Detección in silico de fitomoléculas con potenciales actividades inhibitorias de Nucleolinas (NCL)
DOI:
https://doi.org/10.56152/StevianaFacenV14N1A2_2022Keywords:
Molecular docking, Phytomolecules, Inhibitors, NucleolinAbstract
Nucleolins are proteins found in cell’s nucleus, cytoplasm, and on membrane surfaces, performing critical functions for the cell physiology. Due to it malfunction is linked to various types of cancer, they were considered as target proteins in the search of molecules with potential anticancer effects. This research aims to detect phytoconstituents that show interaction affinities for the RNA-binding domain (RBD) of nucleolins and to characterize said protein-ligand interactions through molecular docking analysis. Fifteen phytomolecules with different biological profiles were preselected for study, the drugability index of the nucleolins RBD domain was determined, which presented a value equal to 0.80, said site being highly druggable. Subsequently, molecular docking tests were carried out between the selected phytoconstituents and the nucleolin. Results of the molecular docking revealed that triterpenes Maytenin, Taraxerol, Cucurbitacin B, and Pristimerin have a higher in silico binding affinity, with interaction free energies (ΔG) equal to -10.80 ± 0.03 kcal.mol-1, -10.58 ± 0.14 kcal.mol-1, -9.58 ± 0.12 kcal.mol-1 and -9.48 ± 0.35 kcal.mol-1 respectively. The residues actively involved in the interactions with biomolecules, stabilizing the formation and the structure of the protein-ligand complexes were Asn100, Tyr103, Tyr134 and Arg158. The findings suggest that these triterpenes could act as potential nucleolin inhibitors due to the affinities found, however, these results need to be confirmed by in vitro and in vivo tests.
Downloads
References
Abdelmohsen, K., & Gorospe, M. (2012). RNA-binding protein nucleolin in disease. RNA Biology, 9(6), 799–808. https://doi.org/10.4161/rna.19718
Akhtar, M. S., & Swamy, M. K. (2018). Anticancer plants: Properties and application. In Anticancer plants: Properties and Application (Vol. 1). https://doi.org/10.1007/978-981-10-8548-2
Anwar, T., Kumar, P., & Khan, A. U. (2021). Modern Tools and Techniques in Computer-Aided Drug Design. In Molecular Docking for Computer-Aided Drug Design (pp. 1–30). Elsevier. https://doi.org/10.1016/B978-0-12-822312-3.00011-4
Arumugam, S., Clarke Miller, M., Maliekal, J., Bates, P. J., Trent, J. O., & Lane, A. N. (2010). Solution structure of the RBD1,2 domains from human nucleolin. Journal of Biomolecular NMR, 47(1), 79–83. https://doi.org/10.1007/s10858-010-9412-1
Baig, M. H., Ahmad, K., Rabbani, G., Danishuddin, M., & Choi, I. (2018). Computer Aided Drug Design and its Application to the Development of Potential Drugs for Neurodegenerative Disorders. Current Neuropharmacology, 16(6), 740–748. https://doi.org/10.2174/1570159X15666171016163510
Berman, H., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T., & Weissig, H. (2000). The Protein Data Bank. Nucleic Acids Res, 28(1), 235–242.
Bulusu, G., & Desiraju, G. R. (2020). Strong and Weak Hydrogen Bonds in Protein–Ligand Recognition. Journal of the Indian Institute of Science, 100(1), 31–41. https://doi.org/10.1007/s41745-019-00141-9
Carvalho, L. S., Gonçalves, N., Fonseca, N. A., & Moreira, J. N. (2021). Cancer Stem Cells and Nucleolin as Drivers of Carcinogenesis. Pharmaceuticals, 14(60), 1–21. https://doi.org/10.3390/ph14010060
Cevatemre, B., Erkısa, M., Aztopal, N., Karakas, D., Alper, P., Tsimplouli, C., Sereti, E., Dimas, K., Armutak, E. I. I., Gurevin, E. G., Uvez, A., Mori, M., Berardozzi, S., Ingallina, C., D’Acquarica, I., Botta, B., Ozpolat, B., & Ulukaya, E. (2018). A promising natural product, pristimerin, results in cytotoxicity against breast cancer stem cells in vitro and xenografts in vivo through apoptosis and an incomplete autopaghy in breast cancer. Pharmacological Research, 129, 500–514. https://doi.org/10.1016/j.phrs.2017.11.027
Chan, K. T., Li, K., Liu, S. L., Chu, K. H., Toh, M., & Xie, W. D. (2010). Cucurbitacin B inhibits STAT3 and the Raf/MEK/ERK pathway in leukemia cell line K562. Cancer Letters, 289(1), 46–52. https://doi.org/10.1016/j.canlet.2009.07.015
Chan, K. T., Meng, F. Y., Li, Q., Ho, C. Y., Lam, T. S., To, Y., Lee, W. H., Li, M., Chu, K. H., & Toh, M. (2010). Cucurbitacin B induces apoptosis and S phase cell cycle arrest in BEL-7402 human hepatocellular carcinoma cells and is effective via oral administration. Cancer Letters, 294(1), 118–124. https://doi.org/10.1016/j.canlet.2010.01.029
Chen, R.-Z., Yang, F., Zhang, M., Sun, Z.-G., & Zhang, N. (2021). Cellular and Molecular Mechanisms of Pristimerin in Cancer Therapy: Recent Advances. Frontiers in Oncology, 11. https://doi.org/10.3389/fonc.2021.671548
Cheng, S., Zhang, Z., Hu, C., Xing, N., Xia, Y., & Pang, B. (2020). Pristimerin Suppressed Breast Cancer Progression via miR-542-5p/DUB3 Axis. OncoTargets and Therapy, Volume 13, 6651–6660. https://doi.org/10.2147/OTT.S257329
Dakeng, S., Duangmano, S., Jiratchariyakul, W., U-Pratya, Y., Bögler, O., & Patmasiriwat, P. (2012). Inhibition of Wnt signaling by cucurbitacin B in breast cancer cells: Reduction of Wnt-associated proteins and reduced translocation of galectin-3-mediated β-catenin to the nucleus. Journal of Cellular Biochemistry, 113(1), 49–60. https://doi.org/10.1002/jcb.23326
Dandawate, P., Subramaniam, D., Panovich, P., Standing, D., Krishnamachary, B., Kaushik, G., Thomas, S. M., Dhar, A., Weir, S. J., Jensen, R. A., & Anant, S. (2020). Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway. Scientific Reports, 10(1), 1290. https://doi.org/10.1038/s41598-020-57940-9
Deeb, D., Gao, X., Liu, Y. B., Pindolia, K., & Gautam, S. (2014). Pristimerin, a quinonemethide triterpenoid, induces apoptosis in pancreatic cancer cells through the inhibition of pro-survival Akt/NF-κB/mTOR signaling proteins and anti-apoptotic Bcl-2. International Journal of Oncology, 44(5), 1707–1715. https://doi.org/10.3892/ijo.2014.2325
Dittharot, K., Dakeng, S., Suebsakwong, P., Suksamrarn, A., Patmasiriwat, P., & Promkan, M. (2019). Cucurbitacin B Induces Hypermethylation of Oncogenes in Breast Cancer Cells. Planta Medica, 85(05), 370–378. https://doi.org/10.1055/a-0791-1591
Duangmano, S., Dakeng, S., Jiratchariyakul, W., Suksamrarn, A., Smith, D. R., & Patmasiriwat, P. (2010). Antiproliferative Effects of Cucurbitacin B in Breast Cancer Cells: Down-Regulation of the c-Myc/hTERT/Telomerase Pathway and Obstruction of the Cell Cycle. International Journal of Molecular Sciences, 11(12), 5323–5338. https://doi.org/10.3390/ijms11125323
Duangmano, S., Sae-lim, P., Suksamrarn, A., Patmasiriwat, P., & Domann, F. E. (2012). Cucurbitacin B Causes Increased Radiation Sensitivity of Human Breast Cancer Cells via G2/M Cell Cycle Arrest. Journal of Oncology, 2012, 1–8. https://doi.org/10.1155/2012/601682
Ferreira de Freitas, R., & Schapira, M. (2017). A systematic analysis of atomic protein–ligand interactions in the PDB. MedChemComm, 8(10), 1970–1981. https://doi.org/10.1039/C7MD00381A
Fricker, P., Gastreich, M., & Rarey, M. (2004). Automated Generation of Structural Molecular Formulas under Constraints. Journal of Chemical Information and Computer Sciences, 44, 1065–1078.
Gao, Y., Islam, M. S., Tian, J., Lui, V. W. Y., & Xiao, D. (2014). Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth. Cancer Letters, 349(1), 15–25. https://doi.org/10.1016/j.canlet.2014.03.015
Gill, B. S., Kumar, S., & Navgeet. (2016). Triterpenes in cancer: significance and their influence. Molecular Biology Reports, 43(9), 881–896. https://doi.org/10.1007/s11033-016-4032-9
Guedes, I. A., de Magalhães, C. S., & Dardenne, L. E. (2013). Receptor-ligand molecular docking. Biophysical Reviews, 6(1), 75–87. https://doi.org/10.1007/s12551-013-0130-2
Hammer, Ø., Harper, D. A. T., & Ryan, P. D. (2001). PAST : Paleontological Statistics Software Package for Education and Data Analysis. Paleontologia Electronica, 4(1), 9.
Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, 4(1), 1–17.
Hernandes, C., Miguita, L., de Sales, R. O., Silva, E. de P., Mendonça, P. O. R. de, Lorencini da Silva, B., Klingbeil, M. de F. G., Mathor, M. B., Rangel, E. B., Marti, L. C., Coppede, J. da S., Nunes, F. D., Pereira, A. M. S., & Severino, P. (2020). Anticancer Activities of the Quinone-Methide Triterpenes Maytenin and 22-β-hydroxymaytenin Obtained from Cultivated Maytenus ilicifolia Roots Associated with Down-Regulation of miRNA-27a and miR-20a/miR-17-5p. Molecules, 25(3), 760. https://doi.org/10.3390/molecules25030760
Hong, J. F., Song, Y. F., Liu, Z., Zheng, Z. C., Chen, H. J., & Wang, S. S. (2016). Anticancer activity of taraxerol acetate in human glioblastoma cells and a mouse xenograft model via induction of autophagy and apoptotic cell death, cell cycle arrest and inhibition of cell migration. Molecular Medicine Reports, 13(6), 4541–4548. https://doi.org/10.3892/mmr.2016.5105
Irvine, J. E., & Freyre, R. H. (1959). Source Materials for Rotenone, Occurrence of Rotenoids in Some Species of the Genus Tephrosia. Journal of Agricultural and Food Chemistry, 7(2), 106–107. https://doi.org/10.1021/jf60096a002
Iwanski, G. B., Lee, D. H., En-Gal, S., Doan, N. B., Castor, B., Vogt, M., Toh, M., Bokemeyer, C., Said, J. W., Thoennissen, N. H., & Koeffler, H. P. (2010). Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer. British Journal of Pharmacology, 160(4), 998–1007. https://doi.org/10.1111/j.1476-5381.2010.00741.x
Jäger, S., Trojan, H., Kopp, T., Laszczyk, M. N., & Scheffler, A. (2009). Pentacyclic triterpene distribution in various plants - rich sources for a new group of multi-potent plant extracts. Molecules, 14(6), 2016–2031. https://doi.org/10.3390/molecules14062016
Kacprzak, M. K. (2013). Chemistry and Biology of Cinchona Alkaloids. In K. G. Ramawat & J. M. Mérillon (Eds.), Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes (pp. 1–4242). https://doi.org/10.1007/978-3-642-22144-6
Kaufman, P. B., Duke, J. A., Brielmann, H., Boik, J., & Hoyt, J. E. (1997). A Comparative Survey of Leguminous Plants as Sources of the Isoflavones, Genistein and Daidzein: Implications for Human Nutrition and Health. The Journal of Alternative and Complementary Medicine, 3(1), 7–12. https://doi.org/10.1089/acm.1997.3.7
Kim, S., Thiessen, P. A., Bolton, E., Chen, J., Fu, G., & Gindulyte, A. (2016). PubChem Substance and Compound databases. Nucleic Acids Res, 1, 1202–1213.
Lee, J. S., Yoon, I. S., Lee, M. S., Cha, E. Y., Thuong, P. T., Diep, T. T., & Kim, J. R. (2013). Anticancer Activity of Pristimerin in Epidermal Growth Factor Receptor 2-Positive SKBR3 Human Breast Cancer Cells. Biological and Pharmaceutical Bulletin, 36(2), 316–325. https://doi.org/10.1248/bpb.b12-00685
Lee, S.-O., Kim, J.-S., Lee, M.-S., & Lee, H.-J. (2016). Anti-cancer effect of pristimerin by inhibition of HIF-1α involves the SPHK-1 pathway in hypoxic prostate cancer cells. BMC Cancer, 16(1), 701. https://doi.org/10.1186/s12885-016-2730-2
Li, J., Guo, Q., Lei, X., Zhang, L., Su, C., Liu, Y., Zhou, W., Chen, H., Wang, H., Wang, F., Yan, Y., & Zhang, J. (2020). Pristimerin induces apoptosis and inhibits proliferation, migration in H1299 Lung Cancer Cells. Journal of Cancer, 11(21), 6348–6355. https://doi.org/10.7150/jca.44431
Liao, J., Wu, F., Lin, W., & Huang, Z. (2018). Taraxerol exerts potent anticancer effects via induction of apoptosis and inhibition of Nf-Kb signalling pathway in human middle ear epithelial cholesteatoma cells. Tropical Journal of Pharmaceutical Research, 17(6), 1011–1017. https://doi.org/10.4314/tjpr.v17i6.5
Liu, T., Peng, H., Zhang, M., Deng, Y., & Wu, Z. (2010). Cucurbitacin B, a small molecule inhibitor of the Stat3 signaling pathway, enhances the chemosensitivity of laryngeal squamous cell carcinoma cells to cisplatin. European Journal of Pharmacology, 641(1), 15–22. https://doi.org/10.1016/j.ejphar.2010.04.062
Lu, P., Yu, B., & Xu, J. (2012). Cucurbitacin B Regulates Immature Myeloid Cell Differentiation and Enhances Antitumor Immunity in Patients with Lung Cancer. Cancer Biotherapy and Radiopharmaceuticals, 27(8), 495–503. https://doi.org/10.1089/cbr.2012.1219
Mu, X.-M., Shi, W., Sun, L.-X., Li, H., Wang, Y.-R., Jiang, Z.-Z., & Zhang, L.-Y. (2012). Pristimerin Inhibits Breast Cancer Cell Migration by Up-regulating Regulator of G Protein Signaling 4 Expression. Asian Pacific Journal of Cancer Prevention, 13(4), 1097–1104. https://doi.org/10.7314/APJCP.2012.13.4.1097
Oberlies, N. H., Burgess, J. P., Navarro, H. A., Pinos, R. E., Soejarto, D. D., Farnsworth, N. R., Kinghorn, A. D., Wani, M. C., & Wall, M. E. (2001). Bioactive Constituents of the Roots of Licania i ntrapetiolaris. Journal of Natural Products, 64(4), 497–501. https://doi.org/10.1021/np0005006
Park, J.-H., & Kim, J.-K. (2018). Pristimerin, a naturally occurring triterpenoid, attenuates tumorigenesis in experimental colitis-associated colon cancer. Phytomedicine, 42, 164–171. https://doi.org/10.1016/j.phymed.2018.03.033
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612.
Pettersen, E. F., Goddard, T. D., Huang, C. C., Meng, E. C., Couch, G. S., Croll, T. I., Morris, J. H., & Ferrin, T. E. (2021). UCSF ChimeraX: Structure visualization for researchers, educators, and developers. Protein Science, 30(1), 70–82. https://doi.org/10.1002/pro.3943
Ren, G., Sha, T., Guo, J., Li, W., Lu, J., & Chen, X. (2015). Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells. Journal of Natural Medicines, 69(4), 522–530. https://doi.org/10.1007/s11418-015-0918-4
Ringuelet, J., & Viña, S. (2013). Productos Naturales Vegetales (1a ed.). Universidad Nacional de la Plata.
Sinha, S., Khan, S., Shukla, S., Lakra, A. D., Kumar, S., Das, G., Maurya, R., & Meeran, S. M. (2016). Cucurbitacin B inhibits breast cancer metastasis and angiogenesis through VEGF-mediated suppression of FAK/MMP-9 signaling axis. The International Journal of Biochemistry & Cell Biology, 77, 41–56. https://doi.org/10.1016/j.biocel.2016.05.014
Stierand, K., Maaß, P., & Rarey, M. (2006). Complexes at a Glance: Automated Generation of two-dimensional Complex Diagrams. Molecular Bioinformatics, 22, 1710–1716.
Suárez, A. I., Chavez, K., Mateu, E., Compagnone, R. S., Muñoz, A., Sojo, F., Arvelo, F., Mijares, M., & De Sanctis, J. B. (2009). Cytotoxic Activity of seco -Entkaurenes from Croton caracasana on Human Cancer Cell Lines. Natural Product Communications, 4(11), 1934578X0900401. https://doi.org/10.1177/1934578X0900401117
Surapaneni, S. (2019). Apoptosis of LNCaP and PC-3 cell lines and testosterone-induced prostate cancer by taraxerol and reticulatacin isolated from Annona reticulata l. (Vol. 1, Issue 1). ABMRCP.
Tajrishi, M. M., Tuteja, R., & Tuteja, N. (2011). Nucleolin: The most abundant multifunctional phosphoprotein of nucleolus. Communicative and Integrative Biology, 4(3), 267–275. https://doi.org/10.4161/cib.4.3.14884
Takasaki, M., Konoshima, T., Tokuda, H., Masuda, K., Arai, Y., Shiojima, K., & Ageta, H. (1999). Anti-carcinogenic Activiti of Taraxacum Plant. II. Chemical Pharmaceutical Bulletin, 22(6), 606–610.
Tallamy, D. W., Hibbard, B. E., Clark, T. L., & Gillespie, J. J. (2005). Western Corn Rootworm, Cucurbits and Cucurbitacins Purported Origin of Western Corn Rootworm. In S. Vidal, B. E. Hibbard, T. L. Clark, & J. J. Gillespie (Eds.), Western Corn Rootworm: Ecology and Management (pp. 67–94). CAB Internarional.
Tan, B. (2011). Effects of taraxerol and taraxeryl acetate on cell cycle and apoptosis of human gastric epithelial cell line AGS. Journal of Chinese Integrative Medicine, 9(6), 638–642. https://doi.org/10.3736/jcim20110610
Thoennissen, N. H., Iwanski, G. B., Doan, N. B., Okamoto, R., Lin, P., Abbassi, S., Song, J. H., Yin, D., Toh, M., Xie, W. D., Said, J. W., & Koeffler, H. P. (2009). Cucurbitacin B Induces Apoptosis by Inhibition of the JAK/STAT Pathway and Potentiates Antiproliferative Effects of Gemcitabine on Pancreatic Cancer Cells. Cancer Research, 69(14), 5876–5884. https://doi.org/10.1158/0008-5472.CAN-09-0536
Thomas, C. M., Wood, R. C., Wyatt, J. E., Pendleton, M. H., Torrenegra, R. D., Rodriguez, O. E., Harirforoosh, S., Ballester, M., Lightner, J., Krishnan, K., & Ramsauer, V. P. (2012). Anti-neoplastic activity of two flavone isomers derived from Gnaphalium elegans and achyrocline bogotensis. PLoS ONE, 7(6). https://doi.org/10.1371/journal.pone.0039806
Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455–461. https://doi.org/10.1002/jcc.21334
Volkamer, A., Kuhn, D., Grombacher, T., Rippmann, F., & Rarey, M. (2012). Combining global and local measures for structure-based druggability predictions. . . J. Chem. Inf. Model., 52, 360–372.
Wang, Y., Zhou, Y., Zhou, H., Jia, G., Liu, J., Han, B., Cheng, Z., Jiang, H., Pan, S., & Sun, B. (2012). Pristimerin Causes G1 Arrest, Induces Apoptosis, and Enhances the Chemosensitivity to Gemcitabine in Pancreatic Cancer Cells. PLoS ONE, 7(8), e43826. https://doi.org/10.1371/journal.pone.0043826
Wink, M. (2015). Modes of Action of Herbal Medicines and Plant Secondary Metabolites. Medicines, 2, 251–286. https://doi.org/10.3390/medicines2030251
Yang, H., Landis-Piwowar, K. R., Lu, D., Yuan, P., Li, L., Reddy, G. P.-V., Yuan, X., & Dou, Q. P. (2008). Pristimerin induces apoptosis by targeting the proteasome in prostate cancer cells. Journal of Cellular Biochemistry, 103(1), 234–244. https://doi.org/10.1002/jcb.21399
Yao, X., Lu, B., Lü, C., Bai, Q., Yan, D., & Xu, H. (2017). Taraxerol Induces Cell Apoptosis through A Mitochondria-Mediated Pathway in HeLa Cells. Cell Journal, 19(3), 512–519. https://doi.org/10.22074/cellj.2017.4543.
Yin, M. C. (2012). Anti-glycative potential of triterpenes: A mini-review. In BioMedicine (Netherlands) (Vol. 2, Issue 1, pp. 2–9). No longer published by Elsevier. https://doi.org/10.1016/j.biomed.2011.12.001
Yousef, B. A., Hassan, H. M., Guerram, M., Hamdi, A. M., Wang, B., Zhang, L.-Y., & Jiang, Z.-Z. (2016). Pristimerin inhibits proliferation, migration and invasion, and induces apoptosis in HCT-116 colorectal cancer cells. Biomedicine & Pharmacotherapy, 79, 112–119. https://doi.org/10.1016/j.biopha.2016.02.003
Zafar, R., & Sharma, K. (2015). Occurrence of taraxerol and taraxasterol in medicinal plants. Pharmacognosy Reviews, 9(17), 19. https://doi.org/10.4103/0973-7847.156317
Zhao, Q., Bi, Y., Guo, J., Liu, Y., Zhong, J., Liu, Y., Pan, L., Guo, Y., Tan, Y., & Yu, X. (2021). Effect of pristimerin on apoptosis through activation of ROS/ endoplasmic reticulum (ER) stress-mediated noxa in colorectal cancer. Phytomedicine, 80, 153399. https://doi.org/10.1016/j.phymed.2020.153399
Zhao, Q., Liu, Y., Zhong, J., Bi, Y., Liu, Y., Ren, Z., Li, X., Jia, J., Yu, M., & Yu, X. (2019). Pristimerin induces apoptosis and autophagy via activation of ROS/ASK1/JNK pathway in human breast cancer in vitro and in vivo. Cell Death Discovery, 5(1), 125. https://doi.org/10.1038/s41420-019-0208-0
Zhou, J., Liu, M., Chen, Y., Xu, S., Guo, Y., & Zhao, L. (2019). Cucurbitacin B suppresses proliferation of pancreatic cancer cells by ceRNA: Effect of miR-146b-5p and lncRNA-AFAP1-AS1. Journal of Cellular Physiology, 234(4), 4655–4667. https://doi.org/10.1002/jcp.27264
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Steviana
This work is licensed under a Creative Commons Attribution 4.0 International License.
![](https://revistascientificas.una.py/index.php/stevia/management/settings/<a rel="license" href="http:/creativecommons.org/licenses/by/4.0/"><img alt="Licencia de Creative Commons" style="border-width:0" src="https:/i.creativecommons.org/l/by/4.0/88x31.png" /></a><br /><span xmlns:dct="http:/purl.org/dc/terms/" href="http:/purl.org/dc/dcmitype/Text" property="dct:title" rel="dct:type">Facultad de Ciencias Exactas y Naturales -UNA. Revista Steviana</span> is licensed under a <a rel="license" href="http:/creativecommons.org/licenses/by/4.0/">Creative Commons Reconocimiento 4.0 Internacional License</a>.)
