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Planta Med 2019; 85(05): 412-423
DOI: 10.1055/a-0824-1316
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Triterpenoids from Hibiscus sabdariffa L. with PPARδ/γ Dual Agonist Action: In Vivo, In Vitro and In Silico Studies

Abraham Giacoman-Martínez
1   Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, México
,
Francisco J. Alarcón-Aguilar
2   Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, México
,
Alejandro Zamilpa
3   Departamento de Fitoquímica Farmacológica, Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec, Morelos, México
,
Sergio Hidalgo-Figueroa
4   CONACyT, IPICYT/Consorcio de Investigación, Innovación y Desarrollo para las Zonas Áridas, San Luis Potosí, México
,
Gabriel Navarrete-Vázquez
5   Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México
,
Rebeca García-Macedo
6   Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
,
Rubén Román-Ramos
2   Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, México
,
Julio C. Almanza-Pérez
2   Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México, México
› Author Affiliations
Further Information

Publication History

received 03 October 2018
revised 04 December 2018

accepted 16 December 2018

Publication Date:
16 January 2019 (online)

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Abstract

Hibiscus sabdariffa is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors δ and γ may play a role in the actions of H. sabdariffa. These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from H. sabdariffa to identify compounds with peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of H. sabdariffa and the dichloromethane extract of H. sabdariffa was performed. The dichloromethane extract of H. sabdariffa exhibited an antihyperglycemic effect. The dichloromethane extract of H. sabdariffa was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor δ/γ dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were α-amyrin and lupeol. These molecules were subjected to molecular docking analysis. α-Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor δ, peroxisome proliferator-activated receptor γ, fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, α-amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, α-amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that α-amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor δ/γ dual agonist action.

Key words

diabetes - Hibiscus sabdariffa - Malvaceae - PPAR - α-amyrin - lupeol

Supporting Information

    Flow conditions of HPLC, TLC of 4 selected fractions and TLC that showing the identification of α-amyrin and lupeol in the HS-DCM and subfractions F3-1 and F3-2 are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 Alarcon-Aguilar FJ, Zamilpa A, Perez-Garcia MD, Almanza-Perez JC, Romero-Nunez E, Campos-Sepulveda EA, Vazquez-Carrillo LI, Roman-Ramos R. Effect of Hibiscus sabdariffa on obesity in MSG mice. J Ethnopharmacol 2007; 114: 66-71
    CrossrefPubMedGoogle Scholar
  • 2 Ajiboye TO, Raji HO, Adeleye AO, Adigun NS, Giwa OB, Ojewuyi OB, Oladiji AT. Hibiscus sabdariffa calyx palliates insulin resistance, hyperglycemia, dyslipidemia and oxidative rout in fructose-induced metabolic syndrome rats. J Sci Food Agric 2016; 96: 1522-1531
    CrossrefPubMedGoogle Scholar
  • 3 Hopkins AL, Lamm MG, Funk JL, Ritenbaugh C. Hibiscus sabdariffa L. in the treatment of hypertension and hyperlipidemia: a comprehensive review of animal and human studies. Fitoterapia 2013; 85: 84-94
    CrossrefPubMedGoogle Scholar
  • 4 Chen W, Zhou XB, Liu HY, Xu C, Wang LL, Li S. P633H, a novel dual agonist at peroxisome proliferator-activated receptors alpha and gamma, with different anti-diabetic effects in db/db and KK-Ay mice. Br J Pharmacol 2009; 157: 724-735
    CrossrefPubMedGoogle Scholar
  • 5 Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 2008; 29: 2959-2971
    CrossrefPubMedGoogle Scholar
  • 6 Reilly SM, Lee CH. PPAR delta as a therapeutic target in metabolic disease. FEBS Lett 2008; 582: 26-31
    CrossrefPubMedGoogle Scholar
  • 7 Giordano Attianese GM, Desvergne B. Integrative and systemic approaches for evaluating PPARbeta/delta (PPARD) function. Nucl Recept Signal 2015; 13: e001
    PubMedGoogle Scholar
  • 8 Matsuura N, Gamo K, Miyachi H, Iinuma M, Kawada T, Takahashi N, Akao Y, Tosa H. gamma-Mangostin from Garcinia mangostana pericarps as a dual agonist that activates both PPARalpha and PPARdelta. Biosci Biotechnol Biochem 2013; 77: 2430-2435
    CrossrefPubMedGoogle Scholar
  • 9 Ding Y, Yang KD, Yang Q. The role of PPARdelta signaling in the cardiovascular system. Prog Mol Biol Transl Sci 2014; 121: 451-473
    PubMedGoogle Scholar
  • 10 Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARgamma): a review. Biochem Pharmacol 2014; 92: 73-89
    CrossrefPubMedGoogle Scholar
  • 11 Chen Z, Zhang L, Yi J, Yang Z, Zhang Z, Li Z. Promotion of adiponectin multimerization by emodin: a novel AMPK activator with PPARgamma-agonist activity. J Cell Biochem 2012; 113: 3547-3558
    CrossrefPubMedGoogle Scholar
  • 12 Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci 2005; 26: 244-251
    CrossrefPubMedGoogle Scholar
  • 13 Chinetti-Gbaguidi G, Fruchart JC, Staels B. Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. Curr Opin Pharmacol 2005; 5: 177-183
    CrossrefPubMedGoogle Scholar
  • 14 Salam NK, Huang TH, Kota BP, Kim MS, Li Y, Hibbs D. Novel PPAR-gamma agonists identified from a natural product library: a virtual screening, induced-fit docking and biological assay study. Chem Biol Drug Des 2008; 71: 57-70
    PubMedGoogle Scholar
  • 15 Takahashi N, Kawada T, Goto T, Yamamoto T, Taimatsu A, Matsui N, Kimura K, Saito M, Hosokawa M, Miyashita K. Dual action of isoprenols from herbal medicines on both PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes. FEBS Lett 2002; 514: 315-322
    CrossrefPubMedGoogle Scholar
  • 16 Guardiola S, Mach N. Therapeutic potential of Hibiscus sabdariffa: a review of the scientific evidence. Endocrinol Nutr 2014; 61: 274-295
    CrossrefPubMedGoogle Scholar
  • 17 Alarcon-Alonso J, Zamilpa A, Aguilar FA, Herrera-Ruiz M, Tortoriello J, Jimenez-Ferrer E. Pharmacological characterization of the diuretic effect of Hibiscus sabdariffa Linn (Malvaceae) extract. J Ethnopharmacol 2012; 139: 751-756
    CrossrefPubMedGoogle Scholar
  • 18 Pettersson I, Ebdrup S, Havranek M, Pihera P, Korinek M, Mogensen JP, Jeppesen CB, Johansson E, Sauerberg P. Design of a partial PPARdelta agonist. Bioorg Med Chem Lett 2007; 17: 4625-4629
    CrossrefPubMedGoogle Scholar
  • 19 Hidalgo-Figueroa S, Navarrete-Vazquez G, Estrada-Soto S, Giles-Rivas D, Alarcon-Aguilar FJ, Leon-Rivera I, Giacoman-Martinez A, Miranda Perez E, Almanza-Perez JC. Discovery of new dual PPARgamma-GPR40 agonists with robust antidiabetic activity: Design, synthesis and in combo drug evaluation. Biomed Pharmacother 2017; 90: 53-61
    CrossrefPubMedGoogle Scholar
  • 20 Bano G. Glucose homeostasis, obesity and diabetes. Best Pract Res Clin Obstet Gynaecol 2013; 27: 715-726
    CrossrefPubMedGoogle Scholar
  • 21 Viswakarma N, Jia Y, Bai L, Vluggens A, Borensztajn J, Xu J, Reddy JK. Coactivators in PPAR-regulated gene expression. PPAR Res 2010; 2010: 250126
    PubMedGoogle Scholar
  • 22 Xu C, Wang LL, Liu HY, Ruan CM, Zhou XB, Cao YL, Li S. A novel dual peroxisome proliferator-activated receptors alpha and gamma agonist with beneficial effects on insulin resistance and lipid metabolism. Biotechnol Lett 2006; 28: 863-868
    CrossrefPubMedGoogle Scholar
  • 23 Suh HN, Huong HT, Song CH, Lee JH, Han HJ. Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes. Am J Physiol Cell Physiol 2008; 295: C1518-C1527
    CrossrefPubMedGoogle Scholar
  • 24 Wu HT, Chen W, Cheng KC, Ku PM, Yeh CH, Cheng JT. Oleic acid activates peroxisome proliferator-activated receptor delta to compensate insulin resistance in steatotic cells. J Nutr Biochem 2012; 23: 1264-1270
    CrossrefPubMedGoogle Scholar
  • 25 Santos FA, Frota JT, Arruda BR, de Melo TS, da Silva AA, Brito GA, Chaves MH, Rao VS. Antihyperglycemic and hypolipidemic effects of alpha, beta-amyrin, a triterpenoid mixture from Protium heptaphyllum in mice. Lipids Health Dis 2012; 11: 98
    CrossrefPubMedGoogle Scholar
  • 26 da Silva Júnior WF, Pinheiro JGO, de Menezes DLB, de Sobral E Silva NE, de Almeida PDO, Lima ES, da Veiga Júnior VF, de Azevedo EP, de Lima ÁAN. Development, physicochemical characterization and in vitro anti-inflammatory activity of solid dispersions of α,β amyrin isolated from Protium oilresin. Molecules 2017; 22: E1512
    CrossrefPubMedGoogle Scholar
  • 27 Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation 2000; 101: 235-238
    CrossrefPubMedGoogle Scholar
  • 28 Warensjo E, Riserus U, Gustafsson IB, Mohsen R, Cederholm T, Vessby B. Effects of saturated and unsaturated fatty acids on estimated desaturase activities during a controlled dietary intervention. Nutr Metab Cardiovasc Dis 2008; 18: 683-690
    CrossrefPubMedGoogle Scholar
  • 29 Petronelli A, Pannitteri G, Testa U. Triterpenoids as new promising anticancer drugs. Anticancer Drugs 2009; 20: 880-892
    CrossrefPubMedGoogle Scholar
  • 30 Liby KT, Yore MM, Sporn MB. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 2007; 7: 357-369
    CrossrefPubMedGoogle Scholar
  • 31 Xu GB, Xiao YH, Zhang QY, Zhou M, Liao SG. Hepatoprotective natural triterpenoids. Eur J Med Chem 2018; 145: 691-716
    CrossrefPubMedGoogle Scholar
  • 32 Feng J, Yi X, Huang W, Wang Y, He X. Novel triterpenoids and glycosides from durian exert pronounced anti-inflammatory activities. Food Chem 2018; 241: 215-221
    CrossrefPubMedGoogle Scholar
  • 33 Zhao WW, Zan K, Wu JY, Gao W, Yang J, Ba YY, Wu X, Chen XQ. Antibacterial triterpenoids from the leaves of Ilex hainanensis Merr. Nat Prod Res 2018; DOI: 10.1080/14786419.2018.1452010.
    CrossrefPubMedGoogle Scholar
  • 34 Gupta R, Sharma AK, Sharma MC, Dobhal MP, Gupta RS. Evaluation of antidiabetic and antioxidant potential of lupeol in experimental hyperglycaemia. Nat Prod Res 2012; 26: 1125-1129
    CrossrefPubMedGoogle Scholar
  • 35 Geetha T, Varalakshmi P. Anti-inflammatory activity of lupeol and lupeol linoleate in rats. J Ethnopharmacol 2001; 76: 77-80
    CrossrefPubMedGoogle Scholar
  • 36 Tannehill-Gregg SH, Sanderson TP, Minnema D, Voelker R, Ulland B, Cohen SM, Arnold LL, Schilling BE, Waites CR, Dominick MA. Rodent carcinogenicity profile of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar. Toxicol Sci 2007; 98: 258-270
    CrossrefPubMedGoogle Scholar
  • 37 Lindblom P, Berg AL, Zhang H, Westerberg R, Tugwood J, Lundgren H, Marcusson-Stahl M, Sjogren N, Blomgren B, Ohman P. Tesaglitazar, a dual PPAR-alpha/gamma agonist, hamster carcinogenicity, investigative animal and clinical studies. Toxicol Pathol 2012; 40: 18-32
    CrossrefPubMedGoogle Scholar
  • 38 Pillai HK, Fang M, Beglov D, Kozakov D, Vajda S, Stapleton HM, Webster TF, Schlezinger JJ. Ligand binding and activation of PPARgamma by Firemaster® 550: effects on adipogenesis and osteogenesis in vitro . Environ Health Perspect 2014; 122: 1225-1232
    CrossrefPubMedGoogle Scholar
  • 39 Dehoux MJ, van Beneden RP, Fernandez-Celemin L, Lause PL, Thissen JP. Induction of MafBx and Murf ubiquitin ligase mRNAs in rat skeletal muscle after LPS injection. FEBS Lett 2003; 544: 214-217
    CrossrefPubMedGoogle Scholar
  • 40 Garcia-Macedo R, Sanchez-Munoz F, Almanza-Perez JC, Duran-Reyes G, Alarcon-Aguilar F, Cruz M. Glycine increases mRNA adiponectin and diminishes pro-inflammatory adipokines expression in 3T3-L1 cells. Eur J Pharmacol 2008; 587: 317-321
    CrossrefPubMedGoogle Scholar
  • 41 Connors RV, Wang Z, Harrison M, Zhang A, Wanska M, Hiscock S, Fox B, Dore M, Labelle M, Sudom A. Identification of a PPARdelta agonist with partial agonistic activity on PPARgamma. Bioorg Med Chem Lett 2009; 19: 3550-3554
    CrossrefPubMedGoogle Scholar
  • 42 Balakumar P, Rose M, Ganti SS, Krishan P, Singh M. PPAR dual agonists: are they opening Pandoraʼs box?. Pharmacol Res 2007; 56: 91-98
    CrossrefPubMedGoogle Scholar
  • 43 Yamada P, Nemoto M, Shigemori H, Yokota S, Isoda H. Isolation of 5-(hydroxymethyl)furfural from Lycium chinense and its inhibitory effect on the chemical mediator release by basophilic cells. Planta Med 2011; 77: 434-440
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Hidalgo-Figueroa S, Ramirez-Espinosa JJ, Estrada-Soto S, Almanza-Perez JC, Roman-Ramos R, Alarcon-Aguilar FJ, Hernandez-Rosado JV, Moreno-Diaz H, Diaz-Coutino D, Navarrete-Vazquez G. Discovery of thiazolidine-2, 4-dione/biphenylcarbonitrile hybrid as dual PPAR alpha/gamma modulator with antidiabetic effect: in vitro, in silico and in vivo approaches. Chem Biol Drug Des 2013; 81: 474-483
    CrossrefPubMedGoogle Scholar