PDF herunterladen
Planta Med 2017; 83(01/02): 40-50
DOI: 10.1055/s-0042-107357
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Therapeutic Potential of Hydroxypropyl-β-Cyclodextrin-Based Extract of Medicago sativa in the Treatment of Mucopolysaccharidoses

Barbara Fumić
1   Department of Pharmacognosy, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
2   Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
,
Marijana Zovko Končić
1   Department of Pharmacognosy, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
,
Mario Jug
3   Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 30. Oktober 2015
revised 13. April 2016

accepted 15. April 2016

Publikationsdatum:
24. Mai 2016 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Mucopolysaccharidoses are inherited metabolic disorders resulting in the dysfunction of enzymes involved in the degradation of glycosaminoglycans, leading to severe clinical symptoms and a significantly shortened life span of patients. Flavonoids are recognized as glycosaminoglycan metabolism modulators, able to correct glycosaminoglycan cell storage. Therefore, the aim of this work was the development of an efficient and eco-friendly extraction process of phytochemicals from Medicago sativa by simultaneous use of ultrasound extraction and hydroxypropyl-β-cyclodextrin complexation, and investigation of the potential of such an extract as a glycosaminoglycan metabolism modulator. The Box-Behnken design and response surface methodology were used in order to optimize the extraction process, considering hydroxypropyl-β-cyclodextrin concentration, ultrasonic power, and extraction time as the key parameters. The dependent variables included total phenolicand total flavonoid content, DPPH radical scavenging activity, and Fe2+ chelating activity, due to the importance of oxidative stress in the pathology of mucopolysaccharidoses. The developed technology using hydroxypropyl-β-cyclodextrin led to more selective flavonoid extraction from M. sativa than obtained either by the use of water or ethanol. The lyophilization of extracts resulted in products with high radical scavenging activity, suitable for further use. The application of 20 mM hydroxypropyl-β-cyclodextrin solution, 432 W ultrasonic power, and an extraction time of 45 min resulted in an extract with both the highest total flavonoid content and the lowest radical scavenging activity IC50. This extract reduced the levels of glycosaminoglycans in skin fibroblasts of mucopolysaccharidose III patient in a dose-dependent manner. At concentrations of 3 and 6 µg/mL, the observed levels of glycosaminoglycans were reduced by 41.2 and 51.1 %, respectively, clearly demonstrating the validity of the selected approach.

Key words

Medicago sativa - Fabaceae - hydroxypropyl-β-cyclodextrin - polyphenols - radical scavenging activity - chelating activity - glycosaminoglycans

Supporting Information

 

  • References

  • 1 Bora KS, Sharma A. Phytochemical and pharmacological potential of Medicago sativa: a review. Pharm Biol 2011; 49: 211-220
    CrossrefPubMedGoogle Scholar
  • 2 Gholami A, De Geyter N, Pollier J, Goormachtig S, Goossens A. Natural product biosynthesis in Medicago species. Nat Prod Rep 2014; 31: 356-380
    CrossrefPubMedGoogle Scholar
  • 3 Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, editors The metabolic and molecular bases of inherited disease. 8th edition, Vol III. New York: McGraw-Hill; 2001: 3421-3452
    Google Scholar
  • 4 Muenzer J. Mucopolysaccharidoses. Adv Pediatr 1986; 33: 269-302
    PubMedGoogle Scholar
  • 5 Neufeld EF, Fratantoni JC. Inborn errors of mucopolysaccharide metabolism. Science 1970; 169: 141-146
    CrossrefPubMedGoogle Scholar
  • 6 Walkley SU. Pathogenic cascades in lysosomal disease – why so complex?. J Inherit Metab Dis 2009; 32: 181-189
    CrossrefPubMedGoogle Scholar
  • 7 Villani GRD, Gargiulo N, Faraonio R, Castaldo S, Gonzalez Y Reyero E, Di Natale P. Cytokines, neurotrophins, and oxidative stress in brain disease from mucopolysaccharidosis IIIB. J Neurosci Res 2007; 85: 612-622
    CrossrefPubMedGoogle Scholar
  • 8 Trudel S, Trécherel E, Gomila C, Peltier M, Aubignat M, Gubler B, Morlière P, Heard JM, Ausseil J. Oxidative stress is independent of inflammation in the neurodegenerative Sanfilippo syndrome type B. J Neurosci Res 2015; 93: 424-432
    CrossrefPubMedGoogle Scholar
  • 9 Moskot M, Jakóbkiewicz-Banecka J, Kloska A, Smolińska E, Mozolewski P, Malinowska M, Rychłowski M, Banecki B, Węgrzyn G, Gabig-Cimińska M. Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids. Sci Rep 2015; 23: 9378
    PubMedGoogle Scholar
  • 10 Pingret D, Fabiano-Tixier AS, La Bourvellec C, Renard CMGC, Chemat F. Lab and pilot-scale ultrasound assisted extraction of polyphenols from apple pomace. J Food Eng 2012; 111: 73-81
    CrossrefPubMedGoogle Scholar
  • 11 Shirsath SR, Sonawane SH, Gogate PR. Intensification of extraction of natural products using ultrasonic irradiation – A review of current status. Chem Eng Process 2012; 53: 10-23
    CrossrefPubMedGoogle Scholar
  • 12 Ratnasooriya CC, Rupasonghe HPV. Extraction of phenolic compounds from grapes and their pomace using β-cyclodextrin. Food Chem 2012; 134: 625-631
    CrossrefPubMedGoogle Scholar
  • 13 Rahmawati SI, Ishimaru K, Hou DX, Hayashi N. Antioxidant and anticancer activities of mistletoe tea prepared by high temperature extraction with cyclodextrin. Bulg J Agric Sci 2014; 4: 818-823
    PubMedGoogle Scholar
  • 14 Mantegna S, Binello L, Boffa L, Giorgis M, Cena C, Cravotto G. A one pot-ultrasound-assisted water extraction/cyclodextrin encapsulation of resveratrol from Polygonum cuspidatum . Food Chem 2012; 130: 746-750
    CrossrefPubMedGoogle Scholar
  • 15 Kurkov SV, Loftsson T. Cyclodextrins. Int J Pharm 2013; 453: 167-180
    CrossrefPubMedGoogle Scholar
  • 16 Pinho E, Grootveld M, Soarez G, Henriques M. Cyclodextrin as encapsulation agents for plant bioactive compounds. Carbohydr Polym 2014; 101: 121-135
    CrossrefPubMedGoogle Scholar
  • 17 López-Nicolás JM, Rodríguez-Bonilla P, García-Carmona F. Cyclodextrins and antioxidants. Crit Rev Food Sci Nutr 2014; 54: 251-276
    CrossrefPubMedGoogle Scholar
  • 18 Yatsu FKJ, Koester LS, Lula I, Passos JJ, Sinisterra R, Bassani VL. Multiple complexation of cyclodextrins with soy isoflavones present in an enriched fraction. Carbohydr Polym 2013; 98: 726-735
    CrossrefPubMedGoogle Scholar
  • 19 Qiao L, Sun Y, Fu Y, Zhang W, Li X, Chen J, Shen Y, Ye X. Sonochemical effects on 14 flavonoids common in citrus: relation to stability. PLoS One 2014; 9: e87766
    CrossrefPubMedGoogle Scholar
  • 20 Nadeem SH, Torun M, Özdemir F. Spray drying of the mountain tea (Sideritis stricta) water exracts by using different hydrocolloid carriers. LWT Food Sci Tech 2011; 44: 1626-1635
    CrossrefPubMedGoogle Scholar
  • 21 Kasper JC, Friess W. The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals. Eur J Pharm Biopharm 2011; 78: 248-263
    CrossrefPubMedGoogle Scholar
  • 22 Kloska A, Jakóbkiewicz-Banecka J, Narajczyk M, Banecka-Majkutewicz Z, Węgrzyn G. Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses. Metab Brain Dis 2011; 26: 1-8
    CrossrefPubMedGoogle Scholar
  • 23 Devi KP, Malar DS, Nabavi SF, Sureda A, Xiao J, Nabavi SM, Daglia M. Kaempferol and inflammation: from chemistry to medicine. Pharmacol Res 2015; 99: 1-10
    CrossrefPubMedGoogle Scholar
  • 24 Nabavi SF, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, Skalicka-Woźniak K, Nabavi SM. Luteolin as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res Bull 2015; 119: 1-11
    CrossrefPubMedGoogle Scholar
  • 25 Sak K. Site-specific anticancer effects of dietary flavonoid quercetin. Nutr Cancer 2014; 66: 177-193
    CrossrefPubMedGoogle Scholar
  • 26 Del Rio D, Rodriguez-Mateos A, Spencer JP, Tognolini M, Borges G, Crozier A. Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal 2013; 18: 1818-1892
    CrossrefPubMedGoogle Scholar
  • 27 Zhang M, Li J, Zhang L, Chao J. Preparation and spectral investigation of inclusion complex of caffeic acid with hydroxypropyl-β-cyclodextrin. Spectrochim Acta A 2009; 71: 1891-1895
    CrossrefPubMedGoogle Scholar
  • 28 Kim H, Choi J, Jung S. Inclusion complexes of modified cyclodextrins with some flavonols. J Incl Phenom Macrocycl Chem 2009; 64: 43-47
    CrossrefPubMedGoogle Scholar
  • 29 Shulman M, Cohen M, Soto-Gutierez A, Yagi H, Wang H, Goldwasser J, Lee-Parsons CW, Benny-Ratsaby O, Yarmush ML, Nahmias Y. Enhancement of naringerin bioavailability by complexation with hydroxypropyl-β-cyclodextrin. PLoS One 2011; 6: e188033
    PubMedGoogle Scholar
  • 30 Goritzi O, Styliani C, Ioannis RG. Coencapsulation of ferulic and galic acid in hp-β-cyclodextrin. Food Chem 2015; 185: 33-40
    CrossrefPubMedGoogle Scholar
  • 31 Lucas-Abellán C, Fortea MI, Gabaldón J, Núñez-Delicado E. Complexation of resveratrol by native and modified cyclodextrins: Determination of complexation constant by enzymatic, solubility and fluorimetric assays. Food Chem 2008; 111: 262-267
    CrossrefPubMedGoogle Scholar
  • 32 Mercader-Ros MT, Lucas-Abellán C, Fortea MI, Gabaldón JA, Núñez-Delicado E. Effect of HP-β-cyclodextrins complexation on the antioxidant activity of flavonols. Food Chem 2010; 118: 769-773
    CrossrefPubMedGoogle Scholar
  • 33 García-Padial M, Martínez-Ohárriz MC, Navarro-Blasco I, Zornoza A. The role of cyclodextrins in ORAC-fluorescence assays. antioxidant capacity of tyrosol and caffeic acid with hydroxypropyl-β-cyclodextrin. J Agric Food Chem 2013; 61: 12260-12264
    CrossrefPubMedGoogle Scholar
  • 34 Nguyen TA, Liu B, Zhao J, Thomas DS, Hook JM. An investigation into the supramolecular structure, solubility, stability and antioxidant activity of rutin/cyclodextrin inclusion complex. Food Chem 2013; 136: 186-192
    CrossrefPubMedGoogle Scholar
  • 35 Kasote DM, Katyare SS, Hegde MV, Bae H. Significance of antioxidant potential of plants and its relevance to therapeutic applications. Int J Biol Sci 2015; 11: 982-991
    CrossrefPubMedGoogle Scholar
  • 36 Julian C, Cifuentes C, Alfaro M, Miranda S, Barriga G, Olea-Azar C. Spectroscopic characterization of the inclusion complexes of luteolin with native and derivatized β-cyclodextrin. Bioorg Med Chem 2010; 18: 5025-5031
    CrossrefPubMedGoogle Scholar
  • 37 Carlotti ME, Sapino S, Ugazio E, Caron G. On the complexation of quercetin with methyl-β-cyclodextrin: photostability and antioxidant studies. J Incl Phenom Macrocycl Chem 2011; 70: 81-90
    CrossrefPubMedGoogle Scholar
  • 38 Norkus E. Metal ion complexes with native cyclodextrins. An overview. J Incl Phenom Macrocycl Chem 2009; 65: 237-248
    CrossrefPubMedGoogle Scholar
  • 39 Ren J, Meng S, Lekka CE, Kaxiras E. Complexation of flavonoids with iron: structure and optical signatures. J Phys Chem B 2008; 112: 1845-1850
    CrossrefPubMedGoogle Scholar
  • 40 Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm 2011; 420: 1-10
    CrossrefPubMedGoogle Scholar
  • 41 Del Valle EMM. Cyclodextrins and their uses: a review. Process Biochem 2004; 39: 1033-1046
    CrossrefPubMedGoogle Scholar
  • 42 Souza DS, Marques LG, de Barros Gomes E, Narain N. Lyophilisation of avocado (Persea americana Mill.): Effect of freezing and lyophilization pressure on antioxidant activity, texture and browning of pulp. Dry Technol 2015; 33: 194-204
    CrossrefPubMedGoogle Scholar
  • 43 Sogi SD, Siddq M, Dolan KD. Total phenolics, carotenoids and antioxidant properties of Tommy Atkin mango cubes as affected by drying technique. LWT Food Sci Technol 2015; 62: 564-568
    CrossrefPubMedGoogle Scholar
  • 44 Guiné RP, Barroca MJ, Gonçalves FJ, Alves M, Oliveira S, Mendes M. Artificial neural network modelling of the antioxidant activity and phenolic compounds of bananas submitted to different drying treatments. Food Chem 2015; 168: 454-459
    CrossrefPubMedGoogle Scholar
  • 45 Yemis O, Mazza G. Optimization of furfural and 5-hydroxymethylfurfural production from wheat straw by a microwave-assisted process. Bioresour Technol 2012; 109: 215-223
    CrossrefPubMedGoogle Scholar
  • 46 Donga CH, Xie XQ, Wang XL, Zhana Y, Yao YJ. Application of Box-Behnken design in optimization for polysaccharides extraction from cultured mycelium of Cordyceps sinensis . Food Bioprod Process 2009; 87: 139-144
    CrossrefPubMedGoogle Scholar
  • 47 Singleton VL, Orthofer R, Lamuela-Raventos RM. Analysis of total phenols and other oxidation substrates and antioxidants by means of Folin-Ciocalteau reagent. Methods Enzymol 1999; 299: 152-178
    PubMedGoogle Scholar
  • 48 Kumazawa S, Hamasaka T, Nakayama T. Antioxidant activity of propolis of various geographic origins. Food Chem 2004; 84: 329-339
    CrossrefPubMedGoogle Scholar
  • 49 Jug M, Zovko Končić M, Kosalec I. Modulation of antioxidant, chelating and antimicrobial activity of poplar chemo-type propolis by extraction procures. LWT Food Sci Technol 2014; 57: 530-537
    CrossrefPubMedGoogle Scholar
  • 50 Decker EA, Welch B. Role of ferritin as lipid oxidation catalyst in muscle food. J Agric Food Chem 1990; 38: 674-677
    CrossrefPubMedGoogle Scholar
  • 51 Zovko Končić M, Barbarić M, Perković I, Zorc B. Antiradical, chelating and antioxidant activities of hydroxamic acids and hydroxyureas. Molecules 2011; 16: 6232-6242
    CrossrefPubMedGoogle Scholar
  • 52 Martin L, Castilho C, Silveira I, Abreu JM. Liquid chromatographic validation of a quantitation method for phytoestrogens, biochanin -A, coumestrol, daidzein, formononetin, and genistein, in lucerne. J Liq Chromatogr Relat Technol 2006; 29: 2875-2884
    CrossrefPubMedGoogle Scholar
  • 53 Farndale RW, Buttle DJ, Barrett AJ. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta 1986; 883: 173-177
    CrossrefPubMedGoogle Scholar
  • 54 Kim YJ, Sah RL, Doong JY, Grodzinsky AJ. Fluorometric assay of DNA in cartilage explants using Hoechst 33258. Anal Biochem 1988; 174: 168-176
    CrossrefPubMedGoogle Scholar