PMID- 31016813 OWN - NLM STAT- MEDLINE DCOM- 20190823 LR - 20190823 IS - 1099-1573 (Electronic) IS - 0951-418X (Linking) VI - 33 IP - 6 DP - 2019 Jun TI - Nobiletin exhibits potent inhibition on tumor necrosis factor alpha-induced calcification of human aortic valve interstitial cells via targeting ABCG2 and AKR1B1. PG - 1717-1725 LID - 10.1002/ptr.6360 [doi] AB - Inflammation is considered to be one of the initial critical factors in the occurrence of calcific heart valve disease. This study was to prove Nobiletin (NBT) inhibits inflammation-caused calcification of human valve interstitial cells (hVICs) and to elucidate the involved molecular mechanisms. Tumor necrosis factor-alpha (TNF-alpha)-induced hVICs were treated with or without NBT. Cell growth and calcification of hVICs were assessed. RNA sequencing was utilized to investigate the gene expression changes. Molecular target prediction and docking assay were further performed. NBT interfered with hVIC growth under TNF-alpha condition in a dose-dependent manner also presented a gradual decrease of positive Alizarin Red S staining, down-regulation of BMP2, and RUNX2 gene expression. Based on the global gene expression cluster, control and TNF-alpha plus NBT group showed a high similarity versus TNF-alpha only group. After Venn interaction of differential expression genes (DEGs), 2,236 common DEGs were identified to display different biological functions and signaling pathways. ABCG2 and AKR1B1 were further selected as prediction targets of NBT involved in RELA, TNF, BMP2, RUNX2, etc. interactions in mediating hVIC calcification. The results show that NBT is a natural product to prevent the occurrence of heart valve calcification. CI - (c) 2019 John Wiley & Sons, Ltd. FAU - Xu, Kang AU - Xu K AUID- ORCID: 0000-0002-8492-2058 AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Huang, Yuming AU - Huang Y AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Zhou, Tingwen AU - Zhou T AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Wang, Chunli AU - Wang C AD - National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China. FAU - Chi, Qingjia AU - Chi Q AD - Department of Mechanics and Engineering Structure, Hubei Key Laboratory of Theory and Application of Advanced Materials Mechanics, Wuhan University of Technology, Wuhan, China. FAU - Shi, Jiawei AU - Shi J AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Zhu, Peng AU - Zhu P AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Dong, Nianguo AU - Dong N AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. LA - eng GR - 2016YFA0101100/National Key R&D Plan/ GR - B06023/Innovation and Attracting Talents Program for College and University/ GR - 2018IB005/Fundamental Research Funds for the Central Universities/ GR - 2016IVB063/Fundamental Research Funds for the Central Universities/ GR - CQKLBST-2018-006/Visiting Scholar Foundation of Key Laboratory of Biorheological Science and Technology (Chongqing University)/ GR - CQKLBST-2018-009/Visiting Scholar Foundation of Key Laboratory of Biorheological Science and Technology (Chongqing University)/ GR - 2018M630867/China Postdoctoral Science Foundation/ GR - 81770387/National Natural Science Foundation of China/ GR - 30371414/National Natural Science Foundation of China/ GR - 30571839/National Natural Science Foundation of China/ GR - 30872540/National Natural Science Foundation of China/ GR - 31330029/National Natural Science Foundation of China/ GR - 81170214/National Natural Science Foundation of China/ GR - 81270297/National Natural Science Foundation of China/ GR - 11602181/National Natural Science Foundation of China/ GR - 11532004/National Natural Science Foundation of China/ PT - Journal Article DEP - 20190423 PL - England TA - Phytother Res JT - Phytotherapy research : PTR JID - 8904486 RN - 0 (ABCG2 protein, human) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 2) RN - 0 (Flavones) RN - 0 (Neoplasm Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - D65ILJ7WLY (nobiletin) RN - EC 1.1.1.21 (AKR1B1 protein, human) RN - EC 1.1.1.21 (Aldehyde Reductase) RN - Aortic Valve, Calcification of MH - ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/metabolism MH - Adult MH - Aldehyde Reductase/genetics/metabolism MH - Aortic Valve/*drug effects/metabolism/*pathology MH - Aortic Valve Stenosis/genetics/metabolism/pathology/*prevention & control MH - Calcinosis/genetics/metabolism/pathology/*prevention & control MH - Cells, Cultured MH - Down-Regulation/drug effects/genetics MH - Female MH - Flavones/chemistry/*pharmacology MH - Gene Expression Regulation/drug effects MH - Heart Valve Diseases/genetics/metabolism/pathology/prevention & control MH - Humans MH - Molecular Docking Simulation MH - Neoplasm Proteins/genetics/metabolism MH - Signal Transduction/drug effects/genetics MH - Tumor Necrosis Factor-alpha/adverse effects/*antagonists & inhibitors OTO - NOTNLM OT - anti-inflammation OT - bioinformatics OT - calcific aortic valve disease OT - molecular docking OT - target prediction EDAT- 2019/04/25 06:00 MHDA- 2019/08/24 06:00 CRDT- 2019/04/25 06:00 PHST- 2018/12/05 00:00 [received] PHST- 2019/02/25 00:00 [revised] PHST- 2019/03/06 00:00 [accepted] PHST- 2019/04/25 06:00 [pubmed] PHST- 2019/08/24 06:00 [medline] PHST- 2019/04/25 06:00 [entrez] AID - 10.1002/ptr.6360 [doi] PST - ppublish SO - Phytother Res. 2019 Jun;33(6):1717-1725. doi: 10.1002/ptr.6360. Epub 2019 Apr 23.