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Suppressive effects of three diketopiperazines from marine-derived bacteria on TGFBIp-mediated septic responses in human endothelial cells and mice

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Abstract

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.

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Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2012R1A5A2A42671316) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI15C0001).

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    Authors and Affiliations

    1. 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 Jung & Jong-Sup Bae

    2. Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Republic of Korea

      Sae-Kwang Ku

    3. College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea

      Ming Gao & Hyukjae Choi

    4. Division of Plant Biosciences, School of Applied BioSciences, College of Agriculture and Life Science, Kyungpook National University, Daegu, 41566, Republic of Korea

      Kyung-Min Kim

    5. Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu, 701-724, Republic of Korea

      Min-Su Han

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    1. Byeongjin Jung
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    Byeongjin Jung, Sae-Kwang Ku, and Ming Gao have contributed equally to this work.

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    Jung, B., Ku, SK., Gao, M. et al. Suppressive effects of three diketopiperazines from marine-derived bacteria on TGFBIp-mediated septic responses in human endothelial cells and mice. Arch. Pharm. Res. 39, 843–854 (2016). https://doi.org/10.1007/s12272-016-0743-7

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