039/100001582
                Award ID: . 0193.001020/2015]
                Funded by: CNPq 10.13039/501100003593
                Award ID: 447.628/2014-3
                This research work was financially supported by the National Natural Science Foundation of China [Nos. 21672082, 31671214], Shandong Key Development Project [No. 2016GSF201209], the Young Taishan Scholars Program [No. tsqn20161037], Shandong Talents Team Cultivation Plan of University Preponderant Discipline [No. 10027], Fund of Shandong Province Natural Science Foundation [ZR2017BH038], Scientific Research fund of University of Jinan [Nos. XKY1609, 160100202], the Shanghai “ChenGuang” Project [No. 16CG42] and the Shanghai Municipal Commission of Health and Family Planning [No. 2017YQ052], and by the Brazilian Government Agencies FAP/DF [No. 0193.001020/2015] and CNPq [No. 447.628/2014-3].
                Research Paper


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