PMID- 25454762 OWN - NLM STAT- MEDLINE DCOM- 20150728 LR - 20141205 IS - 1879-0739 (Electronic) IS - 0271-5317 (Linking) VI - 34 IP - 12 DP - 2014 Dec TI - Isobutyrylshikonin inhibits lipopolysaccharide-induced nitric oxide and prostaglandin E2 production in BV2 microglial cells by suppressing the PI3K/Akt-mediated nuclear transcription factor-kappaB pathway. PG - 1111-9 LID - S0271-5317(14)00199-7 [pii] LID - 10.1016/j.nutres.2014.10.002 [doi] AB - Microglia are important macrophages to defend against pathogens in the central nervous system (CNS); however, persistent or acute inflammation of microglia lead to CNS disorders via neuronal cell death. Therefore, we theorized that a good strategy for the treatment of CNS disorders would be to target inflammatory mediators from microglia in disease. Consequently, we investigated whether isobutyrylshikonin (IBS) attenuates the production of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Treatment with IBS inhibited the secretion of NO and prostaglandin E2 (as well as the expression of their key regulatory genes), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). Isobutyrylshikonin also suppressed LPS-induced DNA-binding activity of nuclear transcription factor-kappaB (NF-kappaB), by inhibiting the nuclear translocation of p50 and p65 in addition to blocking the phosphorylation and degradation of IkappaBalpha. Pretreatment with pyrrolidine dithiocarbamate, a specific NF-kappaB inhibitor, showed the down-regulation of LPS-induced iNOS and COX-2 messenger RNA by suppressing NF-kappaB activity. This indirectly suggests that IBS-mediated NF-kappaB inhibition is the main signaling pathway involved in the inhibition of iNOS and COX-2 expression. In addition, IBS attenuated LPS-induced phosphorylation of PI3K and Akt, which are upstream molecules of NF-kappaB, in LPS-stimulated BV2 microglial cells. The functional aspects of the PI3K/Akt signaling pathway were analyzed with LY294002, which is a specific PI3K/Akt inhibitor that attenuated LPS-induced iNOS and COX-2 expression by suppressing NF-kappaB activity. These data suggest that an IBS-mediated anti-inflammatory effect may be involved in suppressing the PI3K/Akt-mediated NF-kappaB signaling pathway. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Jayasooriya, Rajapaksha Gedara Prasad Tharanga AU - Jayasooriya RG AD - Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea. FAU - Lee, Kyoung-Tae AU - Lee KT AD - Division of Wood Chemistry & Microbiology, Department of Forest Products, Korea forest Research Institute, 57 Hoegiro, Dongdaemun-gu, Seoul 130-712, Republic of Korea. FAU - Kang, Chang-Hee AU - Kang CH AD - Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea. FAU - Dilshara, Matharage Gayani AU - Dilshara MG AD - Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea. FAU - Lee, Hak-Ju AU - Lee HJ AD - Division of Wood Chemistry & Microbiology, Department of Forest Products, Korea forest Research Institute, 57 Hoegiro, Dongdaemun-gu, Seoul 130-712, Republic of Korea. FAU - Choi, Yung Hyun AU - Choi YH AD - Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-050, Republic of Korea. FAU - Choi, Il-Whan AU - Choi IW AD - Department of Microbiology, College of Medicine, Inje University, Busan 614-735 Republic of Korea. Electronic address: cihima@inje.ac.kr. FAU - Kim, Gi-Young AU - Kim GY AD - Department of Marine Life Sciences, Jeju National University, Jeju 690-756, Republic of Korea. Electronic address: immunkim@jejunu.ac.kr. LA - eng PT - Journal Article DEP - 20141007 PL - United States TA - Nutr Res JT - Nutrition research (New York, N.Y.) JID - 8303331 RN - 0 (Antioxidants) RN - 0 (Inflammation Mediators) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (Naphthoquinones) RN - 0 (Plant Extracts) RN - 0 (Pyrrolidines) RN - 0 (Thiocarbamates) RN - 0 (isobutyrylshikonin) RN - 25769-03-3 (pyrrolidine dithiocarbamic acid) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (NOS2 protein, human) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Antioxidants/pharmacology MH - Cell Line MH - Central Nervous System Diseases/drug therapy/metabolism MH - Cyclooxygenase 2/metabolism MH - Dinoprostone/*biosynthesis MH - Down-Regulation MH - Inflammation/chemically induced/drug therapy/*metabolism MH - Inflammation Mediators/metabolism MH - Lipopolysaccharides MH - Lithospermum/*chemistry MH - Macrophages/drug effects/metabolism MH - Microglia/*drug effects/metabolism MH - NF-kappa B/*metabolism MH - Naphthoquinones/isolation & purification/*pharmacology/therapeutic use MH - Nitric Oxide/*biosynthesis MH - Nitric Oxide Synthase Type II/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation MH - Phytotherapy MH - Plant Extracts/chemistry/pharmacology/therapeutic use MH - Proto-Oncogene Proteins c-akt/metabolism MH - Pyrrolidines/pharmacology MH - Signal Transduction MH - Thiocarbamates/pharmacology OTO - NOTNLM OT - Isobutyrylshikonin OT - Nitric oxide OT - Nuclear factor-kappaB OT - PI3K/Akt OT - Prostaglandin E(2) EDAT- 2014/12/03 06:00 MHDA- 2015/07/29 06:00 CRDT- 2014/12/03 06:00 PHST- 2013/11/26 00:00 [received] PHST- 2014/09/29 00:00 [revised] PHST- 2014/10/02 00:00 [accepted] PHST- 2014/12/03 06:00 [entrez] PHST- 2014/12/03 06:00 [pubmed] PHST- 2015/07/29 06:00 [medline] AID - S0271-5317(14)00199-7 [pii] AID - 10.1016/j.nutres.2014.10.002 [doi] PST - ppublish SO - Nutr Res. 2014 Dec;34(12):1111-9. doi: 10.1016/j.nutres.2014.10.002. Epub 2014 Oct 7.