title: Suppressive effects of three diketopiperazines from marine-derived bacteria on polyphosphate-mediated septic responses.
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. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of diketopiperazine and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Diketopiperazine suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, diketopiperazine demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of diketopiperazine on various systemic inflammatory diseases, such as sepsis or septic shock.
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: Seongdo
authors.initials: S
authors.lastname: Jeong
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, 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: Gahee
authors.initials: G
authors.lastname: Min
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
authors.forename: Hyukjae
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Ophthalmology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea. Electronic address: sarasate2222@gmail.com.
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Park
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: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000382:microbiology; D001419:Bacteria / Q000737:chemistry; D015415:Biomarkers / Q000032:analysis; D054659:Diketopiperazines / Q000494:pharmacology* / Q000627:therapeutic use; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D011122:Polyphosphates / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy*; D015996:Survival Rate
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; D054659:Diketopiperazines; D010456:Peptides, Cyclic; D011122:Polyphosphates
keywords: Barrier integrity; Diketopiperazine; Inflammation; Polyphosphate