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image of Diverse Therapeutic Potentials of Hypericin: An In-Depth Review

Abstract

Background

This review is delving into determining the content and significance of hypericin, a pharmacologically important constituent commonly known as St. John's Wort (SJW). The paper explores the rich history of Hypericin's traditional use in alternative medicine and the recent surge in scientific interest surrounding its bioactive properties.

Objective

This review aims to provide a comprehensive analysis the therapeutic potentials of hypericin, focusing on its chemistry, extraction, sources, stability, pharmacokinetics, safety profile, and multifunctional applications in drug and medicinal fields as well as advancements in Bioengineering Approaches for Enhanced Hypericin Delivery.

Methods

We performed a non-systematic search of journals. Literature using computerized methods was conducted, utilizing databases such as Medline (PubMed), ChemSciFinder, China National Knowledge Infrastructure (CNKI) and Scirus Library. To effectively identify the most important and relevant research articles, scientific studies, clinical studies and review articles on hypericin were searched using different keywords: “Hypericum”, “traditional use”, “phytochemistry”, “pharmacology”, “drug delivery” and “bioactivity”. Thus, articles available from 1984 to 2024 were analyzed and collected. The selection process for the review primarily considered the originality of the paper and its clinical applications.

Results

Although hypericin is not a novel compound within the research community, it is gaining renewed recognition and showing great effectiveness as a promising agent in the field of medical diagnostics and has promising applications as a therapeutic.

Conclusion

Here, our current comprehensive review of hypericin, its potential and its activities is intended to contribute to this ongoing process actively. Overall, this review provided theoretical direction for future hypericin research. Future studies should, therefore, focus further on the pharmacological processes, pharmacokinetics, and chemistry of hypericin and hypericin-based drug delivery systems. This comprehensive review of hypericin aims to actively contribute to ongoing research and provide a theoretical direction for future studies.

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2025-02-27
2025-05-30
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References

  1. Radusiene J. Stanius Z. Cirak C. Odabas M.S. Quantitative effects of temperature and light intensity on accumulation of] bioactive compounds in St. John’s worth. Acta Hortic 2010 925 135 140
    [Google Scholar]
  2. Zhang J. Gao L. Hu J. Wang C. Hagedoorn P.L. Li N. Zhou X. Hypericin: source, determination, separation, and properties. Separ. Purif. Rev. 2022 51 1 1 10 10.1080/15422119.2020.1797792
    [Google Scholar]
  3. Davatgaran Taghipour Y. Hajialyani M. Naseri R. Hesari M. Mohammadi P. Stefanucci A. Mollica A. Farzaei M.H. Abdollahi M. Nanoformulations of natural products for management of metabolic syndrome. Int. J. Nanomedicine 2019 14 5303 5321 10.2147/IJN.S213831 31406461
    [Google Scholar]
  4. Çlrak C. Radušiene J. Janulis V. Ivanauskas L. Arslan B. Chemical constituents of some Hypericum species growing in Turkey. J. Plant Biol. 2007 50 6 632 635 10.1007/BF03030606
    [Google Scholar]
  5. Onoue S. Seto Y. Ochi M. Inoue R. Ito H. Hatano T. Yamada S. In vitro photochemical and phototoxicological characterization of major constituents in St. John’s Wort (Hypericum perforatum) extracts. Phytochemistry 2011 72 14-15 1814 1820 10.1016/j.phytochem.2011.06.011 21782201
    [Google Scholar]
  6. Tawaha K. Gharaibeh M. El-Elimat T. Alali F.Q. Determination of hypericin and hyperforin content in selected Jordanian Hypericum species. Ind. Crops Prod. 2010 32 3 241 245 10.1016/j.indcrop.2010.04.017
    [Google Scholar]
  7. Penjweini R. Loew H.G. Eisenbauer M. Kratky K.W. Modifying excitation light dose of novel photosensitizer PVP-Hypericin for photodynamic diagnosis and therapy. J. Photochem. Photobiol. B 2013 120 120 129 10.1016/j.jphotobiol.2012.12.013 23375215
    [Google Scholar]
  8. Skalkos D. Gioti E. Stalikas C.D. Meyer H. Papazoglou T.G. Filippidis G. Photophysical properties of Hypericum perforatum L. extracts – Novel photosensitizers for PDT. J. Photochem. Photobiol. B 2006 82 2 146 151 10.1016/j.jphotobiol.2005.11.001 16388961
    [Google Scholar]
  9. Wynn J.L. Cotton T.M. Spectroscopic properties of hypericin in solution and at surfaces. J. Phys. Chem. 1995 99 12 4317 4323 10.1021/j100012a063
    [Google Scholar]
  10. Galeotti N. Hypericum perforatum (St John’s wort) beyond depression: A therapeutic perspective for pain conditions. J. Ethnopharmacol. 2017 200 136 146 10.1016/j.jep.2017.02.016 28216196
    [Google Scholar]
  11. Zhang R. Ji Y. Zhang X. Kennelly E.J. Long C. Ethnopharmacology of Hypericum species in China: A comprehensive review on ethnobotany, phytochemistry and pharmacology. J. Ethnopharmacol. 2020 254 112686 10.1016/j.jep.2020.112686 32101776
    [Google Scholar]
  12. Yadav N. Deshmukh R. Majumder R. A Comprehensive Review on the Use of Traditional Chinese Medicine for Cancer Treatment. Pharmacological Research -. Zhongguo Xiandai Zhongyao 2024 ••• 100423
    [Google Scholar]
  13. Barnes J. Anderson L.A. Phillipson J.D. St John’s wort ( Hypericum perforatum L.): a review of its chemistry, pharmacology and clinical properties. J. Pharm. Pharmacol. 2001 53 5 583 600 10.1211/0022357011775910 11370698
    [Google Scholar]
  14. Ru J. Li P. Wang J. Zhou W. Li B. Huang C. Li P. Guo Z. Tao W. Yang Y. Xu X. Li Y. Wang Y. Yang L. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform. 2014 6 1 13 10.1186/1758‑2946‑6‑13 24735618
    [Google Scholar]
  15. Černý C. Über das Hypericin (Hypericumrot). Mit zwei Abbildungen im Text. Hoppe Seylers Z. Physiol. Chem. 1911 73 5 371 382 10.1515/bchm2.1911.73.5.371
    [Google Scholar]
  16. Brockmann H. Kluge F. Muxfeldt H. Totalsynthese des Hypericins. Chem. Ber. 1957 90 10 2302 2318 10.1002/cber.19570901027
    [Google Scholar]
  17. Ion V. Ielciu I. Cârje A.G. Muntean D.L. Crişan G. Păltinean R. Hypericum spp.—An Overview of the Extraction Methods and Analysis of Compounds. Separations 2022 9 1 17 10.3390/separations9010017
    [Google Scholar]
  18. Draves A.H. Walker S.E. Determination of hypericin and pseudohypericin in pharmaceutical preparations by liquid chromatography with fluorescence detection. J. Chromatogr., Biomed. Appl. 2000 749 1 57 66 10.1016/S0378‑4347(00)00383‑2 11129079
    [Google Scholar]
  19. Liu F. Pan C. Drumm P. Ang C.Y.W. Liquid chromatography–mass spectrometry studies of St. John’s wort methanol extraction: active constituents and their transformation. J. Pharm. Biomed. Anal. 2005 37 2 303 312 10.1016/j.jpba.2004.10.034 15708671
    [Google Scholar]
  20. Williams F.B. Sander L.C. Wise S.A. Girard J. Development and evaluation of methods for determination of naphthodianthrones and flavonoids in St. John’s wort. J. Chromatogr. A 2006 1115 1-2 93 102 10.1016/j.chroma.2006.02.078 16554056
    [Google Scholar]
  21. Smelcerovic A. Spiteller M. Zuehlke S. Comparison of methods for the exhaustive extraction of hypericins, flavonoids, and hyperforin from Hypericum perforatum L. J. Agric. Food Chem. 2006 54 7 2750 2753 10.1021/jf0527246 16569071
    [Google Scholar]
  22. Benthin B. Danz H. Hamburger M. Pressurized liquid extraction of medicinal plants. J. Chromatogr. A 1999 837 1-2 211 219 10.1016/S0021‑9673(99)00071‑0 10227181
    [Google Scholar]
  23. Catchpole O.J. Perry N.B. da Silva B.M.T. Grey J.B. Smallfield B.M. Supercritical extraction of herbs I: Saw Palmetto, St John’s Wort, Kava Root, and Echinacea. J. Supercrit. Fluids 2002 22 2 129 138 10.1016/S0896‑8446(01)00110‑3
    [Google Scholar]
  24. Ramezani Z. Zamani M. A simple method for extraction and purification of hypericins from St John’s wort. Jundishapur J. Nat. Pharm. Prod. 2017 12 1 10.5812/jjnpp.13864
    [Google Scholar]
  25. Wirz A. Analytical and phytochemical investigations on hypericin and related compounds of Hypericum perforatum. Switzerland ETH Zurich 2000
    [Google Scholar]
  26. Karioti A. Vincieri F.F. Bilia A.R. Rapid and efficient purification of naphthodianthrones from St. John’s wort extract by using liquid–liquid extraction and SEC. J. Sep. Sci. 2009 32 9 1374 1382 10.1002/jssc.200800700 19360729
    [Google Scholar]
  27. Vandenbogaerde A.L. Kamuhabwa A. Delaey E. Himpens B.E. Merlevede W.J. de Witte P.A. Photocytotoxic effect of pseudohypericin versus hypericin. J. Photochem. Photobiol. B 1998 45 2-3 87 94 10.1016/S1011‑1344(98)00163‑8 9868799
    [Google Scholar]
  28. Santarém E.R. Astarita L.V. Multiple shoot formation in Hypericum perforatum L.and hypericin production. Braz. J. Plant Physiol. 2003 15 1 43 47 10.1590/S1677‑04202003000100006
    [Google Scholar]
  29. Karioti A. Bilia A.R. Hypericins as potential leads for new therapeutics. Int. J. Mol. Sci. 2010 11 2 562 594 10.3390/ijms11020562 20386655
    [Google Scholar]
  30. Zubek S. Mielcarek S. Turnau K. Hypericin and pseudohypericin concentrations of a valuable medicinal plant Hypericum perforatum L. are enhanced by arbuscular mycorrhizal fungi. Mycorrhiza 2012 22 2 149 156 10.1007/s00572‑011‑0391‑1 21626142
    [Google Scholar]
  31. Crockett S.L. Schaneberg B. Khan I.A. Phytochemical profiling of new and old world Hypericum (St. John’s Wort) species. Phytochem. Anal. 2005 16 6 479 485 10.1002/pca.875 16315494
    [Google Scholar]
  32. Zobayed S.M.A. Afreen F. Goto E. Kozai T. Plant-environment interactions: Accumulation of hypericin in dark glands of Hypericum perforatum. Ann. Bot. (Lond.) 2006 98 4 793 804 10.1093/aob/mcl169 16891333
    [Google Scholar]
  33. Soták M. Czeranková O. Klein D. Jurčacková Z. Li L. Čellárová E. Comparative transcriptome reconstruction of four hypericum species focused on Hypericin biosynthesis. Front. Plant Sci. 2016 7 1039 10.3389/fpls.2016.01039 27468294
    [Google Scholar]
  34. Kirakosyan A. Sirvent T.M. Gibson D.M. Kaufman P.B. The production of hypericins and hyperforin by in vitro cultures of St. John’s wort ( Hypericum perforatum ). Biotechnol. Appl. Biochem. 2004 39 1 71 81 10.1042/BA20030144 14521510
    [Google Scholar]
  35. Zdunic G Godjevac D Savikin K Comparative analysis of phenolic compounds in seven hypericum species and their antioxidant properties. Nat Prod Commun 2017 12 11 1805 1811
    [Google Scholar]
  36. Cirak C. Radusiene J. Jakstas V. Ivanauskas L. Seyis F. Yayla F. Secondary metabolites of seven Hypericum species growing in Turkey. Pharm. Biol. 2016 54 10 2244 2253 10.3109/13880209.2016.1152277 26958815
    [Google Scholar]
  37. Doukani K Selles AS Bouhenni H Hypericin and pseudohypericin. Naturally Occurring Chemicals Against Alzheimer's Disease Academic Press 2021 155 165 10.1016/B978‑0‑12‑819212‑2.00013‑X
    [Google Scholar]
  38. Hosni K. Msaâda K. Taârit M.B. Hammami M. Marzouk B. Bioactive components of three Hypericum species from Tunisia: A comparative study. Ind. Crops Prod. 2010 31 1 158 163 10.1016/j.indcrop.2009.09.018
    [Google Scholar]
  39. Çιrak C. Radušienė J. Janulis V. Ivanauskas L. Secondary metabolites in Hypericum perfoliatum: variation among plant parts and phenological stages. Bot. Helv. 2007 117 1 29 36 10.1007/s00035‑007‑0777‑z
    [Google Scholar]
  40. Kakouri E. Trigas P. Daferera D. Skotti E. Tarantilis P.A. Kanakis C. Chemical Characterization and Antioxidant Activity of Nine Hypericum Species from Greece. Antioxidants 2023 12 4 899 10.3390/antiox12040899 37107274
    [Google Scholar]
  41. Alahmad A. Alghoraibi I. Zein R. Kraft S. Dräger G. Walter J.G. Scheper T. Identification of major constituents of Hypericum perforatum L. extracts in Syria by development of a rapid, simple, and reproducible HPLC-ESI-Q-TOF MS analysis and their antioxidant activities. ACS Omega 2022 7 16 13475 13493 10.1021/acsomega.1c06335 35559140
    [Google Scholar]
  42. Fico G Vitalini S Colombo N Phytochemical and morphological studies. Nat Prod Commun 2006
    [Google Scholar]
  43. Cirak C. Radusiene J. Jakstas V. Ivanauskas L. Yayla F. Seyis F. Camas N. Secondary metabolites of Hypericum species from the Drosanthe and Olympia sections. S. Afr. J. Bot. 2016 104 82 90 10.1016/j.sajb.2015.09.022
    [Google Scholar]
  44. Kwiecień I. Miceli N. Kędzia E. Cavò E. Taviano M.F. Beerhues L. Ekiert H. Different Types of Hypericum perforatum cvs. (Elixir, Helos, Topas) In vitro Cultures: A Rich Source of Bioactive Metabolites and Biological Activities of Biomass Extracts. Molecules 2023 28 5 2376 10.3390/molecules28052376 36903619
    [Google Scholar]
  45. Ayan A.K. Cirak C. Variation of hypericins in Hypericum triquetrifolium Turra growing in different locations of Turkey during plant growth. Nat. Prod. Res. 2008 22 18 1597 1604 10.1080/14786410701838213 19085414
    [Google Scholar]
  46. Seyrekoglu F. Temiz H. Eser F. Yildirim C. Comparison of the antioxidant activities and major constituents of three Hypericum species (H. perforatum, H. scabrum and H. origanifolium) from Turkey. S. Afr. J. Bot. 2022 146 723 727 10.1016/j.sajb.2021.12.012
    [Google Scholar]
  47. Kucharíková A. Kimáková K. Janfelt C. Čellárová E. Interspecific variation in localization of hypericins and phloroglucinols in the genus Hypericum as revealed by desorption electrospray ionization mass spectrometry imaging. Physiol. Plant. 2016 157 1 2 12 10.1111/ppl.12422 26822391
    [Google Scholar]
  48. Ayan A.K. Çirak C. Hypericin and Pseudohypericin Contents in Some Hypericum. Species Growing in Turkey. Pharm. Biol. 2008 46 4 288 291 10.1080/13880200701741211
    [Google Scholar]
  49. Yasuda T. Yamaki M. Iimura A. Shimotai Y. Shimizu K. Noshita T. Funayama S. Anti-influenza virus principles from Muehlenbeckia hastulata. J. Nat. Med. 2010 64 2 206 211 10.1007/s11418‑009‑0386‑9 20082146
    [Google Scholar]
  50. Kusari S. Lamshöft M. Zühlke S. Spiteller M. An endophytic fungus from Hypericum perforatum that produces hypericin. J. Nat. Prod. 2008 71 2 159 162 10.1021/np070669k 18220354
    [Google Scholar]
  51. Murthy H.N. Kim Y.S. Park S.Y. Paek K.Y. Hypericins: biotechnological production from cell and organ cultures. Appl. Microbiol. Biotechnol. 2014 98 22 9187 9198 10.1007/s00253‑014‑6119‑3 25301586
    [Google Scholar]
  52. Scharfenberg S Franke K Helmut B Discovery of key regulators of dark gland development and hypericin biosynthesis in St. John's Wort (Hypericum perforatum). Plant Biotechnol. J. 2019 17 12 2299 2312
    [Google Scholar]
  53. Tavakoli F. Rafieiolhossaini M. Ravash R. Ebrahimi M. Subject: UV-B radiation and low temperature promoted hypericin biosynthesis in adventitious root culture of Hypericum perforatum. Plant Signal. Behav. 2020 15 7 1764184 10.1080/15592324.2020.1764184 32419579
    [Google Scholar]
  54. Arbeitsvorschrft A. Bestmann H.J. Synthese von Protohypericin aus Emodin. 2000 89 55 56
    [Google Scholar]
  55. Košuth J. Smelcerovic A. Borsch T. Zuehlke S. Karppinen K. Spiteller M. Hohtola A. Čellárová E. The hyp-1 gene is not a limiting factor for hypericin biosynthesis in the genus Hypericum. Funct. Plant Biol. 2011 38 1 35 43 10.1071/FP10144 32480860
    [Google Scholar]
  56. Gonçalves R.S. Rabello B.R. César G.B. Pereira P.C.S. Ribeiro M.A.S. Meurer E.C. Hioka N. Nakamura C.V. Bruschi M.L. Caetano W. An efficient multigram synthesis of hypericin improved by a low power LED based photoreactor. Org. Process Res. Dev. 2017 21 12 2025 2031 10.1021/acs.oprd.7b00317
    [Google Scholar]
  57. Bais H.P. Vepachedu R. Lawrence C.B. Stermitz F.R. Vivanco J.M. Molecular and biochemical characterization of an enzyme responsible for the formation of hypericin in St. John’s wort (Hypericum perforatum L.). J. Biol. Chem. 2003 278 34 32413 32422 10.1074/jbc.M301681200 12799379
    [Google Scholar]
  58. Southwell I.A. Bourke C.A. Seasonal variation in hypericin content of Hypericum perforatum L. (St. John’s Wort). Phytochemistry 2001 56 5 437 441 10.1016/S0031‑9422(00)00411‑8 11261576
    [Google Scholar]
  59. Michalska K. Fernandes H. Sikorski M. Jaskolski M. Crystal structure of Hyp-1, a St. John’s wort protein implicated in the biosynthesis of hypericin. J. Struct. Biol. 2010 169 2 161 171 10.1016/j.jsb.2009.10.008 19853038
    [Google Scholar]
  60. Sliwiak J. Dauter Z. Jaskolski M. Crystal structure of Hyp-1, a Hypericum perforatum PR-10 protein, in complex with melatonin. Front. Plant Sci. 2016 7 668 10.3389/fpls.2016.00668 27242869
    [Google Scholar]
  61. Karppinen K. Hokkanen J. Mattila S. Neubauer P. Hohtola A. Octaketide‐producing type III polyketide synthase from Hypericum perforatum is expressed in dark glands accumulating hypericins. FEBS J. 2008 275 17 4329 4342 10.1111/j.1742‑4658.2008.06576.x 18647343
    [Google Scholar]
  62. Kusari S. Zühlke S. Košuth J. Čellárová E. Spiteller M. Light-independent metabolomics of endophytic Thielavia subthermophila provides insight into microbial hypericin biosynthesis. J. Nat. Prod. 2009 72 10 1825 1835 10.1021/np9002977 19746917
    [Google Scholar]
  63. Karppinen K. Hohtola A. Molecular cloning and tissue-specific expression of two cDNAs encoding polyketide synthases from Hypericum perforatum. J. Plant Physiol. 2008 165 10 1079 1086 10.1016/j.jplph.2007.04.008 17931742
    [Google Scholar]
  64. Zobayed S.M.A. Afreen F. Kozai T. Temperature stress can alter the photosynthetic efficiency and secondary metabolite concentrations in St. John’s wort. Plant Physiol. Biochem. 2005 43 10-11 977 984 10.1016/j.plaphy.2005.07.013 16310362
    [Google Scholar]
  65. Mosaleeyanon K. Zobayed S.M.A. Afreen F. Kozai T. Relationships between net photosynthetic rate and secondary metabolite contents in St. John’s wort. Plant Sci. 2005 169 3 523 531 10.1016/j.plantsci.2005.05.002
    [Google Scholar]
  66. Cui X.H. Chakrabarty D. Lee E.J. Paek K.Y. Production of adventitious roots and secondary metabolites by Hypericum perforatum L. in a bioreactor. Bioresour. Technol. 2010 101 12 4708 4716 10.1016/j.biortech.2010.01.115 20171884
    [Google Scholar]
  67. Odabaş M.S. Radušienė J. Çırak C. Çamaş N. Models of estimation of the content of secondary metabolites in some Hypericum species. Pharm. Biol. 2009 47 12 1117 1122 10.3109/13880200903008666
    [Google Scholar]
  68. Zobayed S.M.A. Afreen F. Kozai T. Phytochemical and physiological changes in the leaves of St. John’s wort plants under a water stress condition. Environ. Exp. Bot. 2007 59 2 109 116 10.1016/j.envexpbot.2005.10.002
    [Google Scholar]
  69. Waser M. Falk H. Progress in the chemistry of second generation hypericin based photosensitizers. Curr. Org. Chem. 2011 15 23 3894 3907 10.2174/138527211798072458
    [Google Scholar]
  70. Eggelkraut-Gottanka S.G. Abed S.A. Müller W. Schmidt P.C. Quantitative analysis of the active components and the by‐products of eight dry extracts of Hypericum perforatum L. (St John’s wort). Phytochem. Anal. 2002 13 3 170 176 10.1002/pca.638
    [Google Scholar]
  71. Smietanska J. Sliwiak J. Gilski M. Dauter Z. Strzalka R. Wolny J. Jaskolski M. A new modulated crystal structure of the ANS complex of the St John’s wort Hyp-1 protein with 36 protein molecules in the asymmetric unit of the supercell. Acta Crystallogr. D Struct. Biol. 2020 76 7 653 667 10.1107/S2059798320006841 32627738
    [Google Scholar]
  72. Huang L.F. Wang Z.H. Chen S.L. Hypericin: chemical synthesis and biosynthesis. Chin. J. Nat. Med. 2014 12 2 81 88 10.1016/S1875‑5364(14)60014‑5 24636057
    [Google Scholar]
  73. Bruni R. Sacchetti G. Factors affecting polyphenol biosynthesis in wild and field grown St. John’s Wort (Hypericum perforatum L. Hypericaceae/Guttiferae). Molecules 2009 14 2 682 725 10.3390/molecules14020682 19214156
    [Google Scholar]
  74. Yavari I. Alborzi A. Mohtat B. Synthesis of highly functionalized 9,10-anthraquinones. Dyes Pigments 2006 68 2-3 85 88 10.1016/j.dyepig.2005.01.005
    [Google Scholar]
  75. Naeimi H. Namdari R. Rapid, efficient and one pot synthesis of anthraquinone derivatives catalyzed by Lewis acid/methanesulfonic acid under heterogeneous conditions. Dyes Pigments 2009 81 3 259 263 10.1016/j.dyepig.2008.10.019
    [Google Scholar]
  76. Tauchert M.E. Kaiser T.R. Göthlich A.P.V. Rominger F. Warth D.C.M. Hofmann P. Phosphonite ligand design for nickel-catalyzed 2-methyl-3-butenenitrile isomerization and styrene hydrocyanation. ChemCatChem 2010 2 6 674 682 10.1002/cctc.201000022
    [Google Scholar]
  77. Qiu H. Liu R. Long L. Analysis of chemical composition of extractives by acetone and the chromatic aberration of teak (Tectona Grandis LF) from China. Molecules 2019 24 10 1989 10.3390/molecules24101989 31126143
    [Google Scholar]
  78. Motoyoshiya J Masue Y Nishi Y Aoyama H Synthesis of hypericin via emodin anthrone derived from a two-fold Diels-Alder reaction of 1, 4-benzoquinone. Nat. Prod. Commun. 2007 2 1 67 70
    [Google Scholar]
  79. Oumer A Bisrat D Mazumder A Asres K. A new antimicrobial anthrone from the leaf latex of Aloe trichosantha. Nat. Prod. Commun. 2014 9 7 949 952 10.1177/1934578X1400900717
    [Google Scholar]
  80. Murch S.J. Rupasinghe H.P. Saxena P.K. An in vitro and hydroponic growing system for hypericin, pseudohypericin, and hyperforin production of St. John’s wort (Hypericum perforatum CV new stem). Planta Med. 2002 68 12 1108 1112 10.1055/s‑2002‑36352 12494339
    [Google Scholar]
  81. Çirak C. Radušiene J. Karpaviciene B. Changes in phenolic content of wild and greenhouse-grown Hypericum triquetrifolium during plant development. Turk. J. Agric. For. 2013 37 307 314
    [Google Scholar]
  82. Pavlík M. Vacek J. Klejdus B. Kubáň V. Hypericin and hyperforin production in St. John’s wort in vitro culture: influence of saccharose, polyethylene glycol, methyl jasmonate, and Agrobacterium tumefaciens. J. Agric. Food Chem. 2007 55 15 6147 6153 10.1021/jf070245w 17608493
    [Google Scholar]
  83. Rizzo P. Altschmied L. Ravindran B.M. Rutten T. D’Auria J.C. The Biochemical and Genetic Basis for the Biosynthesis of Bioactive Compounds in Hypericum perforatum L., One of the Largest Medicinal Crops in Europe. Genes 2020 11 10 1210 10.3390/genes11101210 33081197
    [Google Scholar]
  84. Punegov V.V. Kostromin V.I. Fomina M.G. Zaynullin V.G. Yushkova E.A. Belyh D.V. Chukicheva I.U. Zaynullin G.G. Microwave-assisted extraction of hypericin and pseudohypericin from Hypericum perforatum. Russ. J. Bioorganic Chem. 2015 41 7 757 761 10.1134/S1068162015070122
    [Google Scholar]
  85. Hölzl J Petersen M. Chemical constituents of Hypericum ssp. Hypericum: the genus Hypericum Taylor & Francis London 2003 77 90
    [Google Scholar]
  86. Huygens A. Kamuhabwa A.R. de Witte P.A.M. Stability of different formulations and ion pairs of hypericin. Eur. J. Pharm. Biopharm. 2005 59 3 461 468 10.1016/j.ejpb.2004.09.014 15760726
    [Google Scholar]
  87. Kerb R. Brockmöller J. Staffeldt B. Ploch M. Roots I. Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob. Agents Chemother. 1996 40 9 2087 2093 10.1128/AAC.40.9.2087 8878586
    [Google Scholar]
  88. Jacobson J.M. Feinman L. Liebes L. Ostrow N. Koslowski V. Tobia A. Cabana B.E. Lee D.H. Spritzler J. Prince A.M. Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John’s wort plant, in patients with chronic hepatitis C virus infection. Antimicrob. Agents Chemother. 2001 45 2 517 524 10.1128/AAC.45.2.517‑524.2001 11158749
    [Google Scholar]
  89. Schulz H.U. Schürer M. Bässler D. Weiser D. Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers. Arzneimittelforschung 2005 55 10 561 568 16294501
    [Google Scholar]
  90. Brockmöller J Reum T Bauer S Kerb R Hübner WD Roots I Hypericin and pseudohypericin: Pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 1997 30 Suppl 2 94 101 10.1055/s‑2007‑979527
    [Google Scholar]
  91. Russo E. Scicchitano F. Whalley B.J. Mazzitello C. Ciriaco M. Esposito S. Patanè M. Upton R. Pugliese M. Chimirri S. Mammì M. Palleria C. De Sarro G. Hypericum perforatum: Pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytother. Res. 2014 28 5 643 655 10.1002/ptr.5050 23897801
    [Google Scholar]
  92. Staffeldt B. Kerb R. Brockmöller J. Ploch M. Roots I. Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J. Geriatr. Psychiatry Neurol. 1994 7 1_suppl Suppl. 1 47 53 10.1177/089198879400701s13 7857509
    [Google Scholar]
  93. Unterweger H. Subatzus D. Tietze R. Janko C. Poettler M. Stiegelschmitt A. Schuster M. Maake C. Boccaccini A. Alexiou C. Hypericin-bearing magnetic iron oxide nanoparticles for selective drug delivery in photodynamic therapy. Int. J. Nanomedicine 2015 10 6985 6996 10.2147/IJN.S92336 26648714
    [Google Scholar]
  94. Fourneron J.D. Herbette G. Caloprisco E. Pseudohypericin and hypericin in St. John’s wort extracts. Breakdown of pseudohypericin. C. R. Acad. Sci. Ser. IIc Chim. 1999 2 3 127 131 10.1016/S1251‑8069(99)80024‑3
    [Google Scholar]
  95. Jendželovský R. Jendželovská Z. Kuchárová B. Fedoročko P. Breast cancer resistance protein is the enemy of hypericin accumulation and toxicity of hypericin-mediated photodynamic therapy. Biomed. Pharmacother. 2019 109 2173 2181 10.1016/j.biopha.2018.11.084 30551474
    [Google Scholar]
  96. Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front. Pharmacol. 2014 4 177 10.3389/fphar.2013.00177 24454289
    [Google Scholar]
  97. Sofi S.H. Nuraddin S.M. Amin Z.A. Al-Bustany H.A. Nadir M.Q. Gastroprotective activity of Hypericum perforatum extract in ethanol-induced gastric mucosal injury in Wistar rats: A possible involvement of H+/K+ ATPase α inhibition. Heliyon 2020 6 10 e05249 10.1016/j.heliyon.2020.e05249 33102861
    [Google Scholar]
  98. Gregoretti B. Stebel M. Candussio L. Crivellato E. Bartoli F. Decorti G. Toxicity of Hypericum perforatum (St. John’s wort) administered during pregnancy and lactation in rats. Toxicol. Appl. Pharmacol. 2004 200 3 201 205 10.1016/j.taap.2004.04.020 15504456
    [Google Scholar]
  99. Ferrara M. Mungai F. Starace F. St John’s wort (Hypericum perforatum)-induced psychosis: A case report. J. Med. Case Reports 2017 11 1 137 10.1186/s13256‑017‑1302‑7 28502251
    [Google Scholar]
  100. Goey A.K.L. Mooiman K.D. Beijnen J.H. Schellens J.H.M. Meijerman I. Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb–drug interactions in cancer patients. Cancer Treat. Rev. 2013 39 7 773 783 10.1016/j.ctrv.2012.12.008 23394826
    [Google Scholar]
  101. Borrelli F. Izzo A.A. Herb-drug interactions with St John’s wort (Hypericum perforatum): An update on clinical observations. AAPS J. 2009 11 4 710 727 10.1208/s12248‑009‑9146‑8 19859815
    [Google Scholar]
  102. Henderson L. Yue Q.Y. Bergquist C. Gerden B. Arlett P. St John’s wort ( Hypericum perforatum ): Drug interactions and clinical outcomes. Br. J. Clin. Pharmacol. 2002 54 4 349 356 10.1046/j.1365‑2125.2002.01683.x 12392581
    [Google Scholar]
  103. Johne A. Brockmöller J. Bauer S. Pharmacokinetics and drug disposition pharmacokinetic interaction of digoxin with an herbal extract from St John’ s wort. Clin. Pharmacol. Ther. 1999 ••• 338 345 10.1053/cp.1999.v66.a101944 10546917
    [Google Scholar]
  104. Tannergren C. Engman H. Knutson L. Hedeland M. Bondesson U. Lennernäs H. St John’s wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism*1. Clin. Pharmacol. Ther. 2004 75 4 298 309 10.1016/j.clpt.2003.12.012 15060508
    [Google Scholar]
  105. Andrén L. Andreasson Å. Eggertsen R. Interaction between a commercially available St. John’s wort product (Movina) and atorvastatin in patients with hypercholesterolemia. Eur. J. Clin. Pharmacol. 2007 63 10 913 916 10.1007/s00228‑007‑0345‑x 17701167
    [Google Scholar]
  106. Murphy P.A. Kern S.E. Stanczyk F.Z. Westhoff C.L. Interaction of St. John’s Wort with oral contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 2005 71 6 402 408 10.1016/j.contraception.2004.11.004 15914127
    [Google Scholar]
  107. McCance-Katz E.F. Sullivan L.E. Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: A review. Am. J. Addict. 2010 19 1 4 16 10.1111/j.1521‑0391.2009.00005.x 20132117
    [Google Scholar]
  108. Ho Y.F. Huang D.K. Hsueh W.C. Lai M.Y. Yu H.Y. Tsai T.H. Effects of St. John’s wort extract on indinavir pharmacokinetics in rats: Differentiation of intestinal and hepatic impacts. Life Sci. 2009 85 7-8 296 302 10.1016/j.lfs.2009.06.008 19559714
    [Google Scholar]
  109. Nieminen T.H. Hagelberg N.M. Saari T.I. Neuvonen M. Laine K. Neuvonen P.J. Olkkola K.T. St John’s wort greatly reduces the concentrations of oral oxycodone. Eur. J. Pain 2010 14 8 854 859 10.1016/j.ejpain.2009.12.007 20106684
    [Google Scholar]
  110. Izzo A.A. Interactions between herbs and conventional drugs: Overview of the clinical data. Med. Princ. Pract. 2012 21 5 404 428 10.1159/000334488 22236736
    [Google Scholar]
  111. Hebert M.F. Park J.M. Chen Y.L. Akhtar S. Larson A.M. Effects of St. John’s wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. J. Clin. Pharmacol. 2004 44 1 89 94 10.1177/0091270003261078 14681346
    [Google Scholar]
  112. Morimoto T. Kotegawa T. Tsutsumi K. Ohtani Y. Imai H. Nakano S. Effect of St. John’s wort on the pharmacokinetics of theophylline in healthy volunteers. J. Clin. Pharmacol. 2004 44 1 95 101 10.1177/0091270003261496 14681347
    [Google Scholar]
  113. Wada A. Sakaeda T. Takara K. Hirai M. Kimura T. Ohmoto N. Zhou J. Nakamura T. Kobayashi H. Okamura N. Yagami T. Okumura K. Effects of St John’s wort and hypericin on cytotoxicity of anticancer drugs. Drug Metab. Pharmacokinet. 2002 17 5 467 474 10.2133/dmpk.17.467 15618698
    [Google Scholar]
  114. Odabas M.S. Radusiene J. Cirak C. Camas N. Prediction models for the phenolic contents in some Hypericum species from Turkey. Asian J. Chem. 2008 20 6 4792
    [Google Scholar]
  115. Becker L.C. Bergfeld W.F. Belsito D.V. Hill R.A. Klaassen C.D. Liebler D.C. Marks J.G. Jr Shank R.C. Slaga T.J. Snyder P.W. Andersen F.A. Amended safety assessment of Hypericum perforatum-derived ingredients as used in cosmetics. Int. J. Toxicol. 2014 33 3_suppl Suppl. 5S 23S 10.1177/1091581814533354 25297909
    [Google Scholar]
  116. Çirak C.Ü. Radusiene J. Aksoy H.M. Mackinaite R. Stanius Z. Camas N. Odabas M.S. Differential phenolic accumulation in two Hypericum species in response to inoculation with Diploceras hypericinum and Pseudomonasputida. Plant Prot. Sci. 2014 50 3 119 128 10.17221/67/2012‑PPS
    [Google Scholar]
  117. Silva A.R. Taofiq O. Ferreira I.C.F.R. Barros L. Hypericum genus cosmeceutical application – A decade comprehensive review on its multifunctional biological properties. Ind. Crops Prod. 2021 159 113053 10.1016/j.indcrop.2020.113053
    [Google Scholar]
  118. Butterweck V. Böckers T. Korte B. Wittkowski W. Winterhoff H. Long-term effects of St. John’s wort and hypericin on monoamine levels in rat hypothalamus and hippocampus. Brain Res. 2002 930 1-2 21 29 10.1016/S0006‑8993(01)03394‑7 11879791
    [Google Scholar]
  119. Mennini T. Gobbi M. The antidepressant mechanism of Hypericum perforatum. Life Sci. 2004 75 9 1021 1027 10.1016/j.lfs.2004.04.005 15207650
    [Google Scholar]
  120. Suzuki O. Katsumata Y. Oya M. Bladt S. Wagner H. Inhibition of monoamine oxidase by hypericin. Planta Med. 1984 50 3 272 274 10.1055/s‑2007‑969700 6484033
    [Google Scholar]
  121. Kleber E. Obry T. Hippeli S. Schneider W. Elstner E.F. Biochemical activities of extracts from Hypericum perforatum L. 1st Communication: Inhibition of dopamine-β-hydroxylase. Arzneimittelforschung 1999 49 2 106 109 10083977
    [Google Scholar]
  122. Liang C. Hao F. Yao X. Qiu Y. Liu L. Wang S. Yu C. Song Z. Bao Y. Yi J. Huang Y. Wu Y. Zheng L. Sun Y. Wang G. Yang X. Yang S. Sun L. Li Y. Hypericin maintians PDX1 expression via the Erk pathway and protects islet β-cells against glucotoxicity and lipotoxicity. Int. J. Biol. Sci. 2019 15 7 1472 1487 10.7150/ijbs.33817 31337977
    [Google Scholar]
  123. Yuan X. Yan F. Gao L.H. Ma Q.H. Wang J. Hypericin as a potential drug for treating Alzheimer’s disease and type 2 diabetes with a view to drug repositioning. CNS Neurosci. Ther. 2023 29 11 3307 3321 10.1111/cns.14260 37183545
    [Google Scholar]
  124. Kubin A. Wierrani F. Burner U. Alth G. Grünberger W. Hypericin--The facts about a controversial agent. Curr. Pharm. Des. 2005 11 2 233 253 10.2174/1381612053382287 15638760
    [Google Scholar]
  125. Hudson J.B. Lopez-Bazzocchi I. Towers G.H.N. Antiviral activities of hypericin. Antiviral Res. 1991 15 2 101 112 10.1016/0166‑3542(91)90028‑P 1650164
    [Google Scholar]
  126. Kartnig T. Göbel I. Heydel B. Production of hypericin, pseudohypericin and flavonoids in cell cultures of various Hypericum species and their chemotypes. Planta Med. 1996 62 1 51 53 10.1055/s‑2006‑957796 8720388
    [Google Scholar]
  127. Jain N. Jain P. Rajput D. Patil U.K. Green synthesized plant-based silver nanoparticles: Therapeutic prospective for anticancer and antiviral activity. Micro and Nano Systems Letters 2021 9 1 5 10.1186/s40486‑021‑00131‑6
    [Google Scholar]
  128. Kitanov G.M. Hypericin and pseudohypericin in some Hypericum species. Biochem. Syst. Ecol. 2001 29 2 171 178 10.1016/S0305‑1978(00)00032‑6 11106845
    [Google Scholar]
  129. Odabas M.S. Radusiene J. Karpaviciene B. Camas N. Prediction model of the effect of light intensity on phenolic contents in hypericum triquetrifolium turra. Izv. Him. 2015 47 2 467 471
    [Google Scholar]
  130. Liu Y. Wen F. Li J. Zuo C. Li M. Transitions of multifocal electroretinography in patients with age-related macular degeneration after combination therapy with photodynamic therapy and intravitreal bevacizumab. Doc. Ophthalmol. 2009 119 3 163 169 10.1007/s10633‑009‑9189‑2 20101800
    [Google Scholar]
  131. Vantieghem A. Xu Y. Declercq W. Vandenabeele P. Denecker G. Vandenheede J.R. Merlevede W. de Witte P.A. Agostinis P. Different pathways mediate cytochrome c release after photodynamic therapy with hypericin. Photochem. Photobiol. 2001 74 2 133 142 10.1562/0031‑8655(2001)074<0133:DPMCCR>2.0.CO;2 11547546
    [Google Scholar]
  132. Agostinis P. Assefa Z. Vantieghem A. Vandenheede J.R. Merlevede W. De Witte P. Apoptotic and anti-apoptotic signaling pathways induced by photodynamic therapy with hypericin. Adv. Enzyme Regul. 2000 40 1 157 182 10.1016/S0065‑2571(99)00021‑7 10828351
    [Google Scholar]
  133. Bender O. Llorent-Martínez E.J. Zengin G. Mollica A. Ceylan R. Molina-García L. Fernández-de Córdova M.L. Atalay A. Integration of in vitro and in silico perspectives to explain chemical characterization, biological potential and anticancer effects of Hypericum salsugineum: A pharmacologically active source for functional drug formulations. PLoS One 2018 13 6 e0197815 10.1371/journal.pone.0197815 29864137
    [Google Scholar]
  134. Maurya SK Divakar S Patil UK Potentials of plant derived products for the treatment of skin disorders. German J. Pharm. Biomater. 2023 2 3 9 31
    [Google Scholar]
  135. Agostinis P. Vantieghem A. Merlevede W. de Witte P.A.M. Hypericin in cancer treatment: More light on the way. Int. J. Biochem. Cell Biol. 2002 34 3 221 241 10.1016/S1357‑2725(01)00126‑1 11849990
    [Google Scholar]
  136. Fiers W. Beyaert R. Declercq W. Nature More than one way to die necrosis apoptosis ROS. Oncogene 1999 18 7719 7730 10.1038/sj.onc.1203249 10618712
    [Google Scholar]
  137. Chen B. Xu Y. Roskams T. Delaey E. Agostinis P. Vandenheede J.R. de Witte P. Efficacy of antitumoral photodynamic therapy with hypericin: Relationship between biodistribution and photodynamic effects in the RIF-1 mouse tumor model. Int. J. Cancer 2001 93 2 275 282 10.1002/ijc.1324 11410877
    [Google Scholar]
  138. Theodossiou T.A. Hothersall J.S. De Witte P.A. Pantos A. Agostinis P. The multifaceted photocytotoxic profile of hypericin. Mol. Pharm. 2009 6 6 1775 1789 10.1021/mp900166q 19739671
    [Google Scholar]
  139. Chen B. de Witte P.A. Photodynamic therapy efficacy and tissue distribution of hypericin in a mouse P388 lymphoma tumor model. Cancer Lett. 2000 150 1 111 117 10.1016/S0304‑3835(99)00381‑X 10755394
    [Google Scholar]
  140. Schempp C.M. Simon-Haarhaus B. Termeer C.C. Simon J.C. Hypericin photo‐induced apoptosis involves the tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and activation of caspase‐8. FEBS Lett. 2001 493 1 26 30 10.1016/S0014‑5793(01)02268‑2 11277999
    [Google Scholar]
  141. Davids L.M. Kleemann B. Kacerovská D. Pizinger K. Kidson S.H. Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells. J. Photochem. Photobiol. B 2008 91 2-3 67 76 10.1016/j.jphotobiol.2008.01.011 18342534
    [Google Scholar]
  142. Chen B. Roskams T. de Witte P.A.M. Antivascular tumor eradication by hypericin-mediated photodynamic therapy. Photochem. Photobiol. 2002 76 5 509 513 10.1562/0031‑8655(2002)076<0509:ATEBHM>2.0.CO;2 12462645
    [Google Scholar]
  143. Chen B. Zupkó I. de Witte P. Photodynamic therapy with hypericin in a mouse P388 tumor model: Vascular effects determine the efficacy. Int. J. Oncol. 2001 18 4 737 742 10.3892/ijo.18.4.737 11251168
    [Google Scholar]
  144. Mollica A. Zengin G. Locatelli M. Stefanucci A. Mocan A. Macedonio G. Carradori S. Onaolapo O. Onaolapo A. Adegoke J. Olaniyan M. Aktumsek A. Novellino E. Anti-diabetic and anti-hyperlipidemic properties of Capparis spinosa L.: In vivo and in vitro evaluation of its nutraceutical potential. J. Funct. Foods 2017 35 32 42 10.1016/j.jff.2017.05.001
    [Google Scholar]
  145. Rafailovska E. Tushevski O. Shijakova K. Simic S.G. Kjovkarovska S.D. Miova B. Hypericum perforatum L. extract exerts insulinotropic effects and inhibits gluconeogenesis in diabetic rats by regulating AMPK expression and PKCε concentration. J. Ethnopharmacol. 2023 302 Pt A 115899 10.1016/j.jep.2022.115899 36336219
    [Google Scholar]
  146. Cao R. Tian H. Zhang Y. Liu G. Xu H. Rao G. Tian Y. Fu X. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm 2023 4 3 e283 10.1002/mco2.283 37303813
    [Google Scholar]
  147. Fang C. Pan J. Qu N. Lei Y. Han J. Zhang J. Han D. The AMPK pathway in fatty liver disease. Front. Physiol. 2022 13 970292 Epub ahead of print 10.3389/fphys.2022.970292 36203933
    [Google Scholar]
  148. Liang C. Li Y. Bai M. Huang Y. Yang H. Liu L. Wang S. Yu C. Song Z. Bao Y. Yi J. Sun L. Li Y. Hypericin attenuates nonalcoholic fatty liver disease and abnormal lipid metabolism via the PKA-mediated AMPK signaling pathway in vitro and in vivo. Pharmacol. Res. 2020 153 104657 10.1016/j.phrs.2020.104657 31982488
    [Google Scholar]
  149. Shaik Mohamed Sayed U.F. Moshawih S. Goh H.P. Kifli N. Gupta G. Singh S.K. Chellappan D.K. Dua K. Hermansyah A. Ser H.L. Ming L.C. Goh B.H. Natural products as novel anti-obesity agents: Insights into mechanisms of action and potential for therapeutic management. Front. Pharmacol. 2023 14 1182937 10.3389/fphar.2023.1182937 37408757
    [Google Scholar]
  150. Brondz I. Greibrokk T. Groth P.A. Aasen A.J. The relative stereochemistry of hyperforin-an antibiotic from hypericum perforatum L. Tetrahedron Lett. 1982 23 12 1299 1300 10.1016/S0040‑4039(00)87088‑4
    [Google Scholar]
  151. Schempp C.M. Winghofer B. Langheinrich M. Schöpf E. Simon J.C. Hypericin levels in human serum and interstitial skin blister fluid after oral single-dose and steady-state administration of Hypericum perforatum extract (St. John’s wort). Skin Pharmacol. Physiol. 1999 12 5 299 304 10.1159/000066256 10461100
    [Google Scholar]
  152. Voss A. Verweij P.E. Fiebich B.L. Antibacterial activity of hyperforin from St John’s wort. Lancet 1999 354 9180 777 10.1016/S0140‑6736(05)76018‑9 10475221
    [Google Scholar]
  153. Phulmogare G. Rani S. Lodhi S. Patil U.K. Sinha S. Ajazuddin Gupta U. Fucoidan loaded PVA/Dextran blend electrospun nanofibers for the effective wound healing. Int. J. Pharm. 2024 650 123722 10.1016/j.ijpharm.2023.123722 38110012
    [Google Scholar]
  154. Lavagna S.M. Secci D. Chimenti P. Bonsignore L. Ottaviani A. Bizzarri B. Efficacy of Hypericum and Calendula oils in the epithelial reconstruction of surgical wounds in childbirth with caesarean section. Farmaco 2001 56 5-7 451 453 10.1016/S0014‑827X(01)01060‑6 11482776
    [Google Scholar]
  155. Süntar I.P. Akkol E.K. Yılmazer D. Baykal T. Kırmızıbekmez H. Alper M. Yeşilada E. Investigations on the in vivo wound healing potential of Hypericum perforatum L. J. Ethnopharmacol. 2010 127 2 468 477 10.1016/j.jep.2009.10.011 19833187
    [Google Scholar]
  156. N Oztürk. Wound-healing activity of St. John's Wort (Hypericum perforatum L.) on chicken embryonic fibroblasts. J. Ethnopharmacol. 2007 111 1 33 39
    [Google Scholar]
  157. McDonnell A.M. Dang C.H. Basic review of the cytochrome p450 system. J. Adv. Pract. Oncol. 2013 4 4 263 268 25032007
    [Google Scholar]
  158. Wanwimolruk S. Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (Part 1). EXCLI J. 2014 13 347 391 26417265
    [Google Scholar]
  159. Finnerup N.B. Kuner R. Jensen T.S. Neuropathic pain: From mechanisms to treatment. Physiol. Rev. 2021 101 1 259 301 10.1152/physrev.00045.2019 32584191
    [Google Scholar]
  160. Galeotti N. Farzad M. Bianchi E. Ghelardini C. PKC-mediated potentiation of morphine analgesia by St. John’s Wort in rodents and humans. J. Pharmacol. Sci. 2014 124 4 409 417 10.1254/jphs.13226FP 24739262
    [Google Scholar]
  161. Spiess D. Abegg V.F. Chauveau A. Rath J. Treyer A. Reinehr M. Kuoni S. Oufir M. Potterat O. Hamburger M. Simões-Wüst A.P. Transplacental passage of hyperforin, hypericin, and valerenic acid. Front. Pharmacol. 2023 14 1123194 10.3389/fphar.2023.1123194 37063288
    [Google Scholar]
  162. Campos L.V. Vieira V.A. Silva L.R. Jasmin J. Guerra M.O. Peters V.M. Sá R.C.S. Rats treated with Hypericum perforatum during pregnancy generate offspring with behavioral changes in adulthood. Rev. Bras. Farmacogn. 2017 27 3 361 368 10.1016/j.bjp.2017.01.004
    [Google Scholar]
  163. Jendželovská Z. Jendželovský R. Kuchárová B. Fedoročko P. Hypericin in the light and in the dark: Two sides of the same coin. Front. Plant Sci. 2016 7 560 10.3389/fpls.2016.00560 27200034
    [Google Scholar]
  164. Sørensen M.G. Karsdal M.A. Dziegiel M.H. Boutin J.A. Nosjean O. Henriksen K. Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption. BMC Musculoskelet. Disord. 2010 11 1 250 10.1186/1471‑2474‑11‑250 20977756
    [Google Scholar]
  165. Mansouri P. Mirafzal S. Najafizadeh P. Safaei-Naraghi Z. Salehi-Surmaghi M.H. Hashemian F. The impact of topical Saint John’s Wort (Hypericum perforatum) treatment on tissue tumor necrosis factor-alpha levels in plaque-type psoriasis. J. Postgrad. Med. 2017 63 4 215 220 10.4103/0022‑3859.201423 28272075
    [Google Scholar]
  166. Yan B.X. Chen X.Y. Ye L.R. Chen J.Q. Zheng M. Man X.Y. Cutaneous and systemic psoriasis: Classifications and classification for the distinction. Front. Med. 2021 8 649408 10.3389/fmed.2021.649408 34722555
    [Google Scholar]
  167. Wendelboe A.M. Raskob G.E. Global burden of thrombosis. Circ. Res. 2016 118 9 1340 1347 10.1161/CIRCRESAHA.115.306841 27126645
    [Google Scholar]
  168. Wei L.H. Chen T.R. Fang H.B. Jin Q. Zhang S.J. Hou J. Yu Y. Dou T.Y. Cao Y.F. Guo W.Z. Ge G.B. Natural constituents of St. John’s Wort inhibit the proteolytic activity of human thrombin. Int. J. Biol. Macromol. 2019 134 622 630 10.1016/j.ijbiomac.2019.04.181 31047931
    [Google Scholar]
  169. Vargason A.M. Anselmo A.C. Mitragotri S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 2021 5 9 951 967 10.1038/s41551‑021‑00698‑w 33795852
    [Google Scholar]
  170. Wu J.J. Zhang J. Xia C.Y. Ding K. Li X.X. Pan X.G. Xu J.K. He J. Zhang W.K. Hypericin: A natural anthraquinone as promising therapeutic agent. Phytomedicine 2023 111 154654 10.1016/j.phymed.2023.154654 36689857
    [Google Scholar]
  171. de Morais F.A.P. De Oliveira A.C.V. Balbinot R.B. Lazarin-Bidóia D. Ueda-Nakamura T. de Oliveira Silva S. da Silva Souza Campanholi K. da Silva Junior R.C. Gonçalves R.S. Caetano W. Nakamura C.V. Multifunctional nanoparticles as high-efficient targeted hypericin system for theranostic melanoma. Polymers 2022 15 1 179 10.3390/polym15010179 36616529
    [Google Scholar]
  172. Gao Y. Wang K. Zhang J. Duan X. Sun Q. Men K. Multifunctional nanoparticle for cancer therapy. MedComm 2023 4 1 e187 10.1002/mco2.187 36654533
    [Google Scholar]
  173. Zeisser-Labouèbe M. Lange N. Gurny R. Delie F. Hypericin-loaded nanoparticles for the photodynamic treatment of ovarian cancer. Int. J. Pharm. 2006 326 1-2 174 181 10.1016/j.ijpharm.2006.07.012 16930882
    [Google Scholar]
  174. Youssef T. Fadel M. Fahmy R. Kassab K. Evaluation of hypericin-loaded solid lipid nanoparticles: Physicochemical properties, photostability and phototoxicity. Pharm. Dev. Technol. 2012 17 2 177 186 10.3109/10837450.2010.529148 21047275
    [Google Scholar]
  175. Siciliano G. Monteduro A.G. Turco A. Primiceri E. Rizzato S. Depalo N. Curri M.L. Maruccio G. Polydopamine-coated magnetic iron oxide nanoparticles: From design to applications. Nanomaterials 2022 12 7 1145 10.3390/nano12071145 35407264
    [Google Scholar]
  176. Han X. Taratula O. Taratula O. Xu K. St Lorenz A. Moses A. Jahangiri Y. Yu G. Farsad K. Biodegradable hypericin-containing nanoparticles for necrosis targeting and fluorescence imaging. Mol. Pharm. 2020 17 5 1538 1545 10.1021/acs.molpharmaceut.9b01238 32212709
    [Google Scholar]
  177. de Morais F.A.P. Gonçalves R.S. Vilsinski B.H. de Oliveira É.L. Rocha N.L. Hioka N. Caetano W. Hypericin photodynamic activity in DPPC liposome. PART I: Biomimetism of loading, location, interactions and thermodynamic properties. J. Photochem. Photobiol. B 2019 190 118 127 10.1016/j.jphotobiol.2018.11.019 30513414
    [Google Scholar]
  178. Abu Dayyih A. Alawak M. Ayoub A.M. Amin M.U. Abu Dayyih W. Engelhardt K. Duse L. Preis E. Brüßler J. Bakowsky U. Thermosensitive liposomes encapsulating hypericin: Characterization and photodynamic efficiency. Int. J. Pharm. 2021 609 121195 10.1016/j.ijpharm.2021.121195 34673168
    [Google Scholar]
  179. Wang Y. Zhang Y. Jin M. Lv Y. Pei Z. Pei Y. A hypericin delivery system based on polydopamine coated cerium oxide nanorods for targeted photodynamic therapy. Polymers 2019 11 6 1025 10.3390/polym11061025 31185679
    [Google Scholar]
  180. Kim Y. Kim H. Kang H.W. Enhancement of gold nanorods‐assisted photothermal treatment on cancer with laser power in stepwise modulation. Lasers Surg. Med. 2022 54 6 841 850 10.1002/lsm.23549 35419820
    [Google Scholar]
  181. Galinari C.B. Conrado P.C.V. Arita G.S. Mosca V.A.B. Melo R.C. Bianchi T.P. Faria D.R. Sakita K.M. Malacarne L.C. Gonçalves R.S. Pereira P.C.S. Cesar G.B. Caetano W. de Souza M. da Silva Palácios R. Baesso M.L. Svidzinski T.I.E. Cotica É.S.K. Bonfim-Mendonça P.S. Nanoencapsulated hypericin in P-123 associated with photodynamic therapy for the treatment of dermatophytosis. J. Photochem. Photobiol. B 2021 215 112103 10.1016/j.jphotobiol.2020.112103 33383558
    [Google Scholar]
  182. Lazzara S. Militello M. Carrubba A. Napoli E. Saia S. Arbuscular mycorrhizal fungi altered the hypericin, pseudohypericin, and hyperforin content in flowers of Hypericum perforatum grown under contrasting P availability in a highly organic substrate. Mycorrhiza 2017 27 4 345 354 10.1007/s00572‑016‑0756‑6 27999964
    [Google Scholar]
  183. de Morais F.A.P. Gonçalves R.S. Vilsinski B.H. Lazarin-Bidóia D. Balbinot R.B. Tsubone T.M. Brunaldi K. Nakamura C.V. Hioka N. Caetano W. Hypericin photodynamic activity in DPPC liposomes – part II: Stability and application in melanoma B16-F10 cancer cells. Photochem. Photobiol. Sci. 2020 19 5 620 630 10.1039/c9pp00284g 32248218
    [Google Scholar]
  184. Ma H.L. Varanda L.C. Perussi J.R. Carrilho E. Hypericin-loaded oil-in-water nanoemulsion synthesized by ultrasonication process enhances photodynamic therapy efficiency. J. Photochem. Photobiol. B 2021 223 112303 10.1016/j.jphotobiol.2021.112303 34509718
    [Google Scholar]
  185. Priyadarshini M. Raj N.A.N. Green synthesis and in vitro photodynamic efficacy of hypericin: Cytotoxicity assessment on MCF-7 breast cancer cells. Photodiagn. Photodyn. Ther. 2024 50 104411 10.1016/j.pdpdt.2024.104411 39579841
    [Google Scholar]
  186. Abd-El-Azim H. Abbas H. El Sayed N. Mousa M.R. Elbardisy H.M. Zewail M. Hypericin emulsomes combined with hollow microneedles as a non-invasive photodynamic platform for rheumatoid arthritis treatment. Int. J. Pharm. 2024 653 123876 10.1016/j.ijpharm.2024.123876 38331331
    [Google Scholar]
  187. Abd-El-Azim H. Tekko I.A. Ali A. Ramadan A. Nafee N. Khalafallah N. Rahman T. Mcdaid W. Aly R.G. Vora L.K. Bell S.J. Furlong F. McCarthy H.O. Donnelly R.F. Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer. J. Control. Release 2022 348 849 869 10.1016/j.jconrel.2022.06.027 35728715
    [Google Scholar]
  188. Zimath P. Pinto S. Dias S. Rafacho A. Sarmento B. Zein nanoparticles as oral carrier for mometasone furoate delivery. Drug Deliv. Transl. Res. 2023 13 11 2948 2959 10.1007/s13346‑023‑01367‑y 37208563
    [Google Scholar]
  189. Abdelsalam A.M. Somaida A. Ambreen G. Ayoub A.M. Tariq I. Engelhardt K. Garidel P. Fawaz I. Amin M.U. Wojcik M. Bakowsky U. Surface tailored zein as a novel delivery system for hypericin: Application in photodynamic therapy. Mater. Sci. Eng. C 2021 129 112420 10.1016/j.msec.2021.112420 34579929
    [Google Scholar]
  190. Meruelo D. Lavie G. Lavie D. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin. Proc. Natl. Acad. Sci. USA 1988 85 14 5230 5234 10.1073/pnas.85.14.5230 2839837
    [Google Scholar]
  191. Odabas M.S. Kayhan G. Ergun E. Senyer N. Using artificial neural network and multiple linear regression for predicting the chlorophyll concentration index of Saint John’s wort leaves. Commun. Soil Sci. Plant Anal. 2016 47 2 237 245 10.1080/00103624.2015.1104342
    [Google Scholar]
  192. Wurglics M. Westerhoff K. Kaunzinger A. Wilke A. Baumeister A. Dressman J. Schubert-Zsilavecz M. Comparison of German St. John’s wort products according to hyperforin and total hypericin content. J. Am. Pharm. Assoc. 2001 41 4 560 566 10.1016/S1086‑5802(16)31280‑3 11486982
    [Google Scholar]
  193. Schwarz D. Kisselev P. Roots I. St. John’s wort extracts and some of their constituents potently inhibit ultimate carcinogen formation from benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1. Cancer Res. 2003 63 22 8062 8068 14633740
    [Google Scholar]
  194. Mannel M. Drug interactions with St John’s wort : Mechanisms and clinical implications. Drug Saf. 2004 27 11 773 797 10.2165/00002018‑200427110‑00003 15350151
    [Google Scholar]
  195. Fornal C. Metzler C.W. Mirescu C. Stein S.K. Jacobs B.L. Effects of standardized extracts of St. John’s wort on the single-unit activity of serotonergic dorsal Raphe neurons in awake cats: Comparisons with fluoxetine and sertraline. Neuropsychopharmacology 2001 25 6 858 870 10.1016/S0893‑133X(01)00297‑4 11750179
    [Google Scholar]
  196. Adams J. Steel A. Broom A. Frawley J. Women’s health and complementary and integrative medicine. Routledge London 2019
    [Google Scholar]
  197. Adams J. Steel A. Broom A. Frawley J. Women’s health and complementary and integrative medicine. Routledge London 2019
    [Google Scholar]
  198. Costache I.I. Miron A. Hăncianu M. Aursulesei V. Costache A.D. Aprotosoaie A.C. Pharmacokinetic interactions between cardiovascular medicines and plant products. Cardiovasc. Ther. 2019 2019 1 1 19 10.1155/2019/9402781 32089733
    [Google Scholar]
  199. Nobakht S.Z. Akaberi M. Mohammadpour A.H. Tafazoli Moghadam A. Emami S.A. Hypericum perforatum: Traditional uses, clinical trials, and drug interactions. Iran. J. Basic Med. Sci. 2022 25 9 1045 1058 36246064
    [Google Scholar]
  200. Rook A.H. Wood G.S. Duvic M. Vonderheid E.C. Tobia A. Cabana B. A phase II placebo-controlled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. J. Am. Acad. Dermatol. 2010 63 6 984 990 10.1016/j.jaad.2010.02.039 20889234
    [Google Scholar]
  201. Tatsis EC Exarchou V Troganis AN Gerothanassis IP 1H NMR determination of hypericin and pseudohypericin in complex natural mixtures by the use of strongly deshielded OH groups. Anal. Chim. Acta 2008 607 2 219 226
    [Google Scholar]
  202. Williamson E.M. Drug interactions between herbal and prescription medicines. Drug Saf. 2003 26 15 1075 1092 10.2165/00002018‑200326150‑00002 14640772
    [Google Scholar]
  203. Delcanale P. Uriati E. Mariangeli M. Mussini A. Moreno A. Lelli D. Cavanna L. Bianchini P. Diaspro A. Abbruzzetti S. Viappiani C. The interaction of hypericin with SARS-CoV-2 reveals a multimodal antiviral activity. ACS Appl. Mater. Interfaces 2022 14 12 14025 14032 10.1021/acsami.1c22439 35302731
    [Google Scholar]
  204. Waqar M.A. Zaman M. Hameed H. Jamshaid M. Irfan A. Shazly G.A. Paiva-Santos A.C. Bin Jardan Y.A. Formulation, characterization, and evaluation of β-Cyclodextrin functionalized hypericin loaded nanocarriers. ACS Omega 2023 8 41 38191 38203 10.1021/acsomega.3c04444 37867680
    [Google Scholar]
  205. Galinari C.B. Biachi T.P. Gonçalves R.S. Cesar G.B. Bergmann E.V. Malacarne L.C. Kioshima Cotica É.S. Bonfim-Mendonça P.S. Svidzinski T.I.E. Photoactivity of hypericin: From natural product to antifungal application. Crit. Rev. Microbiol. 2023 49 1 38 56 10.1080/1040841X.2022.2036100 35171731
    [Google Scholar]
  206. Taşkonak B. Aylaz G. Andac M. Güven E. Ozkahraman B. Perçin I. Kılıç Süloğlu A. Hypericin-loaded chitosan nanoparticles for enhanced photodynamic therapy in A549 lung cancer cells. Bionanoscience 2023 13 2 352 364 10.1007/s12668‑023‑01099‑w
    [Google Scholar]
  207. Buľková V. Vargová J. Babinčák M. Jendželovský R. Zdráhal Z. Roudnický P. Košuth J. Fedoročko P. New findings on the action of hypericin in hypoxic cancer cells with a focus on the modulation of side population cells. Biomed. Pharmacother. 2023 163 114829 10.1016/j.biopha.2023.114829 37146419
    [Google Scholar]
  208. Olek M. Machorowska-Pieniążek A. Czuba Z.P. Cieślar G. Kawczyk-Krupka A. Immunomodulatory effect of hypericin-mediated photodynamic therapy on oral cancer cells. Pharmaceutics 2023 16 1 42 10.3390/pharmaceutics16010042 38258051
    [Google Scholar]
  209. Woźniak M. Nowak-Perlak M. Hypericin-based photodynamic therapy displays higher selectivity and phototoxicity towards melanoma and squamous cell cancer compared to normal keratinocytes in vitro. Int. J. Mol. Sci. 2023 24 23 16897 10.3390/ijms242316897 38069219
    [Google Scholar]
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