PDF herunterladen
Planta Med 2014; 80(18): 1712-1720
DOI: 10.1055/s-0034-1383252
Natural Product Chemistry
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Isomeric C12-Alkamides from the Roots of Echinacea purpurea Improve Basal and Insulin-Dependent Glucose Uptake in 3T3-L1 Adipocytes

Dorota Kotowska   *
1   Department of Biology, University of Copenhagen, Copenhagen, Denmark
,
Rime B. El-Houri   *
2   Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
,
Kamil Borkowski
1   Department of Biology, University of Copenhagen, Copenhagen, Denmark
,
Rasmus K. Petersen
1   Department of Biology, University of Copenhagen, Copenhagen, Denmark
,
Xavier C. Fretté
2   Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
,
Gerhard Wolber
3   Computer-Aided Drug Design, Institute of Pharmacy, Medicinal and Pharmaceutical Chemistry, Freie Universität Berlin, Berlin, Germany
,
Kai Grevsen
4   Department of Food Science, Aarhus University, Aarslev, Denmark
,
Kathrine B. Christensen
2   Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
,
Lars P. Christensen
2   Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, Denmark
,
Karsten Kristiansen
1   Department of Biology, University of Copenhagen, Copenhagen, Denmark
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 24. Juni 2014
revised 23. August 2014

accepted 12. Oktober 2014

Publikationsdatum:
05. November 2014 (online)

   Lizenzen und Reprints

Abstract

Echinacea purpurea has been used in traditional medicine as a remedy for the treatment and prevention of upper respiratory tract infections and the common cold. Recent investigations have indicated that E. purpurea also has an effect on insulin resistance. A dichloromethane extract of E. purpurea roots was found to enhance glucose uptake in adipocytes and to activate peroxisome proliferator-activated receptor γ. The purpose of the present study was to identify the bioactive compounds responsible for the potential antidiabetic effect of the dichloromethane extract using a bioassay-guided fractionation approach. Basal and insulin-dependent glucose uptake in 3T3-L1 adipocytes were used to assess the bioactivity of extract, fractions and isolated metabolites. A peroxisome proliferator-activated receptor γ transactivation assay was used to determine the peroxisome proliferator-activated receptor γ activating properties of the extract, active fractions and isolated metabolites. Two novel isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic acid 2-methylbutylamides together with two known C12-alkamides and α-linolenic acid were isolated from the active fractions. The isomeric C12-alkamides were found to activate peroxisome proliferator-activated receptor γ, to increase basal and insulin-dependent glucose uptake in adipocytes in a dose-dependent manner, and to exhibit characteristics of a peroxisome proliferator-activated receptor γ partial agonist.

Key words

Echinacea purpurea - Asteraceae - alkamides - adipocytes - glucose uptake - PPARγ partial agonist

* Dorota Kotowska and Rime B. El-Houri contributed equally to the work.


Supporting Information

 

  • References

  • 1 Barnes J, Anderson L, Gibbons S, Phillipson J. Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): a review of their chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2005; 57: 929-954
    CrossrefPubMedGoogle Scholar
  • 2 Woelkart K, Bauer R. The role of alkamides as an active principle of Echinacea . Planta Med 2007; 73: 615-623
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 3 Christensen KB, Minet A, Svenstrup H, Grevsen K, Zhang H, Schrader E, Rimbach G, Wein S, Wolfram S, Kristiansen K, Christensen LP. Identification of plant extracts with potential antidiabetic properties: effect on human peroxisome proliferator-activated receptor (PPAR), adipocyte differentiation and insulin-stimulated glucose uptake. Phytother Res 2009; 23: 1316-1325
    CrossrefPubMedGoogle Scholar
  • 4 Christensen KB, Petersen RK, Petersen S, Kristiansen K, Christensen LP. Activation of PPARγ by metabolites from the flowers of purple coneflower (Echinacea purpurea). J Nat Prod 2009; 72: 933-937
    CrossrefPubMedGoogle Scholar
  • 5 Nawrocki AR, Scherer PE. Keynote review: the adipocyte as a drug discovery target. Drug Discov Today 2005; 10: 1219-1230
    CrossrefPubMedGoogle Scholar
  • 6 Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 2000; 16: 145-171
    CrossrefPubMedGoogle Scholar
  • 7 Cariou B, Charbonnel B, Staels B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol Metab 2012; 23: 205-215
    CrossrefPubMedGoogle Scholar
  • 8 Yeh GY, Eisenberg DM, Kaptchnuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care 2013; 26: 1277-1294
    PubMedGoogle Scholar
  • 9 Starvaggi Cucuzza L, Motta M, Accornero P, Baratta M. Effect of Echinacea augustifolia extract on cell viability and differentiation in mammary epithelial cells. Phytomed 2008; 15: 555-562
    CrossrefPubMedGoogle Scholar
  • 10 Spelman K, Liams-Hauser K, Cech NB, Taylor EW, Smirnoff N, Wenner CA. Role of PPARγ in IL-2 inhibition in T cells by Echinacea-derived undeca-2E-ene-8, 10-diynoic acid isobutylamide. Int Immunopharmacol 2009; 9: 1260-1264
    CrossrefPubMedGoogle Scholar
  • 11 Goey AKL, Rosing H, Meijerman I, Sparidans RW, Schellens JHM, Beijnen JH. The bioanalysis of the major Echinacea purpurea constituents dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides in human plasma using LC-MS/MS. J Chromatogr B 2012; 902: 151-156
    CrossrefPubMedGoogle Scholar
  • 12 Bauer R, Remiger P, Wagner H. Alkamides from the roots of Echinacea purpurea . Phytochem 1988; 27: 2339-2342
    CrossrefPubMedGoogle Scholar
  • 13 Spelman K, Wetschler MH, Cech NB. Comparison of alkylamide yield in ethanolic extracts prepared from fresh versus dry Echinacea purpurea utilizing HPLC-ESI-MS. J Pharm Biomed Anal 2009; 49: 1141-1149
    CrossrefPubMedGoogle Scholar
  • 14 Thomsen MO, Fretté XC, Christensen KB, Christensen LP, Grevsen K. Seasonal variations in the concentrations of lipophilic compounds and phenolic acids in the roots of Echinacea purpurea and Echinacea pallida . J Agric Food Chem 2012; 60: 12131-12141
    CrossrefPubMedGoogle Scholar
  • 15 Takahara Y, Kobayashi T, Takemoto K, Adachi T, Osaki K, Kawahara K, Tsujimoto G. Pharmacogenomics of cardiovascular pharmacology: development of an informatics system for analysis of DNA microarray data with focus on lipid metabolism. J Pharmacol Sci 2008; 107: 1-7
    CrossrefPubMedGoogle Scholar
  • 16 Ghafoorunissa. Ibrahim A, Natarajan S. Substituting dietary linoleic acid with α-linolenic acid improves insulin sensitivity in sucrose fed rats. Biochim Biophys Acta 2005; 21: 67-75
    PubMedGoogle Scholar
  • 17 Poudyal H, Panchal SK, Ward LC, Brown L. Effects of ALA, EPA and DHA in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. J Nutr Biochem 2013; 24: 1041-1052
    CrossrefPubMedGoogle Scholar
  • 18 Bauer R, Remiger P. TLC and HPLC analysis of alkamides in Echinacea drugs. Planta Med 1989; 55: 367-371
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Cech NB, Eleazer MS, Shoffner LT, Crosswhite MR, Davis AC, Mortenson AM. High performance liquid chromatography/electrospray ionization mass spectrometry for simultaneous analysis of alkamides and caffeic acid derivatives from Echinacea purpurea extracts. J Chromatogr A 2006; 1103: 219-228
    CrossrefPubMedGoogle Scholar
  • 20 Mudge E, Loes-Lutz D, Brown P, Scheiber A. Analysis of alkylamides in Echinacea purpurea materials and dietary supplements by ultrafast liquid chromatography with diode array and mass spectrometric detection. J Agric Food Chem 2011; 59: 8086-8094
    CrossrefPubMedGoogle Scholar
  • 21 Pellati F, Epifano F, Contaldo N, Orlandini G, Cavicchi L, Genovese S, Bertelli D, Bevenuti S, Curini M, Bertaccini A, Bellardi MG. Chromatographic methods for metabolite profiling of virus- and phytoplasma-infected plants of Echinacea purpurea . J Agric Food Chem 2011; 59: 10425-10434
    CrossrefPubMedGoogle Scholar
  • 22 Nakatani N, Nagashima M. Pungent alkamides from Spilanthes acmella L. var. oleracae Clarke. Biosci Biotechnol Biochem 1992; 56: 759-762
    CrossrefPubMedGoogle Scholar
  • 23 Atanasov AG, Wang JN, Gu SP, Bu J, Kramer MP, Baumgartner L, Fakhrudin N, Ladurner A, Malainer C, Vuorinen A, Noha SM, Schwaiger S, Rollinger JM, Schuster D, Stuppner H, Dirsch VM, Heiss EH. Honokiol: A non-adipogenic PPARγ agonist from nature. Biochim Biophys Acta 2013; 1830: 4813-4819
    CrossrefPubMedGoogle Scholar
  • 24 Guasch L, Sala E, Valls C, Blay M, Mulero M, Arola L, Pujadas G, Garcia-Vallvé S. Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity. J Comput Aided Mol Des 2011; 25: 717-728
    CrossrefPubMedGoogle Scholar
  • 25 Zoete V, Grosdidier A, Michielin O. Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta 2007; 1771: 915-925
    CrossrefPubMedGoogle Scholar
  • 26 Berger JP, Petro AE, Macnaul KL, Kelly LJ, Zhang BB, Richards K, Elbrecht A, Johnson BA, Zhou G, Doebber TW, Biswas C, Parikh M, Sharma N, Tanen MR, Thompson GM, Ventre J, Adams AD, Mosley R, Surwit RS, Moller DE. Distinct properties and advantages of a novel peroxisome proliferator-activated protein γ selective modulator. Mol Endocrinol 2003; 17: 662-676
    CrossrefPubMedGoogle Scholar
  • 27 Thoennes SR, Tate PL, Price TM, Kilgore MW. Differential transcriptional activation of peroxisome proliferator-activated receptor gamma by omega-3 and omega-6 fatty acids in MCF-7 cells. Mol Cell Endocrinol 2000; 160: 67-73
    CrossrefPubMedGoogle Scholar
  • 28 Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999; 20: 649-688
    CrossrefPubMedGoogle Scholar
  • 29 Dussault I, Forman BM. Prostaglandins and fatty acids regulate transcriptional signaling via the peroxisome proliferator activated receptor nuclear receptors. Prostaglandins Other Lipid Mediat 2000; 62: 1-13
    CrossrefPubMedGoogle Scholar
  • 30 Hammond VJ, Morgan AH, Lauder S, Thomas CP, Brown S, Freeman BA, Lloyd CM, Davies J, Bush A, Levonen AL, Kansanen E, Villacorta L, Chen YE, Porter N, Garcia-Diaz YM, Schopfer FJ, OʼDonnell VB. Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ . J Biol Chem 2012; 287: 41651-41666
    CrossrefPubMedGoogle Scholar
  • 31 Atanasov AG, Blunder M, Fakhrudin N, Liu X, Noha SM, Malainer C, Kramer MP, Cocic A, Kunert O, Schinkovitz A, Heiss EH, Schuster D, Dirsch VM, Bauer R. Polyacetylenes from Notopterygium incisum – new selective partial agonists of peroxisome proliferator-activated receptor-gamma. PLoS ONE 2013; 8: e61755
    CrossrefPubMedGoogle Scholar
  • 32 Waku T, Shiraki T, Oyama T, Fujimoto Y, Maebara K, Kamiya N, Jingami H, Morikawa K. Structural insight into PPARγ activation through covalent modification with endogenous fatty acids. J Mol Biol 2009; 385: 188-199
    CrossrefPubMedGoogle Scholar
  • 33 Itoh T, Fairall L, Amin K, Inaba Y, Szanto A, Balint BL, Nagy L, Yamamoto K, Schwabe JWR. Structural basis for the activation of PPARγ by oxidized fatty acids. Nat Struct Mol Biol 2008; 15: 924-931
    CrossrefPubMedGoogle Scholar
  • 34 Shiraki T, Kamiya N, Shiki S, Kodama TS, Kakizuka A, Jingami H. α,β-Unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor γ . J Biol Chem 2005; 280: 14145-14153
    CrossrefPubMedGoogle Scholar
  • 35 McLaughlin T, Sherman A, Tsao P, Gonzalez O, Yee G, Lamendola C, Reaven GM, Cushman SW. Enhanced proportion of small adipose cells in insulin-resistant vs. insulin-sensitive obese individuals implicates impaired adipogenesis. Diabetologia 2007; 50: 1707-1715
    CrossrefPubMedGoogle Scholar
  • 36 Hallenborg P, Jorgensen C, Petersen RK, Feddersen S, Araujo P, Markt P, Langer T, Furstenberger G, Krieg P, Koppen A, Kalkhoven E, Madsen L, Kristiansen K. Epidermis-type lipoxygenase 3 regulates adipocyte differentiation and peroxisome proliferator-activated receptor gamma activity. Mol Cell Biol 2010; 16: 4077-4091
    PubMedGoogle Scholar
  • 37 Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507-514
    CrossrefPubMedGoogle Scholar
  • 38 Ribon V, Johnson JH, Camp HS, Saltiel AR. Thiazolidinediones and insulin resistance: peroxisome proliferator activated receptor γ activation stimulates expression of CAP gene. Proc Natl Acad Sci USA 1998; 95: 14751-14756
    CrossrefPubMedGoogle Scholar
  • 39 Wood IS, Trayhurn P. Glucose transporter (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 2003; 89: 3-9
    PubMedGoogle Scholar
  • 40 Gregoire FM, Johnson PR, Greenwood MR. Comparison of the adipoconversion of preadipocytes derived from lean and obese Zucker rats in serum-free cultures. Int J Obes Relat Metab Disord 1995; 19: 664-670
    PubMedGoogle Scholar
  • 41 Shang W, Yang Y, Jiang B, Jin H, Zhou L, Liu S, Chen M. Ginsenoside Rb1 promotes adipogenesis in 3T3-L1 cells by enhacing PPARγ2 and C/EBPα gene expression. Life Sci 2007; 80: 618-625
    CrossrefPubMedGoogle Scholar
  • 42 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941-946
    CrossrefPubMedGoogle Scholar
  • 43 Jones G, Willett P, Glen RC. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 1995; 245: 43-53
    CrossrefPubMedGoogle Scholar
  • 44 Halgren TA. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 1996; 17: 490-519
    CrossrefPubMedGoogle Scholar
  • 45 Seidel T, Ibis G, Bendix F, Wolber G. Strategies for 3D pharmacophore-based virtual screening. Drug Discov Today Technol 2010; 7: 221-228
    CrossrefPubMedGoogle Scholar
  • 46 Wolber G, Dornhofer AA, Langer T. Efficient overlay of small organic molecules using 3D pharmacophores. J Comput Aided Mol Des 2006; 20: 773-788
    PubMedGoogle Scholar
  • 47 Wolber G, Langer T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inform Model 2005; 45: 160-169
    CrossrefPubMedGoogle Scholar