PMID- 31862476 OWN - NLM STAT- MEDLINE DCOM- 20201103 LR - 20201103 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 123 DP - 2020 Mar TI - A new zinc chelator, IPZ-010 ameliorates postoperative ileus. PG - 109773 LID - S0753-3322(19)35395-8 [pii] LID - 10.1016/j.biopha.2019.109773 [doi] AB - Zinc was discovered to be a novel second messenger in immunoreactive cells. We synthesized a novel free zinc chelator, IPZ-010. Here, we investigated the effects of IPZ-010 in a mouse postoperative ileus model and determined the effects of zinc signal inhibition as a new therapeutic strategy against postoperative ileus. Zinc waves were measured in bone marrow-derived mast cells (BMMCs) loaded with a zinc indicator, Newport green. Degranulation and cytokine expression were measured in BMMCs and bone marrow-derived macrophages (BMDMs). Postoperative ileus model mice were established with intestinal manipulation. Mice were treated with IPZ-010 (30 mg/kg, s.c. or p.o.) 1 h before and 2 h and 4 h after intestinal manipulation. Gastrointestinal transit, inflammatory cell infiltration, and expression of inflammatory mediators were measured. Free zinc waves occurred following antigen stimulation in BMMCs and were blocked by IPZ-010. IPZ-010 inhibited interleukin-6 secretion and degranulation in BMMCs. IPZ-010 inhibited tumor necrosis factor-alpha mRNA expression in BMMCs stimulated with lipopolysaccharide or adenosine triphosphate, whereas IPZ-010 had no effects on tumor necrosis factor-alpha mRNA expression in BMDMs stimulated with lipopolysaccharide or adenosine triphosphate. In postoperative ileus model mice, IPZ-010 inhibited leukocyte infiltration and cytokine expression, which ameliorated gastrointestinal transit. Furthermore, ketotifen (1 mg/kg) induced similar effects as IPZ-010. These effects were not amplified by co-administration of IPZ-010 and ketotifen. IPZ-010 inhibited zinc waves, resulting in inhibition of inflammatory responses in activated BMMCs in vitro. Targeting zinc waves in inflammatory cells may be a novel therapeutic strategy for treating postoperative ileus. CI - Copyright (c) 2019. Published by Elsevier Masson SAS. FAU - Kimura, Hitomi AU - Kimura H AD - Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Yoneya, Yutaka AU - Yoneya Y AD - Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Mikawa, Shoma AU - Mikawa S AD - Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Kaji, Noriyuki AU - Kaji N AD - Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Ito, Hiroki AU - Ito H AD - Interprotein Corporation, 3-10-2 Toyosaki, Kita-ku, Osaka-city, Osaka 531-0072, Japan. FAU - Tsuchida, Yasuaki AU - Tsuchida Y AD - Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya-city, Hyogo 663-8501, Japan. FAU - Komatsu, Hirotsugu AU - Komatsu H AD - Interprotein Corporation, 3-10-2 Toyosaki, Kita-ku, Osaka-city, Osaka 531-0072, Japan. FAU - Murata, Takahisa AU - Murata T AD - Department of Animal Radiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Ozaki, Hiroshi AU - Ozaki H AD - Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Uchida, Ryota AU - Uchida R AD - Laboratory of Immune Regulation, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki-cho, Suzuka-city, Mie 513-8607, Japan. FAU - Nishida, Keigo AU - Nishida K AD - Laboratory for Homeostatic Network, RCAI, RIKEN Research Center for Integrative Medical Sciences (IMS-RCAI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama-city, Kanagawa 230-0045, Japan; Laboratory of Immune Regulation, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki-cho, Suzuka-city, Mie 513-8607, Japan. FAU - Hori, Masatoshi AU - Hori M AD - Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. LA - eng PT - Journal Article DEP - 20191218 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antigens, CD) RN - 0 (Antigens, Differentiation, Myelomonocytic) RN - 0 (CD68 antigen, human) RN - 0 (Chelating Agents) RN - 0 (Ethylenediamines) RN - 0 (Inflammation Mediators) RN - 0 (Lipopolysaccharides) RN - 0 (RNA, Messenger) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - J41CSQ7QDS (Zinc) RN - R9PTU1U29I (N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine) RN - X49220T18G (Ketotifen) SB - IM MH - Adenosine Triphosphate/pharmacology MH - Animals MH - Anti-Inflammatory Agents/pharmacology/therapeutic use MH - Antigens, CD/metabolism MH - Antigens, Differentiation, Myelomonocytic/metabolism MH - Chelating Agents/chemistry/pharmacology/*therapeutic use MH - Disease Models, Animal MH - Ethylenediamines/pharmacology/therapeutic use MH - Gastrointestinal Transit/drug effects MH - Ileus/*drug therapy/pathology/physiopathology MH - Inflammation Mediators/metabolism MH - Ketotifen/pharmacology MH - Lipopolysaccharides/pharmacology MH - Macrophages/metabolism MH - Mast Cells/drug effects/metabolism MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Neutrophils/metabolism MH - Postoperative Complications/*drug therapy/pathology/physiopathology MH - RNA, Messenger/genetics/metabolism MH - Zinc/*metabolism OTO - NOTNLM OT - Inflammation OT - Macrophages OT - Mast cells OT - Postoperative ileus OT - Zinc COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2019/12/22 06:00 MHDA- 2020/11/04 06:00 CRDT- 2019/12/22 06:00 PHST- 2019/10/01 00:00 [received] PHST- 2019/11/29 00:00 [revised] PHST- 2019/12/04 00:00 [accepted] PHST- 2019/12/22 06:00 [pubmed] PHST- 2020/11/04 06:00 [medline] PHST- 2019/12/22 06:00 [entrez] AID - S0753-3322(19)35395-8 [pii] AID - 10.1016/j.biopha.2019.109773 [doi] PST - ppublish SO - Biomed Pharmacother. 2020 Mar;123:109773. doi: 10.1016/j.biopha.2019.109773. Epub 2019 Dec 18.