Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Xanthine Oxidase Inhibitory Activity of Euphorbia peplus L. Phenolics

Author(s): Emadeldin M. Kamel, Noha A. Ahmed, Ashraf A. El-Bassuony, Omnia E. Hussein, Barakat Alrashdi, Sayed A. Ahmed, Al Mokhtar Lamsabhi, Hany H. Arab and Ayman M. Mahmoud*

Volume 25, Issue 8, 2022

Published on: 09 June, 2021

Page: [1336 - 1344] Pages: 9

DOI: 10.2174/1386207324666210609104456

Price: $65

conference banner
Abstract

Background: Various phenolics show inhibitory activity towards xanthine oxidase (XO), an enzyme that generates reactive oxygen species which cause oxidative damage.

Objective: This study investigated the XO inhibitory activity of Euphorbia peplus phenolics.

Methods: The dried powdered aerial parts of E. peplus were extracted, fractioned and phenolics were isolated and identified. The XO inhibitory activity of E. peplus extract (EPE) and the isolated phenolics was investigated in vitro and in vivo.

Results: Three phenolics were isolated from the ethyl acetate fraction of E. peplus. All isolated compounds and the EPE showed inhibitory activity towards XO in vitro. In hyperuricemic rats, EPE and the isolated phenolics decreased uric acid and XO activity. Molecular docking showed the binding modes of isolated phenolics with XO, depicting significant interactions with the active site amino acid residues. Molecular dynamics simulation trajectories confirmed the interaction of isolated phenolics with XO by forming hydrogen bonds with the active site residues. Also, the root mean square (RMS) deviations of XO and phenolics-XO complexes achieved equilibrium and fluctuated during the 10 ns MD simulations. The radius of gyration and solvent accessible surface area investigations showed that different systems were stabilized at ≈ 2500 ps. The RMS fluctuations profile depicted that the drug binding site exhibited a rigidity behavior during the simulation.

Conclusion: In vitro, in vivo and computational investigations showed the XO inhibitory activity of E. peplus phenolics. These phenolics might represent promising candidates for the development of XO inhibitors.

Keywords: Xanthine oxidase, docking, molecular dynamics simulations, phenolics, oxidative stress, ROS.

« Previous Next »
Graphical Abstract

[1]
Enroth, C.; Eger, B.T.; Okamoto, K.; Nishino, T.; Nishino, T.; Pai, E.F. Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion. PNAS, 2000, 97(20), 10723-10728.
[http://dx.doi.org/10.1073/pnas.97.20.10723]
[2]
Santi, M.D.; Zunini, M.P.; Vera, B.; Bouzidi, C.; Dumontet, V.; Abin-Carriquiry, A.; Grougnet, R.; Ortega, M.G. Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (Rubiaceae) in vitro and molecular docking studies. Eur. J. Med. Chem., 2018, 143, 577-582.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.071]
[3]
Hozayen, W.G.; Mahmoud, A.M.; Desouky, E.M.; El-Nahass, E-S.; Soliman, H.A.; Farghali, A.A. Cardiac and pulmonary toxicity of mesoporous silica nanoparticles is associated with excessive ROS production and redox imbalance in Wistar rats. Biomed. Pharmacother., 2019, 109, 2527-2538.
[http://dx.doi.org/10.1016/j.biopha.2018.11.093] [PMID: 30551513]
[4]
Mahmoud, A.M.; Hussein, O.E.; Abd El-Twab, S.M.; Hozayen, W.G. Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPAR and suppression of NF-B/NLRP3 inflammasome axis. Food Funct., 2019, 10(8), 4593-4607.
[http://dx.doi.org/10.1039/C9FO00114J] [PMID: 31289794]
[5]
Toral, M; Romero, M; Jiménez, R; Mahmoud, AM; Barroso, E; Gómez-Guzmán, M; Sánchez, M; Cogolludo, Á; García-Redondo, AB; Briones, AM; Vázquez-Carrera, M; Pérez-Vizcaíno, F; Duarte, J Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipidinduced endothelial dysfunction. Clin Sci (Lond) 2015, Nov;129(9), 823-37.
[http://dx.doi.org/10.1042/CS20150111] [PMID: 26253087]
[6]
Jimenez, R.; Toral, M.; Gómez-Guzmán, M.; Romero, M.; Sanchez, M.; Mahmoud, A.M.; Duarte, J. The role of Nrf2 signaling in PPARβ/δ-mediated vascular protection against hyperglycemia-induced oxidative stress. Oxid. Med. Cell. Longev., 2018, 2018, 5852706.
[http://dx.doi.org/10.1155/2018/5852706] [PMID: 30046379]
[7]
Halliwell, B.; Gutteridge, J.M. Free radicals in biology and medicine; Oxford University Press: USA, 2015.
[http://dx.doi.org/10.1093/acprof:oso/9780198717478.001.0001]
[8]
Kamel, E.M.; Mahmoud, A.M.; Ahmed, S.A.; Lamsabhi, A.M. A phytochemical and computational study on flavonoids isolated from Trifolium resupinatum L. and their novel hepatoprotective activity. Food Funct., 2016, 7(4), 2094-2106.
[http://dx.doi.org/10.1039/C6FO00194G] [PMID: 27053086]
[9]
Elsayed, R.H.; Kamel, E.M.; Mahmoud, A.M.; El-Bassuony, A.A.; Bin-Jumah, M.; Lamsabhi, A.M.; Ahmed, S.A. Rumex dentatus, L phenolics ameliorate hyperglycemia by modulating hepatic key enzymes of carbohydrate metabolism, oxidative stress and PPAR in diabetic rats. Food Chem. Toxicol., 2020, 138, 111202.
[10]
Mahmoud, A.M.; Abd El-Twab, S.M.; Abdel-Reheim, E.S. Consumption of polyphenol-rich Morus alba leaves extract attenuates early diabetic retinopathy: the underlying mechanism. Eur. J. Nutr., 2017, 56(4), 1671-1684.
[http://dx.doi.org/10.1007/s00394-016-1214-0] [PMID: 27059477]
[11]
Yousefian, M.; Shakour, N.; Hosseinzadeh, H.; Hayes, A.W.; Hadizadeh, F.; Karimi, G. The natural phenolic compounds as modulators of NADPH oxidases in hypertension. Phytomedicine, 2019, 55, 200-213.
[http://dx.doi.org/10.1016/j.phymed.2018.08.002] [PMID: 30668430]
[12]
Chang, W.S.; Chang, Y.H.; Lu, F.J.; Chiang, H.C. Inhibitory effects of phenolics on xanthine oxidase. Anticancer Res., 1994, 14(2A), 501-506.
[PMID: 8017853]
[13]
Nagao, A.; Seki, M.; Kobayashi, H.J.B. Inhibition of xanthine oxidase by flavonoids. Biotechnol. Biochem. Inhibit. Xanthine Oxidase Flavonoids, 1999, 63(10), 1787-1790.
[14]
Cos, P.; Ying, L.; Calomme, M.; Hu, J.P.; Cimanga, K.; Van Poel, B.; Pieters, L.; Vlietinck, A.J.; Berghe, D.V.J. Structure activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers. J. Nat. Prod., 1998, 61(1), 71-76.
[15]
Shi, Q-W.; Su, X-H.; Kiyota, H.J. Chemical and pharmacological research of the plants in genus Euphorbia. Chem. Rev., 2008, 108(10), 4295-4327.
[16]
Lahmadi, S.; Belhamra, M.; Karoune, S.; Imad, K.; Bensouici, C.; Kechebar, M.S.A.; Halis, Y.; Ksouri, R. Phenolic constituents and antioxidant activity of Euphorbia retusa Forssk. Nat. Prod. Res., 2019, 34(24), 3545-3547.
[http://dx.doi.org/10.1080/14786419.2019.1582040] [PMID: 30835550]
[17]
Zhi-Qin, S.; Shu-Zhen, M.; Ying-Tong, D.; Xiao-Jiang, H.J. A new jatrophane diterpenoid from Euphorbia peplus. Chinese J. Nat. Med., 2010, 8(2), 81-83.
[18]
Frezza, C.; Venditti, A.; Sciubba, F.; Tomai, P.; Antonetti, M.; Franceschin, M.; Di Cocco, M.E.; Gentili, A.; Delfini, M.; Serafini, M.J.; Bianco, A. Phytochemical profile of Euphorbia peplus L. collected in Central Italy and NMR semi-quantitative analysis of the diterpenoid fraction. J. Pharm. Biomed. Anal., 2018, 160, 152-159.
[19]
Jakupovic, J.; Morgenstern, T.; Bittner, M.; Silva, M.J.P. Diterpenes from Euphorbia peplus. Phytochemistry, 1998, 47(8), 1601-1609.
[http://dx.doi.org/10.1016/S0031-9422(97)00831-5]
[20]
Ramsay, J.; Suhrbier, A.; Aylward, J.; Ogbourne, S.; Cozzi, S.J.; Poulsen, M.; Baumann, K.; Welburn, P.; Redlich, G.; Parsons, P. The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers. Br. J. Dermatol., 2011, 164(3), 633-636.
[http://dx.doi.org/10.1111/j.1365-2133.2010.10184.x]
[21]
Ertas, A.; Yilmaz, M.A.; Firat, M. Chemical profile by LC–MS/MS, GC/MS and antioxidant activities of the essential oils and crude extracts of two Euphorbia species. Natural Product Res., 2015, 29(6), 529-534.
[22]
Ali, A.A.; Sayed, H.M.; Ibrahim, S.R.; Zaher, A. Chemical constituents, antimicrobial, analgesic, antipyretic, and anti-inflammatory activities of Euphorbia peplus L. Phytopharmacology, 2013, 4(1), 69-80.
[23]
Li, P.; Tian, Y.; Zhai, H.; Deng, F.; Xie, M.; Zhang, X. Study on the activity of non-purine xanthine oxidase inhibitor by 3D-QSAR modeling and molecular docking. J. Mol. Struct., 2013, 1051, 56-65.
[24]
Mohamed Isa, S.S.P.; Ablat, A.; Mohamad, J. The antioxidant and xanthine oxidase inhibitory activity of Plumeria rubra flowers. Molecules, 2018, 23(2), 400.
[http://dx.doi.org/10.3390/molecules23020400] [PMID: 29438299]
[25]
Kong, L.D.; Cai, Y.; Huang, W.W.; Cheng, C.H.K.; Tan, R.X. Inhibition of xanthine oxidase by some Chinese medicinal plants used to treat gout. J. Ethnopharmacol., 2000, 73(1-2), 199-207.
[http://dx.doi.org/10.1016/S0378-8741(00)00305-6] [PMID: 11025157]
[26]
Umamaheswari, M. AsokKumar, K.; Somasundaram, A.; Sivashanmugam, T.; Subhadradevi, V.; Ravi, T.K. Xanthine oxidase inhibitory activity of some Indian medical plants. J. Ethnopharmacol., 2007, 109(3), 547-551.
[http://dx.doi.org/10.1016/j.jep.2006.08.020] [PMID: 17014977]
[27]
Liu, L.M.; Cheng, S.F.; Shieh, P.C.; Lee, J.C.; Chen, J.J.; Ho, C.T.; Kuo, S.C.; Kuo, D.H.; Huang, L.J.; Way, T.D. The methanol extract of Euonymus laxiflorus, Rubia lanceolata and Gardenia jasminoides inhibits xanthine oxidase and reduce serum uric acid level in rats. FCT, 2014, 70, 179-184.
[28]
Stavric, B.; Clayman, S.; Gadd, R.E.; Hébert, D. Some in vivo effects in the rat induced by chlorprothixene and potassium oxonate. Pharmacol. Res. Commun., 1975, 7(2), 117-124.
[http://dx.doi.org/10.1016/S0031-6989(75)80015-4] [PMID: 1144488]
[29]
Wang, M.; Zhao, J.; Zhang, N.; Chen, J. Astilbin improves potassium oxonate-induced hyperuricemia and kidney injury through regulating oxidative stress and inflammation response in mice. Biomed. Pharmacother., 2016, 83, 975-988.
[30]
Al-Okbi, S.Y.; El-Sayed, E.M.; Ammar, N.M.; El-Sayed, N.K.; Abou-El Kassem, L.T. Effect of Ruta graveolens L. and Euphorbia peplus L. anti-inflammatory extracts on nutritional status of rats and the safety of their use. Indian J. Exp. Biol., 2002, 40(1), 45-48.
[PMID: 12561967]
[31]
Rzodkiewicz, P. Gska, E.; Gajewski, M.; Bujalska-Zadrony, M.; Szukiewicz, D.; Maliski, S. Esculetin reduces leukotriene B4 level in plasma of rats with adjuvant-induced arthritis. Reumatologia, 2016, 54(4), 161-164.
[http://dx.doi.org/10.5114/reum.2016.62469] [PMID: 27826169]
[32]
Ramezani, M.; Darbandi, N.; Khodagholi, F.; Hashemi, A. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer’s disease. Neural Regen. Res., 2016, 11(12), 1976-1980.
[http://dx.doi.org/10.4103/1673-5374.197141] [PMID: 28197195]
[33]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[34]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A., Jr; Peralta, J.E.; Ogliaro, F.; Bearpark, M.J.; Heyd, J.; Brothers, E.N.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.P.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N.J.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.; Zakrzewski, V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.; Daniels, A.D.; Farkas, Ö.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. Gaussian 09, revision D. 01; Gaussian, Inc.: Wallingford, CT, 2009.
[35]
Becke, A.D. Density functional thermochemistry. III. The role of exact exchange. J. Chem. Phys., 1993, 98(7), 5648-5652.
[http://dx.doi.org/10.1063/1.464913]
[36]
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789.
[http://dx.doi.org/10.1103/PhysRevB.37.785] [PMID: 9944570]
[37]
Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A Gen. Phys., 1988, 38(6), 3098-3100.
[http://dx.doi.org/10.1103/PhysRevA.38.3098] [PMID: 9900728]
[38]
Hehre, W.J.; Radom, L.; Schleyer, P.R.; Pople, J.A. Ab initio molecular orbital theory; Wiley: New York, 1986, Vol. 67, .
[39]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[40]
Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I. CHARMM general force field: A force field for druglike molecules compatible with the CHARMM allatom additive biological force fields. J. Comput. Chem., 2010, 31(4), 671-690.
[41]
Berendsen, H.J.; van der Spoel, D.; van Drunen, R. GROMACS: a message-passing parallel molecular dynamics implementation. Comput. Phys. Commun., 1995, 91(1-3), 43-56.
[http://dx.doi.org/10.1016/0010-4655(95)00042-E]
[42]
Lindahl, E.; Hess, B.; Van Der Spoel, D. GROMACS 3.0: a package for molecular simulation and trajectory analysis. Molecular Modeling Annual, 2001, 7(8), 306-317.
[43]
Lee, J.; Cheng, X.; Swails, J.M.; Yeom, M.S.; Eastman, P.K.; Lemkul, J.A.; Wei, S.; Buckner, J.; Jeong, J.C.; Qi, Y.J. CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J. Chem. Theory Comput., 2015, 12(1), 405-413.
[44]
Berendsen, H.; Postma, J.; Van Gunsteren, W.; Hermans, J. Intermolecular Forces; Reidel: Dordrecht, 1981.
[45]
Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput., 2008, 4(3), 435-447.
[http://dx.doi.org/10.1021/ct700301q] [PMID: 26620784]
[46]
Parrinello, M.; Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys., 1981, 52(12), 7182-7190.
[http://dx.doi.org/10.1063/1.328693]
[47]
Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N log (N) method for Ewald sums in large systems. J. Chem. Phys., 1993, 98(12), 10089-10092.
[http://dx.doi.org/10.1063/1.464397]
[48]
Essmann, U.; Perera, L.; Berkowitz, M.L.; Darden, T.; Lee, H.; Pedersen, L.G. A smooth particle mesh Ewald method. J. Chem. Phys., 1995, 103(19), 8577-8593.
[http://dx.doi.org/10.1063/1.470117]
[49]
Kim, N.M.; Kim, J.; Chung, H.Y.; Choi, J. Isolation of luteolin 7-O-rutinoside and esculetin with potential antioxidant activity from the aerial parts of Artemisia montana. Archives Pharmacal Res., 2000, 23(3), 237-239.
[50]
Nasser, A.L.; Carli, C.B.; Rodrigues, C.M.; Maia, D.C.; Carlos, I.Z.; Eberlin, M.N.; Hiruma-Lima, C.A.; Vilegas, W. Identification of ellagic acid derivatives in methanolic extracts from Qualea species. J. Nature Res. C, 2008, 63(11-12), 794-800.
[http://dx.doi.org/10.1515/znc-2008-11-1203]
[51]
Shen, C-C.; Chang, Y-S.; Ho, L. Nuclear magnetic resonance studies of 5, 7-dihydroxyflavonoids. Phytochemistry, 1993, 34(3), 843-845.
[52]
Richette, P.; Bardin, T. Gout. Lancet, 2010, 375(9711), 318-328.
[http://dx.doi.org/10.1016/S0140-6736(09)60883-7] [PMID: 19692116]
[53]
Gliozzi, M.; Malara, N.; Muscoli, S.; Mollace, V. The treatment of hyperuricemia. Int. J. Cardiol., 2016, 213, 23-27.
[http://dx.doi.org/10.1016/j.ijcard.2015.08.087] [PMID: 26320372]
[54]
Zuo, J.; Zhang, W.; Jian, H.; Bou-Chacra, N.; Löbenberg, R. Esculetin as bioactive marker: towards a rational scientific approach for the treatment of hyperuricemia using Traditional Chinese Medicine. Braz. J. Pharm. Sci., 2020, 56.
[http://dx.doi.org/10.1590/s2175-97902019000417827]
[55]
Mo, S.F.; Zhou, F.; Lv, Y.Z.; Hu, Q.H.; Zhang, D.M.; Kong, L.D. Hypouricemic action of selected flavonoids in mice: structure-activity relationships. Biol. Pharm. Bull., 2007, 30(8), 1551-1556.
[http://dx.doi.org/10.1248/bpb.30.1551] [PMID: 17666819]
[56]
Hunter, C.A. Singh, J.; Thornton, J. interactions: the geometry and energetics of phenylalanine-phenylalanine interactions in proteins. JMB, 1991, 218(4), 837-846.
[57]
Pauff, J.M.; Cao, H.; Hille, R. Substrate orientation and catalysis at the molybdenum site in xanthine oxidase crystal structures in complex with xanthine and lumazine. J. Biol. Chem., 2009, 284(13), 8760-8767.
[58]
Lin, S.; Zhang, G.; Liao, Y.; Pan, J. Inhibition of chrysin on xanthine oxidase activity and its inhibition mechanism. Int. J. Biol. Macromol., 2015, 81, 274-282.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.08.017]

Rights & Permissions Print Cite
Article Metrics
25
1
© 2024 Bentham Science Publishers | Privacy Policy