Coffee Leaves: An Upcoming Novel Food?^{[ # ]}

Abstract

Unlike those of coffee beans, the healthy properties of coffee leaves have been overlooked for a long time, even if they are consumed as a beverage by local communities of several African countries. Due to the presence of xanthines, diterpenes, xanthones, and several other polyphenol derivatives as main secondary metabolites, coffee leaves might be useful to prevent many daily disorders. At the same time, as for all bioactive molecules, careless use of coffee leaf infusions may be unsafe due to their adverse effects, such as the excessive stimulant effects on the central nervous system or their interactions with other concomitantly administered drugs. Moreover, the presence of some toxic diterpene derivatives requires careful analytical controls on manufactured products made with coffee leaves. Accordingly, knowledge about the properties of coffee leaves needs to be increased to know if they might be considered a good source for producing new supplements. The purpose of the present review is to highlight the biosynthesis, metabolism, and distribution of the 4 main classes of secondary metabolites present in coffee leaves, their main pharmacological and toxicological aspects, and their main roles in planta. Differences in coffee leaf chemical composition depending on the coffee species will also be carefully considered.

Key words

Coffea - coffee leaves - Rubiaceae - biosynthesis - metabolome - food supplement

^# Dedicated to Professor Arnold Vlietinck on the occasion of his 80th birthday.

Publikationsverlauf

Eingereicht: 11. Dezember 2020

Angenommen nach Revision: 14. Juni 2021

Artikel online veröffentlicht:
24. September 2021

• References

• 1 Bedford E. World arabica coffee production 2021. 2020 Accessed January 13, 2021 at: https://www.statista.com/statistics/225400/world-arabica-coffee-production/
• 2 Bedford E. World robusta coffee production 2021. 2020 Accessed January 13, 2021 at: https://www.statista.com/statistics/225402/world-robusta-coffee-production/
• 3 Bawin Y, Ruttink T, Staelens A, Haegeman A, Stoffelen P, Mwanga JCI, Roldán-Ruiz I, Honnay O, Janssens SB. Phylogenomic analysis clarifies the evolutionary origin of Coffea arabica L. J Syst Evol 2020;
• 4 Ngamsuk S, Huang TC, Hsu JL. Determination of phenolic compounds, procyanidins, and antioxidant activity in processed Coffea arabica L. leaves. Foods Basel Switz 2019; 8: 389
• 5 Belayneh A, Bussa NF. Ethnomedicinal plants used to treat human ailments in the prehistoric place of Harla and Dengego valleys, eastern Ethiopia. J Ethnobiol Ethnomedicine 2014; 10: 18
• 6 Ross IA. Medicinal Plants of the World, Volume 3: Chemical Constituents, traditional and modern medicinal Uses. Totowa, NJ: Humana Press; 2005
• 7 European Food Safety Authority (EFSA). Technical report on the notification of infusion from coffee leaves (Coffea arabica L. and/or Coffea canephora Pierre ex A. Froehner) as a traditional food from a third country pursuant to Article 14 of Regulation (EU) 2015/2283. EFSA J 2020;
• 8 Lall RK, Syed DN, Adhami VM, Khan IM, Srivastava SK. Dietary polyphenols in prevention and treatment of prostate cancer. Int J Mol Sci 2015; 16: 3350-3376
• 9 Malar DS, Devi KP. Dietary polyphenols for treatment of Alzheimerʼs disease-future research and development. Curr Pharm Biotechnol 2014; 15: 330-342
• 10 Monteiro Â, Colomban S, Azinheira HG, Guerra-Guimarães L, Do Céu Silva M, Navarini L, Resmini M. Dietary antioxidants in coffee leaves: impact of botanical origin and maturity on chlorogenic acids and xanthones. Antioxid Basel Switz 2019; 9: 6
• 11 Hicks MB, Hsieh YHP, Bell LN. Tea preparation and its influence on methylxanthine concentration. Food Res Int 1996; 29: 325-330
• 12 Farah A. Coffee: Production, Quality and Chemistry. London: Royal Society of Chemistry; 2019
• 13 Mehari B, Redi-Abshiro M, Chandravanshi BS, Atlabachew M, Combrinck S, McCrindle R. simultaneous determination of alkaloids in green coffee beans from Ethiopia: chemometric evaluation of geographical origin. Food Anal Methods 2016; 9: 1627-1637
• 14 Bicho NC, Leitão AE, Ramalho JC, Alvarenga NB, Cebola Lidon F. Identification of chemical clusters discriminators of arabica and Robusta green coffee. Int J Food Prop 2013; 16: 895-904
• 15 Silvarolla MB, Mazzafera P, de Lima MMA. Caffeine content of Ethiopian Coffea Arabica beans. Genet Mol Biol 2000; 23: 213-215
• 16 Dias RCE, Benassi MDT. Discrimination between Arabica and Robusta coffees using hydrosoluble compounds: is the efficiency of the parameters dependent on the roast degree?. Beverages 2015; 1: 127-139
• 17 Gramza-Michałowska A. Caffeine in tea Camellia sinensis-content, absorption, benefits and risks of consumption. J Nutr Health Aging 2014; 18: 143-149
• 18 Spiller GA. Caffeine. Boca Raton, FL: CRC Press; 2019
• 19 Marx F, Janssens MJJ, Urfer P, Scherer R. Caffeine and theobromine composition of mate (Ilex paraguariensis) leaves in five plantations of Misiones, Argentina. Plant Foods Hum Nutr 2003; 58: 1-8
• 20 Chen XM, Ma Z, Kitts DD. Effects of processing method and age of leaves on phytochemical profiles and bioactivity of coffee leaves. Food Chem 2018; 249: 143-153
• 21 Ky CL, Louarn J, Dussert S, Guyot B, Hamon S, Noirot M. Caffeine, trigonelline, chlorogenic acids and sucrose diversity in wild Coffea Arabica L. and C. canephora P. accessions. Food Chem 2001; 75: 223-230
• 22 Farah A, Monteiro MC, Calado V, Franca AS, Trugo LC. Correlation between cup quality and chemical attributes of Brazilian coffee. Food Chem 2006; 98: 373-380
• 23 Campa C, Mondolot L, Rakotondravao A, Bidel LPR, Gargadennec A, Couturon E, La Fisca P, Rakotomalala JJ, Jay-Allemand C, Davis AP. A survey of mangiferin and hydroxycinnamic acid ester accumulation in coffee (Coffea) leaves: biological implications and uses. Ann Bot 2012; 110: 595-613
• 24 Preedy V. Processing and Impact on Antioxidants in Beverages. Amsterdam: Elsevier; 2014
• 25 Vignoli JA, Viegas MC, Bassoli DG, De Toledo Benassi M. Roasting process affects differently the bioactive compounds and the antioxidant activity of Arabica and Robusta coffees. Food Res Int 2014; 61: 279-285
• 26 Jeszka-Skowron M, Sentkowska A, Pyrzyńska K, Paz De Peña M. Chlorogenic acids, caffeine content and antioxidant properties of green coffee extracts: influence of green coffee bean preparation. Eur Food Res Technol 2016; 242: 1403-1409
• 27 Macheiner L, Schmidt A, Schreiner M, Mayer HK. Green coffee infusion as a source of caffeine and chlorogenic acid. J Food Compos Anal 2019; 84: 103307
• 28 Trevisan MTS, de Almeida RF, Soto G, De Melo Virginio Filho E, Ulrich CM, Owen RW. Quantitation by HPLC-UV of mangiferin and isomangiferin in coffee (Coffea Arabica) leaves from Brazil and Costa Rica after solvent extraction and infusion. Food Anal Methods 2016; 9: 2649-2655
• 29 De Almeida RF, Trevisan MTS, Thomaziello RA, Breuer A, Klika KD, Ulrich CM, Owen RW. Nutraceutical compounds: echinoids, flavonoids, xanthones and caffeine identified and quantitated in the leaves of Coffea Arabica trees from three regions of Brazil. Food Res Int 2019; 115: 493-503
• 30 Dias RCE, Campanha FG, Vieira LGE, Ferreira LP, Pot D, Marraccini P, De Toledo Benassi M. Evaluation of kahweol and cafestol in coffee tissues and roasted coffee by a new high-performance liquid chromatography methodology. J Agric Food Chem 2010; 58: 88-93
• 31 Chen X. A review on coffee leaves: Phytochemicals, bioactivities and applications. Crit Rev Food Sci Nutr 2019; 59: 1008-1025
• 32 Aneja M, Gianfagna T. Induction and accumulation of caffeine in young, actively growing leaves of cocoa (Theobroma cacao L.) by wounding or infection with Crinipellis perniciosa . Physiol Mol Plant Pathol 2001; 59: 13-16
• 33 Metro D, Cernaro V, Santoro D, Papa M, Buemi M, Benvenga S, Manasseri L. Beneficial effects of oral pure caffeine on oxidative stress. J Clin Transl Endocrinol 2017; 10: 22-27
• 34 Mellbye FB, Jeppesen PB, Shokouh P, Laustsen C, Hermansen K, Gregersen S. Cafestol, a bioactive substance in coffee, has antidiabetic properties in KKAy mice. J Nat Prod 2017; 80: 2353-2359
• 35 Choi MJ, Park EJ, Oh JH, Min KJ, Yang ES, Kim YH, Lee TJ, Kim SH, Choi YH, Park JW, Kwon TK. Cafestol, a coffee-specific diterpene, induces apoptosis in renal carcinoma Caki cells through down-regulation of anti-apoptotic proteins and Akt phosphorylation. Chem Biol Interact 2011; 190: 102-108
• 36 Ashihara H, Monteiro AM, Gillies FM, Crozier A. biosynthesis of caffeine in leaves of coffee. Plant Physiol 1996; 111: 747-753
• 37 Salgado PR, Favarin JL, Leandro RA, De Lima Filho OF. Total phenol concentrations in coffee tree leaves during fruit development. Sci Agric 2008; 65: 354-359
• 38 European Food Safety Authority. Food supplements. Accessed April 7, 2021 at: https://www.efsa.europa.eu/en/topics/topic/food-supplements
• 39 Frischknecht PM, Ulmer-Dufek J, Baumann TW. Purine alkaloid formation in buds and developing leaflets of Coffea arabica: expression of an optimal defence strategy?. Phytochemistry 1986; 25: 613-616
• 40 Ashihara H, Sano H, Crozier A. Caffeine and related purine alkaloids: biosynthesis, catabolism, function and genetic engineering. Phytochemistry 2008; 69: 841-856
• 41 McCarthy AA, McCarthy JG. The structure of two N-methyltransferases from the caffeine biosynthetic pathway. Plant Physiol 2007; 144: 879-889
• 42 Fujimori N, Ashihara H. Biosynthesis of theobromine and caffeine in developing leaves of Coffea arabica . Phytochemistry 1994; 36: 1359-1361
• 43 Zheng X, Ashihara H. Distribution, biosynthesis and function of purine and pyridine alkaloids in Coffea Arabica seedlings. Plant Sci 2004; 166: 807-813
• 44 Ashihara H, Crozier A. Biosynthesis and metabolism of caffeine and related purine alkaloids in plants. Adv Bot Res 1999; 30: 117-205
• 45 Dewick MD. Medicinal natural Products: A biosynthetic Approach. Hoboken, NJ: John Wiley & Sons; 2009
• 46 Ashihara H. Metabolism of alkaloids in coffee plants. Braz J Plant Physiol 2006; 18: 1-8
• 47 Kong H, Jones PP, Koop A, Zhang L, Duff HJ, Chen SRW. Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor. Biochem J 2008; 414: 441-452
• 48 Boswell-Smith V, Spina D, Page CP. Phosphodiesterase inhibitors. Br J Pharmacol 2006; 147 (Suppl. 01) 252-257
• 49 Azam S, Hadi N, Khan NU, Hadi SM. Antioxidant and prooxidant properties of caffeine, theobromine and xanthine. Med Sci Monit 2003; 9: 325-330
• 50 Devasagayam TPA, Kamat JP, Mohan H, Kesavan PC. Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species. Biochim Biophys Acta 1996; 1282: 63-70
• 51 Dulloo AG, Seydoux J, Girardier L, Chantre P, Vandermander J. Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity. Int J Obes 2000; 24: 252-258
• 52 Kolahdouzan M, Hamadeh MJ. The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neurosci Ther 2017; 23: 272-290
• 53 Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M, Sonsalla PK, Castagnoli K, Castagnoli jr. N, Schwarzschild MA. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinsonʼs disease. J Neurosci Off J Soc Neurosci 2001; 21: RC143
• 54 Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J. Caffeine protects Alzheimerʼs mice against cognitive impairment and reduces brain β-amyloid production. Neuroscience 2006; 142: 941-952
• 55 Renner B, Clarke G, Grattan T, Beisel A, Mueller C, Werner U, Kobal G, Brune K. Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen. J Clin Pharmacol 2007; 47: 715-726
• 56 Dewar L, Heuberger R. The effect of acute caffeine intake on insulin sensitivity and glycemic control in people with diabetes. Diabetes Metab Syndr Clin Res Rev 2017; 11: 631-635
• 57 Richardson T, Thomas P, Ryder J, Kerr D. Influence of caffeine on frequency of hypoglycemia detected by continuous interstitial glucose monitoring system in patients with long-standing type 1 diabetes. Diabetes Care 2005; 28: 1316-1320
• 58 Robinson LE, Savani S, Battram DS, McLaren DH, Sathasivam P, Graham TE. Caffeine ingestion before an oral glucose tolerance test impairs blood glucose management in men with type 2 diabetes. J Nutr 2004; 134: 2528-2533
• 59 Krebs JD, Parry-Strong A, Weatherall M, Carroll RW, Downie M. A crossover study of the acute effects of espresso coffee on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus. Metabolism 2012; 61: 1231-1237
• 60 James J. The influence of user status and anxious disposition on the hypertensive effects of caffeine. Int J Psychophysiol 1990; 10: 171-179
• 61 Drake C, Roehrs T, Shambroom J, Roth T. Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. J Clin Sleep Med 2013; 9: 1195-1200
• 62 Bonnet M, Tancer M, Uhde T, Yeragani VK. Effects of caffeine on heart rate and QT variability during sleep. Depress Anxiety 2005; 22: 150-155
• 63 Caprioli G, Cortese M, Maggi F, Minnetti C, Odello L, Sagratini G, Vittori S. Quantification of caffeine, trigonelline and nicotinic acid in espresso coffee: The influence of espresso machines and coffee cultivars. Int J Food Sci Nutr 2014; 65: 465-469
• 64 Zhou J, Zhou S, Zeng S. Experimental diabetes treated with trigonelline: Effect on β cell and pancreatic oxidative parameters. Fundam Clin Pharmacol 2013; 27: 279-287
• 65 Hong BN, Yi TH, Kim SY, Kang TH. High-dosage pyridoxine-induced auditory neuropathy and protection with coffee in mice. Biol Pharm Bull 2009; 32: 597-603
• 66 Mirzaie M, Khalili M, Kiasalari Z, Roghani M. Neuroprotective and Antiapoptotic potential of trigonelline in a striatal 6-hydroxydopamine rat model of Parkinsonʼs disease. Neurophysiology 2016; 48: 176-183
• 67 Tice R. Trigonelline: review of toxicological literature. 1997 Accessed June 10, 2020 at: https://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/trigonelline_508.pdf
• 68 Carmona-Hernandez JC, Taborda-Ocampo G, Valdez JC, Bolling BW, Gonzalez-Correa CH. Polyphenol extracts from three Colombian passifloras (passion fruits) prevent inflammation-induced barrier dysfunction of caco-2 cells. Molecules 2019; 24: 4614
• 69 Boudet AM. Evolution and current status of research in phenolic compounds. Phytochemistry 2007; 68: 2722-2735
• 70 Eyles A, Bonello P, Ganley R, Mohammed C. Induced resistance to pests and pathogens in trees. New Phytol 2010; 185: 893-908
• 71 Orians CM. The effects of hybridization in plants on secondary chemistry: Implications for the ecology and evolution of plant-herbivore interactions. Am J Bot 2000; 87: 1749-1756
• 72 Clifford MN, Jaganath IB, Ludwig IA, Crozier A. Chlorogenic acids and the acyl-quinic acids: Discovery, biosynthesis, bioavailability and bioactivity. Nat Prod Rep 2017; 34: 1391-1421
• 73 Rodríguez-Gómez R, Vanheuverzwjin J, Souard F, Delporte C, Stevigny C, Stoffelen P, De Braekeleer K, Kauffmann JM. Determination of three main chlorogenic acids in water extracts of coffee leaves by liquid chromatography coupled to an electrochemical detector. Antioxid Basel Switz 2018; 7: 143
• 74 Hanson KR. Chlorogenic acid biosynthesis. Chemical synthesis and properties of the mono-o-cinnamoylquinic acids*. Biochemistry 1965; 4: 2719-2731
• 75 Niggeweg R, Michael AJ, Martin C. Engineering plants with increased levels of the antioxidant chlorogenic acid. Nat Biotechnol 2004; 22: 746-754
• 76 Lukitasari M, Nugroho DA, Widodo N. Chlorogenic acid: The conceivable chemosensitizer leading to cancer growth suppression. J Evid-Based Integr Med 2018; 23: 1-6
• 77 Lu Z, Xu S. ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life 2006; 58: 621-631
• 78 Yan Y, Li J, Han J, Hou N, Song Y, Dong L. Chlorogenic acid enhances the effects of 5-fluorouracil in human hepatocellular carcinoma cells through the inhibition of extracellular signal-regulated kinases. Anticancer Drugs 2015; 26: 540-546
• 79 Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J. mTORC2 Activity is elevated in gliomas and promotes growth and cell motility via overexpression of Rictor. Cancer Res 2007; 67: 11712-11720
• 80 Chantaravisoot N, Wongkongkathep P, Loo JA, Mischel PS, Tamanoi F. Significance of filamin A in mTORC2 function in glioblastoma. Mol Cancer 2015; 14: 127
• 81 Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122-1128
• 82 Tan S, Dong X, Liu D, Hao S, He F. Anti-tumor activity of chlorogenic acid by regulating the mTORC2 signaling pathway and disrupting F-actin organization. Int J Clin Exp Med 2019; 12: 4818-4828
• 83 Cho AS, Jeon SM, Kim MJ, Yeo J, Seo KI, Choi MS, Lee MK. Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induced-obese mice. Food Chem Toxicol 2010; 48: 937-943
• 84 Naveed M, Hejazi V, Abbas M, Kamboh AA, Khan GJ, Shumzaid M, Ahmad F, Babazadeh D, FangFang X, Modarresi-Ghazani F, WenHua L, XiaoHui Z. Chlorogenic acid (CGA): A pharmacological review and call for further research. Biomed Pharmacother Biomedecine Pharmacother 2018; 97: 67-74
• 85 Huang K, Liang X, Zhong Y, He W, Wang Z. 5-Caffeoylquinic acid decreases diet-induced obesity in rats by modulating PPARα and LXRα transcription. J Sci Food Agric 2015; 95: 1903-1910
• 86 Suzuki A, Kagawa D, Ochiai R, Tokimitsu I, Saito I. Green coffee bean extract and its metabolites have a hypotensive effect in spontaneously hypertensive rats. Hypertens Res Off J Jpn Soc Hypertens 2002; 25: 99-107
• 87 Tom ENL, Girard-Thernier C, Demougeot C. The Janus face of chlorogenic acid on vascular reactivity: a study on rat isolated vessels. Phytomedicine Int J Phytother Phytopharm 2016; 23: 1037-1042
• 88 Chaube S, Swinyard CA. Teratological and toxicological studies of alkaloidal and phenolic compounds from Solanum Tuberosum L. Toxicol Appl Pharmacol 1976; 36: 227-237
• 89 Hagiwara A, Hirose M, Takahashi S, Ogawa K, Shirai T, Ito N. Forestomach and kidney carcinogenicity of caffeic acid in F344 rats and C57BL/6N x C3H/HeN F1 mice. Cancer Res 1991; 51: 5655-5660
• 90 Tice R. Chlorogenic acid and caffeic acid: Review of toxicological literature. 1998 Accessed June 13, 2020 at: https://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/chlorogenicacid_508.pdf
• 91 Yoshiyuki K, Hiromichi O, Takuo O, Tsutomu H, Isao A, Shigeru A. Studies on the activities of tannins and related compounds from medicinal plants and drugs. VI. Inhibitory Effects of caffeoylquinic acids on histamine release from rat peritoneal mast cells. Chem Pharm Bull (Tokyo) 1985; 33: 690-696
• 92 Cardona ML, Fernández I, Pedro JR, Serrano A. Xanthones from Hypericum reflexum . Phytochemistry 1990; 29: 3003-3006
• 93 Schmidt W, Beerhues L. Alternative pathways of xanthone biosynthesis in cell cultures of Hypericum androsaemum L. FEBS Lett 1997; 420: 143-146
• 94 Wezeman T, Bräse S, Masters KS. Xanthone dimers: a compound family which is both common and privileged. Nat Prod Rep 2015; 32: 6-28
• 95 Yang C, Ma L, Wei Z, Han F, Gao J. Advances in isolation and synthesis of xanthone derivatives. Chinese Herbal Medicines 2012; 4: 87-102
• 96 Stoffelen P, Noirot M, Couturon E, Bontems S, De Block P, Anthony F. Coffea anthonyi, a new self-compatible Central African coffee species, closely related to an ancestor of Coffea Arabica . Taxon 2009; 58: 133-140
• 97 Prabhu S, Jainu M, Sabitha KE, Devi CSS. Cardioprotective effect of mangiferin on isoproterenol induced myocardial infarction in rats. Indian J Exp Biol 2006; 44: 209-215
• 98 Ghosal S, Rao G, Saravanan V, Misra N, Rana D. A plausible chemical mechanism of the bioactivities of mangiferin. Indian J Chem Sect B 1996; 35: 561-566
• 99 Jiang DJ, Tan GS, Ye F, Du YH, Xu KP, Li YJ. Protective effects of xanthones against myocardial ischemia-reperfusion injury in rats. Acta Pharmacol Sin 2003; 24: 175-180
• 100 Kavitha M, Nataraj J, Essa MM, Memon MA, Manivasagam T. Mangiferin attenuates MPTP induced dopaminergic neurodegeneration and improves motor impairment, redox balance and Bcl-2/Bax expression in experimental Parkinsonʼs disease mice. Chem Biol Interact 2013; 206: 239-247
• 101 Han J, Yi J, Liang F, Jiang B, Xiao Y, Gao S, Yang N, Hu H, Xie WF, Chen W. X-3, a mangiferin derivative, stimulates AMP-activated protein kinase and reduces hyperglycemia and obesity in db/db mice. Mol Cell Endocrinol 2015; 405: 63-73
• 102 Pal PB, Sinha K, Sil PC. Mangiferin attenuates diabetic nephropathy by inhibiting oxidative stress mediated signaling cascade, TNFα related and mitochondrial dependent apoptotic pathways in streptozotocin-induced diabetic rats. PloS One 2014; 9: e115364
• 103 Jeong JJ, Jang SE, Hyam SR, Han MJ, Kim DH. Mangiferin ameliorates colitis by inhibiting IRAK1 phosphorylation in NF-κB and MAPK pathways. Eur J Pharmacol 2014; 740: 652-661
• 104 Imran M, Arshad MS, Butt MS, Kwon JH, Arshad MU, Sultan MT. Mangiferin: a natural miracle bioactive compound against lifestyle related disorders. Lipids Health Dis 2017; 16: 84
• 105 Kanokporn C, Patamaporn S, Thanaporn P, Kanjana K. Acute and subchronic oral toxicity of xanthones extracted from the pericarp of Garcinia mangostana Linn.in rat. 2015 Accessed September 11, 2020 at: https://www.asianarchpath.com/view/57
• 106 Khaw KY, Chong CW, Murugaiyah V. LC-QTOF-MS analysis of xanthone content in different parts of Garcinia mangostana and its influence on cholinesterase inhibition. J Enzyme Inhib Med Chem 2020; 35: 1433-1441
• 107 Speer K, Kölling-Speer I. The lipid fraction of the coffee bean. Braz J Plant Physiol 2006; 18: 201-216
• 108 Singh B, Sharma RA. Plant terpenes: defense responses, phylogenetic analysis, regulation and clinical applications. 3 Biotech 2015; 5: 129-151
• 109 Singsaas EL. Terpenes and the thermotolerance of photosynthesis. New Phytol 2000; 146: 1-2
• 110 Pot D, Ferreira L, Dias RCE, Noel D, Guyot B, Ramos J, Perthuis B, Sandrin P, Benassi MT, Marraccini P, Perreira LFP, Leroy T, Vieira LGE. Genetic and molecular determinism of diterpenes metabolism in Coffea spp. 14–19.09.2008. Accessed June 12, 2020 at: https://www.researchgate.net/publication/311518539_Genetic_and_molecular_determinism_of_diterpenes_metabolism_in_Coffea_spp/link/596f4cf8aca27227101360db/download
• 111 Ferreira Lucia P, Dias Rafael C, Noel D, Bernard G, Juliana R, Perthuis B, Sandrin-Garcia P, Benassi MT, Marraccini P, Pereira LF, Leroy T, Vieira LG, Pot D. Determinismo génetico e molecular do metabolismo de diterpenos em Coffea spp. 02. 05.06.2009 Accessed June 12, 2020 at: https://agritrop.cirad.fr/551318/
• 112 Souard F, Delporte C, Stoffelen P, Thévenot EA, Noret N, Dauvergne B, Kauffmann JM, Van Antwerpen P, Stévigny C. Metabolomics fingerprint of coffee species determined by untargeted-profiling study using LC-HRMS. Food Chem 2018; 245: 603-612
• 113 Oh JH, Lee JT, Yang ES, Chang JS, Lee DS, Kim SH, Choi YH, Park JW, Kwon TK. The coffee diterpene kahweol induces apoptosis in human leukemia U937 cells through down-regulation of Akt phosphorylation and activation of JNK. Apoptosis Int J Program Cell Death 2009; 14: 1378-1386
• 114 Kim HG, Hwang YP, Jeong HG. Kahweol blocks STAT3 phosphorylation and induces apoptosis in human lung adenocarcinoma A549 cells. Toxicol Lett 2009; 187: 28-34
• 115 Ekert PG, Silke J, Vaux DL. Caspase inhibitors. Cell Death Differ 1999; 6: 1081-1086
• 116 Moeenfard M, Cortez A, Machado V, Costa R, Luís C, Coelho P, Soares R, Alves A, Borges N, Santos A. Anti-angiogenic properties of cafestol and kahweol palmitate diterpene esters. J Cell Biochem 2016; 117: 2748-2756
• 117 Wattenberg LW, Lam LK. Protective effects of coffee constituents on carcinogenesis in experimental animals. Banbury Rep 1984; 17: 137-145
• 118 Cavin C, Holzhäuser D, Constable A, Huggett AC, Schilter B. The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism. Carcinogenesis 1998; 19: 1369-1375
• 119 Baek JH, Kim NJ, Song JK, Chun KH. Kahweol inhibits lipid accumulation and induces Glucose-uptake through activation of AMP-activated protein kinase (AMPK). BMB Rep 2017; 50: 566-571
• 120 Weusten-Van der Wouw MP, Katan MB, Viani R, Huggett AC, Liardon R, Lund-Larsen PG, Thelle DS, Ahola I, Aro A, Meyboom S, Beynen AC. Identity of the cholesterol-raising factor from boiled coffee and its effects on liver function enzymes. J Lipid Res 1994; 35: 721-733
• 121 Hutchings A, Terblanche SE. Observations on the use of some known and suspected toxic Liliiflorae in Zulu and Xhosa medicine. South Afr Med J Suid-Afr Tydskr Vir Geneeskd 1989; 75: 62-69
• 122 Santi R, Luciani S. Atractyloside: Chemistry, Biochemistry and Toxicology. Padova: Piccin Editore; 1978
• 123 Lang R, Fromme T, Beusch A, Wahl A, Klingenspor M, Hofmann T. 2-O-β-D-Glucopyranosyl-carboxyatractyligenin from Coffea L. inhibits adenine nucleotide translocase in isolated mitochondria but is quantitatively degraded during coffee roasting. Phytochemistry 2013; 93: 124-135
• 124 Obatomi DK, Bach PH. Biochemistry and Toxicology of the Diterpenoid Glycoside Atractyloside. Food Chem Toxicol 1998; 36: 335-346
• 125 Chen LY, Hu A, Chang CJ. The degradation mechanism of toxic atractyloside in herbal medicines by decoction. Molecules 2013; 18: 2018-2028
• 126 Buscemi S, Rosselli S, Bruno M, Vivona N, Piozzi F. Photoinduced functionalization of diterpenes: transformation of the C-20 methyl of atractyligenin into a carbomethoxymethyl or carbamoylmethyl group. J Photochem Photobiol Chem 2003; 155: 145-149
• 127 Segheto L, Santos BCS, Werneck AFL, Pinto Vilela FM, Vieira de Sousa O, Pereira Rodarte M. Antioxidant extracts of coffee leaves and its active ingredient 5-caffeoylquinic acid reduce chemically-induced inflammation in mice. Ind Crops Prod 2018; 126: 48-57
• 128 Galam NZ, Gambo IM, Rabiu A, Chinelo N, Dami S. Anti-inflammatory effect of aqueous extract of coffee plant leaves (Coffea canephora) in rats. J Nat Sci Res 2013; 3: 191-193
• 129 Chiang HM, Lin TJ, Chiu CY, Chang CW, Hsu KC, Fan PC, Wen KC. Coffea arabica extract and its constituents prevent photoaging by suppressing MMPs expression and MAP kinase pathway. Food Chem Toxicol 2011; 49: 309-318