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
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 10. November 2017
revised 19. Dezember 2017

accepted 28. Dezember 2017

Publikationsdatum:
31. Januar 2018 (online)

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.

 
  • References

  • 1 McKee F, Hawkins B. Phlorhizin glucosuria. Physiol Rev 1945; 25: 255-280
  • 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
  • 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
  • 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
  • 5 Blaschek W. Natural products as lead compounds for sodium glucose cotransporter (SGLT) inhibitors. Planta Med 2017; 83: 985-993
  • 6 Liu W, Wang H, Meng F. In silico modeling of aspalathin and nothofagin against SGLT2. J Theor Comput Chem 2015; 14: 1550056
  • 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
  • 8 Chemspider CSID: 9457391. Available at. http://www.chemspider.com/Chemical-Structure9457391.html Accessed September 13, 2017
  • 9 Koeppen BH, Roux DG. Aspalathin: a novel C-glycosylflavonoid from Aspalathus linearis . Tetrahedron Lett 1965; 39: 3497-3503
  • 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
  • 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
  • 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
  • 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
  • 14 Dahlgren R. Crotalarieae (Aspalathus). Flora South Africa 1988; 16: 84-90
  • 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
  • 16 Van Wyk BE, Gorelik B. The history and ethnobotany of Cape herbal teas. South African J Bot 2017; 110: 18-38
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 26 Joubert E, De Beer D. Phenolic content and antioxidant activity of rooibos food ingredient extracts. J Food Compos Anal 2012; 27: 45-51
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 40 Koeppen B. The Ethyl Acetate soluble Polyphenols of Rooibos Tea [MSc in Food Technology thesis]. Stellenbosch, South Africa: Stellenbosch University; 1959
  • 41 Koeppen B. The flavonoid Constituents of Aspalathus acuminatus [PhD in Food Technology thesis]. Stellenbosch, South Africa: Stellenbosch University; 1961
  • 42 Koeppen BH, Roux DG. C-glycosylflavonoids. The chemistry of aspalathin. Biochem J 1966; 99: 604-609
  • 43 Rabe C, Steenkamp JA, Joubert E, Burger JFW, Ferreira D. Phenolic metabolites from rooibos tea (Aspalathus linearis). Phytochemistry 1994; 35: 1559-1565
  • 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
  • 45 Krafczyk N, Glomb MA. Characterization of phenolic compounds in rooibos tea. J Agric Food Chem 2008; 56: 3368-3376
  • 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
  • 47 Heinrich T, Willenberg I, Glomb MA. Chemistry of color formation during rooibos fermentation. J Agric Food Chem 2012; 60: 5221-5228
  • 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
  • 49 Scalbert A, Johnson IT, Saltmarsh M. Polyphenols: antioxidants and beyond. Am J Clin Nutr 2005; 81: 215-217
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 56 Krafczyk N, Woyand F, Glomb MA. Structure-antioxidant relationship of flavonoids from fermented rooibos. Mol Nutr Food Res 2009; 53: 635-642
  • 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
  • 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
  • 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
  • 60 Yepremyan A, Salehani B, Minehan TG. Concise total syntheses of aspalathin and nothofagin. Org Lett 2010; 12: 1580-1583
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 68 Di L, Kerns EH. Profiling drug-like properties in discovery research. Curr Opin Chem Biol 2003; 7: 402-408
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 78 Braune A, Blaut M. Intestinal bacterium Eubacterium cellulosolvens deglycosylates flavonoid C- and O-glucosides. Appl Environ Microbiol 2012; 78: 8151-8153
  • 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
  • 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
  • 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
  • 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
  • 83 Cerf ME. Beta cell dysfunction and insulin resistance. Front Endocrinol 2013; 4: 37
  • 84 Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005; 42: 987-1000
  • 85 Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010; 2010: 289645
  • 86 Aude YW, Mego P, Mehta JL. Metabolic syndrome: dietary interventions. Curr Opin Cardiol 2004; 19: 473-479
  • 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
  • 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
  • 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
  • 90 Tang W, Jiang YF, Ponnusamy M, Diallo M. Role of Nrf2 in chronic liver disease. World J Gastroenterol 2014; 20: 13079-13087
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 98 Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 2013; 123: 2764-2772
  • 99 Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab 2007; 5: 237-252
  • 100 OʼNeill HM. AMPK and exercise: glucose uptake and insulin sensitivity. Diabetes Metab J 2013; 37: 1-21
  • 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
  • 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
  • 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
  • 104 Dyck JRB, Lopaschuk GD. AMPK alterations in cardiac physiology and pathology: enemy or ally?. J Physiol 2006; 574: 95-112
  • 105 Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 2009; 50: S138-S143
  • 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
  • 107 Serra D, Mera P, Malandrino MI, Mir JF, Herrero L. Mitochondrial fatty acid oxidation in obesity. Antioxid Redox Signal 2013; 19: 269-284
  • 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
  • 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
  • 110 Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010; 107: 1058-1070
  • 111 Lu SC. Regulation of glutathione synthesis. Mol Aspects Med 2009; 30: 42-59
  • 112 Pham-Huy L, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008; 4: 89-96
  • 113 Niedowicz DM, Daleke DL. The role of oxidative stress in diabetic complications. Cell Biochem Biophys 2005; 43: 289-330
  • 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
  • 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
  • 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
  • 117 Avci E, Avci GA, Cevher SC. The role of malondialdehyde and glutathione in metabolic syndromeʼs complications. J Biotechnol 2017; 256: S32
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 124 Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol 2013; 4: 71
  • 125 De Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 2008; 54: 945-955
  • 126 Sharma A, Holland W. Adiponectin and its hydrolase-activated receptors. J Nat Sci 2017; 3: e396
  • 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
  • 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
  • 129 Lee S, Kwak HB. Role of adiponectin in metabolic and cardiovascular disease. J Exerc Rehabil 2014; 10: 54-59
  • 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
  • 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
  • 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
  • 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
  • 134 Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016; 65: 1038-1048
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 150 Hardie DG. Regulation of AMP-activated protein kinase by natural and synthetic activators. Acta Pharm Sin B 2016; 6: 1-19
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 164 Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355: 134-138
  • 165 Sinisalo M, Enkovaara AL, Kivistö KT. Possible hepatotoxic effect of rooibos tea: a case report. Eur J Clin Pharmacol 2010; 66: 427-428
  • 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
  • 167 Zacharia CC, Whitlatch H. Rooibos herbal tea linked to hepatotoxicity and severe hypercholesterolemia. Endocrinol Rev 2013; 34: SUN-730
  • 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