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Planta Med
DOI: 10.1055/a-2294-7042
Original Papers

Vasorelaxant Activity of (2S)-Sakuranetin and Other Flavonoids Isolated from the Green Propolis of the Caatinga Mimosa tenuiflora

Ninh The Son‡
2   Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
3   Department of Chemistry, Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Caugiay, Hanoi, Vietnam
,
Beatrice Gianibbi‡
4   Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Siena, Italy
,
Alice Panti‡
5   Dipartimento di Scienze della Vita, Università di Siena, Siena, Italy
,
Ottavia Spiga
4   Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Siena, Italy
,
Jairo Kenupp Bastos
1   School of Pharmaceutical Sciences of Ribeirão Preto, Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, Brazil
,
Fabio Fusi
4   Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Siena, Italy
› Author AffiliationsSupported by: National Council for Scientific and Technological Development (CNPq)
Supported by: São Paulo Research Foundation FAPESP, grant #2017/04138-8 and fellowship #2021/0
Supported by: Coordination for the Improvement of Higher Education Personnel (CAPES)
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Abstract

Some in vitro and in vivo evidence is consistent with the cardiovascular beneficial activity of propolis. As the single actors responsible for this effect have never been identified, an in-depth investigation of flavonoids isolated from the green propolis of the Caatinga Mimosa tenuiflora was performed and their mechanism of action was described. A comprehensive electrophysiology, functional, and molecular docking approach was applied. Most flavanones and flavones were effective CaV1.2 channel blockers with a potency order of (2S)-sakuranetin > eriodictyol-7,3′-methyl ether > quercetin 3-methyl ether > 5,4′-dihydroxy-6,7-dimethoxyflavanone > santin > axillarin > penduletin > kumatakenin, ermanin and viscosine being weak or modest stimulators. Except for eriodictyol 5-O-methyl ether, all the flavonoids were also effective spasmolytic agents of vascular rings, kumatakenin and viscosine also showing an endothelium-dependent activity. (2S)-Sakuranetin also stimulated KCa1.1 channels both in single myocytes and vascular rings. In silico analysis provided interesting insights into the mode of action of (2S)-sakuranetin within both CaV1.2 and KCa1.1 channels. The green propolis of the Caatinga Mimosa tenuiflora is a valuable source of multi-target vasoactive flavonoids: this evidence reinforces its nutraceutical value in the cardiovascular disease prevention arena.

Keywords

Green propolis - (2S)-sakuranetin - Mimosa tenuiflora - CaV1.2 channels - KCa1.1 channels - Fabaceae


Publication History

Received: 03 December 2023

Accepted after revision: 13 March 2024

Article published online:
10 April 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Toreti VC, Sato HH, Pastore GM, Park YK. Recent progress of propolis for its biological and chemical compositions and its botanical origin. Evid Based Complement Alternat Med 2013; 2013: 697390
    PubMedGoogle Scholar
  • 2 Yang H, Dong Y, Du H, Shi H, Peng Y, Li X. Antioxidant compounds from propolis collected in Anhui, China. Molecules 2011; 16 (04) 3444-3455
    PubMedGoogle Scholar
  • 3 Agüero MB, Svetaz L, Sánchez M, Luna L, Lima B, López ML, Zacchino S, Palermo J, Wunderlin D, Feresin GE, Tapia A. Argentinean Andean propolis associated with the medicinal plant Larrea nitida Cav. (Zygophyllaceae). HPLC-MS and GC-MS characterization and antifungal activity. Food Chem Toxicol 2011; 49 (09) 1970-1978
    PubMedGoogle Scholar
  • 4 Freires IA, de Alencar SM, Rosalen PL. A pharmacological perspective on the use of Brazilian Red Propolis and its isolated compounds against human diseases. Eur J Med Chem 2016; 110: 267-279
    PubMedGoogle Scholar
  • 5 Hossain R, Quispe C, Khan RA, Saikat ASM, Ray P, Ongalbek D, Yeskaliyeva B, Jain D, Smeriglio A, Trombetta D, Kiani R, Kobarfard F, Mojgani N, Saffarian P, Ayatollahi SA, Sarkar C, Islam MT, Keriman D, Uçar A, Martorell M, Sureda A, Pintus G, Butnariu M, Sharifi-Rad J, Cho WC. Propolis: An update on its chemistry and pharmacological applications. Chin Med 2022; 17 (01) 100
    PubMedGoogle Scholar
  • 6 Moret S, Purcaro G, Conte LS. Polycyclic aromatic hydrocarbons (PAHs) levels in propolis and propolis-based dietary supplements from the Italian market. Food Chem 2010; 122: 333-338
    PubMedGoogle Scholar
  • 7 Mendonça L, Frota VM, Pinto BJF, dos Santos Moita EC, da Hora JP, Costa MF, Fernandes JAB, Zocolo GJ, Gomes GA, do Vale JPC, Bandeira PN, dos Santos HS, Rodrigues THS. Seasonality in the volatile oil composition of green propolis from the Caatinga biome. Rev Bras Farmacogn 2021; 31: 497-501
    PubMedGoogle Scholar
  • 8 Silva H, Francisco R, Saraiva A, Francisco S, Carrascosa C, Raposo A. The cardiovascular therapeutic potential of propolis-a comprehensive review. Biology (Basel) 2021; 10 (01) 27
    PubMedGoogle Scholar
  • 9 Son NT, Gianibbi B, Panti A, Spiga O, Bastos JK, Fusi F. 3,3′-O-Dimethylquercetin: A bi-functional vasodilator isolated from green propolis of the Caatinga Mimosa tenuiflora . Eur J Pharmacol 2024; 967: 176400
    PubMedGoogle Scholar
  • 10 Sartori AA, Son NT, da Silva Honorio M, Ripari N, Santiago KB, Gomes AM, Zambuzzi WF, Bastos JK, Sforcin JM. Effects of caatinga propolis from Mimosa tenuiflora and its constituents (santin, sakuranetin and kaempferide) on human immune cells. J Ethnopharmacol 2024; 319(Pt 2): 117297
    PubMedGoogle Scholar
  • 11 Son NT, Ribeiro VP, Bastos JK. Flavonoids from green propolis of the Northeastern Brazilian caatinga Mimosa tenuiflora (Wild.) Poir: a chemotaxonomic aspect. Biochem Syst Ecol 2022; 104: 104473
    PubMedGoogle Scholar
  • 12 Fusi F, Spiga O, Trezza A, Sgaragli G, Saponara S. The surge of flavonoids as novel, fine regulators of cardiovascular Cav channels. Eur J Pharmacol 2017; 796: 158-174 DOI: 10.1016/j.ejphar.2016.12.033.
    CrossrefPubMedGoogle Scholar
  • 13 Saponara S, Carosati E, Mugnai P, Sgaragli G, Fusi F. The flavonoid scaffold as a template for the design of modulators of the vascular Ca(v)1.2 channels. Br J Pharmacol 2011; 164 (06) 1684-1697
    PubMedGoogle Scholar
  • 14 Saponara S, Sgaragli G, Fusi F. Quercetin as a novel activator of L-type Ca(2+) channels in rat tail artery smooth muscle cells. Br J Pharmacol 2002; 135 (07) 1819-1827
    PubMedGoogle Scholar
  • 15 Kuriyama H, Kitamura K, Nabata H. Pharmacological and physiological significance of ion channels and factors that modulate them in vascular tissues. Pharmacol Rev 1995; 47 (03) 387-573
    PubMedGoogle Scholar
  • 16 Bean BP. Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Natl Acad Sci U S A 1984; 81 (20) 6388-6392
    PubMedGoogle Scholar
  • 17 McDonald TF, Pelzer S, Trautwein W, Pelzer DJ. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev 1994; 74 (02) 365-507
    PubMedGoogle Scholar
  • 18 Zhao Y, Huang G, Wu J, Wu Q, Gao S, Yan Z, Lei J, Yan N. Molecular basis for ligand modulation of a mammalian voltage-gated Ca2+ channel. Cell 2019; 177 (06) 1495-1506.e12
    PubMedGoogle Scholar
  • 19 Cuong NM, Son NT, Nhan NT, Fukuyama Y, Ahmed A, Saponara S, Trezza A, Gianibbi B, Vigni G, Spiga O, Fusi F. Vietnamese Dalbergia tonkinensis: a promising source of mono- and bifunctional vasodilators. Molecules 2022; 27 (14) 4505
    PubMedGoogle Scholar
  • 20 Fusi F, Cavalli M, Mulholland D, Crouch N, Coombes P, Dawson G, Bova S, Sgaragli G, Saponara S. Cardamonin is a bifunctional vasodilator that inhibits Ca(v)1.2 current and stimulates K(Ca)1.1 current in rat tail artery myocytes. J Pharmacol Exp Ther 2010; 332 (02) 531-540
    PubMedGoogle Scholar
  • 21 Gurney AM. Mechanisms of drug-induced vasodilation. J Pharm Pharmacol 1994; 46 (04) 242-251
    PubMedGoogle Scholar
  • 22 Gessner G, Cui YM, Otani Y, Ohwada T, Soom M, Hoshi T, Heinemann SH. Molecular mechanism of pharmacological activation of BK channels. Proc Natl Acad Sci U S A 2012; 109 (09) 3552-3557
    PubMedGoogle Scholar
  • 23 Tao X, MacKinnon R. Molecular structures of the human Slo1 K+ channel in complex with β4. Elife 2019; 8: e51409
    PubMedGoogle Scholar
  • 24 Fusi F, Saponara S, Pessina F, Gorelli B, Sgaragli G. Effects of quercetin and rutin on vascular preparations: a comparison between mechanical and electrophysiological phenomena. Eur J Nutr 2003; 42 (01) 10-17 DOI: 10.1007/s00394-003-0395-5.
    CrossrefPubMedGoogle Scholar
  • 25 Benito S, Lopez D, Sáiz MP, Buxaderas S, Sánchez J, Puig-Parellada P, Mitjavila MT. A flavonoid-rich diet increases nitric oxide production in rat aorta. Br J Pharmacol 2002; 135 (04) 910-916
    CrossrefPubMedGoogle Scholar
  • 26 Mugnai P, Durante M, Sgaragli G, Saponara S, Paliuri G, Bova S, Fusi F. L-type Ca(2+) channel current characteristics are preserved in rat tail artery myocytes after one-day storage. Acta Physiol (Oxf ) 2014; 211 (02) 334-345
    PubMedGoogle Scholar
  • 27 Iozzi D, Schubert R, Kalenchuk VU, Neri A, Sgaragli G, Fusi F, Saponara S. Quercetin relaxes rat tail main artery partly via a PKG-mediated stimulation of KCa 1.1 channels. Acta Physiol (Oxf) 2013; 208 (04) 329-339
    PubMedGoogle Scholar
  • 28 Tykocki NR, Boerman EM, Jackson WF. Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles. Compr Physiol 2017; 7 (02) 485-581
    CrossrefPubMedGoogle Scholar
  • 29 Magnon M, Calderone V, Floch A, Cavero I. Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings. Naunyn Schmiedebergs Arch Pharmacol 1998; 358 (04) 452-463
    PubMedGoogle Scholar
  • 30 Fusi F, Manetti F, Durante M, Sgaragli G, Saponara S. The vasodilator papaverine stimulates L-type Ca(2+) current in rat tail artery myocytes via a PKA-dependent mechanism. Vascul Pharmacol 2016; 76: 53-61
    PubMedGoogle Scholar
  • 31 Carullo G, Durante M, Sciubba F, Restuccia D, Spizzirri UG, Ahmed A, Di Cocco ME, Saponara S, Aiello F, Fusi F. Vasoactivity of Mantonico and Pecorello grape pomaces on rat aorta rings: an insight into nutraceutical development. J Funct Foods 2019; 57: 328-334
    PubMedGoogle Scholar
  • 32 Fusi F, Ferrara A, Zalatnai A, Molnar J, Sgaragli G, Saponara S. Vascular activity of two silicon compounds, ALIS 409 and ALIS 421, novel multidrug-resistance reverting agents in cancer cells. Cancer Chemother Pharmacol 2008; 61 (03) 443-451
    PubMedGoogle Scholar
  • 33 Gurney AM. Mechanisms of drug-induced vasodilation. J Pharm Pharmacol 1994; 46 (04) 242-251
    PubMedGoogle Scholar
  • 34 Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M. Epik: a software program for pKa prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 2007; 21 (12) 681-691
    PubMedGoogle Scholar
  • 35 Greenwood JR, Calkins D, Sullivan AP, Shelley JC. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J Comput Aided Mol Des 2010; 24(6 – 7): 591-604
    PubMedGoogle Scholar
  • 36 Schrödinger Release 2022-3:. LigPrep, Schrödinger, LLC, New York, NY, 2022.
    PubMedGoogle Scholar
  • 37 Lu C, Wu C, Ghoreishi D, Chen W, Wang L, Damm W, Ross GA, Dahlgren MK, Russell E, Von Bargen CD, Abel R, Friesner RA, Harder ED. OPLS4: improving force field accuracy on challenging regimes of chemical space. J Chem Theory Comput 2021; 17 (07) 4291-4300
    PubMedGoogle Scholar
  • 38 Trezza A, Spiga O, Mugnai P, Saponara S, Sgaragli G, Fusi F. Functional, electrophysiology, and molecular dynamics analysis of quercetin-induced contraction of rat vascular musculature. Eur J Pharmacol 2022; 918: 174778
    PubMedGoogle Scholar
  • 39 Carullo G, Saponara S, Ahmed A, Gorelli B, Mazzotta S, Trezza A, Gianibbi B, Campiani G, Fusi F, Aiello F. Novel labdane diterpenes-based synthetic derivatives: identification of a bifunctional vasodilator that inhibits CaV1.2 and stimulates KCa1.1 channels. Mar Drugs 2022; 20 (08) 515
    PubMedGoogle Scholar
  • 40 Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004; 47 (07) 1739-1749
    PubMedGoogle Scholar
  • 41 Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 2004; 47 (07) 1750-1759
    PubMedGoogle Scholar
  • 42 Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006; 49 (21) 6177-6196
    PubMedGoogle Scholar
  • 43 Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, Wei S, Buckner J, Jeong JC, Qi Y, Jo S, Pande VS, Case DA, Brooks 3rd CL, MacKerell Jr AD, Klauda JB, Im W. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput 2016; 12 (01) 405-413
    PubMedGoogle Scholar
  • 44 Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot BL, Grubmüller H, MacKerell Jr. AD. CHARMM36 m: an improved force field for folded and intrinsically disordered proteins. Nat Methods 2017; 14 (01) 71-73
    PubMedGoogle Scholar
  • 45 Abraham MJ, van der Spoel D, Lindahl E, Hess B. the GROMACS development team, GROMACS User Manual version 2019.3,. http://www.gromacs.org (accessed 30 October 2023)
    PubMedGoogle Scholar
  • 46 UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res 2023; 51(D1): D523-D531
    PubMedGoogle Scholar
  • 47 Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol 1990; 215 (03) 403-410
    CrossrefPubMedGoogle Scholar
  • 48 Papadopoulos JS, Agarwala R. COBALT: constraint-based alignment tool for multiple protein sequences. Bioinformatics 2007; 23 (09) 1073-1079
    PubMedGoogle Scholar
  • 49 Crooks GE, Hon G, Chandonia JM, Brenner SE. WebLogo: a sequence logo generator. Genome Res 2004; 14 (06) 1188-1190
    CrossrefPubMedGoogle Scholar