PMID- 31877277 OWN - NLM STAT- MEDLINE DCOM- 20201019 LR - 20210816 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 869 DP - 2020 Feb 15 TI - Estrogenic and anti-inflammatory effects of pseudoprotodioscin in atherosclerosis-prone mice: Insights into endothelial cells and perivascular adipose tissues. PG - 172887 LID - S0014-2999(19)30839-8 [pii] LID - 10.1016/j.ejphar.2019.172887 [doi] AB - Pseudoprotodioscin (PPD), a phytoestrogen isolated from Dioscorea nipponica Makino, is recognized to possess anti-inflammatory and antiadipogenic capacities. However, little is known about the antiatherosclerotic effects of PPD and the underlying mechanisms. Here, the contribution of estrogen receptors (ERs) and inflammation to PPD-mediated amelioration of endothelial dysfunction has been fully assessed. PPD administration alleviated atherosclerotic lesions by lowering total cholesterol in ovariectomized apoE(-/-) mice fed a high-cholesterol diet. Molecular docking analysis suggested a selective interaction of PPD with ERalpha. Upon PPD treatment, ERalpha and endothelial nitric oxide synthase (eNOS) protein levels were increased, whereas cell adhesion molecule and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were suppressed in human umbilical vein endothelial cells (HUVECs) after injury caused by oxidized low-density lipoprotein (ox-LDL). These effects could be abolished by an ERalpha antagonist or a NOS inhibitor. Whereas, PPD can ERalpha-independently suppress TNFalpha expression in peritoneal macrophages upon LPS induction. Estrogen deficiency induced inflammatory phenotypes in perivascular adipose tissue (PAT), which could be partially attenuated by PPD. The increased release of adiponectin in PAT after PPD treatment is in accordance with previous reported data showing that adiponectin exerts anti-inflammatory effects in multiple cell types. ERalpha-dependent antiadipogenic effects of PPD were also detected in PAT-derived stromal cells. The present study reveals a novel mechanism through which PPD exerts estrogenic and anti-inflammatory properties in atherosclerosis-prone mice. Thus, PPD is a promising compound which has potential therapeutic effects on atherosclerotic cardiovascular diseases in postmenopausal women. CI - Copyright (c) 2019 Elsevier B.V. All rights reserved. FAU - Sun, Bing AU - Sun B AD - Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China. FAU - Yang, Dan AU - Yang D AD - Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China. FAU - Yin, Yue-Zhang AU - Yin YZ AD - Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China; Shandong University of Traditional Chinese Medicine, Shandong, 250355, PR China. FAU - Xiao, Jing AU - Xiao J AD - Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China. Electronic address: jxiao@implad.ac.cn. LA - eng PT - Journal Article DEP - 20191223 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Anti-Inflammatory Agents) RN - 0 (CCL2 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (ESR1 protein, human) RN - 0 (Estrogen Receptor alpha) RN - 0 (Estrogen Receptor beta) RN - 0 (Estrogens) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (pseudo-protodioscin) RN - 4Y8F71G49Q (Malondialdehyde) RN - EC 1.14.13.39 (NOS3 protein, human) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - K49P2K8WLX (Diosgenin) SB - IM MH - Adipose Tissue/drug effects/metabolism MH - Animals MH - Anti-Inflammatory Agents/pharmacology/*therapeutic use MH - Aorta, Thoracic/drug effects/pathology/physiopathology MH - Apoptosis/drug effects MH - Atherosclerosis/*drug therapy/pathology/physiopathology MH - Cells, Cultured MH - Chemokine CCL2/genetics MH - Diosgenin/*analogs & derivatives/pharmacology/therapeutic use MH - Estrogen Receptor alpha/genetics/metabolism MH - Estrogen Receptor beta/genetics/metabolism MH - Estrogens/pharmacology/*therapeutic use MH - Female MH - Human Umbilical Vein Endothelial Cells/drug effects/metabolism MH - Humans MH - Macrophages, Peritoneal/drug effects/metabolism MH - Malondialdehyde/metabolism MH - Mice, Knockout, ApoE MH - Molecular Docking Simulation MH - Nitric Oxide Synthase Type III/metabolism MH - Postmenopause MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Endothelial function OT - Estrogen receptors OT - Inflammation OT - Nitric oxide OT - Pseudoprotodioscin EDAT- 2019/12/27 06:00 MHDA- 2020/10/21 06:00 CRDT- 2019/12/27 06:00 PHST- 2019/06/07 00:00 [received] PHST- 2019/12/03 00:00 [revised] PHST- 2019/12/18 00:00 [accepted] PHST- 2019/12/27 06:00 [pubmed] PHST- 2020/10/21 06:00 [medline] PHST- 2019/12/27 06:00 [entrez] AID - S0014-2999(19)30839-8 [pii] AID - 10.1016/j.ejphar.2019.172887 [doi] PST - ppublish SO - Eur J Pharmacol. 2020 Feb 15;869:172887. doi: 10.1016/j.ejphar.2019.172887. Epub 2019 Dec 23.