Subscribe to RSS
DOI: 10.1055/s-0043-111240
The Foxgloves (Digitalis) Revisited[*]
Publication History
received 17 March 2017
revised 27 April 2017
accepted 08 May 2017
Publication Date:
23 May 2017 (online)
Abstract
This review provides a renewed look at the genus Digitalis. Emphasis will be put on those issues that attracted the most attention or even went through paradigmatic changes since the turn of the millennium. PubMed and Google Scholar were used (“Digitalis” and “Foxglove” were the key words) to identify research from 2000 till 2017 containing data relevant enough to be presented here. Intriguing new results emerged from studies related to the phylogeny and taxonomy of the genus as well as to the biosynthesis and potential medicinal uses of the key active compounds, the cardiac glycosides. Several Eastern and Western Foxgloves were studied with respect to their propagation in vitro. In this context, molecular biology tools were applied and phytochemical analyses were conducted. Structure elucidation and analytical methods, which have experienced less exciting progress, will not be considered here in great detail.
Key words
Digitalis - Plantaginaceae - cardiac glycosides - plant biotechnology - biosynthesis - plant tissue culture - phylogeny* Dedicated to Professor Dr. Max Wichtl in recognition of his outstanding contribution to pharmacognosy research.
Supporting Information
- Supporting Information
Tables showing the taxonomy of the genus Digitalis, the effects of cardenolides in systolic heart failure, and the effects of cardenolides on cancer cells are available as Supporting Information.
-
References
- 1 Canter PH, Thomas H, Ernst E. Bringing medicinal plant species into cultivation: opportunities and challenges for biotechnology. Trends Biotechnol 2005; 23: 180-185
- 2 Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 2006; 440: 940-943
- 3 Narcross L, Fossati E, Bourgeois L, Dueber JE, Martin VJJ. Microbial factories for the production of benzylisoquinoline alkaloids. Trends Biotechol 2016; 34: 228-241
- 4 Zhong JJ. Plant cell culture for production of paclitaxel and other taxanes. J Biosci Bioeng 2002; 94: 591-599
- 5 Clemente ES, Müller-Uri F, Nebauer SG, Segura J, Kreis W, Arrillaga I. Digitalis, Chapter 5. In: Kole C. ed. Wild Crop Relatives: genomic and breeding Resources, Plantation and ornamental Crops. Berlin, Heidelberg: Springer; 2011: 73-112
- 6 Luckner M, Wichtl M. Digitalis – Geschichte, Biologie, Chemie, Physiologie, Molekularbiologie, Pharmakologie, medizinische Anwendung. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2000
- 7 Gerard J. The herbal or general History of Plants. The complete 1633 Edition as revised and enlarged by Thomas Johnson. New York: Calla Editions; 2015: 789-791
- 8 Groves MJ, Bisset NG. A note on the use of topical digitalis prior to William Withering. Ethnopharmacol 1991; 35: 99-103
- 9 Withering W. An Account of the Foxglove and some of its medical Uses, with practical Remarks on Dropsy, and other Diseases. In: Willins FA, Keys TE. eds. Classics of Cardiology. New York: Henry Schuman Dover Publications; 1941: 231-252
- 10 Aronson JK. An Account of the Foxglove and its medical Uses 1785 – 1985. Oxford: Oxford University Press; 1986
- 11 Pughe J, Williams J. The Physicians of Myddvai: Meddygon Myddvai, or the medical Practice of the celebrated Rhiwallon and his Sons, of Myddvai, in Caermarthenshire, Physicians to Rhys Gryg, Lord of Dynevor and Ystrad Towy, about the Middle of the thirteenth Century. Felinfach: Llanerch; 1993
- 12 Darwin E. The botanic Garden. Part II. Containing the Loves of the Plants. A Poem. With philosophical Notes. London: J. Johnson; 1789
- 13 Darwin E. Experiments establishing a Criterion, between mucilaginous and purulent Matter. London, Edinburgh: J. Jackson; 1780
- 14 Fulton J. Charles Darwin (1785–1778) and the history of the early use of Digitalis . J Urban Health 1999; 76: 533-541
- 15 Whitfield AG. The William Withering bicentennial lecture. William Withering and ‘an account of the foxglove’. Q J Med 1985; 57: 709-711
- 16 Dahlgren RMT. A revised system of classificaton of the angiosperms. Bot J Linn Soc 1980; 80: 91-124
- 17 Taskova RM, Gotfredsen CH, Jensen SR. Chemotaxonomic markers in Digitalideae (Plantaginaceae). Phytochemistry 2005; 66: 1440-1447
- 18 Douglas E, Soltis P, Doyle JJ. Molecular Systematics of Plants II. DNA Sequencing. Boston: Kluwer Academic Publishers; 1998: 574
- 19 Werner K. Wuchsform und Verbreitung als Grundlagen der taxonomischen Gliederung von Digitalis L. [Dissertation]. Halle: Martin-Luther-Universität Halle-Wittenberg; 1961
- 20 Werner K. Taxonomie und Phylogenie der Gattungen Isoplexis (Lindl.) Benth. und Digitalis L. Feddes Repert 1965; 70: 109-135
- 21 Carvalho JA, Culham A. Phylogenetic and biogeographic relationships of the genera Isoplexis (Lindl.) Benth. and Digitalis L. (Scrophulariaceae – tribe Digitaleae): nuclear DNA evidence. Amer J Bot 1997; 84: 180
- 22 Carvalho JA, Culham A. Conservation status and preliminary results on the phylogenetics of Isoplexis (Lindl.) Benth. (Scrophulariaceae). Bol Mus Mun Funchal 1998; (Suppl. 05) 109-127
- 23 Nebauer SG, Del Castillo-Agudo L, Segura J. An assessment of genetic relationships within the genus Digitalis based on PCR-generated RAPD markers. Theor Appl Genet 2000; 100: 1209-1216
- 24 Olmstead RG, de Pamphilis CW, Wolfe AD, Young ND, Elisons WJ, Reeves PD. Disintegration of the Scrophulariaceae. Amer J Bot 2005; 88: 348-361
- 25 Albach D, Chase M. Incongruence in Veroniceae (Plantaginaceae): evidence form to plastide and nuclear ribosomal DNA region. Mol Phylogenet Evol 2004; 32: 183-197
- 26 Albach DC, Meudt M, Oxelman B. Piecing together the „new“ Plantaginaceae. Am J Bot 2005; 92: 297-315
- 27 Bräuchler C, Meimberg H, Heubl G. Molecular phylogeny of the genera Digitalis L. and Isoplexis (Lindley) Loudon (Veronicaceae) based on ITS and trnL-F sequences. Plant Syst Evol 2004; 248: 111-128
- 28 Herl V, Albach DC, Müller-Uri F, Bräuchler C, Heubl G, Kreis W. Using progesterone 5β-reductase, a gene encoding a key enzyme in the cardenolide biosynthesis, to infer the phylogeny of the genus Digitalis . Plant Syst Evol 2008; 271: 65-78
- 29 Sang T. Utility of low-copy nuclear gene sequences in plant phylogenetics. Crit Rev Biochem Mol Biol 2002; 37: 121-147
- 30 Lindley J. Digitalium monographia: sistens historiam botanicam generis, tabulis omnium specierum hactenus cognitarum. London: Arthur Taylor for J.H. Bohte; 1821: 1-27
- 31 Eker I, Yücesan B, Sameeullah M, Welβ W, Müller-Uri F, Gürel E, Kreis W. Phylogeny of Anatolian (Turkey) species in the Digitalis sect. Globiflorae (Plantaginaceae). Phytotaxa 2016; 244: 263-282
- 32 Davis PH. Digitalis. In: Davis PH. ed. Flora of Turkey and the East Aegean Islands. Edinburgh: Edinburgh University Press; 1978: 680-687
- 33 Sventenius ER. Plantae macronesiensis novae vel minus cognitae. Index seminum quae hortus acclimatationis plantarum Arautapae. Madrid: INIA-MAPA; 1968: 47
- 34 Nazir R, Reshi Z, Wafai BA. Reproductive ecology of medicinally important Kashmir Himalayan species of Digitalis L. Plant Spec Biol 2008; 23: 59-70
- 35 Roca-Pérez L, Boluda R, Pérez-Bermúdez P. Soil-plant relationships, micronutrient contents, and cardenolide production in natural populations in Digitalis obscura . J Plant Nutr Soil Sci 2004; 167: 79-84
- 36 Roca-Pérez L, Pérez-Bermúdez P, Boluda R. Soil characteristics, mineral nutrients, biomass, and cardenolide production in Digitalis obscura wild populations. J Plant Nutr 2002; 25: 2015-2026
- 37 Roca-Pérez L, Pérez-Bermúdez P, Gavidia I, Boluda R. Relationships among soil characteristics, plant macronutrients, and cardenolide accumulation in natural populations of Digitalis obscura . J Plant Nutr Soil Sci 2005; 168: 774-780
- 38 Roca-Pérez L, Boluda R, Gavidia I, Pérez-Bermúdez P. Seasonal cardenolide production and Dop5βr gene expression in natural populations of Digitalis obscura . Phytochemistry 2004; 65: 1869-1878
- 39 Freier R. Untersuchungen zur Biogenese der herzwirksamen Glykoside in Digitalis lanata Ehrh. [Dissertation]. Marburg: Philipps-Universität; 1977
- 40 Luckner M, Diettrich B. Formation of Cardenolides in Cell and Organ Cultures of Digitalis lanata . In: Neumann KH, Barz W, Reinhard E. eds. Primary and secondary Metabolism of Plant Cell Cultures. Berlin: Springer; 1985: 154-163
- 41 Seidel S, Reinhard E. Major cardenolide glycosides in embryogenic suspension cultures of Digitalis lanata . Planta Med 1987; 53: 308-309
- 42 Stuhlemmer U, Kreis W, Eisenbeiss M, Reinhard E. Cardiac glycosides in partly submerged shoots of Digitalis lanata . Planta Med 1993; 59: 539-545
- 43 Hagimori M, Matsumoto T, Obi Y. Studies of the production of Digitalis cardenolides by plant tissue cultures. II. Effect of light and plant growth substances on digitoxin formation by undifferentiated cells and shoot-forming cultures of Digitalis purpurea L. grown in liquid media. Plant Physiol 1982; 69: 653-656
- 44 Reinhard E, Boy M, Kaiser F. Umwandlung von Digitalisglykosiden durch Zellsuspensionskulturen. Planta Med (Suppl ) 1975; 28: 163-168
- 45 Christmann J, Kreis W, Reinhard E. Uptake, transport and storage of cardenolides in foxglove: cardenolide sinks and occurence cardenolides in the sieve tubes of Digitalis lanata . Bot Acta 1993; 106: 419-427
- 46 Kreis W, Hoelz H, Sutor R, Reinhard E. Cellular organization of cardenolide biotransformation in Digitalis grandiflora . Planta 1993; 191: 246-251
- 47 Theurer C, Kreis W, Reinhard E. Effects of digitoxigenin, digoxigenin, and various cardiac glycosides on cardenolide accumulation in shoot cultures of Digitalis lanata Ehrh. Planta Med 1998; 64: 705-710
- 48 Munkert J, Santiago Franco M, Nolte E, Thaís Silva I, Oliveira Castilho R, Melo Ottoni F, Schneider NFZ, Oliveira MC, Taubert H, Bauer W, Andrade SF, Alves RJ, Simões CMO, Braga FC, Kreis W, de Pádua RM. Production of the cytotoxic cardenolide glucoevatromonoside by semisynthesis and biotransformation of evatromonoside by a Digitalis lanata cell culture. Planta Med 2017; DOI: 10.1055/s-0043-109557.
- 49 Verma SK, Das AK, Cingoz GS, Gurel E. In vitro culture of Digitalis L. (Foxglove) and the production of cardenolides: An up-to-date review. Ind Crops Prod 2016; 94: 20-51
- 50 Schaller F, Kreis W. Clonal propagation of Isoplexis canariensis . Planta Med 1996; 62: 450-452
- 51 Pérez-Bermúdez P, Seitz HU, Gavidia I. A protocol for rapid micropropagation of endagered Isoplexis . In Vitro Cell Dev Biol Plant 2002; 38: 178-182
- 52 Arrebola ML, Verpoorte R. Micropropagation of Isoplexis isabelliana (WEBB and BERTH) Masf, a threatened medicinal plant. J Herbs Spices Med Plants 2003; 10: 89-94
- 53 Sales E, Nebauer SG, Arrillaga I, Segura J. Cryopreservation of Digitalis obscura selected genotypes by encapsulation-dehydration. Planta Med 2001; 67: 833-838
- 54 Kreis W, Haug B, Yücesan B. Somaclonal variation of cardenolide content in Heywoodʼs foxglove, a source for the antiviral cardenolide glucoevatromonoside, regenerated from permanent shoot culture and callus. In Vitro Cell Dev Biol Plant 2014; 51: 35-41
- 55 Eisenbeiß M, Kreis W, Reinhard E. Cardenolide biosynthesis in light- and dark-grown Digitalis lanata shoot cultures. Plant Physiol Biochem 1999; 37: 13-23
- 56 Pérez-Alonso N, Wilken D, Gerth A, Anett J, Nitzsche HM, Kerns G, Capote-Perez A, Jiménez E. Cardiotonic glycosides from biomass of Digitalis purpurea L. cultured in temporary immersion systems. Plant Cell Tiss Organ Cult 2009; 99: 151-156
- 57 Patil JG, Ahire ML, Nitnaware KM, Panda S, Bhatt VP, Kishor PBK, Nikam TD. In vitro propagation and production of cardiotonic glycosides in shoot cultures of Digitalis purpurea L. by elicitation and precursor feeding. Appl Microbiol Biotechnol 2013; 97: 2379-2393
- 58 Pérez-Alonso NL, Labrada FA, Pérez AC, Pérez AP, Sosa R, Mollineda A, Gonzáles EJ. Estimulación de cardenólidos en brotes de Digitalis purpurea L. cultivados in vitro mediante elicitores. Rev Colomb Biotecnol 2014; 16: 51-61
- 59 Hagimori M, Matsumoto T, Mikami Y. Photoautotrophic culture of undifferentiated cells and shoot-forming cultures of Digitalis purpurea L. Plant Cell Physiol 1984; 25: 1099-1102
- 60 Stuhlemmer U, Kreis W, Eisenbeiss M, Reinhard E. Cardiac glycosides in partly submerged shoots of Digitalis lanata . Planta Med 1993; 59: 539-545
- 61 Greidziak N, Diettrich B, Luckner M. Batch cultures of somatic embryos of Digitalis lanata in gaslift fermenters. Development and cardenolide accumulation. Planta Med 1990; 56: 175-178
- 62 Ghanem SA, Aboul-Enein AM, El-Sawy A, Rady MR, Ibrahem MM. In vitro propagation and cardiac glycosides content of Digitalis lanata . Int J Acad Res 2010; 2: 349-356
- 63 Cacho M, Morán M, Corchete P, Fernández-Tárrago J. Effect of calcium restriction on cardenolide accumulation in two cell lines of Digitalis thapsi grown under different light regimes. Acta Physiol Plant 1999; 21: 335-340
- 64 Gurel E, Yucesan B, Aglic E, Gurel S, Verma SK, Sokmen M, Sokmen A. Regeneration and cardiotonic glycoside production in Digitalis davisiana Heywood (Alanya Foxglove). Plant Cell Tiss Org Cult 2011; 104: 217-225
- 65 Verma SK, Yücesan BB, Sahin G, Gürel S, Gürel E. Direct shoot regeneration from leaf explants of Digitalis lamarckii, an endemic medicinal species. Turk J Bot 2011; 35: 689-695
- 66 Yücesan B, Müller-Uri F, Kreis W, Gürel E. Cardenolide estimation in callus-mediated regenerants of Digitalis lamarckii Ivanina (dwarf foxglove). In Vitro Cell Dev Biol Plant 2014; 50: 137-142
- 67 Verma SK, Sahin G, Yücesan B, Eker I, Sahbaz N, Gürel S, Gürel E. Direct somatic embryogenesis from hypocotyl segments of Digitalis trojana Ivan and subsequent plant regeneration. Ind Crop Prod 2012; 40: 76-80
- 68 Cingoz GS, Gurel E. Effects of salicylic acid on thermotolerance and cardenolide accumulation under high temperature stress in Digitalis trojana Ivanina. Plant Physiol Biochem 2016; 105: 145-149
- 69 Aliyu M, Bahtiyar B, Öznur DO, Cansu C, Eker I, Kreis W, Gurel E. In vitro regeneration and cardenolide determination of an endemic foxglove, Digitalis cariensis (Aegan Foxglove). In Vitro Cell Dev Biol Plant 2015; 51: 438-444
- 70 Verma SK, Yucesan B, Sahin G, Gurel E. Embryogenesis, plant regeneration and cardiac glycoside determination in Digitalis ferruginea subsp. ferruginea L. Plant Cell Tiss Organ Cult 2014; 119: 625-634
- 71 Ferrie AMR. Doubled haploid production in nutraceutical species: a review. Euphytica 2007; 158: 347-357
- 72 Diettrich B, Ernst S, Luckner M. Haploid plants regenerated from androgenic cell cultures of Digitalis lanata . Planta Med 2000; 66: 237-240
- 73 Seitz U. Cryopreservation of Plant Germplasm. I. Cryopreservation Studies on Digitalis lanata (Foxglove). In: Bajaj YPS. ed. Biotechnology in Agriculture and Forestry. Berlin, Heidelberg: Springer; 1995: 478-486
- 74 Nebauer SG, Del Castillo-Agudo L, Segura J. RAPD variation within and among natural populations of outcrossing willow-leaved foxglove (Digitalis obscura L.). Theor Appl Genet 1999; 98: 985-994
- 75 Moran M, Cacho M, Fernández-Tárrago J. A protocol for the cryopreservation of Digitalis thapsi L. cell cultures. Cryo Letters 1999; 20: 193-198
- 76 Kreis W, Reinhard E. 12β-Hydroxylation of digitoxin by suspension-cultured Digitalis lanata cells. Production of digoxin in 20-litre and 300-litre airlift bioreactors. J Biotechnol 1992; 26: 257-273
- 77 Wilson SA, Roberts SC. Metabolic engineering approaches for production of biochemicals in food and medicinal plants. Curr Opin Biotechnol 2014; 26: 174-182
- 78 Kreis W, Geiger D, Höhn S, Meitinger N, Munkert J, Petersen J, Rieck C. Towards a biomanufacturing platform for cardenolides. Planta Med 2016; 82 (Suppl. 01) S1-S381
- 79 Lehmann U, Moldenhauer D, Thomar S, Diettrich B, Luckner M. Regeneration of plants from Digitalis lanata cells transformed with Agrobacterium tumefaciens carrying bacterial genes encoding neomycin phosphotransferase II and β-glucuronidase. J Plant Physiol 1995; 147: 53-57
- 80 Sales E, Segura J, Arrillaga I. Agrobacterium tumefaciens-mediated genetic transformation of the cardenolide-producing plant Digitalis minor L. Planta Med 2003; 69: 143-147
- 81 Sales E, Munoz-Bertomeu J, Arrilaga I, Segura J. Enhancement of cardenolide and phytosterol levels by expression of an N-terminally truncated 3-hydroxy-3-methylglutaryl CoA reductase in transgenic Digitalis minor . Planta Med 2007; 73: 605-610
- 82 Koelreuter JG. Digitalis hybridae. Acta Acad Imp Sci Petrop 1777; 215-233
- 83 Ikeda Y, Fuji Y. Quantitative determination of lanatosides in the hybrid Digitalis ambigua x Digitalis lanata leaves by HPLC. J Liq Chromatogr Relat Technol 2003; 26: 2013-2021
- 84 Silva J, Gomes ET, Serrano R, Silva O. Identification by microscopy of a natural hybrid between Portuguese Digitalis species. Microsc Microanal 2012; 18: 43-44
- 85 Saeedi Y, Nóbrega F, Gouveia L, Gomes ET, Serrano R, Silva O. Identification of spontaneous Portuguese hybrids using RAPD markers. Planta Med 2012; 78: PE3 1112
- 86 Boronnikova SV, Kokaeva ZG, Gostimsky SA, Dribnokhodova OP, Tikhomirova NN. Analysis of DNA polymorphism in a relict Uralian species, large-flowered foxglove (Digitalis grandiflora Mill.), using RAPD and ISSR markers. Russ J Genet 2007; 43: 530-535
- 87 Probert R, Adam J, Coneybeer J, Crawford A, Hay F. Seed quality for conservation is critically affected by pre-storage factors. Aust J Bot 2007; 55: 326-335
- 88 Butler LH, Hay FR, Ellis RH, Smith RD. Post-abscission, pre-dispersal seeds of Digitalis purpurea remain in a developmental state that is not terminated by desiccation ex planta . Ann Bot London 2009; 103: 785-794
- 89 Mohammed A, Yücesan B, Demir-Ordu Ö, Cihangir C, Eker I, Kreis W, Gürel E. In vitro regeneration and cardenolide determination of an endemic foxglove, Digitalis cariensis (Aegean Foxglove). In Vitro Cell Dev Biol Plant 2015; 51: 438-444
- 90 Fochler U, Gerber H, Hoppe B, Kreis W, Lohwasser U. Fingerhut, Wolliger (Digitalis lanata Ehrh.). In: Hoppe B. ed. Handbuch des Arznei- und Gewürzpflanzenanbaues, Band 4: Arznei- und Gewürzpflanzen A – K. Calbe: Grafisches Centrum Cuno; 2012: 406-426
- 91 Fonin VS, Khorlin AY. Preparation of biologically transformed raw material of woolly foxglove (Digitalis lanata Ehrh.) and isolation of digoxin therefrom. Appl Biochem Micro 2003; 39: 519-523
- 92 Mastenbroek C. Cultivation and breeding of Digitalis lanata in the Netherlands. Br Heart 1985; 54: 262-268
- 93 Lichius JJ, Bugge G, Wichtl M. Cardenolide glycosides in Digitalis cross-breeding. 2 reciprocal cross-breedings of Digitalis lanata . Arch Pharm 1992; 325: 167-171
- 94 Ardelean M, Costea AM, Cordea M. Breeding foxglove (Digitalis sp.) for ornamental and/or medical purposes. Bulletin of University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca. Horticulture 2006; 63: 22-31
- 95 Gavidia I, Pérez-Bermúdez P. Variants of Digitalis obscura from irradiated shoot tips. Euphytica 1999; 110: 153-159
- 96 Wident M, Bouverat-Bernier JP. Example of successful, long-term, breeding program on Digitalis lanata Ehrh. Acta Hortic 2015; 1098: 103-110
- 97 Ganapaty S, Mallika BN, Balaji S, Lakshmi SVVNSM, Thomas PS, Ramana KV. A review of phytochemical studies of Digitalis species. JNR 2003; 3: 104-128
- 98 Pauli GF, Friesen JB, Gödecke T, Farnsworth NR, Glodny B. Occurrence of progesterone and related animal steroids in two higher plants. J Nat Prod 2010; 73: 338-345
- 99 Gavidia I, Seitz H, Pérez-Bermúdez P, Vogler B. LC-NMR applied to the characterisation of cardiac glycosides from three micropropagated Isoplexis species. Phytochem Anal 2002; 13: 266-271
- 100 Schaller F, Kreis W. Cardenolide genin pattern in Isoplexis plants and shoot cultures. Planta Med 2006; 72: 1149-1156
- 101 Steinegger E, Hänsel R. Lehrbuch der Pharmakognosie. Auf phytochemischer Grundlage. 3rd Ed.. Berlin, Heidelberg, New York: Springer; 1972: 183
- 102 Usai M, Atzei AD, Marchetti M. Cardenolides content in wild Sardinian Digitalis purpurea L. populations. Nat Prod Res 2007; 21: 798-804
- 103 Liedke S, Wichtl M. Digitanol-Glykoside der Blätter von Digitalis lanata Ehrh. und Digitalis purpurea L. 1. Mitt.: 14β-Hydroxy-Digitalonin aus Digitalis lanata . Pharmazie 1992; 51: 911-912
- 104 Jacobsohn MK, Jacobsohn GM. Annual variation in the sterol content of Digitalis purpurea . Plant Physiol 1976; 58: 541-543
- 105 Linde H, Ergenc N, Meyer K. Zur Frage der Existenz von „γ-Sitosterol“ Nachweis von Cholesterol als Bestandteil des „γ-Sitosterols“ einer Digitalis-Art. Helv Chim Acta 1966; 49: 1246-1249
- 106 Furuya T, Kojima H, Katsuta T. 3-Methylpurpurin and other anthraquinones from callus tissue of Digitalis lanata . Phytochemistry 1972; 11: 1073-1076
- 107 Kirmizibekmez H, Kúsz N, Hohmann J. Chemical constituents of Digitalis viridiflora . Planta Med 2015; 81: PM_62
- 108 Brieger D, Liedtke S, Weber R, Kirschke M, Lichius JJ. Ein neues, verbascosidähnliches Esterglucosid aus den Blättern von Digitalis lanata Ehrh. – Maxosid = A new ester glucoside derived from Digitalis lanata leaves: Maxoside. Pharmazie 1995; 50: 707-708
- 109 Farkas L, Nogradi M, Wagner H, Hörhammer L. Endgültige Strukturaufklärung und vollständige Synthese des Sophorabiosids, eines Glykosids aus Sophora japonica L. Chem Ber 1965; 101: 2758-2761
- 110 Katanić J, Ceylan R, Matić S, Boroja T, Zengin G, Aktumsek A, Mihailović V, Stanić S. Novel perspectives on two Digitalis species: Phenolic profile, bioactivity, enzyme inhibition, and toxicological evaluation. S Afr J Bot 2017; 109: 50-57
- 111 Hensel A, Schmidgall J, Kreis W. Extracellular polysaccharides produced by suspension-cultured cells from Digitalis lanata . Planta 1997; 63: 441-445
- 112 Hensel A, Schmidgall J, Kreis W. The plant cell wall – a potential source for pharmacologically active polysaccharides. Pharm Acta Helv 1998; 73: 37-43
- 113 Kirmizibekmez H, Masullo M, Festa M, Capasso A, Piacente S. Steroidal glycosides with antiproliferative activities from Digitalis trojana . Phytother Res 2014; 28: 534-538
- 114 Kreis W, Hensel A, Stuhlemmer U. Cardenolide biosynthesis in foxglove. Planta Med 1998; 64: 491-499
- 115 Kreis W, Müller-Uri F. Cardenolide Aglycone Formation in Digitalis . In: Bach TJ, Rohmer M. eds. Isoprenoid Synthesis in Plant and Microorganisms: new Concepts and experimental Approaches. New York: Springer Science and Business; 2013: 425-438
- 116 Milek F, Reinhard E, Kreis W. Influence of precursors and inhibitors of the sterol pathway on sterol and cardenolide metabolism in Digitalis lanata Ehrh. Plant Physiol Biochem 1997; 35: 111-121
- 117 Lindemann P, Finsterbusch A, Pangert A, Luckner M. Partial Cloning of a Δ5-3β-hydroxysteroid Dehydrogenase from Digitalis lanata . In: Okamoto M, Ihimura Y, Nawata H. eds. Molecular Steroidogenesis. Proceedings of the Yamada Conference LII. Frontiers Science Series 29, vol. XXIV. Tokyo: Universal Academy Press; 2000: 333-334
- 118 Herl V, Frankenstein J, Meitinger N, Müller-Uri F, Kreis W. Δ5-3β-Hydroxysteroid dehydrogenase (3βHSD) from Digitalis lanata. Heterologous expression and characterisation of the recombinant enzyme. Planta Med 2007; 73: 704-710
- 119 Finsterbusch A, Lindemann P, Grimm R, Eckerskorn C, Luckner M. Δ5-3β-Hydroxysteroid dehydrogenase from Digitalis lanata Ehrh. – a multifunctional enzyme in steroid metabolism?. Planta 1999; 209: 478-486
- 120 Schebitz P, Nothdurft L, Hensel A, Müller-Uri F, Kreis W. Norcholanic acids as substrates for recombinant enzymes in cardenolide biosynthesis in Digitalis lanata Ehrh. Tetrahedron Lett 2010; 51: 367-370
- 121 Meitinger N, Geiger D, Augusto TW, Maia de Pádua R, Kreis W. Purification of Δ(5)-3-ketosteroid isomerase from Digitalis lanata . Phytochemistry 2015; 109: 6-13
- 122 Meitinger N, Munkert J, Pádua RM, Dias de Souza JF, Maid H, Bauer W, Braga FC, Kreis W. The catalytic mechanism of the 3-ketosteroid isomerase of Digitalis lanata involves an intramolelcular proton transfer and the activity is not associated with the 3β-hydroxysteroid dehydrogenase activity. Tetrahedron Lett 2016; 57: 1567-1571
- 123 Gärtner DE, Seitz HU. Enzyme activities in cardenolide accumulating, mixotrophic shoot cultures of Digitalis purpurea L. J Plant Physiol 1993; 141: 269-275
- 124 Gärtner DE, Keilholz W, Seitz HU. Purification, characterization and partial peptide microsequencing of progesterone 5β-reductase from shoot cultures of Digitalis purpurea . Eur J Biochem 1994; 225: 1125-1132
- 125 Herl V, Fischer G, Reva VA, Stiebritz M, Müller-Uri F, Muller Y, Kreis W. The VEP1 gene (At4g24220) encodes a short-chain dehydrogenase/reductase with 3-oxo-Δ4,5-steroid 5β-reductase activity in Arabidopsis thaliana L. Biochimie 2009; 91: 517-525
- 126 Bauer P, Munkert J, Brydziun M, Burda E, Müller-Uri F, Gröger H, Muller YA, Kreis W. Highly conserved progesterone 5β-reductase (P5βR) genes, from 5β-cardenolide-free and 5β-cardenolide-producing angiosperms. Phytochemistry 2010; 71: 1495-1505
- 127 Bauer P, Rudolph K, Müller-Uri F, Kreis W. Vein patterning 1-encoded progesterone 5β-reductase: activity-guided improvement of catalytic efficiency. Phytochemistry 2012; 77: 53-59
- 128 Burda E, Krausser M, Fischer G, Hummel W, Müller-Uri F, Kreis W, Gröger H. Recombinant Δ4,5-steroid 5β-reductases as biocatalysts for the reduction of activated C=C double bonds in monocyclic and acrylic molecules. Adv Synth Catal 2009; 351: 2787-2790
- 129 Durchschein K, Wallner S, Macheroux P, Schwab W, Winkler T, Kreis W, Faber K. Nicotineamide-dependent ene reductases as alternative biocatalysts for the reduction of activated alkenes. Eur J Org Chem 2012; 26: 4963-4968
- 130 Pérez-Bermúdez P, Garcia AAM, Tunon I, Gavidia I. Digitalis purpurea P5βR2, encoding steroid 5β-reductase, is a novel defence-related gene involved in cardenolide biosynthesis. New Phytol 2009; 185: 687-700
- 131 Geu-Flores F, Sherden NH, Courdavault V, Burlat V, Glenn WS, Wu C, Nims E, Cui Y, OʼConnor SE. An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis. Nature 2012; 492: 138-142
- 132 Petersen J, Lanig H, Munkert J, Bauer P, Müller-Uri F, Kreis W. Progesterone 5β-reductases/iridoid synthases (PRISE): gatekeeper role of highly conserved phenylalanines in substrate preference and trapping is supported by molecular dynamics simulations. J Biomol Struct Dyn 2016; 34: 1667-1680
- 133 Grigat R. Die Progesteron-5β-Reduktase. Hemmbarkeit und Einflüsse auf die Cardenolidbiosynthese in Digitalis lanata und Isoplexis canariensis [Dissertation]. Erlangen-Nürnberg: Friedrich-Alexander-Universität; 2005
- 134 Strasser J. Heterologe Expression putativer Gene des Steroidstoffwechsels in Saccharomyces cerevisisae [Dissertation]. Erlangen-Nürnberg: Friedrich-Alexander-Universität; 2014
- 135 Pádua RM, Waibel R, Kuate SP, Schebitz PK, Hahn S, Gmeiner P, Kreis W. A simple chemical method for synthesizing malonyl hemiesters of 21-hydroxy-pregnanes, potential intermediates in cardenolide biosynthesis. Steroids 2008; 73: 458-465
- 136 Pádua RM, Meitinger N, Hennemann M, Schebitz P, Waibel R, Löber S, Gmeiner P, Clark T, Kreis W. Spontaneous butenolide ring formation of pregnane-21-O-malonyl hemiesters under mild reaction conditions is facilitated by the 14β-hydroxy group present in all natural cardenolides. Tetrahedron 2016; 72: 4556-4563
- 137 Stuhlemmer U, Kreis W. Cardenolide formation and activity of pregnane-modifying enzymes in cell suspension cultures, shoot cultures and leaves of Digitalis lanata . Plant Physiol Bioch 1996; 34: 85-91
- 138 Luber E. Reinigung der Malonyl-Coenzym A: 21-Hydroxypregnan 21-Hydroxy-Malonyltransferase und Versuche zur Isolierung einer Steroid-21-Hydroxylase aus Digitalis lanata Ehrh. [Dissertation]. Erlangen-Nürnberg: Friedrich-Alexander-Universität; 2002
- 139 Kuate SP, Pádua RM, Poumale HMP, Kreis W. Synthesis of a putative substrate for malonyl-coenzyme A: 21-hydroxypregnane 21-O-malonyltransferase and development of an HPLC method for the quantification of the enzyme reaction. J Chromatogr 2007; 860: 195-201
- 140 Pádua RM, Meitinger N, Dias de Souza JF, Waibel R, Gmeiner P, Braga FC, Kreis W. Biotransformation of 21-O-acetyl-deoxycorticosterone by cell suspension cultures of Digitalis lanata (strain W.1.4). Steroids 2012; 77: 1373-1380
- 141 May U, Kreis W. Purification and characterization of the cardenolide-specific β-glucohydrolase CGH I from Digitalis lanata leaves. Plant Physiol Biochem 1997; 35: 523-532
- 142 Schöniger R, Lindemann P, Grimm R, Eckerskorn C, Luckner M. Cardenolide 16′-O-glucohydrolase from Digitalis lanata. Purification and characterization. Planta 1998; 205: 477-482
- 143 Framm JJ, Petersen A, Thoeringer C, Pangert A, Hornung E, Feussner I, Luckner M, Lindemann P. Cloning and functional expression in Escherichia coli of a cDNA encoding cardenolide 16′-O-glucohydrolase from Digitalis lanata Ehrh. Plant Cell Physiol 2000; 41: 1293-1298
- 144 Shi HP, Lindemann P. Expression of recombinant Digitalis lanata EHRH. cardenolide 16′-O-glucohydrolase in Cucumis sativus L. hairy roots. Plant Cell Rep 2006; 25: 1193-1198
- 145 Hornberger M, Böttigheimer U, Hillier-Kaiser A, Kreis W. Purification and characterisation of the cardenolide-specific β-glucohydrolase CGH II from Digitalis lanata leaves. Plant Physiol Biochem 2000; 38: 929-936
- 146 Rodriguez-Rodriguez MC, Valido A. Opportunistic nectar-feeding birds are effective pollinators of bird-flowers from Canary Islands: experimental evidence from Isoplexis canariensis (Scrophulariaceae). Am J Bot 2008; 95: 1408-1415
- 147 Manson JS, Rasman S, Halitschke R, Thomson JD. Cardenolides in nectar may be more than a consequence of allocation to other plant parts: a phylogenetic study of Asclepias . Funct Ecol 2012; 26: 1100-1110
- 148 Jones PL, Agrawal AA. Consequences of toxic secondary compounds in nectar for mutualist bees and antagonist butterflies. Ecology 2016; 97: 2570-2579
- 149 Petschenka G, Agrawal AA. Milkweed butterfly resistance to plant toxins is linked to sequestration, not coping with toxic diet. Proc R Soc B 2015; 282: 20151865
- 150 Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis 2002; 44: 251-266
- 151 Bertol JW, Rigotto C, de Pádua RM, Kreis W, Barardi CR, Braga FC, Simões CM. Antiherpes activity of glucoevatromonoside, a cardenolide isolated from a Brazilian cultivar of Digitalis lanata . Antivir Res 2011; 92: 73-80
- 152 Newman RA, Yang P, Pawlus AD, Block KL. Cardiac glycosides as novel cancer therapeutic agents. Mol Interventions 2008; 8: 36-40
- 153 Prassas I, Diamandis EP. Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov 2008; 7: 926-935
- 154 Calderón-Montano JM, Burgos-Morón E, Orta ML, Maldonado-Navas D, Garcia-Dominguez I, López-Lázaro M. Evaluating the cancer therapeutic potential of cardiac glycosides. Biomed Res Int 2014; 2014: 794930
- 155 Schneider NFZ, Geller FC, Persich L, Marostica LL, Pádua RM, Kreis W, Braga FC, Simões CM. Inhibition of cell proliferation, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line. Nat Prod Res 2016; 30: 1327-1331
- 156 Wang Z, Zheng M, Li Z, Li R, Jia L, Xiong X, Southall N, Wang S, Xia M, Austin CP, Zheng W, Xie Z, Sun Y. Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition. Cancer 2009; 69: 6556-6564
- 157 Srivastava M, Eidelman O, Zhang J, Paweletz C, Caohuy H, Yang QF, Jacobson KA, Heldman E, Huang W, Jozwik C, Pollard BS, Pollard HB. Digotoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. PNAS 2004; 101: 7693-7698
- 158 Su CT, Hsu JTA, Hsieh HP, Lin PH, Chen TC, Kao CL, Lee CN, Chang SY. Anti-HSV activity of digitoxin and its possible mechanisms. Antivir Res 2008; 79: 62-70
- 159 Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses 1999; 53: 543-548
- 160 Haux J, Lam J, Marthinsen ABL, Strickert T, Lundgeren S. Digitoxin, in non toxic concentrations induces cell death in Jurkat T cells in vitro . J Oncol 1999; 31: 14-20
- 161 Mekhail T, Kaur H, Ganapathi R, Budd GT, Elson P, Bukowski RM. Phase 1 trial of Anvirzel in patients with refractory solid tumors. Invest New Drug 2006; 24: 423-427
- 162 Mijatovic T, Kiss R. Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways. Planta Med 2013; 79: 189-198
- 163 De S, Banerjee S, Babu MN, Lakhmi BM, Babu TMS. Review on cardiac glycosides in cancer research and cancer therapy. Indo Am J Pharm Res 2016; 6 (05) 5391
- 164 Krishna AB, Manikyam HK, Sharma VK, Sharma N. Plant cardenolides in therapeutics. Int J Indigenous Med Plants 2015; 48: 1871-1896
- 165 Gheorghiade M, Benatar D, Konstam MA, Stoukides CA, Bonow RO. Pharmacotherapy for systolic dysfunction: a review of randomized clinical trials. Am J Cardiol 1997; 80: 14H-27H
- 166 Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love TE, Aronow WS, Adams KF, Gheorghiade M. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 2006; 114: 397-403
- 167 Hood WB, Dans AL, Guyatt GH, Jaeschke R, McMurray JJV. Digitalis for treatment of congestive heart failure in patients in sinus rhythm: a systematic review and meta-analysis. J Card Fail 2004; 10: 155-164
- 168 Brewer H. Historical perspectives on health. Early Arabian medicine. J Roy Soc Health 2004; 124: 184-187
- 169 Hartwell JL, Abbott BJ. Antineoplastic principles in plants: recent developments in the field. Adv Pharmacol 1969; 7: 117-209
- 170 Shiratori O. Growth inhibitory effects of cardiac glycosides and aglycones on neoplastic cells: in vitro and in vivo studies. Gann 1967; 58: 521-528
- 171 Stenkvist B, Bengtsson E, Eklund G, Eriksson O, Holmquist J, Nordin B, Westman-Naeser S. Evidence of a modifying influence of heart glucosides on the development of breast cancer. Anal Quant Cytol 1980; 2: 49-54
- 172 Stenkvist B, Bengtsson E, Eriksson O, Holmquist J, Nordin B, Westman-Naeser S. Cardiac glycosides and breast cancer. Lancet 1979; 1: 563
- 173 Stenkvist B, Bengtsson E, Dahlqvist B, Eklund G, Eriksson O, Jarkrans T, Nordin B. Predicting breast cancer recurrence. Cancer 1982; 50: 2884-2893
- 174 Winnicka K, Bielawski K, Bielawska A. Cardiac glycosides in cancer research and cancer therapy. Acta Pol Pharm 2006; 63: 109-115
- 175 López-Lázaro M. Dual role of hydrogen peroxide in cancer: possible relevance to cancer chemoprevention and therapy. Cancer Lett 2007; 252: 1-8
- 176 Mijatovic T, Van Quaquebeke E, Delest B, Debeir O, Darro F, Kiss R. Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta 2007; 1776: 32-57
- 177 Buckalev VM. Endogenous digitalis-like factors: an overview of the history. Front Endocrinol (Lausanne) 2015; 6: 49
- 178 Hamlyn JM, Blaustein MP, Bova S, Duchrame DW, Harris DW, Mandel F, Mathews WR, Ludens JH. Identification and characterization of a ouabain-like compound from human plasma. Proc Natl Acad Sci U S A 1991; 88: 6259-6263
- 179 Baecher S, Kroiss M, Fassnacht M, Vogeser M. No endogenous ouabain is detectable in human plasma by ultra-sensitive UPLC-MS/MS. Clin Chim Acta 2014; 431: 87-92
- 180 Hamlyn JM, Blaustein MP. Endogenous ouabain: recent advances and controversies. Hypertension 2016; 68: 526-532
- 181 Lapostolle F, Borron SW, Verdier C, Taboulet P, Guerrier G, Adnet F, Clemessy JL, Bismuth C, Baud F. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med 2008; 36: 3014-3018
- 182 Camphausen C, Haas NA, Mattke AC. Successful treatment of oleander intoxication (cardiac glycosides) with digoxin-specific Fab antibody fragments in a 7-year-old child. Z Kardiol 2005; 94: 817-823
- 183 Maffè S, Cucchi L, Zenone F, Bertoncelli C, Beldi F, Colombo ML, Bielli M, Paino P, Dellavesa P, Perucca A, Parda NF, Signorotti F, Didino C, Zanetta M. Digitalis must be banished from the table: a rare case of acute accidental Digitalis intoxication of a whole family. J Cardiovasc Med 2009; 10: 727-732
- 184 Josephs RD, Daireaux A, Westwood S, Wielgosz RI. Simultaneous determination of various cardiac glycosides by liquid chromatography-hybrid mass spectrometry for the purity assessment of the therapeutic monitored drug digoxin. J Chromatogr A 2010; 27: 4535-4543
- 185 Wichtl M, Mankudidjoho M, Wichtl-Bleier W. Hochleistungs-Flüssigkeits-Chromatographische Analyse von Digitalis-Blattextrakten. J Chromatogr 1982; 234: 503-508
- 186 Wichtl M, Wichtl-Bleier W, Mangkudidjojo M. Hochleistungs-Flüssigkeits-Chromatographische Analyse von Digitalis-Blattextrakten. J Chromatogr 1982; 247: 359-365
- 187 Wiegrebe H, Wichtl M. HPLC-determination of cardenolides in Digitalis leaves after solid-phase extraction. J Chromatogr 1993; 630: 402-407
- 188 Kwon HJ, Sim HJ, Lee SI, Lee YM, Park YD, Hong SP. HPLC method validation for Digitalis and its analogue by pulsed amperometric detection. J Pharm Biomed Anal 2011; 54: 217-221
- 189 Pellatia F, Brunib R, Bellardic MG, Bertaccinic A, Benvenutia S. Optimization and validation of a high-performance liquid chromatography method for the analysis of cardiac glycosides in Digitalis lanata . J Chromatogr A 2009; 1216: 3260-3269