Table of Contents Author Guidelines Submit a Manuscript
The Scientific World Journal
Volume 2014, Article ID 609649, 10 pages
http://dx.doi.org/10.1155/2014/609649
Research Article

Effects of Polysaccharide Elicitors on Secondary Metabolite Production and Antioxidant Response in Hypericum perforatum L. Shoot Cultures

1Laboratoire de Biologie des Ligneux et des Grandes Cultures, UPRES EA 1207, UFR-Faculté des Sciences, Université d’Orléans, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
2Institute of Biology, Faculty of Natural Sciences and Mathematics, University of Ss. Cyril and Methodius, P.O. Box 162, 1000 Skopje, Macedonia

Received 30 July 2014; Revised 26 November 2014; Accepted 27 November 2014; Published 11 December 2014

Academic Editor: Devanand P. Fulzele

Copyright © 2014 Sonja Gadzovska Simic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Nahrstedt and V. Butterweck, “Lessons learned from herbal medicinal products: the example of St. John's wort,” Journal of Natural Products, vol. 73, no. 5, pp. 1015–1021, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. I. P. Süntar, E. K. Akkol, D. Yilmazer et al., “Investigations on the in vivo wound healing potential of Hypericum perforatum L,” Journal of Ethnopharmacology, vol. 127, no. 2, pp. 468–477, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Sosa, R. Pace, A. Bornancin et al., “Topical anti-inflammatory activity of extracts and compounds from Hypericum perforatum L.,” Journal of Pharmacy and Pharmacology, vol. 59, no. 5, pp. 703–709, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. C. Quiney, C. Billard, A.-M. Faussat, C. Salanoubat, and J.-P. Kolb, “Hyperforin inhibits P-gp and BCRP activities in chronic lymphocytic leukaemia cells and myeloid cells,” Leukemia and Lymphoma, vol. 48, no. 8, pp. 1587–1599, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. J. M. Jacobson, L. Feinman, L. Liebes et al., “Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John's wort plant, in patients with chronic hepatitis C virus infection,” Antimicrobial Agents and Chemotherapy, vol. 45, no. 2, pp. 517–524, 2001. View at Publisher · View at Google Scholar · View at Scopus
  6. Z. Saddiqe, I. Naeem, and A. Maimoona, “A review of the antibacterial activity of Hypericum perforatum L.,” Journal of Ethnopharmacology, vol. 131, no. 3, pp. 511–521, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. B. A. Silva, J. O. Malva, and A. C. P. Dias, “St. John's wort (Hypericum perforatum) extracts and isolated phenolic compounds are effective antioxidants in several in vitro models of oxidative stress,” Food Chemistry, vol. 110, no. 3, pp. 611–619, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. C. M. Schempp, B. Simon-Haarhaus, and J. C. Simon, “Phototoxic and apoptosis-inducing capacity of pseudohypericin,” Planta Medica, vol. 68, no. 2, pp. 171–173, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. M. A. Medina, B. Martínez-Poveda, M. I. Amores-Sánchez, and A. R. Quesada, “Hyperforin: more than an antidepressant bioactive compound?” Life Sciences, vol. 79, no. 2, pp. 105–111, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. J. Sarris, M. Fava, I. Schweitzer, and D. Mischoulon, “St. John's wort (Hypericum perforatum) versus sertraline and placebo in major depressive disorder: continuation data from a 26-week RCT,” Pharmacopsychiatry, vol. 45, no. 7, pp. 275–278, 2012. View at Publisher · View at Google Scholar · View at Scopus
  11. J. Barnes, L. A. Anderson, and J. D. Phillipson, “St. John's wort (Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties,” Journal of Pharmacy and Pharmacology, vol. 53, no. 5, pp. 583–600, 2001. View at Publisher · View at Google Scholar · View at Scopus
  12. B. Büter, C. Orlacchio, A. Soldati, and K. Berger, “Significance of genetic and environmental aspects in the field cultivation of Hypericum perforatum,” Planta Medica, vol. 64, no. 5, pp. 431–437, 1998. View at Publisher · View at Google Scholar · View at Scopus
  13. A. Kirakosyan, T. M. Sirvent, D. M. Gibson, and P. B. Kaufman, “The production of hypericins and hyperforin by in vitro cultures of St. John's wort (Hypericum perforatum),” Biotechnology and Applied Biochemistry, vol. 39, no. 1, pp. 71–81, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Zobayed and P. K. Saxena, “Production of St. John's wort plants under controlled environment for maximizing biomass and secondary metabolites,” In Vitro Cellular & Developmental Biology-Plant, vol. 40, no. 1, pp. 108–114, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. S. H. Kopleman, L. L. Augsburger, A. NguyenPho, W. S. Zito, and F. X. Muller, “Selected physical and chemical properties of commercial Hypericum perforatum extracts relevant for formulated product quality and performance,” AAPS PharmSci, vol. 3, no. 4, pp. 1–18, 2001. View at Google Scholar
  16. S. J. Murch and P. K. Saxena, “St. John's wort (Hypericum perforatum L.): challenges and strategies for production of chemically consistent plants,” Canadian Journal of Plant Science, vol. 86, no. 3, pp. 765–771, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. H. N. Murthy, E.-J. Lee, and K.-Y. Paek, “Production of secondary metabolites from cell and organ cultures: strategies and approaches for biomass improvement and metabolite accumulation,” Plant Cell, Tissue and Organ Culture, vol. 118, no. 1, pp. 1–16, 2014. View at Publisher · View at Google Scholar · View at Scopus
  18. S. Ramachandra Rao and G. A. Ravishankar, “Plant cell cultures: chemical factories of secondary metabolites,” Biotechnology Advances, vol. 20, no. 2, pp. 101–153, 2002. View at Publisher · View at Google Scholar · View at Scopus
  19. J. Zhao, L. C. Davis, and R. Verpoorte, “Elicitor signal transduction leading to production of plant secondary metabolites,” Biotechnology Advances, vol. 23, no. 4, pp. 283–333, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. H. Dörnenburg, “Evaluation of immobilisation effects on metabolic activities and productivity in plant cell processes,” Process Biochemistry, vol. 39, no. 11, pp. 1369–1375, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. A. G. Namdeo, “Plant cell elicitation for production of secondary metabolites: a review,” Pharmacognosy Reviews, vol. 1, no. 1, pp. 69–79, 2007. View at Google Scholar
  22. P. J. Weathers, M. J. Towler, and J. Xu, “Bench to batch: advances in plant cell culture for producing useful products,” Applied Microbiology and Biotechnology, vol. 85, no. 5, pp. 1339–1351, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. P. Komaraiah, G. V. Reddy, P. S. Reddy, A. S. Raghavendra, S. V. Ramakrishna, and P. Reddanna, “Enhanced production of antimicrobial sesquiterpenes and lipoxygenase metabolites in elicitor-treated hairy root cultures of Solanum tuberosum,” Biotechnology Letters, vol. 25, no. 8, pp. 593–597, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. J.-L. Zhao, L.-G. Zhou, and J.-Y. Wu, “Effects of biotic and abiotic elicitors on cell growth and tanshinone accumulation in Salvia miltiorrhiza cell cultures,” Applied Microbiology and Biotechnology, vol. 87, no. 1, pp. 137–144, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. Z. Cai, A. Kastell, I. Mewis, D. Knorr, and I. Smetanska, “Polysaccharide elicitors enhance anthocyanin and phenolic acid accumulation in cell suspension cultures of Vitis vinifera,” Plant Cell, Tissue and Organ Culture, vol. 108, no. 3, pp. 401–409, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. F. L. Lim, M. F. Yam, M. Z. Asmawi, and L.-K. Chan, “Elicitation of Orthosiphon stamineus cell suspension culture for enhancement of phenolic compounds biosynthesis and antioxidant activity,” Industrial Crops and Products, vol. 50, pp. 436–442, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Kirakosyan, H. Hayashi, K. Inoue, A. Charchoglyan, and H. Vardapetyan, “Stimulation of the production of hypericins by mannan in Hypericum perforatum shoot cultures,” Phytochemistry, vol. 53, no. 3, pp. 345–348, 2000. View at Publisher · View at Google Scholar · View at Scopus
  28. T. Sirvent and D. Gibson, “Induction of hypericins and hyperforin in Hypericum perforatum L. in response to biotic and chemical elicitors,” Physiological and Molecular Plant Pathology, vol. 60, no. 6, pp. 311–320, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. T. S. Walker, H. Pal Bais, and J. M. Vivanco, “Jasmonic acid-induced hypericin production in cell suspension cultures of Hypericum perforatum L. (St. John's wort),” Phytochemistry, vol. 60, no. 3, pp. 289–293, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Gadzovska, S. Maury, S. Ounnar et al., “Identification and quantification of hypericin and pseudohypericin in different Hypericum perforatum L. in vitro cultures,” Plant Physiology and Biochemistry, vol. 43, no. 6, pp. 591–601, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. H. R. Vardapetyan, A. A. Oganesyan, E. E. Kabasakalyan, and S. G. Tiratsuyan, “The influence of some elicitors on growth and morphogenesis of Hypericum perforatum L. callus cultures,” Russian Journal of Developmental Biology, vol. 37, no. 6, pp. 350–353, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. S. Gadzovska, S. Maury, A. Delaunay, M. Spasenoski, C. Joseph, and D. Hagège, “Jasmonic acid elicitation of Hypericum perforatum L. cell suspensions and effects on the production of phenylpropanoids and naphtodianthrones,” Plant Cell, Tissue and Organ Culture, vol. 89, no. 1, pp. 1–13, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Gadzovska-Simic, O. Tusevski, S. Antevski et al., “Secondary metabolite production in Hypericum perforatum L. cell suspensions upon elicitation with fungal mycelia from Aspergillus flavus,” Archives of Biological Sciences, vol. 64, no. 1, pp. 113–121, 2012. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Gadzovska, S. Maury, A. Delaunay et al., “The influence of salicylic acid elicitation of shoots, callus, and cell suspension cultures on production of naphtodianthrones and phenylpropanoids in Hypericum perforatum L.,” Plant Cell, Tissue and Organ Culture, vol. 113, no. 1, pp. 25–39, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. T. Murashige and F. Skoog, “A revised medium for rapid growth and bioassays with tobacco tissue cultures,” Physiologia Plantarum, vol. 15, no. 3, pp. 473–497, 1962. View at Google Scholar
  36. O. L. Gamborg, R. A. Miller, and K. Ojima, “Nutrient requirements of suspension cultures of soybean root cells,” Experimental Cell Research, vol. 50, no. 1, pp. 148–151, 1968. View at Publisher · View at Google Scholar · View at Scopus
  37. P. Komaraiah, R. Naga Amrutha, P. B. Kavi Kishor, and S. V. Ramakrishna, “Elicitor enhanced production of plumbagin in suspension cultures of Plumbago rosea L.,” Enzyme and Microbial Technology, vol. 31, no. 5, pp. 634–639, 2002. View at Publisher · View at Google Scholar · View at Scopus
  38. V. L. Singleton and J. A. Rossi, “Colorimetry of total phenolics with phosphomolybdic-phosphotungstic acid reagents,” The American Journal of Enology and Viticulture, vol. 16, no. 3, pp. 144–158, 1965. View at Google Scholar
  39. D. P. Makris, G. Boskou, and N. K. Andrikopoulos, “Polyphenolic content and in vitro antioxidant characteristics of wine industry and other agri-food solid waste extracts,” Journal of Food Composition and Analysis, vol. 20, no. 2, pp. 125–132, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. N. Marron, D. Delay, J.-M. Petit et al., “Physiological traits of two Populus x euramericana clones, Luisa Avanzo and Dorskamp, during a water stress and re-watering cycle,” Tree Physiology, vol. 22, no. 12, pp. 849–858, 2002. View at Publisher · View at Google Scholar · View at Scopus
  41. L. F. González, M. C. Rojas, and F. J. Perez, “Diferulate and lignin formation is related to biochemical differences of wall-bound peroxidases,” Phytochemistry, vol. 50, no. 5, pp. 711–717, 1999. View at Publisher · View at Google Scholar · View at Scopus
  42. E. R. Santarem, D. C. Zamban, L. M. Felix, and L. V. Astarita, “Secondary metabolism of Hypericum perforatum induced by Agrobacterium rhizogenes,” In Vitro Cellular & Developmental Biology: Animal, vol. 44, p. S52, 2008. View at Google Scholar
  43. X.-H. Cui, H. N. Murthy, C.-H. Wu, and K.-Y. Paek, “Sucrose-induced osmotic stress affects biomass, metabolite, and antioxidant levels in root suspension cultures of Hypericum perforatum L.,” Plant Cell, Tissue and Organ Culture, vol. 103, no. 1, pp. 7–14, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. R. A. Dixon, L. Achnine, P. Kota, C.-J. Liu, M. S. S. Reddy, and L. Wang, “The phenylpropanoid pathway and plant defence—a genomics perspective,” Molecular Plant Pathology, vol. 3, no. 5, pp. 371–390, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. O. Tusevski, J. Petreska Stanoeva, M. Stefova, and S. Gadzovska Simic, “Agrobacterium enhances xanthone production in Hypericum perforatum cell suspensions,” Plant Growth Regulation, 2014. View at Publisher · View at Google Scholar
  46. M. N. H. Bhuiyan and T. Adachi, “Stimulation of betacyanin synthesis through exogenous methyl jasmonate and other elicitors in suspension-cultured cells of Portulaca,” Journal of Plant Physiology, vol. 160, no. 9, pp. 1117–1124, 2003. View at Publisher · View at Google Scholar · View at Scopus
  47. Y. Fang, M. A. L. Smith, and M.-F. Pépin, “Effects of exogenous methyl jasmonate in elicited anthocyanin-producing cell cultures of ohelo (Vaccinium pahalae),” In Vitro Cellular & Developmental Biology:P Plant, vol. 35, no. 1, pp. 106–113, 1999. View at Publisher · View at Google Scholar · View at Scopus
  48. L. F. R. Conceição, F. Ferreres, R. M. Tavares, and A. C. P. Dias, “Induction of phenolic compounds in Hypericum perforatum L. cells by Colletotrichum gloeosporioides elicitation,” Phytochemistry, vol. 67, no. 2, pp. 149–155, 2006. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Kartnig, I. Göbel, and B. Heydel, “Production of hypericin, pseudohypericin and flavonoids in cell cultures of various Hypericum species and their chemotypes,” Planta Medica, vol. 62, no. 1, pp. 51–53, 1996. View at Publisher · View at Google Scholar · View at Scopus
  50. G. Pasqua, P. Avato, B. Monacelli, A. R. Santamaria, and M. P. Argentieri, “Metabolites in cell suspension cultures, calli, and in vitro regenerated organs of Hypericum perforatum cv. Topas,” Plant Science, vol. 165, no. 5, pp. 977–982, 2003. View at Publisher · View at Google Scholar · View at Scopus
  51. O. Tusevski, J. Petreska Stanoeva, M. Stefova, D. Pavokovic, and S. Gadzovska, “Identification and quantification of phenolic compounds in Hypericum perforatum L. transgenic shoots,” Acta Physiologiae Plantarum, vol. 36, no. 10, pp. 2555–2569, 2014. View at Google Scholar
  52. X.-N. Liu, X.-Q. Zhang, S.-X. Zhang, and J.-S. Sun, “Regulation of metabolite production by precursors and elicitors in liquid cultures of Hypericum perforatum,” Plant Cell, Tissue and Organ Culture, vol. 91, no. 1, pp. 1–7, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. K. Karppinen and A. Hohtola, “Molecular cloning and tissue-specific expression of two cDNAs encoding polyketide synthases from Hypericum perforatum,” Journal of Plant Physiology, vol. 165, no. 10, pp. 1079–1086, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. H. Falk, “From the photosensitizer hypericin to the photoreceptor stentorin—the chemistry of phenantroperylene quinones,” Angewandte Chemie, vol. 38, no. 21, pp. 3116–3136, 1999. View at Google Scholar · View at Scopus
  55. H. P. Bais, R. Vepachedu, C. B. Lawrence, F. R. Stermitz, and J. M. Vivanco, “Molecular and biochemical characterization of an enzyme responsible for the formation of hypericin in St. John's wort (Hypericum perforatum L.),” Journal of Biological Chemistry, vol. 278, no. 34, pp. 32413–32422, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. J. Košuth, Z. Katkovčinová, P. Olexová, and E. Čellárová, “Expression of the hyp-1 gene in early stages of development of Hypericum perforatum L,” Plant Cell Reports, vol. 26, no. 2, pp. 211–217, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. K. Karppinen, “Biosynthesis of hypericins and hyperforins in Hypericum perforatum L. (St. John’s wort)—precursors and genes involved,” Acta Universitatis Ouluensis A: Scientiae Rerum Naturalium, vol. 564, p. 74, 2010. View at Google Scholar
  58. K. Michalska, H. Fernandes, M. Sikorski, and M. Jaskolski, “Crystal structure of Hyp-1, a St. John's wort protein implicated in the biosynthesis of hypericin,” Journal of Structural Biology, vol. 169, no. 2, pp. 161–171, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. M.-J. Xu, J.-F. Dong, and G. Zhang, “Enhancement of hypericin production and cell growth of Hypericum perforatum L. suspension cultures by nitric oxide,” Chinese journal of biotechnology, vol. 21, no. 1, pp. 66–70, 2005. View at Google Scholar · View at Scopus
  60. B. Klejdus, J. Kováčik, and P. Babula, “PAL inhibitor evokes different responses in two Hypericum species,” Plant Physiology and Biochemistry, vol. 63, pp. 82–88, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. Y.-S. Han, R. van der Heijden, and R. Verpoorte, “Biosynthesis of anthraquinones in cell cultures of the Rubiaceae,” Plant Cell, Tissue and Organ Culture, vol. 67, no. 3, pp. 201–220, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. P. P. Pillai and A. R. Nair, “Hypericin biosynthesis in Hypericum hookerianum Wight and Arn: investigation on biochemical pathways using metabolite inhibitors and suppression subtractive hybridization,” Comptes Rendus Biologies, vol. 337, no. 10, pp. 571–580, 2014. View at Google Scholar
  63. R. A. Dixon and N. L. Paiva, “Stress-induced phenylpropanoid metabolism,” Plant Cell, vol. 7, no. 7, pp. 1085–1097, 1995. View at Publisher · View at Google Scholar · View at Scopus
  64. F. Ververidis, E. Trantas, C. Douglas, G. Vollmer, G. Kretzschmar, and N. Panopoulos, “Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I. Chemical diversity, impacts on plant biology and human health,” Biotechnology Journal, vol. 2, no. 10, pp. 1214–1234, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. M. L. Hillwig, K. D. P. Hammer, D. F. Birt, and E. S. Wurtele, “Characterizing the metabolic fingerprint and anti-inflammatory activity of Hypericum gentianoides,” Journal of Agricultural and Food Chemistry, vol. 56, no. 12, pp. 4359–4366, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Kusari, S. Zühlke, T. Borsch, and M. Spiteller, “Positive correlations between hypericin and putative precursors detected in the quantitative secondary metabolite spectrum of Hypericum,” Phytochemistry, vol. 70, no. 10, pp. 1222–1232, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. C. M. Liyana-Pathirana and F. Shahidi, “Antioxidant properties of commercial soft and hard winter wheats (Triticum aestivum L.) and their milling fractions,” Journal of the Science of Food and Agriculture, vol. 86, no. 3, pp. 477–485, 2006. View at Publisher · View at Google Scholar · View at Scopus
  68. Y. Cai, Q. Luo, M. Sun, and H. Corke, “Antioxidant activity and phenolic compounds of 112 traditional Chinese medicinal plants associated with anticancer,” Life Sciences, vol. 74, no. 17, pp. 2157–2184, 2004. View at Publisher · View at Google Scholar · View at Scopus
  69. B. Bozin, N. Mimica-Dukic, I. Samojlik, A. Goran, and R. Igic, “Phenolics as antioxidants in garlic (Allium sativum L., Alliaceae),” Food Chemistry, vol. 111, no. 4, pp. 925–929, 2008. View at Publisher · View at Google Scholar · View at Scopus
  70. F. Conforti, G. A. Statti, R. Tundis, F. Menichini, and P. Houghton, “Antioxidant activity of methanolic extract of Hypericum triquetrifolium Turra aerial part,” Fitoterapia, vol. 73, no. 6, pp. 479–483, 2002. View at Publisher · View at Google Scholar · View at Scopus
  71. S. P. Hatzilazarou, T. D. Syros, T. A. Yupsanis, A. M. Bosabalidis, and A. S. Economou, “Peroxidases, lignin and anatomy during in vitro and ex vitro rooting of gardenia (Gardenia jasminoides Ellis) microshoots,” Journal of Plant Physiology, vol. 163, no. 8, pp. 827–836, 2006. View at Publisher · View at Google Scholar · View at Scopus
  72. B. H. Abbasi, M. Khan, B. Guo, S. A. Bokhari, and M. A. Khan, “Efficient regeneration and antioxidative enzyme activities in Brassica rapa var. turnip,” Plant Cell, Tissue and Organ Culture, vol. 105, no. 3, pp. 337–344, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Kormutak and B. Vookova, “Peroxidase activity in non-embryogenic and embryogenic calli and in developing somatic embryos of white fir (Abies concolor Gord. et Glend),” Plant Biosystems, vol. 135, no. 1, pp. 101–105, 2001. View at Publisher · View at Google Scholar · View at Scopus
  74. L. E. B. Savio, L. V. Astarita, and E. R. Santarém, “Secondary metabolism in micropropagated Hypericum perforatum L. grown in non-aerated liquid medium,” Plant Cell, Tissue and Organ Culture, vol. 108, no. 3, pp. 465–472, 2012. View at Publisher · View at Google Scholar · View at Scopus