Pharmacodynamics simulation of HOEC by a computational model of arachidonic acid metabolic network

doi:10.1007/s40484-018-0163-4

Quant. Biol.

2019, Vol. 7

Issue (1) : 30-41 https://doi.org/10.1007/s40484-018-0163-4

RESEARCH ARTICLE

Pharmacodynamics simulation of HOEC by a computational model of arachidonic acid metabolic network

Wen Yang¹, Xia Wang¹, Kenan Li², Yuanru Liu¹, Ying Liu²(

), Rui Wang¹(

), Honglin Li¹(

)

¹. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
². BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China

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Abstract

Background: Arachidonic acid (AA) metabolic network is activated in the most inflammatory related diseases, and small-molecular drugs targeting AA network are increasingly available. However, side effects of above mentioned drugs have always been the biggest obstacle. (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a natural product acted as an inhibitor of 5-lipoxygenase (5-LOX) and 15-LOX in vitro, exhibited weaker therapeutic effect in high dose than that in low dose to collagen induced arthritis (CIA) rats. In this study, we tried to elucidate the potential regulatory mechanism by using quantitative pharmacology.

Methods: First, we generated an experimental data set by monitoring the dynamics of AA metabolites’ concentration in A23187 stimulated and different doses of HOEC co-incubated RAW264.7. Then we constructed a dynamic model of A23187-stimulated AA metabolic model to evaluate how a model-based simulation of AA metabolic data assists to find the most suitable treatment dose by predicting the pharmacodynamics of HOEC.

Results: Compared to the experimental data, the model could simulate the inhibitory effect of HOEC on 5-LOX and 15-LOX, and reproduced the increase of the metabolic flux in the cyclooxygenase (COX) pathway. However, a concomitant, early-stage of stimulation-related decrease of prostaglandins (PGs) production in HOEC incubated RAW264.7 cells was not simulated in the model.

Conclusion: Using the model, we predict that higher dose of HOEC disrupts the flux balance in COX and LOX of the AA network, and increased COX flux can interfere the curative effects of LOX inhibitor on resolution of inflammation which is crucial for the efficient and safe drug design.

Keywords arachidonic acid metabolic network computational model anti-inflammation natural product

Corresponding Author(s): Ying Liu,Rui Wang,Honglin Li

Just Accepted Date: 06 December 2018 Online First Date: 19 December 2018 Issue Date: 22 March 2019

Cite this article:

Wen Yang,Xia Wang,Kenan Li, et al. Pharmacodynamics simulation of HOEC by a computational model of arachidonic acid metabolic network[J]. Quant. Biol., 2019, 7(1): 30-41.

URL:

https://academic.hep.com.cn/qb/EN/10.1007/s40484-018-0163-4
https://academic.hep.com.cn/qb/EN/Y2019/V7/I1/30

Fig.1 A23187 induced AA metabolites changes in RAW264.7 macrophage.

Fig.2 Effect of HOEC on A23187 stimulated flux changes of AA metabolites in RAW264.7 cells.

Fig.3 The topological structure of AA metabolic network in mouse macrophages RAW264.7.

Fig.4 Simulation of model of AA metabolic network in RAW264.7.

Fig.5 Flux analysis of the four main pathways in the AA metabolic network modulated by HOEC (50 mM).

1	P.Libby, (2007) Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr. Rev., 65, S140–S146 https://doi.org/10.1301/nr.2007.dec.S140-S146. pmid: 18240538
2	P.Davies, , P. J. Bailey, , M. M.Goldenberg, and A. W.Ford-Hutchinson, (1984) The role of arachidonic acid oxygenation products in pain and inflammation. Annu. Rev. Immunol., 2, 335–357 https://doi.org/10.1146/annurev.iy.02.040184.002003. pmid: 6100476
3	J.Marx, (2004) Cancer research: inflammation and cancer: the link grows stronger. Science, 306, 966–968 https://doi.org/10.1126/science.306.5698.966. pmid: 15528423
4	P.Needleman, , J. Truk, , B. A.Jakschik, , A. R.Morrison, and J. B.Lefkowith, (1986) Arachidonic acid metabolism. Annu. Rev. Biochem., 55, 69–102 https://doi.org/10.1146/annurev.bi.55.070186.000441. pmid: 3017195
5	H.Kühn, and V. B.O’Donnell, (2006) Inflammation and immune regulation by 12/15-lipoxygenases. Prog. Lipid Res., 45, 334–356 https://doi.org/10.1016/j.plipres.2006.02.003. pmid: 16678271
6	R. J.Harvey, , U. B.Depner, , H.Wässle, , S.Ahmadi, , C.Heindl, , H.Reinold, , T. G.Smart, , K.Harvey, , B.Schütz, , O. M.Abo-Salem, , et al. (2004) GlyR α3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science, 304, 884–887 https://doi.org/10.1126/science.1094925. pmid: 15131310
7	J.Guay, , K. Bateman, , R.Gordon, , J.Mancini, and D.Riendeau, (2004) Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of microsomal PGE2 synthase-1. J. Biol. Chem., 279, 24866–24872 https://doi.org/10.1074/jbc.M403106200. pmid: 15044444
8	M.Nakanishi, and D. W.Rosenberg, (2013) Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol., 35, 123–137 https://doi.org/10.1007/s00281-012-0342-8. pmid: 22996682
9	J. B.Smith, , H. Araki, and A. M.Lefer, (1980) Thromboxane A2, prostacyclin and aspirin: effects on vascular tone and platelet aggregation. Circulation, 62, V19–V25 pmid: 7002350.
10	K. V.Honn, , B. Cicone, and A.Skoff, (1981) Prostacyclin: a potent antimetastatic agent. Science, 212, 1270–1272 https://doi.org/10.1126/science.7015512. pmid: 7015512
11	J. U.Scher, and M. H.Pillinger, (2005) 15d-PGJ2: the anti-inflammatory prostaglandin? Clin. Immunol., 114, 100–109 https://doi.org/10.1016/j.clim.2004.09.008. pmid: 15639643
12	J.Palmblad, , C. L. Malmsten, , A. M.Udén, , O.Rådmark, , L.Engstedt, and B.Samuelsson, (1981) Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence. Blood, 58, 658–661 pmid: 6266432.
13	Z.Csoma, , S. A. Kharitonov, , B.Balint, , A.Bush, , N. M.Wilson, and P. J.Barnes, (2002) Increased leukotrienes in exhaled breath condensate in childhood asthma. Am. J. Respir. Crit. Care Med., 166, 1345–1349 https://doi.org/10.1164/rccm.200203-233OC. pmid: 12406853
14	M.Peters-Golden, , M. M.Gleason, and A. Togias, (2006) Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis. Clin. Exp. Allergy, 36, 689–703 https://doi.org/10.1111/j.1365-2222.2006.02498.x. pmid: 16776669
15	S.Sozzani, , D. Zhou, , M.Locati, , S.Bernasconi, , W.Luini, , A.Mantovani, and J. T.O’Flaherty, (1996) Stimulating properties of 5-oxo-eicosanoids for human monocytes: synergism with monocyte chemotactic protein-1 and -3. J. Immunol., 157, 4664–4671 pmid: 8906847.
16	K. D.Rainsford, (1999) Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Am. J. Med., 107, 27–35 https://doi.org/10.1016/S0002-9343(99)00365-4. pmid: 10628591
17	B. M.Psaty, and C. D.Furberg, (2005) COX-2 inhibitors–lessons in drug safety. N. Engl. J. Med., 352, 1133–1135 https://doi.org/10.1056/NEJMe058042. pmid: 15713946
18	D.Singh, (2004) Merck withdraws arthritis drug worldwide. BMJ, 329, 816.2 https://doi.org/10.1136/bmj.329.7470.816-a. pmid: 15472245
19	W.Berger, , M. T. De Chandt, and C. B.Cairns, (2007) Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int. J. Clin. Pract., 61, 663–676 https://doi.org/10.1111/j.1742-1241.2007.01320.x. pmid: 17394438
20	C.Pergola, and O.Werz, (2010) 5-Lipoxygenase inhibitors: a review of recent developments and patents. Expert Opin. Ther. Pat., 20, 355–375 https://doi.org/10.1517/13543771003602012. pmid: 20180620
21	A.Bertolini, , A. Ottani, and M.Sandrini, (2001) Dual acting anti-inflammatory drugs: a reappraisal. Pharmacol. Res., 44, 437–450 https://doi.org/10.1006/phrs.2001.0872. pmid: 11735348
22	H.Kitano, (2007) A robustness-based approach to systems-oriented drug design. Nat. Rev. Drug Discov., 6, 202–210 https://doi.org/10.1038/nrd2195. pmid: 17318209
23	K.Yang, , W. Ma, , H.Liang, , Q.Ouyang, , C.Tang, and L.Lai, (2007) Dynamic simulations on the arachidonic acid metabolic network. PLOS Comput. Biol., 3, e55 https://doi.org/10.1371/journal.pcbi.0030055. pmid: 17381237
24	H.Meng, , Y. Liu, and L.Lai, (2015) Diverse ways of perturbing the human arachidonic acid metabolic network to control inflammation. Acc. Chem. Res., 48, 2242–2250 https://doi.org/10.1021/acs.accounts.5b00226. pmid: 26237215
25	Y. Q.Su, , W. D. Zhang, , C.Zhang, , R. H.Liu, and Y. H.Shen, (2008) A new caffeic ester from Incarvillea mairei var. granditlora (Wehrhahn) Grierson. Chin. Chem. Lett., 19, 829–831 https://doi.org/10.1016/j.cclet.2008.05.003.
26	L.Li, , H. Zeng, , F.Liu, , J.Zhang, , R.Yue, , W.Lu, , X. Yuan, , W.Dai, , H.Yuan, , Q.Sun, , et al. (2012) Target identification and validation of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate, an anti-inflammatory natural product. Eur. J. Inflamm., 10, 297–309 https://doi.org/10.1177/1721727X1201000306.
27	M. W.Buczynski, , D. L.Stephens, , R. C.Bowers-Gentry, , A.Grkovich, , R. A.Deems, and E. A.Dennis, (2007) TLR-4 and sustained calcium agonists synergistically produce eicosanoids independent of protein synthesis in RAW264.7 cells. J. Biol. Chem., 282, 22834–22847 https://doi.org/10.1074/jbc.M701831200. pmid: 17535806
28	C. C.Leslie, (2015) Cytosolic phospholipase A2: physiological function and role in disease. J. Lipid Res., 56, 1386–1402 https://doi.org/10.1194/jlr.R057588. pmid: 25838312
29	P.Christmas, , B. M. Weber, , M.McKee, , D.Brown, and R. J.Soberman, (2002) Membrane localization and topology of leukotriene C4 synthase. J. Biol. Chem., 277, 28902–28908 https://doi.org/10.1074/jbc.M203074200. pmid: 12023288
30	C. D.Funk, (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science, 294, 1871–1875 https://doi.org/10.1126/science.294.5548.1871. pmid: 11729303
31	Z.Honda, , M. Nakamura, , I.Miki, , M.Minami, , T.Watanabe, , Y.Seyama, , H.Okado, , H.Toh, , K.Ito, , T.Miyamoto, , et al. (1991) Cloning by functional expression of platelet-activating factor receptor from guinea-pig lung. Nature, 349, 342–346 https://doi.org/10.1038/349342a0. pmid: 1846231
32	J. K.Horton, , A. S.Williams, , Z.Smith-Phillips, , R. C.Martin, and G.O’Beirne, (1999) Intracellular measurement of prostaglandin E2: effect of anti-inflammatory drugs on cyclooxygenase activity and prostanoid expression. Anal. Biochem., 271, 18–28 https://doi.org/10.1006/abio.1999.4118. pmid: 10361000
33	R. M.Kramer, , E. F.Roberts, , S. L.Um, , A. G.Börsch-Haubold, , S. P.Watson, , M. J.Fisher, and J. A.Jakubowski, (1996) p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2. J. Biol. Chem., 271, 27723–27729 https://doi.org/10.1074/jbc.271.44.27723. pmid: 8910365
34	O.Kozawa, , H. Tokuda, , H.Matsuno, and T.Uematsu, (1999) Involvement of p38 mitogen-activated protein kinase in basic fibroblast growth factor-induced interleukin-6 synthesis in osteoblasts. J. Cell. Biochem., 74, 479–485 https://doi.org/10.1002/(SICI)1097-4644(19990901)74:3<479::AID-JCB15>3.0.CO;2-9. pmid: 10412048
35	H.Tokuda, , O. Kozawa, and T.Uematsu, (2000) Basic fibroblast growth factor stimulates vascular endothelial growth factor release in osteoblasts: divergent regulation by p42/p44 mitogen-activated protein kinase and p38 mitogen-activated protein kinase. J. Bone Miner. Res., 15, 2371–2379 https://doi.org/10.1359/jbmr.2000.15.12.2371. pmid: 11127202
36	J.-N.Shen, , L.-X. Xu, , L.Shan, , W.-D.Zhang, , H.-L.Li, and R.Wang, (2015) Neuroprotection of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate against hydrogen peroxide and lipopolysaccharide induced injury via modulating arachidonic acid network and p38-MAPK signaling. Curr. Alzheimer Res., 12, 892–902 https://doi.org/10.2174/156720501209151019111244. pmid: 26510982
37	M.Kanehisa, , S. Goto, , M.Hattori, , K. F.Aoki-Kinoshita, , M.Itoh, , S.Kawashima, , T.Katayama, , M.Araki, and M.Hirakawa, (2006) From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res., 34, D354–D357 https://doi.org/10.1093/nar/gkj102. pmid: 16381885
38	I.Schomburg, , A. Chang, , C.Ebeling, , M.Gremse, , C.Heldt, , G.Huhn, and D.Schomburg, (2004) BRENDA, the enzyme database: updates and major new developments. Nucleic Acids Res., 32, D431–D433 https://doi.org/10.1093/nar/gkh081. pmid: 14681450
39	K.Yang, , H. Bai, , Q.Ouyang, , L.Lai, and C.Tang, (2008) Finding multiple target optimal intervention in disease-related molecular network. Mol. Syst. Biol., 4, 228 https://doi.org/10.1038/msb.2008.60. pmid: 18985027
40	P.Csermely, , T. Korcsmáros, , H. J.Kiss, , G.London, and R.Nussinov, (2013) Structure and dynamics of molecular networks: a novel paradigm of drug discovery. A comprehensive review. Pharmacol. Ther., 138, 333–408 https://doi.org/10.1016/j.pharmthera.2013.01.016. pmid: 23384594
41	A.Rossi, , C. Pergola, , A.Koeberle, , M.Hoffmann, , F.Dehm, , P.Bramanti, , S.Cuzzocrea, , O.Werz, and L.Sautebin, (2010) The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages. Br. J. Pharmacol., 161, 555–570 https://doi.org/10.1111/j.1476-5381.2010.00930.x. pmid: 20880396
42	M. M.-Y.Chan, , A. R.Moore, (2010) Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E(2)-mediated lipoxin A(4) Production. J. Immunol., 184, 6418–6426
43	R.Rajakariar, , M. M. Yaqoob, and D. W.Gilroy, (2006) COX-2 in inflammation and resolution. Mol. Interv., 6, 199–207 https://doi.org/10.1124/mi.6.4.6. pmid: 16960142
44	K.Seibert, , Y. Zhang, , K.Leahy, , S.Hauser, , J.Masferrer, , W.Perkins, , L.Lee, and P.Isakson, (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc. Natl. Acad. Sci. USA, 91, 12013–12017 https://doi.org/10.1073/pnas.91.25.12013. pmid: 7991575
45	B.Samuelsson, , S. E. Dahlén, , J. A.Lindgren, , C. A.Rouzer, and C. N.Serhan, (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science, 237, 1171–1176 https://doi.org/10.1126/science.2820055. pmid: 2820055
46	C. A.Dinarello, (2000) Proinflammatory cytokines. Chest, 118, 503–508 https://doi.org/10.1378/chest.118.2.503. pmid: 10936147
47	B. J.Pettus, , A.Bielawska, , S.Spiegel, , P.Roddy, , Y. A.Hannun, and C. E.Chalfant, (2003) Ceramide kinase mediates cytokine- and calcium ionophore-induced arachidonic acid release. J. Biol. Chem., 278, 38206–38213 https://doi.org/10.1074/jbc.M304816200. pmid: 12855693
48	D.Piomelli, (1993) Arachidonic acid in cell signaling. Curr. Opin. Cell Biol., 5, 274–280 https://doi.org/10.1016/0955-0674(93)90116-8. pmid: 7685181
49	G.De Micheli, and L.Benini, (2006) Networks on Chips: Technology and Tools. Academic Press.
50	L.Benini, , G. De Micheli, (2002) Networks on chips: A new SoC paradigm. Computer, 35, 70–78
51	A. L.Hopkins, (2008) Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol., 4, 682–690 https://doi.org/10.1038/nchembio.118. pmid: 18936753
52	X.Wang, , C. Terfve, , J. C.Rose, and F.Markowetz, (2011) HTSanalyzeR: an R/Bioconductor package for integrated network analysis of high-throughput screens. Bioinformatics, 27, 879–880 https://doi.org/10.1093/bioinformatics/btr028. pmid: 21258062
53	S.Zhao, and R. Iyengar, (2012) Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. Annu. Rev. Pharmacol. Toxicol., 52, 505–521 https://doi.org/10.1146/annurev-pharmtox-010611-134520. pmid: 22235860
54	J.Walpole, , J. A. Papin, and S. M.Peirce, (2013) Multiscale computational models of complex biological systems. Annu. Rev. Biomed. Eng., 15, 137–154 https://doi.org/10.1146/annurev-bioeng-071811-150104. pmid: 23642247
55	S.Gupta, , M. R. Maurya, , D. L.Stephens, , E. A.Dennis, and S.Subramaniam, (2009) An integrated model of eicosanoid metabolism and signaling based on lipidomics flux analysis. Biophys. J., 96, 4542–4551 https://doi.org/10.1016/j.bpj.2009.03.011. pmid: 19486676
56	Y.Kihara, , S. Gupta, , M. R.Maurya, , A.Armando, , I.Shah, , O.Quehenberger, , C. K.Glass, , E. A.Dennis, and S.Subramaniam, (2014) Modeling of eicosanoid fluxes reveals functional coupling between cyclooxygenases and terminal synthases. Biophys. J., 106, 966–975 https://doi.org/10.1016/j.bpj.2014.01.015. pmid: 24559999
57	K.Yang, , W. Ma, , H.Liang, , Q.Ouyang, , C.Tang, and L.Lai, (2007) Dynamic simulations on the arachidonic acid metabolic network. PLOS Comput. Biol., 3, e55 https://doi.org/10.1371/journal.pcbi.0030055. pmid: 17381237
58	K.Yang, , H. Bai, , Q.Ouyang, , L.Lai, and C.Tang, (2008) Finding multiple target optimal intervention in disease-related molecular network. Mol. Syst. Biol., 4, 228 https://doi.org/10.1038/msb.2008.60. pmid: 18985027
59	A.Fajmut, , D. Schäfer, , M.Brumen, , A.Dobovišek, , N.Antić, and T.Emeršič, (2015) Dynamic model of eicosanoid production with special reference to non-steroidal anti-inflammatory drug-triggered hypersensitivity. IET Syst. Biol., 9, 204–215 https://doi.org/10.1049/iet-syb.2014.0037. pmid: 26405144

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