title: Inhibitory effects of three diketopiperazines from marine-derived bacteria on endothelial protein C receptor shedding in human endothelial cells and mice.
abstract: Diketopiperazine is a natural products found from bacteria, fungi, marine sponges, gorgonian and red algae. They are cyclic dipeptides possessing relatively simple and rigid structures with chiral nature and various side chains. The compounds in this structure class have been known to possess diverse bioactivities including antibiotic activity, anti-cancer activity, neuroprotective activity, and anti-inflammatory activity. The endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway and in the activation of protein C. Endothelial cell protein C receptor (EPCR) can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). However, little is known about the effects of diketopiperazine on EPCR shedding. We investigated this issue by monitoring the effects of diketopiperazine on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism. Here, three (1-3) of diketopiperazines were isolated from two strains of marine-derived bacteria and 1-3 induced potent inhibition of PMA-, TNF-α-, IL-1β (in HUVECs), and CLP-induced EPCR shedding (in mice) via inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. 1-3 also inhibited the expression and activity of PMA-induced TACE in HUVECs suggesting that p38, ERK1/2, and JNK could be molecular targets of 1-3. These results demonstrate the potential of 1-3 as an anti-EPCR shedding reagent against PMA-mediated and CLP-mediated EPCR shedding.
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
authors.forename: Hyukjae
authors.initials: H
authors.lastname: Choi
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address: baejs@knu.ac.kr.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001407:Bacillus / Q000737:chemistry*; D054659:Diketopiperazines / Q000737:chemistry*; D000074283:Endothelial Protein C Receptor; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012623:Seawater / Q000382:microbiology; D018805:Sepsis / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha
chemical_list: D015703:Antigens, CD; D054659:Diketopiperazines; D000074283:Endothelial Protein C Receptor; D053583:Interleukin-1beta; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D013755:Tetradecanoylphorbol Acetate
keywords: CLP; Diketopiperazine; EPCR shedding; Vascular inflammation