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Elder (Sambucus nigra)


Elder (Sambucas nigra) Image
Synonyms / Common Names / Related Terms
Almindelig hyld, baccae, baises de sureau, battree, black berried alder, black elder, black elderberry, boor tree, bountry, boure tree, Busine (Russian), Caprifoliaceae (family), cyaniding-3-glucoside, cyaniding-3-sambubioside, devil's eye, elderberry, elderberry anthocyanins, elderberry bark agglutinin , elderberry juice, ellanwood, ellhorn, European alder, European elder, European elder fruit, European elderberry, European elderflower, frau holloe, German elder, Holunderbeeren, Holunderblüten, inking elder, lady elder, nigrin b, old gal, old lady, peonidin 3-glucoside, peonidin 3-sambubioside, peonidin monglucuronide, pipe tree, Rubini® (elderberry extract), Sambreo, Sambuci flos, Sambucipunct Sambucus, sambuco (Italian), Sambucus sieboldiana (Japanese), Schwarzer holunder (German), sieboldin-b, suco (Spanish), sureau noir (French), sweet elder, tree of doom, yakori bengestro.
Note: Several species of Sambucus produce elderberries. Most scientific literature pertains to Sambucus nigra. Other species with similar chemical components include the American elder or common elder (Sambucus canadensis), antelope brush (Sambucus tridentata), blue elderberry (Sambucus caerulea), danewort (Sambucus ebulus), dwarf elder (Sambucus ebulus), red-fruited elder (Sambucus pubens, Sambucus racemosa), and Sambucus formosana. American elder (S. canadensis) and European elder (S. nigra) are often discussed simultaneously in the literature, since they have many of the same uses and contain common constituents.
Note: This review does not include Sambucus nigra agglutinin (SNA) affinity chromatography.


Mechanism of Action

Pharmacology:

  • Constituents: There are multiple chemical and biochemical studies of chemical constituents in S. nigra. The bark contains α-amyrenone, α-amyrin, betulin, oleanolic acid, beta-sitosterol12, as well as nigrin b, a lectin similar to ricin, and other type 2 ribosome inactivating proteins (RIPs) that are less toxic to cells and animals 13. The flowers/leaves contain flavonoids including quercetin (up to 3%), rutin, hyperoside14, and anthocyanins 11, as well as essential oils (responsible for the muscat aroma characteristic of elder flowers)15, mucilage, tannins (3%), organic acids, glycoside (0.042% by weight), plastocyanin 16, and sambunigrin (0.042% by weight). High amounts of N-phenylpropenoyl-L-amino acid amides were found in the flowers of Sambucus nigra.17
  • The fruit contains the protein Sambucus nigra agglutinin Ivf or SNAIVf, which is homologous to type 2 ribosome inactivating protein (RIP)18, while the bark contains a novel type 2 RIP (SNLRP), consisting of an A-chain with N-glycosidase activity and a B-chain devoid of carbohydrate binding activity normally present19,20. Two additional RIPs were further identified in bark (SNAI and SNAI')19, demonstrating the complexity of Type 2 RIP/lectins in S. nigra. The lectin isolated from bark is tetrameric with two distinct subunits and is rich in glutamine/glutamic acid, valine, and leucine.21 The fruit type 2 RIP lectin is 10 amino acids longer than the bark lectin.22 Elder RIPs with N-glycosidase activity are reported to inhibit protein synthesis in rabbits but not in plants.5
  • Quercetin is also present in elder and has been shown to be a potent inhibitor of xanthine oxidase.23 S. nigra has been shown to bind heavy metals.24
  • Experimental assays: The lectin of S. nigra has been used in multiple experimental clinical assays, due to its carbohydrate binding properties and its ability to precipitate highly sialylated glycoproteins25, including the use of S. nigra agglutinin binding to identify pregnant women at risk for pre-term delivery (by detecting fibronectin in cervicovaginal secretions using a glycoprotein lectin immunoabsorbent assay)26; distinguishing normal from stone-forming kidneys (using N-acetylneuraminic acid-calcium binding ratios)27; examining colorectal carcinoma by examining rates of colonic mucin sialylation (by comparing alpha 2,6-linked sialic acid versus sialyl-Tn antigen)28; evaluating ulcerative colitis by monitoring differences in sialylation in Asian versus European colitis patients29; examining increased beta-galactoside alpha 2,6-sialyltransferase activity (by detection of dioxigenin-conjugated S. nigra agglutinin)30; evaluating SNA levels in women with breast and ovarian cancer31; glycohistochemically identifying microglial cells from Alzheimer's disease samples32; measuring decreased sialylation of glycoproteins in nasal glands of patients with sinusitis33; monitoring elevated serum sialic acids associated with increased cardiovascular mortality34; and enriching stem cell samples/depleting T-cells in bone marrow harvests35.
  • Anti-inflammatory effects: S. nigra is reported to modulate the inflammatory cytokines IL-1 and TNF-alpha3,36; increase human basophil secretion of IL-4, IL-13, and histamine9; alter function of human neutrophils37, and inhibit macrophage release of proinflammatory cytokines and nuclear transcription factor kB and phosphatidylinositol 3-kinase4.
  • Antioxidant effects: Elderberries contain flavonoids (flavone, flavonone, isoflavone derivatives and anthocyanins), which are reported to possess antioxidant activity and to protect against oxidative stressors, such as hydrogen peroxide, 2-amidinopropane, dihydrochloride (AAPH), ferrous sulfate, and ascorbic acid.38,39,40,41
  • Antiproliferative effects: S. nigra agglutinin has been reported to inhibit nuclear protein transport in neuroblastoma cells, suggesting a functional significance of sialation.42
  • Antiviral effects: Based on laboratory and animal study, S. nigra may possess antiviral effects by inhibiting influenza virus types A and B and herpes simplex virus-143, reducing hemagglutination of red blood cells, and inhibiting replication of several strains of influenza A and B6. A case report exists of an HIV positive women, taking no HIV drugs, who experienced a viral load drop from 17,000 to 4,000 after ingestion of Sambucol® with olive leaf extract.8 The report also included a placebo controlled, double-blind study of Sambucol associated with a rapid recovery from influenza and inhibited replications of nine other strains of the flu virus by elderberry. The mechanism is believed to be rendering viruses nonfunctional by staining and coating them.
  • Diuretic effects: In a rat study, diuretic effects and sodium excretion were associated with an extract of S. nigra flowers.7
  • Glucose/insulin metabolism: In vitro research10 refutes earlier study44, and reports stimulation of glucose metabolism and promotion of insulin secretion from beta cells.
  • Respiratory effects: The combination herbal product Sinupret®, which contains elder, has been studied for its effects on bronchitis. There is a lack of reliable human evidence evaluating elder monotherapy as a treatment for bronchitis, however, and a mechanism of action is unclear.
  • Vascular effects: The multi-ingredient product OptiBerry IH141 has been shown to possess antiangiogenic properties via inhibition of H2O2 and TNF-alpha-induced Vascular Endothelial Growth Factor.1 In another study, elderberry extracts were associated with significantly impaired angiogenesis in human dermal microvascular endothelial cells.2

Pharmacodynamics/Kinetics:

  • Absorption: Anthocyanins, which are potent flavonoid antioxidants found in elder, are not absorbed in their unchanged glycosylated forms in humans.45 The maximum concentration of anthocyanins found in blood after injection of a highly concentrated solution was 35mg/mL at one hour, followed by a quick decay.39
  • Elimination: The elimination of plasma anthocyanins appears to follow first-order kinetics, and most anthocyanin compounds are excreted in urine within four hours after ingestion.45 After ingestion of about 30mL of elderberry extract (147.3mg total anthocyanins), the t½ was 1.74 hours.46 The urinary excretion rate of intact anthocyanins was fast, and appeared to be monoexponetial with high variability.
  • At a dose of 3g/kg, S. nigra extract did not modify the growth rate of rats.3
  • Flowers are believed to be safe for use in food, provided HCN levels are below 25ppm.

References

  1. Bagchi, D., Sen, C. K., Bagchi, M., and Atalay, M. Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. Biochemistry (Mosc) 2004;69(1):75-80, 1. 14972022
  2. Roy, S., Khanna, S., Alessio, H. M., Vider, J., Bagchi, D., Bagchi, M., and Sen, C. K. Anti-angiogenic property of edible berries. Free Radic Res 2002;36(9):1023-1031. 12448828
  3. Mascolo N, Autore G, Capasso F, and et al. Biological screening of Italian medicinal plants for anti-inflammatory activity. Phytotherapy Research 1987;1(1):28-31.
  4. Harokopakis, E., Albzreh, M. H., Haase, E. M., Scannapieco, F. A., and Hajishengallis, G. Inhibition of proinflammatory activities of major periodontal pathogens by aqueous extracts from elder flower (Sambucus nigra). J Periodontol 2006;77(2):271-279. 16460254
  5. de Benito, F. M., Iglesias, R., Ferreras, J. M., Citores, L., Camafeita, E., Mendez, E., and Girbes, T. Constitutive and inducible type 1 ribosome-inactivating proteins (RIPs) in elderberry (Sambucus nigra L.). FEBS Lett 5-22-1998;428(1-2):75-79. 9645479
  6. Zakay-Rones, Z., Varsano, N., Zlotnik, M., Manor, O., Regev, L., Schlesinger, M., and Mumcuoglu, M. Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama. J Altern Complement Med 1995;1(4):361-369. 9395631
  7. Beaux, D., Fleurentin, J., and Mortier, F. Effect of extracts of Orthosiphon stamineus Benth, Hieracium pilosella L., Sambucus nigra L. and Arctostaphylos uva-ursi (L.) Spreng. in rats. Phytother Res 1999;13(3):222-225. 10353162
  8. Konlee, M. A new triple combination therapy. Posit Health News 1998;(No 17):12-14. 11366542
  9. Haas, H., Falcone, F. H., Schramm, G., Haisch, K., Gibbs, B. F., Klaucke, J., Poppelmann, M., Becker, W. M., Gabius, H. J., and Schlaak, M. Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur J Immunol 1999;29(3):918-927. 10092096
  10. Gray, A. M., Abdel-Wahab, Y. H., and Flatt, P. R. The traditional plant treatment, Sambucus nigra (elder), exhibits insulin-like and insulin-releasing actions in vitro. J Nutr 2000;130(1):15-20. 10613759
  11. Mulleder, U., Murkovic, M., and Pfannhauser, W. Urinary excretion of cyanidin glycosides. J Biochem Biophys Methods 2002;53(1-3):61-66. 12406587
  12. Lawrie W, McLean J, and Paton AC. Triterpenoids in the bark of elder (Sambucus nigra). Phytochemistry 1964;3:267-268.
  13. Battelli, M. G., Citores, L., Buonamici, L., Ferreras, J. M., de Benito, F. M., Stirpe, F., and Girbes, T. Toxicity and cytotoxicity of nigrin b, a two-chain ribosome- inactivating protein from Sambucus nigra: comparison with ricin. Arch Toxicol 1997;71(6):360-364. 9195017
  14. Davidek J. Isolation of chromatographically pure rutin from flowers of elder. Nature 1961;189(4763):487-488.
  15. Toulemonde B and Richard HM. Volatile constituents of dry elder (Sambucus nigra L.) flowers. J Agric Food Chem 1983;31(2):365-370.
  16. Scawen, M. D., Ramshaw, J. A., Brown, R. H., and Boulter, D. The amino-acid sequence of plastocyanin from Sambucus nigra L. (Elder). Eur J Biochem 5-2-1974;44(1):299-303. 4854645
  17. Hensel, A., Deters, A. M., Muller, G., Stark, T., Wittschier, N., and Hofmann, T. Occurrence of N-phenylpropenoyl-L-amino acid amides in different herbal drugs and their influence on human keratinocytes, on human liver cells and on adhesion of Helicobacter pylori to the human stomach. Planta Med 2007;73(2):142-150. 17295182
  18. van Damme, E. J., Roy, S., Barre, A., Rouge, P., van Leuven, F., and Peumans, W. J. The major elderberry (Sambucus nigra) fruit protein is a lectin derived from a truncated type 2 ribosome-inactivating protein. Plant J 1997;12(6):1251-1260. 9450339
  19. van Damme, E. J., Roy, S., Barre, A., Citores, L., Mostafapous, K., Rouge, P., van Leuven, F., Girbes, T., Goldstein, I. J., and Peumans, W. J. Elderberry (Sambucus nigra) bark contains two structurally different Neu5Ac(alpha2,6)Gal/GalNAc-binding type 2 ribosome-inactivating proteins. Eur J Biochem 5-1-1997;245(3):648-655. 9183001
  20. van Damme, E. J., Barre, A., Rouge, P., van Leuven, F., and Peumans, W. J. Isolation and molecular cloning of a novel type 2 ribosome-inactivating protein with an inactive B chain from elderberry (Sambucus nigra) bark. J Biol Chem 3-28-1997;272(13):8353-8360. 9079659
  21. Broekaert, W. F., Nsimba-Lubaki, M., Peeters, B., and Peumans, W. J. A lectin from elder (Sambucus nigra L.) bark. Biochem J 7-1-1984;221(1):163-169. 6466312
  22. Peumans, W. J., Roy, S., Barre, A., Rouge, P., van Leuven, F., and van Damme, E. J. Elderberry (Sambucus nigra) contains truncated Neu5Ac(alpha- 2,6)Gal/GalNAc-binding type 2 ribosome-inactivating proteins. FEBS Lett 3-20-1998;425(1):35-39. 9541002
  23. Chang, W. S., Lee, Y. J., Lu, F. J., and Chiang, H. C. Inhibitory effects of flavonoids on xanthine oxidase. Anticancer Res 1993;13:2165-2170. 8297130
  24. Coupe, S. A., Taylor, J. E., and Roberts, J. A. Characterisation of an mRNA encoding a metallothionein-like protein that accumulates during ethylene-promoted abscission of Sambucus nigra L. leaflets. Planta 1995;197(3):442-447. 8580758
  25. Shibuya, N., Goldstein, I. J., Broekaert, W. F., Nsimba-Lubaki, M., Peeters, B., and Peumans, W. J. The elderberry (Sambucus nigra L.) bark lectin recognizes the Neu5Ac(alpha 2-6)Gal/GalNAc sequence. J Biol Chem 2-5-1987;262(4):1596-1601. 3805045
  26. Hampel, D. J., Kottgen, B., Dudenhausen, J. W., and Kottgen, E. Fetal fibronectin as a marker for an imminent (preterm) delivery. A new technique using the glycoprotein lectin immunosorbent assay. J Immunol Methods 4-22-1999;224(1-2):31-42. 10357204
  27. Hofbauer, J., Fang-Kircher, S., Steiner, G., Wiener, H., Susani, M., Simak, R., Ghoneim, M. A., and Marberger, M. N-acetylneuraminic acids (nana): a potential key in renal calculogenesis. Urol Res 1998;26(1):49-56. 9537697
  28. Murayama, T., Zuber, C., Seelentag, W. K., Li, W. P., Kemmner, W., Heitz, P. U., and Roth, J. Colon carcinoma glycoproteins carrying alpha 2,6-linked sialic acid reactive with Sambucus nigra agglutinin are not constitutively expressed in normal human colon mucosa and are distinct from sialyl-Tn antigen. Int J Cancer 3-4-1997;70(5):575-581. 9052758
  29. McMahon, R. F., Warren, B. F., Jones, C. J., Mayberry, J. F., Probert, C. S., Corfield, A. P., and Stoddart, R. W. South Asians with ulcerative colitis exhibit altered lectin binding compared with matched European cases. Histochem J 1997;29(6):469-477. 9248854
  30. Dall'Olio, F. and Trere, D. Expression of alpha 2,6-sialylated sugar chains in normal and neoplastic colon tissues. Detection by digoxigenin-conjugated Sambucus nigra agglutinin. Eur J Histochem 1993;37(3):257-265. 7693064
  31. Goodarzi, M. T. and Turner, G. A. Decreased branching, increased fucosylation and changed sialylation of alpha-1-proteinase inhibitor in breast and ovarian cancer. Clin Chim Acta 5-15-1995;236(2):161-171. 7554283
  32. Zambenedetti, P., Giordano, R., and Zatta, P. Histochemical localization of glycoconjugates on microglial cells in Alzheimer's disease brain samples by using Abrus precatorius, Maackia amurensis, Momordica charantia, and Sambucus nigra lectins. Exp Neurol 1998;153(1):167-171. 9743580
  33. Ueno, K., Wang, Z. H., Hanamure, Y., Yoshitsugu, M., Fukuda, K., Furuta, S., Uehara, F., and Ohyama, M. Reduced sialylation of glycoproteins in nasal glands of patients with chronic sinusitis. Acta Otolaryngol 1997;117(3):420-423. 9199529
  34. Crook, J. R., Goldman, J. H., Dalziel, M., Madden, B., and McKenna, W. J. Increased ventricular sialylation in patients with heart failure secondary to ischemic heart disease. Clin Cardiol 1997;20(5):455-458. 9134277
  35. Mumcuoglu, M., Manor, D., and Slavin, S. Enrichment for GM-CFU from human bone marrow using Sambucus nigra agglutinin: potential application to bone marrow transplantation. Exp Hematol 1986;14(10):946-950. 3533587
  36. Yesilada, E., Ustun, O., Sezik, E., Takaishi, Y., Ono, Y., and Honda, G. Inhibitory effects of Turkish folk remedies on inflammatory cytokines: interleukin-1alpha, interleukin-1beta and tumor necrosis factor alpha. J Ethnopharmacol 1997;58(1):59-73. 9324006
  37. Timoshenko, A. V. and Cherenkevich, S. N. [H2O2 generation and human neutrophil aggregation as affected by lectins]. Gematol Transfuziol 1995;40(4):32-35. 7557235
  38. Abuja PM, Murkovic M, and Pfannhauser W. Antioxidant and prooxidant activities of elderberry (Sambucus nigra) extract in low density lipoprotein oxidation. J Agric Food Chem 1998;46:4091-4096.
  39. Murkovic, M., Adam, U., and Pfannhauser, W. Analysis of anthocyane glycosides in human serum. Fresenius. J Anal.Chem 2000;366(4):379-381. 11220323
  40. Youdim, K. A., Martin, A., and Joseph, J. A. Incorporation of the elderberry anthocyanins by endothelial cells increases protection against oxidative stress. Free Radic Biol Med 7-1-2000;29(1):51-60. 10962205
  41. Middleton E Jr and Kandaswami, C. Effects of flavonoids on immune and inflammatory cell functions. Biochem Pharmacol 3-17-1992;43(6):1167-1179. 1562270
  42. Emig, S., Schmalz, D., Shakibaei, M., and Buchner, K. The nuclear pore complex protein p62 is one of several sialic acid- containing proteins of the nuclear envelope. J Biol Chem 6-9-1995;270(23):13787-13793. 7775435
  43. Serkedjieva J, Manolova N, Zgorniak-Nowosielska I, and et al. Antiviral activity of the infusion (SHS-174) from flowers of Sambucus nigra L., aerial parts of Hypericum perforatum L., and roots of Saponaria officinalis L. against influenza and herpes simplex viruses. Phytotherapy Research 1990;4(3):97-100.
  44. Swanston-Flatt, S. K., Day, C., Flatt, P. R., Gould, B. J., and Bailey, C. J. Glycaemic effects of traditional European plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice. Diabetes Res 1989;10(2):69-73. 2743711
  45. Milbury, P. E., Cao, G., Prior, R. L., and Blumberg, J. Bioavailablility of elderberry anthocyanins. Mech Ageing Dev 4-30-2002;123(8):997-1006. 12044949
  46. Bitsch, I., Janssen, M., Netzel, M., Strass, G., and Frank, T. Bioavailability of anthocyanidin-3-glycosides following consumption of elderberry extract and blackcurrant juice. Int J Clin Pharmacol Ther 2004;42(5):293-300. 15176653




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