Sekundarni metaboliti v navadni konoplji (Cannabis sativa L.) in njihova vloga pri obrambi rastline pred škodljivci in patogeni

Luka Bitežnik; Marina Dermastia; Stanislav Trdan

doi:10.14720/abs.66.1.12521

Authors

Luka Bitežnik
Marina Dermastia
Stanislav Trdan

DOI:

https://doi.org/10.14720/abs.66.1.12521

Keywords:

cannabinoids, Cannabid sativa L, hemp, flavonoids, pests, pathogens, terpenoids

Abstract

Hemp (Cannabis sativa L.) is a globally distributed plant with a complex phytochemistry. Secondary metabolism is extremely rich. Secondary metabolites are substances whose role is the interaction of the plant with the environment. Their synthesis depends on the presence of stress and is very energy-consuming. They protect plants from pests and pathogens, as well as from abiotic factors. Cannabinoids, terpenoids and flavonoids are the predominant substances concentrated in the inflorescences of female plants. Their ecological role and function are not yet fully understood. The cannabinoids Δ-9-trans-tetrahydrocannabinol (Δ9-THC), cannabidiolic acid (CBDA), and others probably act as antioxidants, and based on their spatially isolated synthesis and cytotoxic byproducts, they are thought to be involved in the plant's defense system. Under stress, their content increases and the chemical profile changes. Stress activates stress signaling molecules - jasmonic acid and its derivatives, which affect the release of terpenoids, and increases the expression of genes in the phenylpropanoid pathway, which is crucial for the synthesis of flavonoids. Secondary metabolites act synergistically and in conjunction with the microbiome - endophytic bacteria and fungi - have a negative effect on harmful organisms and protect the plant.

Metrics

Metrics Loading ...

References

AbuQamar, S., Chen, X., Dhawan, R., Bluhm, B., Salmeron, J., Lam, S. (2006). Expression profiling and mutant analysis reveals complex regulatory networks involved in Arabidopsis response to Botrytis infection. The Plant Journal, 48, 28–44. https://doi.org/10.1111/j.1365-313x.2006.02849.x DOI: https://doi.org/10.1111/j.1365-313X.2006.02849.x

Andre, C.M., Hausman, J.F., Guerriero, G. (2016). Cannabis sativa: the plant of the thousand and one molecules. Frontiers in Plant Science, 7(19), 17 str. https://doi.org/10.3389/fpls.2016.00019 DOI: https://doi.org/10.3389/fpls.2016.00019

Balthazar, C., Novinscak, A., Joly, D.L., Filion, M. (2020). Expression of putative defense responses in cannabis primed by Pseudomonas and/or Bacillus strains and infected by botrytis cinerea. Frontiers in Plant Science, 11. https://doi.org/10.3389/fpls.2020.572112 DOI: https://doi.org/10.3389/fpls.2020.572112

Bartram, S., Jux, A., Gleixner, G., Boland, W. (2006). Dynamic pathway allocation in early terpenoid biosynthesis of stress-induced lima bean leaves. Phytochemistry, 67(15), 1661-1672. https://doi:10.1016/j.phytochem.2006.02.004 DOI: https://doi.org/10.1016/j.phytochem.2006.02.004

Bautista, J.L., Yu, S., Tian, L. (2021). Flavonoids in Cannabis sativa: Biosynthesis, Bioactivities, and Biotechnology. ACS Omega 6(8), 5119-5123. https://doi.org/10.1021/acsomega.1c00318 DOI: https://doi.org/10.1021/acsomega.1c00318

Beek, T.A. in Joulain, D. (2017). The essential oil of patchouli, Pogostemon cablin: A review. Flavour and Fragrance Journal 33(1), 6-51. https://doi.org/10.1002/ffj.3418 DOI: https://doi.org/10.1002/ffj.3418

Bergman, M.E., Davis, B., Phillips, M.A. (2019). Medically useful plant terpenoids: Biosynthesis, occurrence, and mechanism of action. Molecules 24, 3961. https://doi.org/10.3390/molecules24213961 DOI: https://doi.org/10.3390/molecules24213961

Brenneisen, R. (2007). “Chemistry and analysis of phytocannabinoids and other cannabis constituents,” in Marijuana and the Cannabinoids Forensic Science and Medicine, ed. M. ElSohly (New York, NY: Humana Press), 17–49 https://doi.org/10.1007/978-1-59259-947-9_2 DOI: https://doi.org/10.1007/978-1-59259-947-9_2

Byrne, D.N., Miller, W.B. (1990). Carbohydrate and amino acid composition of phloem sap and honeydew produced by Bemisia tabaci. Journal of Insect Physiology 36, 433–439. https://doi.org/10.1016/0022-1910(90)90061-J DOI: https://doi.org/10.1016/0022-1910(90)90061-J

Chi, H., Su, H.Y. (2006). Age-stage, two-sex life tables of Aphidius gifuensis (Ashmead) (Hymenoptera: Braconidae) and its host Myzus persicae (Sulzer) (Homoptera: Aphididae) with mathematical proof of the relationship between female fecundity and the net reproductive rate. Environmental Entomology 35, 10–21. https://doi.org/10.1603/0046-225X-35.1.10 DOI: https://doi.org/10.1603/0046-225X-35.1.10

Dan, J., Kaiping D., Zhen X., Jie C. 2020. Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Scientific Reports 10, 3309 https://doi.org/10.1038/s41598-020-60172-6 1 DOI: https://doi.org/10.1038/s41598-020-60172-6

De Groot, R.C. (1972). Growth of wood-inhabiting fungi in saturated atmospheres of monoterpenoids. Mycologia, 64(4), 863–870. https://doi.org/10.1080/00275514.1972.12019336 DOI: https://doi.org/10.1080/00275514.1972.12019336

Elsohly, H.N., Turner, C.E., Clark, A.M., Elsohly, M.A. (1982). Synthesis and antimicrobial activities of certain cannabichromene and cannabigerol related compounds. Journal of Pharmaceutical Sciences, 71(12), 1319-1323. https://doi.org/10.1002/jps.2600711204. DOI: https://doi.org/10.1002/jps.2600711204

ElSohly, M.A, Slade, D. (2005). Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sciences 78(5), 539-48. https://doi.org/78:539–54810.1016/j.lfs.2005.09.011 DOI: https://doi.org/10.1016/j.lfs.2005.09.011

Ferreyra, M.L.F., Rius, S.P., Casati, P. (2012). Flavonoids: biosynthesis, biological functions, and biotechnological applications. Frontiers in Plant Science 3, 222. https://doi.org/10.3389/fpls.2012.00222 DOI: https://doi.org/10.3389/fpls.2012.00222

Fischedick, J.T., Hazekamp, A., Erkelens, T., Choi, Y.H., Verpoorte, R. (2010). Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry 71, 2058–2073. https://doi.org/10.1016/j.phytochem.2010.10.001

Flores-Sanchez, I.J., Pec, J., Fei, J., Choi, Y.H., Dusek, J., Verpoorte, R. (2009). Elicitation studies in cell suspension cultures of Cannabis sativa L. Biotechnology 143(2), 157–168. https://doi.org/10.1016/j.jbiotec.2009.05.006 DOI: https://doi.org/10.1016/j.jbiotec.2009.05.006

Flores-Sanchez, I.J., Verpoorte, R. (2008). Secondary metabolism in Cannabis. Phytochemistry Review 7, 615–639. https://doi.org/10.1007/s11101-008-9094-4 DOI: https://doi.org/10.1007/s11101-008-9094-4

Gamarra, H., Sporleder, M., Carhuapoma, P., Kroschel, J., Kreuze, J. (2020). A temperature-dependent phenology model for the greenhouse whitefly Trialeurodes vaporariorum (Hemiptera: Aleyrodidae). Virus Research 289, 198107. https://doi.org/10.1016/j.virusres.2020.198107 DOI: https://doi.org/10.1016/j.virusres.2020.198107

Gershenzon, J., Dudareva, N., (2007). The function of terpene natural products in the natural world. Nature Chemical Biology 3, 408–414. https://doi.org/10.1038/nchembio.2007.5 DOI: https://doi.org/10.1038/nchembio.2007.5

Giupponi, L., Leoni, V., Pavlovic, R. Giorgi, A. (2020). Influence of Altitude on Phytochemical Composition of Hemp Inflorescence: A Metabolomic Approach. Molecules, 25(6), 1381. https://doi.org/10.3390/molecules25061381 DOI: https://doi.org/10.3390/molecules25061381

Glattstein, B., Gorski, A. (2001). Marijuana identification: A test for calcium in cystolityhic hairs. Microscopy Today, 9(4), 16. https://doi.org/10.1017/S155192950005728X DOI: https://doi.org/10.1017/S155192950005728X

Glodowska, M. (2016). Cannabis sativa L. and its antimicrobial properties – A review. Badania i Rozwój Młodych Naukowców w Polsce – Agronomia i ochrona roślin

Gorelick, J., Bernstein, N. (2017). Cannabis sativa L. Springer International Publishing. Chandra S. et al. (eds.), - Botany and Biotechnology, 439-456. https://doi.org/10.1007/978-3-319-54564-6_21 DOI: https://doi.org/10.1007/978-3-319-54564-6_21

Górski, R., Sobieralski, K., Siwulski, M. (2016). The effect of hemp essential oil on mortality Aulacorthum solani Kalt. and Tetranychus urticae Koch.. Ecological Chemistry and Engineering, 23(3), 505-511. https://doi.org/10.1515/eces-2016-0037 DOI: https://doi.org/10.1515/eces-2016-0037

Hall, R.A. (1982). Control of whitefly, Trialeurodes vaporariorum and cotton aphid, Aphis gossypii in glasshouses by two isolates of the fungus, Verticillium lecanii. Annals of Applied Biology 101(1), 1–11. https://doi.org/10.1111/j.1744-7348.1982.tb00794.x DOI: https://doi.org/10.1111/j.1744-7348.1982.tb00794.x

Hayat, Q., Hayat, S., Irfan, M., Ahmad, A. (2010). Effect of exogenous salicylic acid under changing environment: A review. Environmental and Experimental Botany 68, 14–25. https://doi.org/10.1016/j.envexpbot.2009.08.005 DOI: https://doi.org/10.1016/j.envexpbot.2009.08.005

Hemphill, J.T., Paul, J.M. (2004). Cannabinoid content of individual plant organs from different geographical strains of Cannabis sativa L. Journal of Natural Products 43. https://doi.org/10.1021/np50007a009 DOI: https://doi.org/10.1021/np50007a009

Hill, K.P. (2015). Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: A clinical review. The Journal of the American Medical Association 313, 2474–2483. https://doi.org/10.1001/jama.2015.6199 DOI: https://doi.org/10.1001/jama.2015.6199

Hood, L.V.S., Dames M.E., Barry, G.T., (1973). Headspace volatiles of marijuana. Nature 24, 402-403. DOI: https://doi.org/10.1038/242402a0

Jalali, S., Salami, S.A., Sharifi, M., Sohrabi, S. (2019). Signaling compounds elicit expression of key genes in cannabinoid pathway and related metabolites in cannabis. Industrial Crops and Products 133, 105-110. https://doi.org/10.1016/j.indcrop.2019.03.004 DOI: https://doi.org/10.1016/j.indcrop.2019.03.004

Keller, A., Leupin, M., Mediavilla, V., Wintermantel, E. (2001). Influence of the growth stage of industrial hemp on chemical and physical properties of the fibres. Industrial Crops and Products 13, 35–48. https://doi.org/10.1016/S0926-6690(00)00051-0 DOI: https://doi.org/10.1016/S0926-6690(00)00051-0

Kennedy, J. S., Booth, C. O., Kershaw, W. J. S. (1959). Host finding by aphids in the field: Aphis fabae scop. (Gynoparae) and Brevicoryne brassicae L.; with a re-appraisal of the role of host-finding behaviour in virus spread. Annals of Applied Biology, 47(3), 424–444. https://doi.org/10.1111/j.1744-7348.1959.tb07277.x DOI: https://doi.org/10.1111/j.1744-7348.1959.tb07277.x

Kostanda, E., Khatib, S. (2022). Biotic stress caused by Tetranychus urticae mites elevates the quantity of secondary metabolites, cannabinoids and terpenes, in Cannabis sativa L., Industrial Crops and Products 176, 114331. https://doi.org/10.1016/j.indcrop.2021.114331 DOI: https://doi.org/10.1016/j.indcrop.2021.114331

Kurita, N., Miyaji, M., Kurane, R., Takahara, Y. (1981). Antifungal activity of components of essential oils. Agricultural and Biological Chemistry, 45(4), 945-952, https://doi.org/10.1080/00021369.1981.10864635 DOI: https://doi.org/10.1080/00021369.1981.10864635

Kusari, P., Kusari, S., Lamshöft, M., Sezgin, S., Spiteller, M., Kayser, O. (2014). Quorum quenching is an antivirulence strategy employed by endophytic bacteria. Applied Microbiology and Biotechnology 98(16), 7173–7183. https://doi.org/10.1007/s00253-014-5807-3 DOI: https://doi.org/10.1007/s00253-014-5807-3

Kusari, P., Kusari, S., Spiteller, M., Kayser, O. (2013) Endophytic fungi harbored in Cannabis sativa L.: diversity and potential as biocontrol agents against host plant-specific phytopathogens. Fungal Diversity 60, 137. https://doi.org/10.1007/s13225-012-0216-3 DOI: https://doi.org/10.1007/s13225-012-0216-3

Leizer, C., Ribnicky, D., Poulev, A. (2000). The composition of hemp seed oil and its potential as an important source of nutrition. Journal of Nutraceuticals, functional & medical foods, 2(4), 35- 53. https://doi.org/10.1300/J133v02n04_04 DOI: https://doi.org/10.1300/J133v02n04_04

Levin, D. A. (1973). The role of trichomes in plant defense. Quarterly Review Biology 48, 3-15. DOI: https://doi.org/10.1086/407484

McCune, F., Morphy, C., Eaves, J., Fournier, V. (2021). Onion thrips, Thrips tabaci (Thysanoptera: Thripidae), reduces yields in indoor-grown cannabis. Phytoprotection, 101(1), 14–20 https://doi.org/10.7202/1076365ar DOI: https://doi.org/10.7202/1076365ar

McPartland, J. (1984). Pathogenicity of Phomopsis ganjae on Cannabis sativa and the fungistatic effect of cannabinoids produced by the host. Mycopathologia 87(3), 149–153. https://doi.org/10.1007/BF00436900 DOI: https://doi.org/10.1007/BF00436900

McPartland, J. M. 1992. A review of Cannabis diseases. Journal of the International Hemp Association 3, 19–23.

McPartland, J. M., Clarke, R. C., Watson, D. P. (2000). Hemp Diseases and Pests Management and Biological Control. University of Vermont, Vermont, USA. Chapter: 4 25-93 https://doi.org/10.1079/9780851994543.0000 DOI: https://doi.org/10.1079/9780851994543.0000

McPartland, J., Sheikh, Z. (2018). A review of Cannabis sativa-based insecticides, miticides, and repellents. Journal of Entomology and Zoology Studies 6(6), 1288-1299. https://doi.org/10.1016/j.phytochem.2010.10.001 DOI: https://doi.org/10.1016/j.phytochem.2010.10.001

Mediavilla, V. Steinemann, S. (1997). Essential oil of Cannabis sativa strains. Journal of the International Hemp Association 4(2), 82-84.

Mishra, A., Singh, S.P., Mahfooz, S., Bhattacharya, A., Mishra, N., Shirke, P.A., Nautiyal, C.S. (2018). Bacterial endophytes modulates the withanolide biosynthetic pathway and physiological performance in Withania somnifera under biotic stress. Microbiological Research, 212–213, 17-28 https://doi.org/10.1016/j.micres.2018.04.006 DOI: https://doi.org/10.1016/j.micres.2018.04.006

Nissen L., Zatta A., Stefanini I., Grandi, S., Sgorbati, B., Biavati, B., Monti A., (2010). Characterization and antimicrobial activity of essential oils of industrial hemp varieties (Cannabis sativa L.). Fitoterapia. 31;81(5):413-9. https://doi.org/10.1016/j.fitote.2009.11.010 DOI: https://doi.org/10.1016/j.fitote.2009.11.010

Nour, M.A. (1958). Studies on Leveillula taurica (Lev.) Arn. and other powdery mildews. Transactions of the British Mycological Society, 41 (1), 17-38. https://doi.org/10.1016/S0007-1536(58)80003-0 DOI: https://doi.org/10.1016/S0007-1536(58)80003-0

Nuutinen, T. (2018). Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus. European Journal of Medicinal Chemistry, 157, 198-228. https://doi.org/10.1016/j.ejmech.2018.07.076 DOI: https://doi.org/10.1016/j.ejmech.2018.07.076

Park, Y.L., Lee, J.H. (2002). Leaf cell and tissue damage of cucumber caused by twospotted spider mite (Acari: Tetranychidae). Journal of Economic Entomology, 95(5), 952-7. https://doi.org/10.1093/jee/95.5.952 DOI: https://doi.org/10.1093/jee/95.5.952

Pate, D. (1994). Chemical ecology of Cannabis. Journal of the International Hemp Association 2, 32-37.

Petanović, R. Magud, B., Smiljanić, D., (2007). The Hemp Russet Mite Aculops cannabicola (Farkas, 1960) (Acari: eriophyoidea) Found on Cannabis sativa l. in Serbia. Supplement to the Description Archives of Biological Sciences, 59(1), 81-85. https://doi.org/10.2298/ABS0701081P DOI: https://doi.org/10.2298/ABS0701081P

Potter, D. The propagation, characterisation and optimisation of Cannabis sativa L. as a phytopharmaceutical. Doctoral thesis, King’s College, London, 2009.

Prado, E., Tjallingii, W.F. (1994). Aphid activities during sieve element punctures. Entomologia Experimentalis et Applicata 72, 157–165. https://doi.org/10.1111/j.1570-7458.1994.tb01813.x DOI: https://doi.org/10.1111/j.1570-7458.1994.tb01813.x

Punja, Z.K., Collyer, D., Scott, C., Lung, S., Holmes, J., Sutton, D. (2019). Pathogens and molds affecting production and quality of Cannabis sativa L. Frontiers in Plant Science 10: 1120. https://doi.org/10.3389/fpls.2019.01120 DOI: https://doi.org/10.3389/fpls.2019.01120

Regev, S., Cone, W.W. (1975). Evidence of Farnesol as a Male Sex Attractant of the Twospotted Spider Mite, Tetranychus urticae Koch (Acarina: Tetranychidae). Environmental Entomology, 4(2), 307–311. https://doi.org/10.1093/ee/4.2.307 DOI: https://doi.org/10.1093/ee/4.2.307

Richins, R.D., Rodriguez-Uribe, L., Lowe, K., Ferral, R., O’Connell, M.A. (2018). Accumulation of bioactive metabolites in cultivated medical Cannabis. PLOS ONE 13, 7. https://doi.org/10.1371/journal.pone.0201119 DOI: https://doi.org/10.1371/journal.pone.0201119

Ruan, J., Zhou, Y., Zhou, M., Yan, J., Khurshid, M., Weng, W., Cheng, J., Zhang, K. (2019). Jasmonic Acid Signaling Pathway in Plants. International Journal of Molecular Sciences 20, 2479. https://doi.org/10.3390/ijms20102479 DOI: https://doi.org/10.3390/ijms20102479

Russo, E.B. (2011). Taming THC: Potential cannabis synergy and phytocannabinoid terpenoid entourage effects. British Journal of Pharmacology 163, 1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x DOI: https://doi.org/10.1111/j.1476-5381.2011.01238.x

Salari, F., Mansori, H. (2013). The effect of jasmonic acid on the terpenoid compounds in Cannabis sativa. Journal of Plant Process and Function 1(2), 51-60. https://doi.org/20.1001.1.23222727.1391.1.2.5.4

Samac, D.A., Graham, M.A. (2007). Recent advances in legume-microbe interactions: recognition, defense response, and symbiosis from a genomic perspective. Plant Physiol. 144, 582–587. https://doi.org/10.1104/pp.107.096503 DOI: https://doi.org/10.1104/pp.107.096503

Satyal, P., Woods, K.E., Dosoky, N.S., Neupane, S., Setzer, W.N. (2012). Biological activities and volatile constituents of Aegle marmelos (L.) Corrêa from Nepal. Journal of Medicinally Active Plants 1(3), 114-122. https://doi.org/10.7275/R5Q23X59

Schafer, H., Wink, M. (2009). Medicinally important secondary metabolites in recombinant microorganisms or plants: progress in alkaloid biosynthesis, Biotechnology Journal 4, 1684–1703. https://doi.org/10.1002/biot.200900229 DOI: https://doi.org/10.1002/biot.200900229

Schultes, R.E., Klein W.M., Plowman T., Lockwood T.E. 1974. Cannabis: An example of taxonomic neglect. Botanical Museum Leaflets, 23(9), 337-367. DOI: https://doi.org/10.5962/p.168565

Setzer, N., Satyal, P., (2014). Chemotyping and Determination of Antimicrobial, Insecticidal, and Cytotoxic Properties of Wild-Grown Cannabis sativa from Nepal. Journal of Medicinally Active Plants 3(1), 9-16. https://doi.org/10.7275/R58W3B8V

Sirikantaramas, S., Taura, F., Tanaka, Y., Ishikawa Y., Morimoto, S., Shoyama, Y. (2005). Tetrahydrocannabinolic acid synthase, the enzyme controlling marijuana psychoactivity, is secreted into the storage cavity of the glandular trichomes. Plant and Cell Physiology 46, 1578–1582. https://doi.org/10.1093/pcp/pci166 DOI: https://doi.org/10.1093/pcp/pci166

Small, E., Cronquist, A. (1976). A practical and natural taxonomy for Cannabis. Taxon 25, 405-435. https://doi.org/10.2307/1220524 DOI: https://doi.org/10.2307/1220524

Taghinasab, M., Jabaji, S. (2020). Cannabis microbiome and the role of endophytes in modulating the production of secondary metabolites: An Overview. Microorganisms, 8, 355. https://doi.org/10.3390/microorganisms8030355 DOI: https://doi.org/10.3390/microorganisms8030355

Tanney, C.A.S., Backer, R., Geitmann, A., Smith D.L. (2021). Cannabis glandular trichomes: A cellular metabolite factory. Frontiers in Plant Science 12, 721986. https://doi.org/10.3389/fpls.2021.721986 DOI: https://doi.org/10.3389/fpls.2021.721986

Taura, F., Morimoto, S. Shoyama, Y. (1996). Purification and characterization of cannabidiolic-acid synthase from Cannabis sativa L. Biochemical analysis of a novel enzyme that catalyzes the oxidocyclization of cannabigerolic acid to cannabidiolic acid. Journal of Biological Chemistry 271, 17411–17416. https://doi.org/10.1074/jbc.271.29.17411 DOI: https://doi.org/10.1074/jbc.271.29.17411

Thomma, B.P., Penninckx, I.A., Cammue, B.P., Broekaert, W.F. (2001). The complexity of disease signaling in Arabidopsis. Current Opinion in Immunology 13, 63–68. https://doi.org/10.1016/s0952-7915(00)00183-7 DOI: https://doi.org/10.1016/S0952-7915(00)00183-7

Thompson, G.R., Tuscano, J.M., Dennis, M., Singapuri, A., Libertini, S., Gaudino, R. (2017). A microbiome assessment of medical marijuana. Clinical Microbiology and Infection 23(4), 269–270. https://doi.org/10.1016/j.cmi.2016.12.001 DOI: https://doi.org/10.1016/j.cmi.2016.12.001

Turner, C.E., Elsohly, M.A. (1981). Biological activity of cannabichromene, its homologs and isomers. The Journal of Clinical Pharmacology 21(S1), 283-291. https://doi.org/10.1002/j.1552-4604.1981.tb02606.x DOI: https://doi.org/10.1002/j.1552-4604.1981.tb02606.x

Van der Werf, H.M., Van Geel, W., Wijlhuizen, M. (1995). Agronomic research on hemp (Cannabis sativa L.) in the Netherlands, 1987-1993. Journal of the International Hemp Association 2, 14–17

Van Rijn, P.C.J., Mollema, C., Steenhuis-Broers, G.M. (1995). Comparative life history studies of Frankliniella occidentalis and Thrips tabaci (Thysanoptera: Thripidae) on cucumber. Bulletin of Entomological Research 85(2), 285 – 297, https://doi.org/10.1017/S0007485300034386 DOI: https://doi.org/10.1017/S0007485300034386

Verdan, A.M., Wang, H.C., García, C.R., Henry, W.P., Brumaghim, J.L. (2011). Iron binding of 3-hydroxychromone, 5-hydroxychromone, and sulfonated morin: implications for the antioxidant activity of flavonols with competing metal binding sites. Journal of Inorganic Biochemistry 105, 1314–1322. https://doi.org/10.1016/j.jinorgbio.2011.07.006 DOI: https://doi.org/10.1016/j.jinorgbio.2011.07.006

Vranová, E., Coman, D., Wilhelm, G. (2013). Network Analysis of the MVA and MEP Pathways for Isoprenoid Synthesis. Annual Review of Plant Biology, 64(1), 665–700. https://doi:10.1146/annurev-arplant-050312-120116 DOI: https://doi.org/10.1146/annurev-arplant-050312-120116

Wasim, K., Haq, I.U., Ashraf, M. (1995). Antimicrobial studies of the leaf of Cannabis sativa L., Pakistan Journal of Pharmaceutical Sciences 8, 22- 38.

Whiting, P.F., Wolff, R.F., Deshpande, S., Di Nisio, M., Duffy, S., Hernandez, A.V., Keurentjes, J.C., Lang, S., Misso, K., Ryder, S., Schmidlkofer, S., Westwood, M., Kleijnen, J. (2015). Cannabinoids for medical use: A Systematic Review and Meta-analysis. The Journal of the American Medical Association 313(24), 2456–2473. https://doi.org/10.1001/jama.2015.6358 DOI: https://doi.org/10.1001/jama.2015.6358

Woolridge, E., Barton, S., Samuel, J., Osorio, J., Dougherty, A., Holdcroft, A. (2005). Cannabis use in HIV for pain and other medical symptoms. Journal of Pain and Symptom Management, 29(4), 358-67. https://doi.org/10.1016/j.jpainsymman.2004.07.011 DOI: https://doi.org/10.1016/j.jpainsymman.2004.07.011

Yazaki, K. 2004. Natural products and metabolites. V: Handbook of plant biotechnology. 1st ed. Christou P, Klee H. (ur.). Chichester, Wiley: 811–857 DOI: https://doi.org/10.1002/0470869143.kc039

Zaynab, M., Fatima, M., Abbas, S., Sharif, Y., Umair, M., Zafar, M.H., Bahadar, K. (2018). Role of secondary metabolites in plant defense against pathogens, Microbial Pathogenesis 124, 198-202 https://doi.org/10.1016/j.micpath.2018.08.034 DOI: https://doi.org/10.1016/j.micpath.2018.08.034