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Planta Med 2018; 84(09/10): 568-583
DOI: 10.1055/s-0044-100622
Reviews
Georg Thieme Verlag KG Stuttgart · New York

Aspalathin from Rooibos (Aspalathus linearis): A Bioactive C-glucosyl Dihydrochalcone with Potential to Target the Metabolic Syndrome

Rabia Johnson
1   Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg, South Africa
2   Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
,
Dalene de Beer
3   Plant Bioactives Group, Post-Harvest and Agro-Processing Technologies, Agricultural Research Council (ARC), Infruitec-Nietvoorbij, Stellenbosch, South Africa
4   Department of Food Science, Stellenbosch University, Stellenbosch, South Africa
,
Phiwayinkosi V. Dludla
1   Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg, South Africa
2   Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
,
Daneel Ferreira
5   Department of BioMolecular Sciences, Division of Pharmacognosy and the Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, Oxford, Mississippi, United States
,
Christo J. F. Muller
1   Biomedical Research and Innovation Platform (BRIP), Medical Research Council (MRC), Tygerberg, South Africa
2   Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa
6   Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa, South Africa
,
Elizabeth Joubert
3   Plant Bioactives Group, Post-Harvest and Agro-Processing Technologies, Agricultural Research Council (ARC), Infruitec-Nietvoorbij, Stellenbosch, South Africa
4   Department of Food Science, Stellenbosch University, Stellenbosch, South Africa
› Author Affiliations
Further Information

Publication History

received 10 November 2017
revised 19 December 2017

accepted 28 December 2017

Publication Date:
31 January 2018 (online)

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Abstract

Aspalathin is a C-glucosyl dihydrochalcone that is abundantly present in Aspalathus linearis. This endemic South African plant, belonging to the Cape Floristic region, is normally used for production of rooibos, a herbal tea. Aspalathin was valued initially only as precursor in the formation of the characteristic red-brown colour of “fermented” rooibos, but the hype about the potential role of natural antioxidants to alleviate oxidative stress, shifted interest in aspalathin to its antioxidant properties and subsequently, its potential role to improve metabolic syndrome, a disease condition interrelated with oxidative stress. The potential use of aspalathin or aspalathin-rich rooibos extracts as a condition-specific nutraceutical is hampered by the limited supply of green rooibos (i.e., “unfermented” plant material) and low levels in “fermented” rooibos, providing incentive for its synthesis. In vitro and in vivo studies relating to the metabolic activity of aspalathin are discussed and cellular mechanisms by which aspalathin improves glucose and lipid metabolism are proposed. Other aspects covered in this review, which are relevant in view of the potential use of aspalathin as an adjunctive therapy, include its poor stability and bioavailability, as well as potential adverse herb-drug interactions, in particular interference with the metabolism of certain commonly prescribed chronic medications for hyperglycaemia and dyslipidaemia.

Key words

Aspalathus linearis - Fabaceae - aspalathin - metabolic syndrome - oxidative stress - molecular mechanism - bioavailability - herb-drug interactions
 

  • References

  • 1 McKee F, Hawkins B. Phlorhizin glucosuria. Physiol Rev 1945; 25: 255-280
    CrossrefPubMedGoogle Scholar
  • 2 Swain T. Economic Importance of flavonoid Compounds: Foodstuffs. In: Geissman T. ed. The Chemistry of flavonoid Compounds. London, UK: Pergamon Press; 1962: 513-552
    Google Scholar
  • 3 Idris I, Donnelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes Metab 2009; 11: 79-88
    CrossrefPubMedGoogle Scholar
  • 4 Jesus AR, Vila-Viçosa D, Machuqueiro M, Marques AP, Dore TM, Rauter AP. Targeting type 2 diabetes with C-glucosyl dihydrochalcones as selective sodium glucose co-transporter 2 (SGLT2) inhibitors: synthesis and biological evaluation. J Med Chem 2017; 60: 568-579
    CrossrefPubMedGoogle Scholar
  • 5 Blaschek W. Natural products as lead compounds for sodium glucose cotransporter (SGLT) inhibitors. Planta Med 2017; 83: 985-993
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Liu W, Wang H, Meng F. In silico modeling of aspalathin and nothofagin against SGLT2. J Theor Comput Chem 2015; 14: 1550056
    CrossrefPubMedGoogle Scholar
  • 7 PubChem Compound Database CID: 11282394. National Center for Biotechnology Information. Available at. https://pubchem.ncbi.nlm.nih.gov/compound/11282394 Accessed September 13, 2017
    PubMedGoogle Scholar
  • 8 Chemspider CSID: 9457391. Available at. http://www.chemspider.com/Chemical-Structure9457391.html Accessed September 13, 2017
    PubMedGoogle Scholar
  • 9 Koeppen BH, Roux DG. Aspalathin: a novel C-glycosylflavonoid from Aspalathus linearis . Tetrahedron Lett 1965; 39: 3497-3503
    PubMedGoogle Scholar
  • 10 Bowles S, Joubert E, De Beer D, Louw J, Brunschwig C, Njoroge M, Lawrence N, Wiesner L, Chibale K, Muller C. Intestinal transport characteristics and metabolism of C-glucosyl dihydrochalcone, aspalathin. Molecules 2017; 22: E554
    CrossrefPubMedGoogle Scholar
  • 11 Huang M, Du Plessis J, Du Preez J, Hamman J, Viljoen A. Transport of aspalathin, a rooibos tea flavonoid, across the skin and intestinal epithelium. Phyther Res 2008; 22: 699-704
    PubMedGoogle Scholar
  • 12 Behzad S, Sureda A, Barreca D, Nabavi SF, Rastrelli L, Nabavi SM. Health effects of phloretin: from chemistry to medicine. Phytochem Rev 2017; 16: 527-533
    CrossrefPubMedGoogle Scholar
  • 13 Dahlgren R. Revision of the genus Aspalathus. II. The species with ericoid and pinoid leaflets. 7. Subgenus Nortieria. With remarks on rooibos tea cultivation. Bot Not 1968; 121: 165-208
    PubMedGoogle Scholar
  • 14 Dahlgren R. Crotalarieae (Aspalathus). Flora South Africa 1988; 16: 84-90
    PubMedGoogle Scholar
  • 15 Stander M, Van Wyk B, Taylor MJC, Long HS. Analysis of phenolic compounds in rooibos tea (Aspalathus linearis) with a comparison of flavonoid-based compounds in natural populations of plants from different regions. J Agric Food Chem 2017; 65: 10270-10281
    CrossrefPubMedGoogle Scholar
  • 16 Van Wyk BE, Gorelik B. The history and ethnobotany of Cape herbal teas. South African J Bot 2017; 110: 18-38
    CrossrefPubMedGoogle Scholar
  • 17 Malgas RR, Potts AJ, Oettlé NM, Koelle B, Todd SW, Verboom GA, Hoffman MT. Distribution, quantitative morphological variation and preliminary molecular analysis of different growth forms of wild rooibos (Aspalathus linearis) in the northern Cederberg and on the Bokkeveld Plateau. South African J Bot 2010; 76: 72-81
    CrossrefPubMedGoogle Scholar
  • 18 Hawkins HJ, Malgas R, Biénabe E. Ecotypes of wild rooibos (Aspalathus linearis (Burm. F) Dahlg., Fabaceae) are ecologically distinct. South African J Bot 2011; 77: 360-370
    CrossrefPubMedGoogle Scholar
  • 19 Van Heerden FR, Van Wyk BE, Viljoen AM, Steenkamp PA. Phenolic variation in wild populations of Aspalathus linearis (rooibos tea). Biochem Syst Ecol 2003; 31: 885-895
    CrossrefPubMedGoogle Scholar
  • 20 Joubert E, Schulz H. Production and quality aspects of rooibos tea and related products. A review. J Appl Bot Food Qual 2006; 80: 138-144
    PubMedGoogle Scholar
  • 21 Joubert E, De Beer D, Malherbe CJ, Muller N, Bonnet SL, Van der Westhuizen JH, Ferreira D. Occurrence and sensory perception of Z-2-(β-D-glucopyranosyloxy)-3-phenylpropenoic acid in rooibos (Aspalathus linearis). Food Chem 2013; 136: 1078-1085
    CrossrefPubMedGoogle Scholar
  • 22 Joubert E, De Beer D. Rooibos (Aspalathus linearis) beyond the farm gate: From herbal tea to potential phytopharmaceutical. South African J Bot 2011; 77: 869-886
    CrossrefPubMedGoogle Scholar
  • 23 Koch IS, Muller M, Joubert E, Van der Rijst M, Næs T. Sensory characterization of rooibos tea and the development of a rooibos sensory wheel and lexicon. Food Res Int 2012; 46: 217-228
    CrossrefPubMedGoogle Scholar
  • 24 Jolley B, Van der Rijst M, Joubert E, Muller M. Sensory profile of rooibos originating from the Western and Northern Cape governed by production year and development of rooibos aroma wheel. South African J Bot 2017; 110: 161-166
    CrossrefPubMedGoogle Scholar
  • 25 De Beer D, Miller N, Joubert E. Production of dihydrochalcone-rich green rooibos (Aspalathus linearis) extract taking into account seasonal and batch-to-batch variation in phenolic composition of plant material. South African J Bot 2017; 110: 138-143
    CrossrefPubMedGoogle Scholar
  • 26 Joubert E, De Beer D. Phenolic content and antioxidant activity of rooibos food ingredient extracts. J Food Compos Anal 2012; 27: 45-51
    CrossrefPubMedGoogle Scholar
  • 27 Viljoen M, Muller M, De Beer D, Joubert E. Identification of broad-based sensory attributes driving consumer preference of ready-to-drink rooibos iced tea with increased aspalathin content. South African J Bot 2017; 110: 177-183
    CrossrefPubMedGoogle Scholar
  • 28 Muller CJF, Malherbe CJ, Chellan N, Yagasaki K, Miura Y, Joubert E. Potential of rooibos, its major C-glucosyl flavonoids and Z-2-(β-D-glucopyranosyloxy)-3-phenylpropenoic acid in prevention of metabolic syndrome. Crit Rev Food Sci Nutr 2018; 58: 227-246
    CrossrefPubMedGoogle Scholar
  • 29 Joubert E, Beelders T, De Beer D, Malherbe CJ, De Villiers A, Sigge GO. Variation in phenolic content and antioxidant activity of fermented rooibos herbal tea infusions: role of production season and quality grade. J Agric Food Chem 2012; 60: 9171-9179
    CrossrefPubMedGoogle Scholar
  • 30 De Beer D, Malherbe CJ, Beelders T, Willenburg EL, Brand DJ, Joubert E. Isolation of aspalathin and nothofagin from rooibos (Aspalathus linearis) using high-performance countercurrent chromatography: sample loading and compound stability considerations. J Chromatogr A 2015; 1381: 29-36
    CrossrefPubMedGoogle Scholar
  • 31 Joubert E. HPLC quantification of the dihydrochalcones, aspalathin and nothofagin in rooibos tea (Aspalathus linearis) as affected by processing. Food Chem 1996; 55: 403-411
    CrossrefPubMedGoogle Scholar
  • 32 Bramati L, Minoggio M, Gardana C, Simonetti P, Mauri P, Pietta P. Quantitative characterization of flavonoid compounds in rooibos tea (Aspalathus linearis) by LC−UV/DAD. J Agric Food Chem 2002; 50: 5513-5519
    CrossrefPubMedGoogle Scholar
  • 33 Breiter T, Laue C, Kressel G, Gröll S, Engelhardt UH, Hahn A. Bioavailability and antioxidant potential of rooibos flavonoids in humans following the consumption of different rooibos formulations. Food Chem 2011; 128: 338-347
    CrossrefPubMedGoogle Scholar
  • 34 Beelders T, Sigge GO, Joubert E, De Beer D, De Villiers A. Kinetic optimisation of the reversed phase liquid chromatographic separation of rooibos tea (Aspalathus linearis) phenolics on conventional high performance liquid chromatographic instrumentation. J Chromatogr A 2012; 1219: 128-139
    CrossrefPubMedGoogle Scholar
  • 35 Schulz H, Joubert E, Schütze W. Quantification of quality parameters for reliable evaluation of green rooibos (Aspalathus linearis). Eur Food Res Technol 2003; 216: 539-543
    CrossrefPubMedGoogle Scholar
  • 36 Stalmach A, Mullen W, Pecorari M, Serafini M, Crozier A. Bioavailability of C-linked dihydrochalcone and flavanone glucosides in humans following ingestion of unfermented and fermented rooibos teas. J Agric Food Chem 2009; 57: 7104-7111
    CrossrefPubMedGoogle Scholar
  • 37 Walters NA, De Villiers A, Joubert E, De Beer D. Improved HPLC method for rooibos phenolics targeting changes due to fermentation. J Food Compos Anal 2017; 55: 20-29
    CrossrefPubMedGoogle Scholar
  • 38 Kazuno S, Yanagida M, Shindo N, Murayama K. Mass spectrometric identification and quantification of glycosyl flavonoids, including dihydrochalcones with neutral loss scan mode. Anal Biochem 2005; 347: 182-192
    CrossrefPubMedGoogle Scholar
  • 39 Arries WJ, Tredoux AG, De Beer D, Joubert E, De Villiers A. Evaluation of capillary electrophoresis for the analysis of rooibos and honeybush tea phenolics. Electrophoresis 2017; 38: 897-905
    CrossrefPubMedGoogle Scholar
  • 40 Koeppen B. The Ethyl Acetate soluble Polyphenols of Rooibos Tea [MSc in Food Technology thesis]. Stellenbosch, South Africa: Stellenbosch University; 1959
    PubMedGoogle Scholar
  • 41 Koeppen B. The flavonoid Constituents of Aspalathus acuminatus [PhD in Food Technology thesis]. Stellenbosch, South Africa: Stellenbosch University; 1961
    PubMedGoogle Scholar
  • 42 Koeppen BH, Roux DG. C-glycosylflavonoids. The chemistry of aspalathin. Biochem J 1966; 99: 604-609
    CrossrefPubMedGoogle Scholar
  • 43 Rabe C, Steenkamp JA, Joubert E, Burger JFW, Ferreira D. Phenolic metabolites from rooibos tea (Aspalathus linearis). Phytochemistry 1994; 35: 1559-1565
    CrossrefPubMedGoogle Scholar
  • 44 Marais C, Van Rensburg WJ, Ferreira D, Steenkamp JA. (S)- and (R)-eriodictyol-6-C-β-D-glucopyranoside, novel keys to the fermentation of rooibos (Aspalathus linearis). Phytochemistry 2000; 55: 43-49
    CrossrefPubMedGoogle Scholar
  • 45 Krafczyk N, Glomb MA. Characterization of phenolic compounds in rooibos tea. J Agric Food Chem 2008; 56: 3368-3376
    CrossrefPubMedGoogle Scholar
  • 46 Krafczyk N, Heinrich T, Porzel A, Glomb MA. Oxidation of the dihydrochalcone aspalathin leads to dimerization. J Agric Food Chem 2009; 57: 6838-6843
    CrossrefPubMedGoogle Scholar
  • 47 Heinrich T, Willenberg I, Glomb MA. Chemistry of color formation during rooibos fermentation. J Agric Food Chem 2012; 60: 5221-5228
    CrossrefPubMedGoogle Scholar
  • 48 Joubert E, Viljoen M, De Beer D, Manley M. Effect of heat on aspalathin, iso-orientin, and orientin contents and color of fermented rooibos (Aspalathus linearis) iced tea. J Agric Food Chem 2009; 57: 4204-4211
    CrossrefPubMedGoogle Scholar
  • 49 Scalbert A, Johnson IT, Saltmarsh M. Polyphenols: antioxidants and beyond. Am J Clin Nutr 2005; 81: 215-217
    CrossrefPubMedGoogle Scholar
  • 50 Joubert E, Gelderblom WCA, Louw A, De Beer D. South African herbal teas: Aspalathus linearis, Cyclopia spp. and Athrixia phylicoides – a review. J Ethnopharmacol 2008; 119: 376-412
    CrossrefPubMedGoogle Scholar
  • 51 Fraga CG, Galleano M, Verstraeten SV, Oteiza PI. Basic biochemical mechanisms behind the health benefits of polyphenols. Mol Aspects Med 2010; 31: 435-445
    CrossrefPubMedGoogle Scholar
  • 52 Joubert E, Winterton P, Britz TJ, Ferreira D. Superoxide anion and α,α-diphenyl-β-picrylhydrazyl radical scavenging capacity of rooibos (Aspalathus linearis) aqueous extracts, crude phenolic fractions, tannin and flavonoids. Food Res Int 2004; 37: 133-138
    CrossrefPubMedGoogle Scholar
  • 53 Joubert E, Winterton P, Britz TJ, Gelderblom WCA. Antioxidant and pro-oxidant activities of aqueous extracts and crude polyphenolic fractions of rooibos (Aspalathus linearis). J Agric Food Chem 2005; 53: 10260-10267
    CrossrefPubMedGoogle Scholar
  • 54 Snijman PW, Joubert E, Ferreira D, Li XC, Ding Y, Green IR, Gelderblom WCA. Antioxidant activity of the dihydrochalcones aspalathin and nothofagin and their corresponding flavones in relation to other rooibos (Aspalathus linearis) flavonoids, epigallocatechin gallate, and Trolox. J Agric Food Chem 2009; 57: 6678-6684
    CrossrefPubMedGoogle Scholar
  • 55 Von Gadow A, Joubert E, Hansmann CF. Comparison of the antioxidant activity of aspalathin with that of other plant phenols of rooibos tea (Aspalathus linearis), α-tocopherol, BHT, and BHA. J Agric Food Chem 1997; 45: 632-638
    CrossrefPubMedGoogle Scholar
  • 56 Krafczyk N, Woyand F, Glomb MA. Structure-antioxidant relationship of flavonoids from fermented rooibos. Mol Nutr Food Res 2009; 53: 635-642
    CrossrefPubMedGoogle Scholar
  • 57 Simpson MJ, Hjelmqvist D, López-Alarcón C, Karamehmedovic N, Minehan TG, Yepremyan A, Salehani B, Lissi E, Joubert E, Udekwu KI, Alarcon EI. Anti-peroxyl radical quality and antibacterial properties of rooibos infusions and their pure glycosylated polyphenolic constituents. Molecules 2013; 18: 11264-11280
    CrossrefPubMedGoogle Scholar
  • 58 Magcwebeba T, Swart P, Swanevelder S, Joubert E, Gelderblom W. Anti-inflammatory effects of Aspalathus linearis and Cyclopia spp. extracts in a UVB/keratinocyte (HaCaT) model utilising interleukin-1α accumulation as biomarker. Molecules 2016; 21: E1323
    CrossrefPubMedGoogle Scholar
  • 59 Rezk BM, Van der Vijgh WJF, Bast A. The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids. Biochem Biophys Res Commun 2002; 295: 9-13
    CrossrefPubMedGoogle Scholar
  • 60 Yepremyan A, Salehani B, Minehan TG. Concise total syntheses of aspalathin and nothofagin. Org Lett 2010; 12: 1580-1583
    CrossrefPubMedGoogle Scholar
  • 61 Han Z, Achilonu MC, Kendrekar PS, Joubert E, Ferreira D, Bonnet SL, Van der Westhuizen JH. Concise and scalable synthesis of aspalathin, a powerful plasma sugar-lowering natural product. J Nat Prod 2014; 77: 583-588
    CrossrefPubMedGoogle Scholar
  • 62 Van der Westhuizen JH, Ferreira D, Joubert E, Bonnet SL. B2 Method for the synthesis of aspalathin and analogues thereof. US Patent US 9181293; 2015.
    PubMedGoogle Scholar
  • 63 Zhang T, Fang Z. The concise synthesis and biological evaluation of C-glycosyl chalcone analogues inspired by the natural product aspalathin. RSC Adv 2017; 7: 3021-3024
    CrossrefPubMedGoogle Scholar
  • 64 Bungaruang L, Gutmann A, Nidetzky B. Leloir glycosyltransferases and natural product glycosylation: Biocatalytic synthesis of the C-glucoside nothofagin, a major antioxidant of redbush herbal tea. Adv Synth Catal 2013; 355: 2757-2763
    CrossrefPubMedGoogle Scholar
  • 65 Bungaruang L, Gutmann A, Nidetzky B. β-Cyclodextrin improves solubility and enzymatic C-glucosylation of the flavonoid phloretin. Adv Synth Catal 2016; 358: 486-493
    CrossrefPubMedGoogle Scholar
  • 66 Eichenberger M, Lehka BJ, Folly C, Fischer D, Martens S, Simón E, Naesby M. Metabolic engineering of Saccharomyces cerevisiae for de novo production of dihydrochalcones with known antioxidant, antidiabetic, and sweet tasting properties. Metab Eng 2017; 39: 80-89
    CrossrefPubMedGoogle Scholar
  • 67 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23: 3-25
    CrossrefPubMedGoogle Scholar
  • 68 Di L, Kerns EH. Profiling drug-like properties in discovery research. Curr Opin Chem Biol 2003; 7: 402-408
    CrossrefPubMedGoogle Scholar
  • 69 Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002; 45: 2615-2623
    CrossrefPubMedGoogle Scholar
  • 70 Courts FL, Williamson G. The occurrence, fate and biological activities of C-glycosyl flavonoids in the human diet. Crit Rev Food Sci Nutr 2015; 10: 1352-1367
    PubMedGoogle Scholar
  • 71 Van der Merwe JD, Joubert E, Manley M, De Beer D, Malherbe CJ, Gelderblom WCA. In vitro hepatic biotransformation of aspalathin and nothofagin, dihydrochalcones of rooibos (Aspalathus linearis), and assessment of metabolite antioxidant activity. J Agric Food Chem 2010; 58: 2214-2220
    CrossrefPubMedGoogle Scholar
  • 72 Courts FL, Williamson G. The C-glycosyl flavonoid, aspalathin, is absorbed, methylated and glucuronidated intact in humans. Mol Nutr Food Res 2009; 53: 1104-1111
    CrossrefPubMedGoogle Scholar
  • 73 Kreuz S, Joubert E, Waldmann KH, Ternes W. Aspalathin, a flavonoid in Aspalathus linearis (rooibos), is absorbed by pig intestine as a C-glycoside. Nutr Res 2008; 28: 690-701
    CrossrefPubMedGoogle Scholar
  • 74 Gonzales GB, Van Camp J, Vissenaekens H, Raes K, Smagghe G, Grootaert C. Review on the use of cell cultures to study metabolism, transport, and accumulation of flavonoids: from mono-cultures to co-culture systems. Compr Rev Food Sci Food Saf 2015; 14: 741-754
    CrossrefPubMedGoogle Scholar
  • 75 Braune A, Blaut M. Deglycosylation of puerarin and other aromatic C-glucosides by a newly isolated human intestinal bacterium. Environ Microbiol 2011; 13: 482-494
    CrossrefPubMedGoogle Scholar
  • 76 Sanugul K, Akao T, Li Y, Kakiuchi N, Nakamura N, Hattori M. Isolation of a human intestinal bacterium that transforms mangiferin to norathyriol and inducibility of the enzyme that cleaves a C-glucosyl bond. Biol Pharm Bull 2005; 28: 1672-1678
    CrossrefPubMedGoogle Scholar
  • 77 Nakamura K, Nishihata T, Jin JS, Ma CM, Komatsu K, Iwashima M, Hattori M. The C-glucosyl bond of puerarin was cleaved hydrolytically by a human intestinal bacterium strain PUE to yield its aglycone daidzein and an intact glucose. Chem Pharm Bull 2011; 59: 23-27
    CrossrefPubMedGoogle Scholar
  • 78 Braune A, Blaut M. Intestinal bacterium Eubacterium cellulosolvens deglycosylates flavonoid C- and O-glucosides. Appl Environ Microbiol 2012; 78: 8151-8153
    CrossrefPubMedGoogle Scholar
  • 79 World Health Organization. World health statistics 2012. World Health Organization. Available at. http://apps.who.int/iris/bitstream/10665/44844/1/9789241564441_eng.pdf?ua=1 Accessed September 25, 2017
    PubMedGoogle Scholar
  • 80 Grundy SM, Brewer HB, Cleeman JI, Smith SC, Lenfant C. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109: 433-438
    CrossrefPubMedGoogle Scholar
  • 81 GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017; 377: 13-27
    CrossrefPubMedGoogle Scholar
  • 82 International Diabetes Federation. IDF diabetes atlas, 7th Edition. International Diabetes Federation. Available at. https://www.idf.org/e-library/epidemiology-research/diabetes-atlas/13-diabetes-atlas-seventh-edition.html Accessed September 25, 2017
    PubMedGoogle Scholar
  • 83 Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol 2013; 4: 37
    PubMedGoogle Scholar
  • 84 Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005; 42: 987-1000
    CrossrefPubMedGoogle Scholar
  • 85 Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010; 2010: 289645
    PubMedGoogle Scholar
  • 86 Aude YW, Mego P, Mehta JL. Metabolic syndrome: dietary interventions. Curr Opin Cardiol 2004; 19: 473-479
    CrossrefPubMedGoogle Scholar
  • 87 Ren J, Zhu W, Dai H, Chen Z, Chen L, Fang L. Nutritional intervention in the metabolic syndrome. Asia Pac J Clin Nutr 2007; 16: 418-421
    PubMedGoogle Scholar
  • 88 Dludla PV, Muller CJF, Joubert E, Louw J, Essop MF, Gabuza KB, Ghoor S, Huisamen B, Johnson R. Aspalathin protects the heart against hyperglycemia-induced oxidative damage by up-regulating Nrf2 expression. Molecules 2017; 22: E129
    CrossrefPubMedGoogle Scholar
  • 89 Zhang Z, Zhou S, Jiang X, Wang YH, Li F, Wang YG, Zheng Y, Cai L. The role of the Nrf2/Keap1 pathway in obesity and metabolic syndrome. Rev Endocr Metab Disord 2015; 16: 35-45
    CrossrefPubMedGoogle Scholar
  • 90 Tang W, Jiang YF, Ponnusamy M, Diallo M. Role of Nrf2 in chronic liver disease. World J Gastroenterol 2014; 20: 13079-13087
    CrossrefPubMedGoogle Scholar
  • 91 Johnson R, Dludla P, Muller C, Huisamen B, Essop M, Louw J. The transcription profile unveils the cardioprotective effect of aspalathin against lipid toxicity in an in vitro H9c2 model. Molecules 2017; 22: E219
    CrossrefPubMedGoogle Scholar
  • 92 Mazibuko SE, Joubert E, Johnson R, Louw J, Opoku AR, Muller CJF. Aspalathin improves glucose and lipid metabolism in 3T3-L1 adipocytes exposed to palmitate. Mol Nutr Food Res 2015; 59: 2199-2208
    CrossrefPubMedGoogle Scholar
  • 93 Yuan G, Wahlqvist ML, He G, Yang M, Li D. Natural products and anti-inflammatory activity. Asia Pac J Clin Nutr 2006; 15: 143-152
    PubMedGoogle Scholar
  • 94 Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol 2013; 3: 1-58
    PubMedGoogle Scholar
  • 95 Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract 2011; 93: S52-S59
    CrossrefPubMedGoogle Scholar
  • 96 Fang X, Yu SX, Lu Y, Bast RC, Woodgett JR, Mills GB. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A 2000; 97: 11960-11965
    CrossrefPubMedGoogle Scholar
  • 97 Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 2001; 276: 38349-38352
    CrossrefPubMedGoogle Scholar
  • 98 Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 2013; 123: 2764-2772
    CrossrefPubMedGoogle Scholar
  • 99 Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab 2007; 5: 237-252
    CrossrefPubMedGoogle Scholar
  • 100 OʼNeill HM. AMPK and exercise: glucose uptake and insulin sensitivity. Diabetes Metab J 2013; 37: 1-21
    CrossrefPubMedGoogle Scholar
  • 101 Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med 2016; 48: e224
    CrossrefPubMedGoogle Scholar
  • 102 Johnson R, Dludla P, Joubert E, February F, Mazibuko S, Ghoor S, Muller C, Louw J. Aspalathin, a dihydrochalcone C-glucoside, protects H9c2 cardiomyocytes against high glucose induced shifts in substrate preference and apoptosis. Mol Nutr Food Res 2016; 60: 922-934
    CrossrefPubMedGoogle Scholar
  • 103 Viollet B, Horman S, Leclerc J, Lantier L, Foretz M, Billaud M, Giri S, Andreelli F. AMPK inhibition in health and disease. Crit Rev Biochem Mol Biol 2010; 45: 276-295
    CrossrefPubMedGoogle Scholar
  • 104 Dyck JRB, Lopaschuk GD. AMPK alterations in cardiac physiology and pathology: enemy or ally?. J Physiol 2006; 574: 95-112
    CrossrefPubMedGoogle Scholar
  • 105 Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 2009; 50: S138-S143
    CrossrefPubMedGoogle Scholar
  • 106 Frayn KN, Arner P, Yki-Jarvinen H. Fatty acid metabolism in adipose tissue, muscle and liver in health and disease. Essays Biochem 2006; 42: 89-103
    CrossrefPubMedGoogle Scholar
  • 107 Serra D, Mera P, Malandrino MI, Mir JF, Herrero L. Mitochondrial fatty acid oxidation in obesity. Antioxid Redox Signal 2013; 19: 269-284
    CrossrefPubMedGoogle Scholar
  • 108 Lara-Castro C, Garvey WT. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinol Metab Clin North Am 2008; 37: 841-856
    CrossrefPubMedGoogle Scholar
  • 109 Turner N, Cooney GJ, Kraegen EW, Bruce CR. Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J Endocrinol 2014; 220: T61-T79
    CrossrefPubMedGoogle Scholar
  • 110 Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107: 1058-1070
    CrossrefPubMedGoogle Scholar
  • 111 Lu SC. Regulation of glutathione synthesis. Mol Aspects Med 2009; 30: 42-59
    CrossrefPubMedGoogle Scholar
  • 112 Pham-Huy L, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008; 4: 89-96
    PubMedGoogle Scholar
  • 113 Niedowicz DM, Daleke DL. The role of oxidative stress in diabetic complications. Cell Biochem Biophys 2005; 43: 289-330
    CrossrefPubMedGoogle Scholar
  • 114 Rani V, Deep G, Singh RK, Palle K, Yadav UCS. Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies. Life Sci 2016; 148: 183-193
    CrossrefPubMedGoogle Scholar
  • 115 Newsholme P, Cruzat VF, Keane KN, Carlessi R, De Bittencourt PIH. Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem J 2016; 473: 4527-4550
    CrossrefPubMedGoogle Scholar
  • 116 Yesilbursa D, Serdar Z, Serdar A, Sarac M, Coskun S, Jale C. Lipid peroxides in obese patients and effects of weight loss with orlistat on lipid peroxides levels. Int J Obes 2005; 29: 142-145
    CrossrefPubMedGoogle Scholar
  • 117 Avci E, Avci GA, Cevher SC. The role of malondialdehyde and glutathione in metabolic syndromeʼs complications. J Biotechnol 2017; 256: S32
    PubMedGoogle Scholar
  • 118 Caimi G, Hopps E, Montana M, Noto D, Canino B, Lo Presti R, Averna MR. Evaluation of nitric oxide metabolites in a group of subjects with metabolic syndrome. Diabetes Metab Syndr Clin Res Rev 2012; 6: 132-135
    CrossrefPubMedGoogle Scholar
  • 119 Nour Eldin EE, Almarzouki A, Assiri A, Elsheikh O, Mohamed BE, Babakr A. Oxidized low density lipoprotein and total antioxidant capacity in type-2 diabetic and impaired glucose tolerance Saudi men. Diabetol Metab Syndr 2014; 6: 94
    CrossrefPubMedGoogle Scholar
  • 120 McArdle MA, Finucane OM, Connaughton RM, McMorrow AM, Roche HM. Mechanisms of obesity-induced inflammation and insulin resistance: Insights into the emerging role of nutritional strategies. Front Endocrinol 2013; 4: 52
    PubMedGoogle Scholar
  • 121 DeBoer MD. Obesity, systemic inflammation, and increased risk for cardiovascular disease and diabetes among adolescents: a need for screening tools to target interventions. Nutrition 2013; 29: 379-386
    CrossrefPubMedGoogle Scholar
  • 122 Moreno-Indias I, Tinahones FJ. Impaired adipose tissue expandability and lipogenic capacities as ones of the main causes of metabolic disorders. J Diabetes Res 2015; 2015: 970375
    PubMedGoogle Scholar
  • 123 Jung U, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 2014; 15: 6184-6223
    CrossrefPubMedGoogle Scholar
  • 124 Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol 2013; 4: 71
    PubMedGoogle Scholar
  • 125 De Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 2008; 54: 945-955
    CrossrefPubMedGoogle Scholar
  • 126 Sharma A, Holland W. Adiponectin and its hydrolase-activated receptors. J Nat Sci 2017; 3: e396
    PubMedGoogle Scholar
  • 127 Liu C, Feng X, Li Q, Wang Y, Li Q, Hua M. Adiponectin, TNF-α and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis. Cytokine 2016; 86: 100-109
    CrossrefPubMedGoogle Scholar
  • 128 Popa C, Netea MG, van Riel PL, van der Meer JWM, Stalenhoef AFH. The role of TNF-α in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J Lipid Res 2007; 48: 751-762
    CrossrefPubMedGoogle Scholar
  • 129 Lee S, Kwak HB. Role of adiponectin in metabolic and cardiovascular disease. J Exerc Rehabil 2014; 10: 54-59
    CrossrefPubMedGoogle Scholar
  • 130 Tsatsanis C, Zacharioudaki V, Androulidaki A, Dermitzaki E, Charalampopoulos I, Minas V, Gravanis A, Margioris AN. Adiponectin induces TNF-α and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem Biophys Res Commun 2005; 335: 1254-1263
    CrossrefPubMedGoogle Scholar
  • 131 Tzanavari T, Giannogonas P, Karalis KP. TNF-α and Obesity. In: Kollias G, Sfikakis P. edis TNF Pathophysiology. Molecular and cellular Mechanisms. Basel, Switzerland: Karger; 2010: 145-156
    Google Scholar
  • 132 Pacifico L, Chiesa C, Anania C, De Merulis A, Osborn JF, Romaggioli S, Gaudio E. Nonalcoholic fatty liver disease and the heart in children and adolescents. World J Gastroenterol 2014; 20: 9055-9071
    PubMedGoogle Scholar
  • 133 Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013; 2013: 139239
    CrossrefPubMedGoogle Scholar
  • 134 Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016; 65: 1038-1048
    Google Scholar
  • 135 Diraison F, Dusserre E, Vidal H, Sothier M, Beylot M. Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity. Am J Physiol Endocrinol Metab 2002; 282: E46-E51
    CrossrefPubMedGoogle Scholar
  • 136 Dichtl W, Nilsson L, Goncalves I, Ares MPS, Banfi C, Calara F, Hamsten A, Eriksson P, Nilsson J. Very low-density lipoprotein activates nuclear factor-κB in endothelial cells. Circ Res 1999; 84: 1085-1094
    CrossrefPubMedGoogle Scholar
  • 137 Lorenzon P, Vecile E, Nardon E, Ferrero E, Harlan JM, Tedesco F, Dobrina A. Endothelial cell E- and P-selectin and vascular cell adhesion molecule-1 function as signaling receptors. J Cell Biol 1998; 142: 1381-1391
    CrossrefPubMedGoogle Scholar
  • 138 Amiot MJ, Riva C, Vinet A. Effects of dietary polyphenols on metabolic syndrome features in humans: a systematic review. Obes Rev 2016; 17: 573-586
    CrossrefPubMedGoogle Scholar
  • 139 Kawano A, Nakamura H, Hata S, Minakawa M, Miura Y, Yagasaki K. Hypoglycemic effect of aspalathin, a rooibos tea component from Aspalathus linearis, in type 2 diabetic model db/db mice. Phytomedicine 2009; 16: 437-443
    CrossrefPubMedGoogle Scholar
  • 140 Muller CJF, Joubert E, De Beer D, Sanderson M, Malherbe CJ, Fey SJ, Louw J. Acute assessment of an aspalathin-enriched green rooibos (Aspalathus linearis) extract with hypoglycemic potential. Phytomedicine 2012; 20: 32-39
    Google Scholar
  • 141 Mikami N, Tsujimura J, Sato A, Narasada A, Shigeta M, Kato M, Hata S, Hitomi E. Green rooibos extract from Aspalathus linearis, and its component, aspalathin, suppress elevation of blood glucose levels in mice and inhibit α-amylase and α-glucosidase activities in vitro. Food Sci Technol Res 2015; 21: 231-240
    Google Scholar
  • 142 Mazibuko SE, Muller CJF, Joubert E, De Beer D, Johnson R, Opoku AR, Louw J. Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis). Phytomedicine 2013; 20: 813-819
    CrossrefPubMedGoogle Scholar
  • 143 Son MJ, Minakawa M, Miura Y, Yagasaki K. Aspalathin improves hyperglycemia and glucose intolerance in obese diabetic ob/ob mice. Eur J Nutr 2013; 52: 1607-1619
    Google Scholar
  • 144 Smit S, Johnson R, Van Vuuren M, Huisamen B. Myocardial glucose clearance by aspalathin treatment in young, mature, and obese insulin-resistant rats. Planta Med 2018; 84: 75-83
    Google Scholar
  • 145 Johnson R, Shabalala S, Louw J, Kappo A, Muller C. Aspalathin reverts doxorubicin-induced cardiotoxicity through ncreased autophagy and decreased expression of p53/mTOR/p62 Signaling. Molecules 2017; 22: E1589
    CrossrefPubMedGoogle Scholar
  • 146 Najafian M, Najafian B, Najafian Z. The effect of aspalathin on levels of sugar and lipids in streptozotocin-induced diabetic and normal rats. Zahedan J Res Med Sci 2016; 18: e4963
    PubMedGoogle Scholar
  • 147 Van der Merwe J, De Beer D, Joubert E, Gelderblom W. Short-term and sub-chronic dietary exposure to aspalathin-enriched green rooibos (Aspalathus linearis) extract affects rat liver function and antioxidant status. Molecules 2015; 20: 22674-22690
    CrossrefPubMedGoogle Scholar
  • 148 Oikari S, Ahtialansaari T, Heinonen MV, Mauriala T, Auriola S, Kiehne K, Fölsch UR, Jänne J, Alhonen L, Herzig KH. Downregulation of PPARs and SREBP by acyl-CoA-binding protein overexpression in transgenic rats. Pflügers Arch 2008; 456: 369-377
    CrossrefPubMedGoogle Scholar
  • 149 Yang G, Lee J, Lee S, Kwak D, Choe W, Kang I, Kim SS, Ha J. Krill oil supplementation improves dyslipidemia and lowers body weight in mice fed a high-fat diet through activation of AMP-activated protein kinase. J Med Food 2016; 19: 1120-1129
    CrossrefPubMedGoogle Scholar
  • 150 Hardie DG. Regulation of AMP-activated protein kinase by natural and synthetic activators. Acta Pharm Sin B 2016; 6: 1-19
    CrossrefPubMedGoogle Scholar
  • 151 Van der Merwe JD, De Beer D, Joubert E, Gelderblom WCA. Erratum: Short-term and sub-chronic dietary exposure to aspalathin-enriched green rooibos (Aspalathus linearis) extract affects rat liver function and antioxidant status. Molecules 2016; 21: E907
    CrossrefPubMedGoogle Scholar
  • 152 Chen W, Sudji IR, Wang E, Joubert E, Van Wyk BE, Wink M. Ameliorative effect of aspalathin from rooibos (Aspalathus linearis) on acute oxidative stress in Caenorhabditis elegans . Phytomedicine 2013; 20: 380-386
    CrossrefPubMedGoogle Scholar
  • 153 Kondo M, Hirano Y, Nishio M, Furuya Y, Nakamura H, Watanabe T. Xanthine oxidase inhibitory activity and hypouricemic effect of aspalathin from unfermented rooibos. J Food Sci 2013; 78: H1935-H1939
    CrossrefPubMedGoogle Scholar
  • 154 Orlando P, Chellan N, Muller C, Louw J, Chapman C, Joubert E, Tiano L. Green rooibos extract improves plasma lipid profile and oxidative status in diabetic non-human primates. Free Radic Biol Med 2017; 108: S96-S97
    PubMedGoogle Scholar
  • 155 Marnewick JL, Rautenbach F, Venter I, Neethling H, Blackhurst DM, Wolmarans P, Macharia M. Effects of rooibos (Aspalathus linearis) on oxidative stress and biochemical parameters in adults at risk for cardiovascular disease. J Ethnopharmacol 2011; 133: 46-52
    Google Scholar
  • 156 Ku SK, Lee W, Kang M, Bae JS. Antithrombotic activities of aspalathin and nothofagin via inhibiting platelet aggregation and FIIa/FXa. Arch Pharm Res 2015; 38: 1080-1089
    CrossrefPubMedGoogle Scholar
  • 157 Ku SK, Kwak S, Kim Y, Bae JS. Aspalathin and nothofagin from rooibos (Aspalathus linearis) inhibits high glucose-induced inflammation in vitro and in vivo . Inflammation 2015; 38: 445-455
    CrossrefPubMedGoogle Scholar
  • 158 Lee W, Kim KM, Bae JS. Ameliorative effect of aspalathin and nothofagin from rooibos (Aspalathus linearis) on HMGB1-induced septic responses in vitro and in vivo . Am J Chin Med 2015; 43: 991-1012
    CrossrefPubMedGoogle Scholar
  • 159 Kurosawa S, Stearns-Kurosawa D, Carson C, DʼAngelo A, Della Valle P, Esmon C. Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: lack of correlation with thrombomodulin suggests involvement of different pathological processes. Blood 1998; 91: 725-728
    CrossrefPubMedGoogle Scholar
  • 160 White C. Inhibitory Effect of selected herbal Supplements on CYP450-mediated Metabolism – an in vitro Approach [MSc in Pharmacology thesis]. Stellenbosch, South Africa: Stellenbosch University; 2016
    PubMedGoogle Scholar
  • 161 Dludla PV, Muller CJF, Louw J, Joubert E, Salie R, Opoku AR, Johnson R. The cardioprotective effect of an aqueous extract of fermented rooibos (Aspalathus linearis) on cultured cardiomyocytes derived from diabetic rats. Phytomedicine 2014; 21: 595-601
    CrossrefPubMedGoogle Scholar
  • 162 Lee W, Bae JS. Anti-inflammatory effects of aspalathin and nothofagin from rooibos (Aspalathus linearis) in vitro and in vivo . Inflammation 2015; 38: 1502-1516
    CrossrefPubMedGoogle Scholar
  • 163 Kwak S, Han MS, Bae JS. Aspalathin and nothofagin from rooibos (Aspalathus linearis) inhibit endothelial protein C receptor shedding in vitro and in vivo . Fitoterapia 2015; 100: 179-186
    CrossrefPubMedGoogle Scholar
  • 164 Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355: 134-138
    CrossrefPubMedGoogle Scholar
  • 165 Sinisalo M, Enkovaara AL, Kivistö KT. Possible hepatotoxic effect of rooibos tea: a case report. Eur J Clin Pharmacol 2010; 66: 427-428
    CrossrefPubMedGoogle Scholar
  • 166 Engels M, Wang C, Matoso A, Maidan E, Wands J. Tea not tincture: hepatotoxicity associated with rooibos herbal tea. ACG Case Reports J 2013; 1: 58-60
    PubMedGoogle Scholar
  • 167 Zacharia CC, Whitlatch H. Rooibos herbal tea linked to hepatotoxicity and severe hypercholesterolemia. Endocrinol Rev 2013; 34: SUN-730
    PubMedGoogle Scholar
  • 168 Patel O, Muller C, Joubert E, Louw J, Rosenkranz B, Awortwe C. Inhibitory interactions of Aspalathus linearis (rooibos) extracts and compounds, aspalathin and Z-2-(β-D-glucopyranosyloxy)-3-phenylpropenoic acid, on cytochromes metabolizing hypoglycemic and hypolipidemic drugs. Molecules 2016; 21: E1515
    CrossrefPubMedGoogle Scholar