Diketopiperazines, natural products found in bacteria, fungi, marine sponges, gorgonian and red algae, 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. The expression of secretory group IIA phospholipase A2 (sPLA2-IIA) is enhanced by development of inflammatory disorders. Aim of this study is to determine the effects of diketopiperazines on the secretion and activity of sPLA2-IIA by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVECs). To do this, sPLA2-IIA expression was induced in the LPS-stimulated HUVECs and mice to evaluate the effect of diketopiperazines. Results showed that diketopiperazines remarkably suppressed the LPS-mediated protein expression and activity of sPLA2-IIA via inhibition of phosphorylation of cytosolic phospholipase A2 (cPLA2) and extracellular signal-regulated kinase (ERK) 1/2. These results demonstrated that diketopiperazines might play an important role in the modulation of sPLA2-IIA expression and activity in response to the inflammatory diseases.
SixDA, DennisEA. (2000) The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochimica et Biophysica Acta, 1488, 1–19.
DennisEA. (1997) The growing phospholipase A2 superfamily of signal transduction enzymes. Trends in Biochemical Sciences, 22, 1–2.
4.
MenschikowskiM, HagelgansA, SiegertG. (2006) Secretory phospholipase A2 of group IIA: is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases?Prostaglandins & Other Lipid Mediators, 79, 1–33.
5.
OkaS, AritaH. (1991) Inflammatory factors stimulate expression of group II phospholipase A2 in rat cultured astrocytes. Two distinct pathways of the gene expression. Journal of Biological Chemistry, 266, 9956–9960.
6.
PruzanskiW, VadasP. (1991) Phospholipase A2–a mediator between proximal and distal effectors of inflammation. Immunology Today, 12, 143–146.
7.
CrowlRM, StollerTJ, ConroyRR, StonerCR. (1991) Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute phase response. Journal of Biological Chemistry, 266, 2647–2651.
8.
WaydhasC, Nast-KolbD, DuswaldKH, LehnertPSchweibererL. (1989) Prognostic value of serum phospholipase A in the multitraumatized patient. Wiener klinische Wochenschrift, 67, 203–206.
9.
NakanoT, OharaO, TeraokaH, AritaH. (1990) Glucocorticoids suppress group II phospholipase A2 production by blocking mRNA synthesis and post-transcriptional expression. Journal of Biological Chemistry, 265, 12745–12748.
10.
KuwataH, NakataniY, MurakamiM, KudoI. (1998) Cytosolic phospholipase A2 is required for cytokine-induced expression of type IIA secretory phospholipase A2 that mediates optimal cyclooxygenase-2-dependent delayed prostaglandin E2 generation in rat 3Y1 fibroblasts. Journal of Biological Chemistry, 273, 1733–1740.
11.
MurakamiM, ShimbaraS, KambeT, KuwataH, WinsteadMV, TischfieldJA, KudoI. (1998) The functions of five distinct mammalian phospholipase A2S in regulating arachidonic acid release. Type IIa and type V secretory phospholipase A2S are functionally redundant and act in concert with cytosolic phospholipase A2. Journal of Biological Chemistry, 273, 14411–14423.
12.
MounierCM, HackengTM, SchaefferF, FaureG, BonC, GriffinJH. (1998) Inhibition of prothrombinase by human secretory phospholipase A2 involves binding to factor Xa. Journal of Biological Chemistry, 273, 23764–23772.
13.
HuangRM, YiXX, ZhouY, SuX, PengY, GaoCH. (2014) An update on 2,5-diketopiperazines from marine organisms. Marine Drugs, 12, 6213–6235.
14.
WangY, WangP, MaH, ZhuW. (2013) Developments around the bioactive diketopiperazines: a patent review. Expert Opinion on Therapeutic Patents, 23, 1415–1433.
15.
CuongPVCucNTKQuyenVTBinhPTKiemPVNamNH, DatNT. (2015) Antimicrobial constituents from the Bacillus megaterium LC isolated from marine sponge Haliclona oculata. Natural Product Sciences, 21, 202–205.
16.
ParkSH, StrobelGA. (1994) Cellular protein receptors of maculosin, a host specific phytotoxin of spotted knapweed (Centaurea maculosa L.). Biochimica et Biophysica Acta, 1199, 13–19.
17.
AdamczeskiM, ReedAR, CrewsP. (1995) New and known diketopiperazines from the Caribbean sponge, Calyx cf. podatypa. Journal of Natural Products, 58, 201–208.
18.
DiehlKH, HullR, MortonD, PfisterR, RabemampianinaY, SmithD, VidalJM, van de VorstenboschC. (2001) A good practice guide to the administration of substances and removal of blood, including routes and volumes. Journal of Applied Toxicology, 21, 15–23.
19.
BalsindeJ, BalboaMA, InselPA, DennisEA. (1999) Regulation and inhibition of phospholipase A2. Annual Review of Pharmacology and Toxicology, 39, 175–189.
20.
BradleyJD, DmitrienkoAA, KivitzAJ, GluckOS, WeaverAL, WiesenhutterC, MyersSL, SidesGD. (2005) A randomized, double-blinded, placebo-controlled clinical trial of LY333013, a selective inhibitor of group II secretory phospholipase A2, in the treatment of rheumatoid arthritis. The Journal of Rheumatology, 32, 417–423.
21.
TanakaK, KatoT, MatsumotoK, YoshidaT. (1993) Anti-inflammatory action of thielocin A1 beta, a group II phospholipase A2 specific inhibitor, in rat carrageenan-induced pleurisy. Inflammation, 17, 107–119.
22.
VadasP, PruzanskiW, KimJ, FornasierV. (1989) The proinflammatory effect of intra-articular injection of soluble human and venom phospholipase A2. American Journal of Pathology, 134, 807–811.
23.
ZeiherBG, SteingrubJ, LaterrePF, DmitrienkoA, FukiishiY, AbrahamE. (2005) LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis. Critical Care Medicine, 33, 1741–1748.
24.
StierleAC, CardellinaJH, StrobelGA. (1988) Maculosin, a host-specific phytotoxin for spotted knapweed from Alternaria alternata. Proceedings of the National Academy of Sciences of the United States of America, 85, 8008–8011.
25.
FdhilaF, VazquezV, SanchezJL, RigueraR. (2003) dd-diketopiperazines: antibiotics active against Vibrio anguillarum isolated from marine bacteria associated with cultures of Pecten maximus. Journal of Natural Products, 66, 1299–1301.
26.
JayatilakeGS, ThorntonMP, LeonardAC, GrimwadeJE, BakerBJ. (1996) Metabolites from an Antarctic sponge-associated bacterium, Pseudomonas aeruginosa. Journal of Natural Products, 59, 293–296.
27.
LeeW, SeoJ, KwakS, ParkEJ, NaDH, KimS, LeeYM, KimIS, BaeJS., (2015) A double-chambered protein nanocage loaded with thrombin receptor agonist peptide (TRAP) and gamma-carboxyglutamic acid of protein C (PC-Gla) for sepsis treatment. Advanced Materials, 27, 6637–6643.
28.
BaeJS, LeeW, NamJO, KimJE, KimSW, KimIS. (2014) Transforming growth factor beta-induced protein promotes severe vascular inflammatory responses. American Journal of Respiratory and Critical Care Medicine, 189, 779–786.
29.
KuSK, BaeJS. (2014) Antiplatelet and antithrombotic activities of purpurogallin in vitro and in vivo.BMB Reports, 47, 376–381.
30.
KuSK, YoonEK, LeeHG, HanMS, LeeT, BaeJS. (2015) Inhibitory effects of lysozyme on endothelial protein C receptor shedding in vitro and in vivo. BMB Reports, 48, 624–629.
31.
YoonEK, KuSK, LeeW, KwakS, KangH, JungB, BaeJS. (2015) Antitcoagulant and antiplatelet activities of scolymoside. BMB Reports, 48, 577–582.
32.
KuSK, LeeHG, BaeJS. (2015) Inhibitory effect of baicalin, baicalein and wogonin on secretory group IIA phospholipase A2. Archives of Pharmacal Research, 38, 1865–1872.
33.
KuSK, LeeW, KangM, BaeJS. (2015) Antithrombotic activities of aspalathin and nothofagin via inhibiting platelet aggregation and FIIa/FXa. Archives of Pharmacal Research, 38, 1080–1089.
34.
LeeW, KuSK, BaeJS. (2015) Antiplatelet, anticoagulant, and profibrinolytic activities of baicalin. Archives of Pharmacal Research, 38, 893–903.
35.
RittirschD, Huber-LangMS, FlierlMA, WardPA. (2009) Immunodesign of experimental sepsis by cecal ligation and puncture. Nature Protocols, 4, 31–36.
36.
ShimoyamaY, SakamotoR, AkaboshiT, TanakaM, OhtsukiK. (2001) Characterization of secretory type IIA phospholipase A2 (sPLA2-IIA) as a glycyrrhizin (GL)-binding protein and the GL-induced inhibition of the CK-II-mediated stimulation of sPLA2-IIA activity in vitro. Biological and Pharmaceutical Bulletin, 24, 1004–1008.
