Suppressive effects of three diketopiperazines from marine-derived bacteria on TGFBIp-mediated septic responses in human endothelial cells and mice.
Diketopiperazine is a naturally occurring cyclic dipeptide found from diverse living organisms. The compounds in this structure class have been known with a broad spectrum of bioactivities including anti-inflammatory activities. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells and functions as a mediator of experimental sepsis. Here, three (1-3) of diketopiperazines were isolated from two strains of marine-derived bacteria and we hypothesized that 1-3 could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here, we investigated the anti-septic effects and underlying mechanisms of 1-3 against TGFBIp-mediated septic responses. 1-3 effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, 1-3 suppressed cecal ligation and puncture (CLP)-induced sepsis lethality and pulmonary injury. In conclusion, 1-3 suppressed TGFBIp-mediated and CLP-induced septic responses. Therefore, 1-3 could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway.
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, 80 Dahak-ro, Buk-gu, Daegu, 41566, Republic of Korea.
Byeongjin
B
Jung
Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Republic of Korea.
Sae-Kwang
SK
Ku
College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
Ming
M
Gao
Division of Plant Biosciences, School of Applied BioSciences, College of Agriculture and Life Science, Kyungpook National University, Daegu, 41566, Republic of Korea.
Kyung-Min
KM
Kim
Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu, 701-724, Republic of Korea.
Min-Su
MS
Han
College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea. h5choi@yu.ac.kr.
Hyukjae
H
Choi
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, 80 Dahak-ro, Buk-gu, Daegu, 41566, Republic of Korea. baejs@knu.ac.kr.
Jong-Sup
JS
Bae
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001407:Bacillus / Q000302:isolation & purification / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D054659:Diketopiperazines / Q000302:isolation & purification / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D019015:Geologic Sediments / Q000382:microbiology; D061307:Human Umbilical Vein Endothelial Cells; D008297:Male; D008810:Mice, Inbred C57BL; D008835:Micrococcaceae / Q000302:isolation & purification / Q000378:metabolism*; D015394:Molecular Structure; D011161:Porifera / Q000382:microbiology; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology; D000099222:betaIG-H3 Protein
D000893:Anti-Inflammatory Agents; D054659:Diketopiperazines; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein
Diketopiperazine; Mice; Sepsis; Severe inflammation; TGFBIp