Biological activity of Hypericum perforatum L. (Hypericaceae): a review

Cover Page

Cite item

Full Text

Abstract

Hypericum perforatum L. (St. John’s wort) is a medicinal plant that has been intensively studied by clinicians, pharmacologists, and chemists. It has resulted in the publication of both original articles and a number of reviews devoted to the general spectrum of the biological activity of its extracts and the separate chemical components of this species. Unlike many other known medicinal plants, the pharmacological study of which is accompanied by the establishment of new (or rediscovered) structures of chemical compounds, the dynamics of the present study of H. perforatum is mostly associated with a detailed study of the mechanisms of its therapeutic effect and less with the search for new components.

The aim of this work is to review and analyze the data on the biological activity of extracts and individual compounds of Hypericum perforatum L. (Hypericaceae), or St. John’s wort, published in the scientific literature over the past 10 years.

Materials and methods. To collect and analyze the information, such electronic databases as PubMed, Scopus, Web of Science, Google Scholar, and other available resources have been used. The following keywords and word combinations were used for search in the databases for 2010–2020: “Hypericum perforatum”, “St. John’s wort”, “the biological activity of St. John’s wort”, “hypericin”, “hyperforin”.

Results. The review provides information on antidepressant, neuroprotective, nootropic, anxiolytic activity, antibacterial, cytotoxic, anti-inflammatory properties, analgesic, hypoglycaemic effects, and other types of activity of H. perforatum extracts, as well as individual compounds (hypericin, hyperforin, amentoflavone, and others) isolated from this species. It is well known that the secondary metabolites of St. John’s wort are naphthodianthrons, flavonoids and other phenolic compounds, several classes of lipophilic substances including phloroglucinol derivatives and terpenoids. Apart from extracts and their fractions, the biological activity of photoreactive naphthodianthrone hypericin and hyperforin (a phloroglucinol derivative) has been studied in detail.

This review provides an analysis of published data from 2010 to 2020 on the biological activity of St. John’s wort. At the present time H. perforatum is primarily well-known for its antidepressant-like properties, which are confirmed by numerous pharmacological studies and clinical trials. Still there is no consensus on the effective treatment of severe or even moderate depression with St. John’s wort. This review also provides information on the neuroprotective, nootropic, antiepileptic, anxiolytic, antimicrobial, antiviral, antiprotozoal, antitumor, cytotoxic, analgesic, anti-inflammatory and other effects of H. perforatum extracts, as well as its individual compounds.

Conclusion. Despite the popularity of H. perforatum as a plant with an antidepressant-like activity, intensive research work continues to be carried out to elucidate the molecular mechanisms of the actions of extracts and individual compounds in disorders of the nervous system. Studying its antibacterial, antiviral, and cytotoxic activity may also open up some great prospects, along with determining the possibility of using St. John’s wort in metabolic disorders, genitourinary disorders, and other fields of medicine.

About the authors

Andrey L. Budantsev

Komarov Botanical Institute of the Russian Academy of Sciences

Author for correspondence.
Email: abudantsev@mail.ru
ORCID iD: 0000-0002-8916-7450

Doctor of Sciences (Biology), Professor, the Head of the Department of Plant Resources

Russian Federation, 2, Prof. Popov St., St. Petersburg, 197376

Veronika A. Prikhodko

Saint Petersburg State Chemical and Pharmaceutical University

Email: veronika.prikhodko@pharminnotech.com
ORCID iD: 0000-0002-4690-1811

Post-graduate student at the Department of Pharmacology and Clinical Pharmacology

Russian Federation, 14, Prof. Popov St., St. Petersburg, 197376

Irina V. Varganova

Komarov Botanical Institute of the Russian Academy of Sciences

Email: varganova_irina@mail.ru
ORCID iD: 0000-0002-5054-6410

Researcher of the Department of Plant Resources

Russian Federation, 2, Prof. Popov St., St. Petersburg, 197376

Sergey V. Okovityi

Saint Petersburg State Chemical and Pharmaceutical University

Email: Sergey.Okovity@pharminnotech.com
ORCID iD: 0000-0003-4294-5531

Doctor of Sciences (Medicine), Professor, the Head of the Department of Pharmacology and Clinical Pharmacology

Russian Federation, 14, Prof. Popov St., St. Petersburg, 197376

References

  1. Istikoglou CI, Mavreas V, Geroulanos G. History and therapeutic properties of Hypericum perforatum from antiquity until today. Psychiatriki. 2010; 21(4): 332–338.
  2. Klemow KM, Bartlow A, Crawford J, Kocher N, Shah J, Ritsick M. Medical Attributes of St. John’s Wort (Hypericum perforatum). In: Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2011. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis.
  3. Russo E, Scicchitano F, Whalley BJ, 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. doi: 10.1002/ptr.5050.
  4. Wölfle U, Seelinger G, Schempp CM. Topical application of St. John’s wort (Hypericum perforatum). Planta Med. 2014; 80(2–3): 109–120. doi: 10.1055/s-0033-1351019.
  5. Marrelli M, Statti G, Conforti F. Hypericum spp.: An update on the biological activities and metabolic profiles. Mini Rev. Med. Chem. 2020; 20(1): 66–87. doi: 10.2174/1389557519666190926120211.
  6. Nahrstedt A, Butterweck V. Lessons learned from herbal medicinal products: the example of St. John’s wort. J. Nat. Prod. 2010; 73(5): 1015–1021. doi: 10.1021/np1000329.
  7. Jakobs D, Hage-Hülsmann A, Prenner L, Kolb C, Weiser D, Häberlein H. Downregulation of β1-adrenergic receptors in rat C6 glioblastoma cells by hyperforin and hyperoside from St John’s wort. J. Pharm. Pharmacol. 2013; 65(6): 907–915. doi: 10.1111/jphp.12050.
  8. Tian J, Zhang F, Cheng J, Guo S, Liu P, Wang H. Antidepressant-like activity of adhyperforin, a novel constituent of Hypericum perforatum L. Sci. Rep. 2014; 4: 5632. doi: 10.1038/srep05632.
  9. Friedland K, Harteneck C. Hyperforin: To be or not to be an activator of TRPC(6). Rev. Physiol. Biochem. Pharmacol. 2015; 169: 1–24. doi: 10.1007/112_2015_25.
  10. Oliveira AI, Pinho C, Sarmento B, Dias ACP. Neuroprotective activity of Hypericum perforatum and its major components. Front. Plant Sci. 2016; 7: 1004. doi: 10.3389/fpls.2016.01004.
  11. Schmidt M, Butterweck V. The mechanisms of action of St. John’s wort: an update. Wiener Medizinische Wochenschrift. 2015; 165(11–12): 229–235. doi: 10.1007/s10354-015-0372-7.
  12. Zhai X, Chen F, Chen C, Zhu C, Lu Y. LC-MS/MS based studies on the anti-depressant effect of hypericin in the chronic unpredictable mild stress rat model. J. Ethnopharmacol. 2015; 169: 363–369. doi: 10.1016/j.jep.2015.04.053.
  13. Pochwat B, Szewczyk B, Kotarska K, Rafało-Ulińska A, Siwiec M, Sowa JE, Tokarski K, Siwek A, Bouron A, Friedland K, Nowak G. Hyperforin potentiates antidepressant-like activity of lanicemine in mice. Front. Mol. Neurosci. 2018; 11: 456. doi: 10.3389/fnmol.2018.00456.
  14. Bukhari IA, Dar A. Behavioral profile of Hypericum perforatum (St. John’s Wort) extract. A comparison with standard antidepressants in animal models of depression. Eur. Rev. Med. Pharmacol. Sci. 2013; 17(8): 1082–1089. doi: 10.1111/bpa.12069.
  15. Apaydin EA, Maher AR, Shanman R, Booth MS, Miles JNV, Sorbero ME, Hempel S. A systematic review of St. John’s wort for major depressive disorder. Syst. Rev. 2016; 5(1): 148. doi: 10.1186/s13643-016-0325-2.
  16. Ng QX., Venkatanarayanan N, Ho CYX. Clinical use of Hypericum perforatum (St John’s wort) in depression: a meta-analysis. J. Affect. Disord. 2017; 210: 211–221. doi: 10.1016/j.jad.2016.12.048.
  17. Sarris J. St. John’s wort for the treatment of psychiatric disorders. Psychiatr. Clin. 2013; 36(1): 65–72. doi: 10.1016/j.psc.2013.01.004.
  18. Zirak N, Shafiee M, Soltani G, Mirzaei M, Sahebkar A. Hypericum perforatum in the treatment of psychiatric and neurodegenerative disorders: Current evidence and potential mechanisms of action. J. Cell. Physiol. 2019; 234(6): 8496–8508. doi: 10.1002/jcp.27781.
  19. Bitran S, Farabaugh AH, Ameral VE, LaRocca RA, Clain AJ, Fava M, Mischoulon D. Do early changes in the HAM-D-17 anxiety/somatization factor items affect treatment outcome among depressed outpatients? Comparison of two controlled trials of St John’s Wort (Hypericum perforatum) versus an SSRI. Int. Clin. Psychopharmacol. 2011; 26(4): 206–212. doi: 10.1097/YIC.0b013e328343ba08.
  20. Kasper S, Caraci F, Forti B, Drago F, Aguglia E. Efficacy and tolerability of Hypericum extract for the treatment of mild to moderate depression. Eur. Neuropsychopharmacol. 2010; 20(11): 747–765. doi: 10.1016/j.euroneuro.2010.07.005.
  21. Gastpar M. Hypericum extract WS® 5570 for depression — An overview. Int. J. Psychiatry Clin. Pract. 2013; 17. Suppl. 1: 1–7. doi: 10.3109/13651501.2013.813554.
  22. Cipriani A, Purgato M, Furukawa TA, Trespidi C, Imperadore G, Signoretti A, Churchill R, Watanabe N, Barbui C. Citalopram versus other antidepressive agents for depression. Cochrane Database Syst. Rev. 2012; 7. CD006534. doi: 10.1002/14651858.CD006534.pub2.
  23. Seifritz E, Hatzinger M, Holsboer-Trachsler E. Efficacy of Hypericum extract WS® 5570 compared with paroxetine in patients with a moderate major depressive episode — a subgroup analysis. Int. J. Psychiatry Clin. Pract. 2016; 20(3): 126–132. doi: 10.1080/13651501.2016.1179765.
  24. Pierro F di, Risso P, Settembre R. Role in depression of a multi-fractionated versus a conventional Hypericum perforatum extract. Panminerva Medica. 2018; 60(4): 156–160. doi: 10.23736/S0031-0808.18.03518-8.
  25. Grobler AC, Matthews G, Molenberghs G. The impact of missing data on clinical trials: a re-analysis of a placebo controlled trial of Hypericum perforatum (St Johns wort) and sertraline in major depressive disorder. Psychopharmacology. 2014; 231(9): 1987–1999. doi: 10.1007/s00213-013-3344-x.
  26. Purgato M, Papola D, Gastaldon C, Trespidi C, Magni LR, Rizzo C, Furukawa TA, Watanabe N, Cipriani A, Barbui C. Paroxetine versus other antidepressive agents for depression. Cochrane Database Syst. Rev. 2014; 4: CD006531. doi: 10.1002/14651858.CD006531.pub2.
  27. Melzer J, Brignoli R, Keck ME, Saller R. A Hypericum extract in the treatment of depressive symptoms in outpatients: an open study. Forschende Komplementärmedizin. 2010; 17(1): 7–14. doi: 10.1159/000277628.
  28. Maher AR, Hempel S, Apaydin E, Shanman RM, Booth M, Miles JN, Sorbero ME. St. John’s Wort for Major Depressive Disorder: A Systematic Review. Rand Health Q. 2016;5(4):12.
  29. Ferrara M, Mungai F, Starace F. St John’s wort (Hypericum perforatum)-induced psychosis: a case report. J. Med. Case Rep. 2017;11(1): 137. doi: 10.1186/s13256-017-1302-7.
  30. Jungke P, Ostrow G, Li J-L, Norton S, Nieber K, Kelber O, Butterweck V. Profiling of hypothalamic and hippocampal gene expression in chronically stressed rats treated with St. John’s wort extract (STW 3-VI) and fluoxetine. Psychopharmacology. 2011; 213(4): 757–772. doi: 10.1007/s00213-010-2032-3.
  31. Herraiz T, Guillén H. Monoamine Oxidase-A Inhibition and Associated Antioxidant Activity in Plant Extracts with Potential Antidepressant Actions. BioMed Res. Int. 2018; 2018: 4810394. doi: 10.1155/2018/4810394.
  32. Wang Y, Shi X, Qi Z. Hypericin prolongs action potential duration in hippocampal neurons by acting on K+ channels. Brit. J. Pharmacol. 2010; 159(7): 1402–1407. doi: 10.1111/j.1476-5381.2009.00513.x.
  33. Vance KM, Ribnicky DM, Hermann GE, Rogers RC. St. John’s Wort enhances the synaptic activity of the nucleus of the solitary tract. Nutrition. 2014; 30(7–8): S37–S42. doi: 10.1016/j.nut.2014.02.008.
  34. Sell TS, Belkacemi T, Flockerzi V, Beck A. Protonophore properties of hyperforin are essential for its pharmacological activity. Sci. Rep. 2014; 4: 7500. doi: 10.1038/srep07500.
  35. Bonaterra GA, Schwendler A, Hüther J, Schwarzbach H, Schwarz A, Kolb C, Abdel-Aziz H, Kinscherf R. Neurotrophic, cytoprotective, and anti-inflammatory effects of St. John’s wort extract on differentiated mouse hippocampal HT-22 neurons. Front. Pharmacol. 2018; 8: 955. doi: 10.3389/fphar.2017.00955.
  36. Zou Y-P, Lu Y-H, Wei D-Z. Protective effects of a flavonoid-rich extract of Hypericum perforatum L. against hydrogen peroxide-induced apoptosis in PC12 cells. Phytother. Res. 2010; 24. Suppl. 1: S6–S10. doi: 10.1002/ptr.2852.
  37. Keksel N, Bussmann H, Unger M, Drewe J, Boonen G, Häberlein H, Franken S. St John’s wort extract influences membrane fluidity and composition of phosphatidylcholine and phosphatidylethanolamine in rat C6 glioblastoma cells. Phytomedicine. 2019; 54: 66–76. doi: 10.1016/j.phymed.2018.06.013.
  38. Altun ML., Yılmaz BS., Orhan IE., Citoglu GS. Assessment of cholinesterase and tyrosinase inhibitory and antioxidant effects of Hypericum perforatum L. (St. John’s wort). Industr. Crops Prod. 2013; 43: 87–92. doi: 10.1016/j.indcrop.2012.07.017.
  39. Nazıroğlu M, Kutluhan S, Övey İS, Aykur M, Yurekli VA. Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum. Nutrit. Neurosci. 2014; 17(5): 214–221. doi: 10.1179/1476830513Y.0000000083.
  40. Nazıroğlu M, Çiğ B, Özgül C. Modulation of oxidative stress and Ca2+ mobilization through TRPM2 channels in rat dorsal root ganglion neuron by Hypericum perforatum. Neuroscience. 2014; 263: 27–35. doi: 10.1016/j.neuroscience.2014.01.006.
  41. Özdemir ÜS, Nazıroğlu M, Şenol N, Ghazizadeh V. Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol. Neurobiol. 2016; 53(6): 3540–3551. doi: 10.1007/s12035-015-9292-1.
  42. Gómez del Río MA, Sánchez-Reus MI, Iglesias I, Pozo MA, García-Arencibia M, Fernández-Ruiz J, García-García L, Delgado M, Benedí J. Neuroprotective properties of standardized extracts of Hypericum perforatum on rotenone model of Parkinson’s disease. CNS Neurolog. Disord.-Drug Targ. 2013; 12(5): 665–679. doi: 10.2174/1871527311312050013.
  43. Kiasalari Z, Baluchnejadmojarad T, Roghani M. Hypericum perforatum hydroalcoholic extract mitigates motor dysfunction and is neuroprotective in intrastriatal 6-hydroxydopamine rat model of Parkinson’s disease. Cell. Mol. Neurobiol. 2016; 36(4): 521–530. doi: 10.1007/s10571-015-0230-6.
  44. Nosratabadi R, Rastin M, Sankian M, Haghmorad D, Tabasi N, Zamani S, Aghaee A, Salehipour Z, Mahmoudi M. St. John’s wort and its component hyperforin alleviate experimental autoimmune encephalomyelitis through expansion of regulatory T-cells. J. Immunotoxicol. 2016; 13(3): 364–374. doi: 10.3109/1547691X.2015.1101512.
  45. Selek Ş, Eşrefoğlu M, Meral I, Bulut H, Caglar HG, Sonuc G, Yildiz C, Teloglu ES, Dogan N, Yuce B, Tiftik E, Bayındır N. Effects of Oenothera biennis L. and Hypericum perforatum L. extracts on some central nervous system myelin proteins, brain histopathology and oxidative stress in mice with experimental autoimmune encephalomyelitis. Biotech. Histochem. 2019; 94(2): 75–83. doi: 10.1080/10520295.2018.1482001.
  46. Cinci L, Cesare Mannelli L di, Maidecchi A, Mattoli L, Ghelardini C. Effects of Hypericum perforatum extract on oxaliplatin-induced neurotoxicity: in vitro evaluations. Zeitschr. Naturforsch., C: Biosci. 2017; 72(5–6): 219–226. doi: 10.1515/znc-2016-0194.
  47. Valvassori SS, Borges C, Bavaresco DV, Varela RB, Resende WR, Peterle BR, Arent CO, Budni J, Quevedo J. Hypericum perforatum chronic treatment affects cognitive parameters and brain neurotrophic factor levels. Brazil. J. Psychiatry. 2018; 40(4): 367–375. doi: 10.1590/1516-4446-2017-2271.
  48. Leuner K, Li W, Amaral MD, Rudolph S, Calfa G, Schuwald AN, Harteneck C, Inoue T, Pozzo-Miller L. Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+-permeable TRPC6 channels. Hippocampus. 2013; 23(1): 40–52. doi: 10.1002/hipo.22052.
  49. Ampuero E, Rubio FJ, Falcon R, Sandoval M, Díaz-Véliz G, González RE, Earle N, Dagnino-Subiabre A, Aboitiz F, Orrego F, Wyneken U. Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neurosci. 2010; 169(1): 98–108.
  50. Marchetti C, Tafi E, Middei S, Rubinacci MA, Restivo L, Ammassari-Teule M, Marie H. Synaptic adaptations of CA1 pyramidal neurons induced by a highly effective combinational antidepressant therapy. Biol. Psychiatry. 2010; 67(2): 146–154. doi: 10.1016/j.biopsych.2009.09.017.
  51. Heiser JH, Schuwald AM, Sillani G, Ye L, Müller WE, Leuner K. TRPC 6 channel-mediated neurite outgrowth in PC 12 cells and hippocampal neurons involves activation of RAS/MEK/ERK, PI 3K, and CAMKIV signaling. J. Neurochem. 2013; 127(3): 303–313.
  52. Jin N, Qian W, Yin X, Zhang L, Iqbal K, Grundke-Iqbal I, Gong C-X, Liu F. CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer’s disease. Nucl. Acids Res. 2013; 41(5): 3240–3256. doi: 10.1093/nar/gks1227.
  53. Teich AF, Nicholls RE, Puzzo D, Fiorito J, Purgatorio R, Fà M, Ottavio A. Synaptic therapy in Alzheimer’s disease: a CREB-centric approach. Neurotherapeutics. 2015; 12(1): 29–41.
  54. Bartolotti N, Bennett DA, Lazarov O. Reduced pCREB in Alzheimer’s disease prefrontal cortex is reflected in peripheral blood mononuclear cells. Mol. Psychiatry. 2016; 21(9): 1158–1166. doi: 10.1038/mp.2016.111.
  55. Hofrichter J, Krohn M, Schumacher T, Lange C, Feistel B, Walbroel B, Heinze HJ, Crockett S, Scharbel TF, Pahnke J. Reduced Alzheimer’s disease pathology by St. John’s Wort treatment is independent of hyperforin and facilitated by ABCC1 and microglia activation in mice. Current Alzheimer Res. 2013; 10(10): 1057–1069. doi: 10.2174/15672050113106660171.
  56. Wang H, Shao B, Yu H, Xu F, Wang P, Yu K, Han Y, Song M, Li Y, Cao Z. Neuroprotective role of hyperforin on aluminum maltolate-induced oxidative damage and apoptosis in PC12 cells and SH-SY5Y cells. Chem.-Biol. Interact. 2019; 299: 15–26. doi: 10.1016/j.cbi.2018.11.016.
  57. Gibon J, Deloulme J-C, Chevallier T, Ladevèze E, Abrous DN, Bouron A. The antidepressant hyperforin increases the phosphorylation of CREB and the expression of TrkB in a tissue-specific manner. Int. J. Neuropsychopharm. 2013; 16(1): 189–198. doi: 10.1017/S146114571100188X.
  58. Brenn A, Grube M, Jedlitschky G, Fischer A, Strohmeier B, Eiden M, Keller M, Groschup MH, Vogelgesang S. St. John’s wort reduces beta-amyloid accumulation in a double transgenic Alzheimer’s disease mouse model – role of P-glycoprotein. Brain Pathol. 2014; 24(1): 18–24. doi: 10.1111/bpa.12069.
  59. Ott M, Huls M, Cornelius MG, Fricker G. St. John’s Wort constituents modulate P-glycoprotein transport activity at the blood-brain barrier. Pharmaceut. Res. 2010; 27(5): 811–822. doi: 10.1007/s11095-010-0074-1.
  60. Cao Z, Wang F, Xiu C, Zhang J, Li Y. Hypericum perforatum extract attenuates behavioral, biochemical, and neurochemical abnormalities in aluminum chloride-induced Alzheimer’s disease rats. Biomed. Pharmacotherapy. 2017; 91: 931–937. doi: 10.1016/j.biopha.2017.05.022.
  61. Uslusoy F, Nazıroğlu M, Övey İS, Sönmez TT. Hypericum perforatum L. supplementation protects sciatic nerve injury-induced apoptotic, inflammatory and oxidative damage to muscle, blood and brain in rats. J. Pharm. Pharmacol. 2019; 71(1): 83–92. doi: 10.1111/jphp.12741.
  62. Lin Y, Zhang J-C, Fu J, Chen F, Wang J, Wu Z-L, Yuan S-Y. Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation. J. Cereb. Blood Flow Metabol. 2013; 33(2): 253–262. doi: 10.1038/jcbfm.2012.164.
  63. Chang Y, Wang SJ. Hypericin, the active component of St. John’s wort, inhibits glutamate release in the rat cerebrocortical synaptosomes via a mitogen-activated protein kinase-dependent pathway. Eur. J. Pharmacol. 2010; 634(1–3): 53–61. doi: 10.1016/j.ejphar.2010.02.035.
  64. Ouyang Z, Zhai Z, Li H, Liu X, Qu X, Li X, Fan Q, Tang T, Qin A, Dai K. Hypericin suppresses osteoclast formation and wear particle-induced osteolysis via modulating ERK signalling pathway. Biochem. Pharmacol. 2014; 90(3): 276–287. doi: 10.1016/j.bcp.2014.06.009.
  65. Do MH, Kim SY. Hypericin, a naphthodianthrone derivative, prevents methylglyoxal-induced human endothelial cell dysfunction. Biomol. Therap. 2017; 25(2): 158–164. doi: 10.4062/biomolther.2016.034.
  66. Jeong EJ, Hwang L, Lee M, Lee KY, Ahn M-J, Sung S-H. Neuroprotective biflavonoids of Chamaecyparis obtusa leaves against glutamate-induced oxidative stress in HT22 hippocampal cells. Food Chem. Toxicol. 2014; 64: 397–402. doi: 10.1016/j.fct.2013.12.003.
  67. Ishola IO, Tota S, Adeyemi OO, Agbaje EO, Narender T, Shukla R. Protective effect of Cnestis ferruginea and its active constituent on scopolamine-induced memory impairment in mice: a behavioral and biochemical study. Pharmaceut. Biol. 2013; 51(7): 825-835. doi: 10.3109/13880209.2013.767360.
  68. Ben-Eliezer D, Yechiam E. Hypericum perforatum as a cognitive enhancer in rodents: A meta-analysis. Sci. Reports. 2016; 6: 35700. doi: 10.1038/srep35700.
  69. Gong S, Miao Y-L, Jiao G-Z, Sun MJ, Li H, Lin J, Luo MJ, Tan JH. Dynamics and correlation of serum cortisol and corticosterone under different physiological or stressful conditions in mice. PLoS One. 2015; 10(2): e0117503. doi: 10.1371/journal.pone.0117503.
  70. El-Bakly WM, Hasanin AH. Hypericum perforatum decreased hippocampus TNF-α and corticosterone levels with no effect on kynurenine/tryptophan ratio in bilateral ovariectomized rats. Korean J. Physiol. Pharmacol. 2014; 18(3): 233–239. doi: 10.4196/kjpp.2014.18.3.233.
  71. Kumar A, Garg R, Prakash AK. Effect of St. John’s Wort (Hypericum perforatum) treatment on restraint stress-induced behavioral and biochemical alteration in mice. BMC Complement. Altern. Med. 2010; 10(1): 18. doi: 10.1186/1472-6882-10-18.
  72. Prakash DJ, Arulkumar S, Sabesan M. Effect of nanohypericum (Hypericum perforatum gold nanoparticles) treatment on restraint stressinduced behavioral and biochemical alteration in male albino mice. Pharmacogn. Res. 2010; 2(6): 330–334. doi: 10.4103/0974-8490.75450.
  73. Hasanein P, Shahidi S. Effects of Hypericum perforatum extract on diabetes-induced learning and memory impairment in rats. Phytother. Res. 2011; 25(4): 544–549. doi: 10.1002/ptr.3298.
  74. Crupi R, Mazzon E, Marino A, La Spada G, Bramanti P, Battaglia F, Cuzzocrea S, Spina E. Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice. BMC Complement. Alternat. Med. 2011; 11(1): 7. doi: 10.1186/1472-6882-11-7.
  75. Trofimiuk E, Holownia A, Braszko JJ. St. John’s wort may relieve negative effects of stress on spatial working memory by changing synaptic plasticity. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2011; 383(4): 415–422. doi: 10.1007/s00210-011-0604-3.
  76. Concerto C, Boo H, Hu C, Sandilya P, Krish A, Chusid E, Coira D, Aguglia E, Battaglia F. Hypericum perforatum extract modulates cortical plasticity in humans. Psychopharmacology. 2018; 235(1): 145–153. doi: 10.1007/s00213-017-4751-1.
  77. Yechiam E, Ben-Eliezer D, Ashby NJS, Bar-Shaked M. The acute effect of Hypericum perforatum on short-term memory in healthy adults. Psychopharmacol. 2019; 236(2): 613–623. doi: 10.1007/s00213-018-5088-0.
  78. Niederhofer H. St John’s Wort treating patients with autistic disorder. Phytother. Res. 2009; 23(11): 1521–1523. doi: 10.1002/ptr.2580.
  79. Diniz TC, Silva JC, de Lima-Saraiva SRG, Ribeiro FPR de A, Pacheco AGM, de Freitas RMQuintans-Júnior LJ, Quintans J de SS, Mendes RL., Almeida JRG da S. The role of flavonoids on oxidative stress in epilepsy. Oxidat. Med. Cell. Longev. 2015. doi: 10.1155/2015/171756.
  80. Zhang Z, Sun T, Niu J-G, He Z-Q, Liu Y, Wang F. Amentoflavone protects hippocampal neurons: anti-inflammatory, antioxidative, and antiapoptotic effects. Neural Regenerat. Res. 2015;10(7):1125. doi: 10.4103/1673-5374.160109.
  81. Rong S, Wan D, Fan Y, Liu S, Sun K, Huo J, Zhang P, Li X, Xie X, Wang F, Sun T. Amentoflavone affects epileptogenesis and exerts neuroprotective effects by inhibiting NLRP3 inflammasome. Front. Pharmacol. 2019; 10: 856. doi: 10.3389/fphar.2019.00856.
  82. Ivetic V, Trivic S, Pogancev MK, Popovic M, Zlinská J. Effects of St John’s wort (Hypericum perforatum L.) extracts on epileptogenesis. Molecules. 2011;16(9): 8062–8075. doi: 10.3390/molecules16098062.
  83. Etemad L, Heidari MR, Heidari M, Moshiri M, Behravan E, Abbasifard M, Azimzadeh BS. Investigation of Hypericum perforatum extract on convulsion induced by picrotoxin in mice. Pak. J. Pharmaceut. Sci. 2011; 24(2): 233–236.
  84. Ishola IO, Chatterjee M, Tota S, Tadigopulla N, Adeyemi OO, Palit G, Shukla R. Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice. Pharmacol. Biochem. Behav. 2012; 103(2): 322–331. doi: 10.1016/j.pbb.2012.08.017.
  85. Çiçek SS. Structure-dependent activity of natural GABA (A) receptor modulators. Molecules. 2018; 23(7): 1512. doi: 10.3390/molecules23071512.
  86. Husain GM, Chatterjee SS, Singh PN, Kumar V. Beneficial effect of Hypericum perforatum on depression and anxiety in a type 2 diabetic rat model. Acta Polon. Pharmaceut. 2011; 68(6): 913–918.
  87. Saddiqe Z, Naeem I, Maimoona A. A review of the antibacterial activity of Hypericum perforatum L. J. Ethnopharmacol. 2010; 131(3): 511–521. doi: 10.1016/j.jep.2010.07.034.
  88. Orhan IE, Kartal M, Gülpinar AR, Cos P, Matheeussen A, Maes L, Tasdemir D. Assessment of antimicrobial and antiprotozoal activity of the olive oil macerate samples of Hypericum perforatum and their LC-DAD-MS analyses. Food Chem. 2013; 138(2–3): 870–875. doi: 10.1016/j.foodchem.2012.11.053.
  89. Lyles JT, Kim A, Nelson K, Bullard-Roberts AL, Hajdari A, Mustafa B, Quave CL. The chemical and antibacterial evaluation of St. John’s Wort oil macerates used in Kosovar traditional medicine. Front. Microbiol. 2017; 8: 1639. doi: 10.3389/fmicb.2017.01639.
  90. Süntar I, Oyardı O, Akkol EK, Ozçelik B. Antimicrobial effect of the extracts from Hypericum perforatum against oral bacteria and biofilm formation. Pharm. Biol. 2016; 54(6): 1065–1070. doi: 10.3109/13880209.2015.1102948.
  91. Khadem Nezhad S, Taghavi Zenouz A, Aghazadeh M, Samadi Kafil H. Strong antimicrobial activity of Hypericum perforatum L. against oral isolates of Lactobacillus spp. Cell. Mol. Biol. (Noisy-le-grand, France). 2017; 63(11): 58–62. doi: 10.14715/cmb/2017.63.11.11.
  92. López-Chicón P, Paz-Cristobal MP, Rezusta A, Aspiroz C, Royo-Cañas M, Andres-Ciriano E, Gilaberte Y, Agut M, Nonell S. On the mechanism of Candida spp. photoinactivation by hypericin. Photochem. Photobiol. Sci. 2012; 11(6): 1099–1107. doi: 10.1039/c2pp25105a.
  93. Yow CM, Tang HM, Chu ES, Huang Z. Hypericin-mediated photodynamic antimicrobial effect on clinically isolated pathogens. Photochem. Photobiol. 2012; 88(3): 626–632. doi: 10.1111/j.1751-1097.2012.01085.x.
  94. Mortensen T, Shen S, Shen F, Walsh MK., Sims RC., Miller CD. Investigating the effectiveness of St John’s wort herb as an antimicrobial agent against mycobacteria. Phytother. Res. 2012; 26(9): 1327–1333. doi: 10.1002/ptr.3716.
  95. Chen H, Muhammad I, Zhang Y, Ren Y, Zhang R, Huang X, Diao L, Liu H, Li X, Sun X, Abbas G, Li G. Antiviral activity against infectious bronchitis virus and bioactive components of Hypericum perforatum L. Front. Pharmacol. 2019; 10: 1272. doi: 10.3389/fphar.2019.01272.
  96. Huang N, Singh N, Yoon K, Loiacono CM, Kohut ML, Birt DF. The immuno-regulatory impact of orally-administered Hypericum perforatum extract on Balb/C mice inoculated with H1n1 influenza A virus. PLoS One. 2013; 8(9): e76491. doi: 10.1371/journal.pone.0076491.
  97. Pu X, Liang J, Shang R, Zhou L, Wang X, Li Y. Therapeutic efficacy of Hypericum perforatum L. extract for mice infected with an influenza A virus. Can. J. Physiol. Pharmacol. 2012; 90(2): 123–130. doi: 10.1139/y11-111.
  98. Pang R, Tao J, Zhang S, Zhu J, Yue X, Zhao L, Ye P, Zhu Y. In vitro anti-hepatitis B virus effect of Hypericum perforatum L. J. Huazhong Univ. Sci. Technolog. Med. Sci. 2010; 30(1): 98–102. doi: 10.1007/s11596-010-0118-0.
  99. Brito LC, Berenger ALR, Figueiredo MR. An overview of anticancer activity of Garcinia and Hypericum. Food Chem. Toxicol. 2017; 109, Pt 2: 847–862. DOI: 0.1016/j.fct.2017.03.053.
  100. Menichini G, Alfano C, Marrelli M, Toniolo C, Provenzano E, Statti GA, Nicoletti M, Menichini F, Conforti F. Hypericum perforatum L. subsp. perforatum induces inhibition of free radicals and enhanced phototoxicity in human melanoma cells under ultraviolet light. Cell Prolif. 2013; 46(2): 193–202. doi: 10.1111/cpr.12020.
  101. Šemeláková M, Mikeš J, Jendželovský R, Fedoročko P. The pro-apoptotic and anti-invasive effects of hypericin-mediated photodynamic therapy are enhanced by hyperforin or aristoforin in HT-29 colon adenocarcinoma cells. J. Photochem. Photobiol. B. 2012; 117: 115–125. doi: 10.1016/j.jphotobiol.2012.09.003.
  102. Kleemann B, Loos B, Scriba TJ, Lang D, Davids LM. St John’s Wort (Hypericum perforatum L.) photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death. PLoS One. 2014; 9(7): e103762. doi: 10.1371/journal.pone.0103762.
  103. Yi J, Yang X, Zheng L, Yang G, Sun L, Bao Y, Wu Y, Huang Y, Yu C, Yang SN, Li Y. Photoactivation of hypericin decreases the viability of RINm5F insulinoma cells through reduction in JNK/ERK phosphorylation and elevation of caspase-9/caspase-3 cleavage and Bax-to-Bcl-2 ratio. Biosci. Rep. 2015; 35(3): pii: e00195. doi: 10.1042/BSR20150028.
  104. Sharma KV, Davids LM. Hypericin-PDT-induced rapid necrotic death in human squamous cell carcinoma cultures after multiple treatment. Cell Biol. Int. 2012; 36(12): 1261–1266. doi: 10.1042/CBI20120108.
  105. Ritz R, Scheidle C, Noell S, Roser F, Schenk M, Dietz K, Strauss WS. In vitro comparison of hypericin and 5-aminolevulinic acid-derived protoporphyrin IX for photodynamic inactivation of medulloblastoma cells. PLoS One. 2012; 7(12): e51974. doi: 10.1371/journal.pone.0051974.
  106. Kim H, Kim SW, Seok KH, Hwang CW, Ahn JC, Jin JO, Kang HW. Hypericin-assisted photodynamic therapy against anaplastic thyroid cancer. Photodiagnosis Photodyn. Ther. 2018; 24: 15–21. doi: 10.1016/j.pdpdt.2018.08.008.
  107. Valletta E, Rinaldi A, Marini M, Franzese O, Roscetti G. Distinct Hypericum perforatum L. total extracts exert different antitumour activity on erythroleukemic K562 cells. Phytother. Res. 2018; 32(9): 1803–1811. doi: 10.1002/ptr.6114.
  108. You MK, Kim HJ, Kook JH, Kim HA. St. John’s wort regulates proliferation and apoptosis in MCF-7 human breast cancer cells by inhibiting AMPK/mTOR and activating the mitochondrial pathway. Int. J. Mol. Sci. 2018; 19(4): pii: E966. doi: 10.3390/ijms19040966.
  109. Zaher M, Tang R, Bombarda I, Merhi F, Bauvois B, Billard C. Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa. Int. J. Oncol. 2012; 40(1): 269–276. doi: 10.3892/ijo.2011.1206.
  110. Mirmalek SA, Azizi MA, Jangholi E, Yadollah-Damavandi S, Javidi MA, Parsa Y, Parsa T, Salimi-Tabatabaee SA, Ghasemzadeh Kolagar H, Alizadeh-Navaei R. Cytotoxic and apoptogenic effect of hypericin, the bioactive component of Hypericum perforatum on the MCF-7 human breast cancer cell line. Cancer Cell. Int. 2017; 16: 3. doi: 10.1186/s12935-016-0279-4.
  111. Ocak Z, Acar M, Gunduz E, Gunduz M, Demircan K, Uyeturk U, Ozlü T. Effect of hypericin on the ADAMTS-9 and ADAMTS-8 gene expression in MCF7 breast cancer cells. Eur. Rev. Med. Pharmacol. Sci. 2013; 17(9): 1185–90.
  112. Merhi F, Tang R, Piedfer M, Mathieu J, Bombarda I, Zaher M, Kolb JP, Billard C, Bauvois B. Hyperforin inhibits Akt1 kinase activity and promotes caspase-mediated apoptosis involving Bad and Noxa activation in human myeloid tumor cells. PLoS One. 2011; 6(10): e25963. doi: 10.1371/journal.pone.0025963.
  113. Kıyan HT, Demirci B, Başer KH, Demirci F. The in vivo evaluation of anti-angiogenic effects of Hypericum essential oils using the chorioallantoic membrane assay. Pharm. Biol. 2014; 52(1): 44–50. doi: 10.3109/13880209.2013.810647.
  114. Raak C, Büssing A, Gassmann G, Boehm K, Ostermann T. A systematic review and meta-analysis on the use of Hypericum perforatum (St. John’s Wort) for pain conditions in dental practice. Homeopathy. 2012; 101(4): 204–210. doi: 10.1016/j.homp.2012.08.001.
  115. Melo MS de, Quintans J de S, Araújo AA., Duarte MC, Bonjardim LR, Nogueira PC, Moraes VR, de Araújo-Júnior JX, Ribeiro EA, Quintans-Júnior LJ. A systematic review for anti-inflammatory property of Clusiaceae family: a preclinical approach. Evid. Based Complement. Alternat. Med. 2014: 960258. doi: 10.1155/2014/960258.
  116. Hammer KD, Birt DF. Evidence for contributions of interactions of constituents to the anti-inflammatory activity of Hypericum perforatum. Crit. Rev. Food Sci. Nutr. 2014; 54(6): 781–789. doi: 10.1080/10408398.2011.607519.
  117. Stojanović NM, Radulović NS, Randjelović PJ, Laketić D. Antinociceptive properties of St. John’s Wort (Hypericum perforatum) and other Hypericum species. Nat. Prod. Commun. 2016; 11(11): 1741–1747.
  118. Galeotti N. Hypericum perforatum (St John’s wort) beyond depression: A therapeutic perspective for pain conditions. J. Ethnopharmacol. 2017; 200: 136–146. doi: 10.1016/j.jep.2017.02.016.
  119. Sanna MD, Ghelardini C, Galeotti N. St. John’s Wort potentiates anti-nociceptive effects of morphine in mice models of neuropathic pain. Pain Med. 2017; 18(7): 1334–1343. doi: 10.1093/pm/pnw241.
  120. Dellafiora L, Galaverna G, Cruciani G, Dall’Asta C, Bruni R. On the mechanism of action of anti-inflammatory activity of hypericin: An in silico study pointing to the relevance of Janus kinases inhibition. Molecules. 2018; 23(12). Pii: E3058. doi: 10.3390/molecules23123058.
  121. Koeberle A, Rossi A, Bauer J, Dehm F, Verotta L, Northoff H, Sautebin L, Werz O. Hyperforin, an anti-inflammatory constituent from St. John’s Wort, inhibits microsomal prostaglandin E(2) synthase-1 and suppresses prostaglandin E(2) formation in vivo. Front. Pharmacol. 2011; 2: 7. doi: 10.3389/fphar.2011.00007.
  122. Hammer KD, Yum MY, Dixon PM, Birt DF. Identification of JAK-STAT pathways as important for the anti-inflammatory activity of a Hypericum perforatum fraction and bioactive constituents in RAW 264.7 mouse macrophages. Phytochemistry. 2010. 71(7): 716–725. doi: 10.1016/j.phytochem.2010.02.006.
  123. Huang N, Rizshsky L, Hauck C, Nikolau BJ, Murphy PA, Birt DF. Identification of anti-inflammatory constituents in Hypericum perforatum and Hypericum gentianoides extracts using RAW 264.7 mouse macrophages. Phytochemistry. 2011; 72(16): 2015–2023. doi: 10.1016/j.phytochem.2011.07.016.
  124. Huang N, Rizshsky L, Hauck CC, Nikolau BJ, Murphy PA, Birt DF. The inhibition of lipopolysaccharide-induced macrophage inflammation by 4 compounds in Hypericum perforatum extract is partially dependent on the activation of SOCS3. Phytochemistry. 2012; 76: 106–116. doi: 10.1016/j.phytochem.2011.12.001.
  125. Hatano T, Sameshima Y, Kawabata M, Yamada S, Shinozuka K, Nakabayashi T, Mizuno H. St. John’s wort promotes adipocyte differentiation and modulates NF-κB activation in 3T3-L1 cells. Biol. Pharm. Bull. 2014; 37(7): 1132–1138.
  126. Samadi S, Khadivzadeh T, Emami A, Moosavi NS, Tafaghodi M, Behnam HR. The effect of Hypericum perforatum on the wound healing and scar of cesarean. J. Altern. Complement. Med. 2010; 16(1): 113–117. doi: 10.1089/acm.2009.0317.
  127. Mansouri P, Mirafzal S, Najafizadeh P, Safaei-Naraghi Z, Salehi-Surmaghi MH, Hashemian F. The impact of topical Saint John’s Wort (Hypericum perforatum) treatment on tissue tumor necrosis factor-alpha levels in plaque-type psoriasis: A pilot study. J. Postgrad. Med. 2017; 63(4): 215–220. doi: 10.4103/0022-3859.201423.
  128. Nazıroğlu M, Sahin M, Ciğ B, Aykur M, Erturan I, Ugan Y. Hypericum perforatum modulates apoptosis and calcium mobilization through voltage-gated and TRPM2 calcium channels in neutrophil of patients with Behcet’s disease. J. Membr. Biol. 2014; 247(3): 253–262. doi: 10.1007/s00232-014-9630-7.
  129. Yücel A, Kan Y, Yesilada E, Akın O. Effect of St.John’s wort (Hypericum perforatum) oily extract for the care and treatment of pressure sores; a case report. J. Ethnopharmacol. 2017; 196: 236–241. doi: 10.1016/j.jep.2016.12.030.
  130. Paterniti I, Briguglio E, Mazzon E, Galuppo M, Oteri G, Cordasco G, Cuzzocrea S. Effects of Hypericum perforatum, in a rodent model of periodontitis. BMC Complement. Altern. Med. 2010; 10: 73. doi: 10.1186/1472-6882-10-73.
  131. Süntar I, Akkol E.K., Yilmazer D., Baykal T., Kirmizibekmez H., Alper M., Yeşilada E. Investigations on the in vivo wound healing potential of Hypericum perforatum L. J. Ethnopharmacol. 2010; 127: 468–477.
  132. Prisăcaru AI, Andriţoiu CV, Andriescu C, Hăvârneanu EC, Popa M, Motoc AG, Sava A. Evaluation of the wound-healing effect of a novel Hypericum perforatum ointment in skin injury. Rom. J. Morphol. Embryol. 2013; 54(4): 1053–1059.
  133. Orhan IE, Kartal M, Gülpinar AR, Yetkin G, Orlikova B, Diederich M, Tasdemir D. Inhibitory effect of St. John’s Wort oil macerates on TNFα-induced NF-κB activation and their fatty acid composition. J. Ethnopharmacol. 2014; 155(2): 1086–1092. doi: 10.1016/j.jep.2014.06.030.
  134. Tanideh N, Namazi F, Andisheh Tadbir A, Ebrahimi H, Koohi-Hosseinabadi O. Comparative assessment of the therapeutic effects of the topical and systemic forms of Hypericum perforatum extract on induced oral mucositis in golden hamsters. Int. J. Oral Maxillofac. Surg. 2014;43(10): 1286–1292. doi: 10.1016/j.ijom.2014.05.013.
  135. Farsak M, Özdağli G, Özmüş D, Çömelekoğlu Ü, Yalın S, Bozdoğan Arpacı R, Gen R, Kanık A, Ümit Talas D. Effects of Hypericum perforatum on an experimentally induced diabetic wound in a rat model. Wounds. 2017; 29(2): E10–E17.
  136. Altan A, Aras MH, Damlar İ, Gökçe H, Özcan O, Alpaslan C. The effect of Hypericum perforatum on wound healing of oral mucosa in diabetic rats. Eur. Oral Res. 2018;52(3): 143–149. doi: 10.26650/eor.2018.505.
  137. Akay MA, Akduman M, Tataroğlu AÇ, Eraldemir C, Kum T, Vural Ç, Yıldız GE. Evaluation of the efficacy of Hypericum perforatum (St. John’s wort) oil in the prevention of stricture due to esophageal corrosive burns. Esophagus. 2019;16(4): 352–361. doi: 10.1007/s10388-019-00671-2.
  138. Yılmaz U, Kaya H, Turan M, Bir F, Şahin B. Investigation the effect of Hypericum perforatum on corneal alkali burns. Cutan. Ocul. Toxicol. 2019; 38(4): 356–359. doi: 10.1080/15569527.2019.1622560.
  139. Füller J, Müller-Goymann CC. Anti-proliferative and anti-migratory effects of hyperforin in 2D and 3D artificial constructs of human dermal fibroblasts – A new option for hypertrophic scar treatment? Eur. J. Pharm. Biopharm. 2018; 126: 108–114. doi: 10.1016/j.ejpb.2017.03.003.
  140. Sharma KV, Davids LM. Depigmentation in melanomas increases the efficacy of hypericin-mediated photodynamic-induced cell death. Photodiagnosis Photodyn. Ther. 2012; 9(2): 156–163. doi: 10.1016/j.pdpdt.2011.09.003.
  141. Arokiyaraj S, Balamurugan R, Augustian P. Antihyperglycemic effect of Hypericum perforatum ethyl acetate extract on streptozotocin-induced diabetic rats. Asian Pac. J. Trop. Biomed. 2011; 1(5): 386–390. doi: 10.1016/S2221-1691(11)60085-3.
  142. Can ÖD, Öztürk Y, Öztürk N, Sagratini G, Ricciutelli M, Vittori S, Maggi F. Effects of treatment with St. John’s Wort on blood glucose levels and pain perceptions of streptozotocin-diabetic rats. Fitoterapia. 2011; 82(4): 576–584. doi: 10.1016/j.fitote.2011.01.008.
  143. You MK, Rhuy J, Jeong KS, Bang MA, Kim MS, Kim HA. Effect of St. John’s Wort (Hypericum perforatum) on obesity, lipid metabolism and uterine epithelial proliferation in ovariectomized rats. Nutr. Res. Pract. 2014; 8(3): 292–296. doi: 10.4162/nrp.2014.8.3.292.
  144. Husain GM, Chatterjee SS, Singh PN, Kumar V. Hypolipidemic and antiobesity-like activity of standardised extract of Hypericum perforatum L. in rats. ISRN Pharmacol. 2011: 505247. doi: 10.5402/2011/505247.
  145. Moghaddam MHG, Roghani M, Maleki M. Effect of Hypericum perforatum aqueous extracts on serum lipids, aminotransferases, and lipid peroxidation in hyperlipidemic rats. Res. Cardiovasc. Med. 2016; 5(2): e31326. doi: 10.5812/cardiovascmed.31326.
  146. Novelli M, Beffy P, Menegazzi M, De Tata V, Martino L, Sgarbossa A, Porozov S, Pippa A, Masini M, Marchetti P, Masiello P. St. John’s wort extract and hyperforin protect rat and human pancreatic islets against cytokine toxicity. Acta Diabetol. 2014; 51(1): 113–121.
  147. Richard AJ, Amini ZJ, Ribnicky DM, Stephens JM. St. John’s Wort inhibits insulin signaling in murine and human adipocytes. Biochim. Biophys. Acta. 2012; 1822(4): 557–563. doi: 10.1016/j.bbadis.2011.12.005.
  148. Abd El Motteleb DM., Abd El Aleem DI. Renoprotective effect of Hypericum perforatum against diabetic nephropathy in rats: Insights in the underlying mechanisms. Clin. Exp. Pharmacol. Physiol. 2017; 44(4): 509–521. doi: 10.1111/1440-1681.12729.
  149. Valeri A, Capasso R, Valoti M, Pessina F. Effects of St John’s wort and its active constituents, hypericin and hyperforin, on isolated rat urinary bladder. J. Pharm. Pharmacol. 2012; 64(12): 1770–1776. doi: 10.1111/j.2042-7158.2012.01556.x.
  150. Khalili M, Jalali MR, Mirzaei-Azandaryani M. Effect of hydroalcoholic extract of Hypericum perforatum L. leaves on ethylene glycol-induced kidney calculi in rats. Urol. J. 2012; 9(2): 472–479.
  151. Eatemadnia A, Ansari S, Abedi P, Najar S. The effect of Hypericum perforatum on postmenopausal symptoms and depression: A randomized controlled trial. Complement. Ther. Med. 2019; 45: 109–113. doi: 10.1016/j.ctim.2019.05.028.
  152. Ghazanfarpour M, Kaviani M, Asadi N, Ghaffarpasand F, Ziyadlou S, Tabatabaee HR, Dehghankhalili M. Hypericum perforatum for the treatment of premenstrual syndrome. Int. J. Gynaecol. Obstet. 2011; 113(1): 84–85. doi: 10.1016/j.ijgo.2010.11.007.
  153. Conceição AO da, Takser L, Lafond J. Effect of St. John’s Wort standardized extract and hypericin on in vitro placental calcium transport. J. Med. Food. 2010; 13(4): 934–942. doi: 10.1089/jmf.2009.0161.
  154. Kahyaoğlu F, Gökçimen A, Demirci B. Investigation of the embryotoxic and teratogenic effect of Hypericum perforatum in pregnant rats. Turk. J. Obstet. Gynecol. 2018; 15(2): 87–90. doi: 10.4274/tjod.84429.
  155. Demirci B, Kahyaoğlu F, Atakul T, Yılmaz M, Özoran Y. Detrimental effect of Hypericum perforatum on ovarian functions. J. Turk. Ger. Gynecol. Assoc. 2019; 20(2): 65–69. doi: 10.4274/jtgga.galenos.2018.2018.0041.
  156. Halicioglu K, Çörekçi B, Akkaş İ, Irgin C, Özan F, Yilmaz F, Türker A. Effect of St John’s wort on bone formation in the orthopaedically expanded premaxillary suture in rats: a histological study. Eur. J. Orthod. 2015; 37(2): 164–169. doi: 10.1093/ejo/cju028.
  157. Seferos N, Petrokokkinos L, Kotsiou A, Rallis G, Tesseromatis C. Hypericum perforatum L. treatment restored bone mass changes in swimming stressed rats. Stomatologija. 2016; 18(1): 9–13.
  158. Mendi A, Gökçınar Yağcı B, Saraç N, Kızıloğlu M, Uğur A, Uçkan D, Yılmaz D. The effects of Hypericum perforatum L. on the proliferation, osteogenic differentiation, and inflammatory response of mesenchymal stem cells from different niches. Cells Tissues. Organs. 2018; 205(4): 208–216. doi: 10.1159/000491633.
  159. Damlar I, Arpağ OF, Tatli U, Altan A. Effects of Hypericum perforatum on the healing of xenografts: a histomorphometric study in rabbits. Br. J. Oral Maxillofac. Surg. 2017; 55(4): 383–387. doi: 10.1016/j.bjoms.2016.12.003.
  160. Aydin A, Sakrak O, Yilmaz TU, Kerem M. The effects of Hypericum perforatum on hepatic ischemia-reperfusion injury in rats. Bratisl. Lek. Listy. 2014; 115(4): 209–215.
  161. Hohmann MS, Cardoso RD, Fattori V, Arakawa NS, Tomaz JC, Lopes N, Casagrande R, Verri W AJr. Hypericum perforatum reduces paracetamol-induced hepatotoxicity and lethality in mice by modulating inflammation and oxidative stress. Phytother. Res. 2015; 29(7): 1097–1101. doi: 10.1002/ptr.5350.
  162. Bayramoglu G, Bayramoglu A, Engur S, Senturk H, Ozturk N, Colak S. The hepatoprotective effects of Hypericum perforatum L. on hepatic ischemia/reperfusion injury in rats. Cytotechnology. 2014; 66(3): 443–448. doi: 10.1007/s10616-013-9595-x.
  163. Mohammadinia S, Abedi SM, Noaparast Z. St. John’s Wort accelerates the liver clearance of technetium-99-sestamibi in rats. Nucl. Med. Commun. 2018; 39(9): 839–844. doi: 10.1097/MNM.0000000000000880.
  164. Khan AU, Gilani AH, Najeeb-ur-Rehman. Pharmacological studies on Hypericum perforatum fractions and constituents. Pharm. Biol. 2011; 49(1): 46–56. doi: 10.3109/13880209.2010.494307.
  165. Heinrich M, Lorenz P, Daniels R, Stintzing FC, Kammerer DR. Lipid and phenolic constituents from seeds of Hypericum perforatum L. and Hypericum tetrapterum Fr. and their antioxidant activity. Chem. Biodivers. 2017; 14(8): e1700100. doi: 10.1002/cbdv.201700100.
  166. Heydarian M, Jooyandeh H, Nasehi B, Noshad M. Characterization of Hypericum perforatum polysaccharides with antioxidant and antimicrobial activities: Optimization based statistical modeling. Int. J. Biol. Macromol. 2017; 104. Pt A: 287–293. doi: 10.1016/j.ijbiomac.2017.06.049.
  167. Meinke MC, Schanzer S, Haag SF, Casetti F, Müller ML, Wölfle U, Kleemann A, Lademann J, Schempp CM. In vivo photoprotective and anti-inflammatory effect of hyperforin is associated with high antioxidant activity in vitro and ex vivo. Eur. J. Pharm. Biopharm. 2012; 81(2): 346–350. doi: 10.1016/j.ejpb.2012.03.002.
  168. Micioni Di Bonaventura MV, Vitale G, Massi M, Cifani C. Effect of Hypericum perforatum Extract in an Experimental Model of Binge Eating in Female Rats. J. Obes. 2012; 2012:956137. doi: 10.1155/2012/956137.
  169. Peron AP, Mariucci RG, de Almeida IV, Düsman E, Mantovani MS, Vicentini VE. Evaluation of the cytotoxicity, mutagenicity and antimutagenicity of a natural antidepressant, Hypericum perforatum L. (St. John’s wort), on vegetal and animal test systems. BMC Complement. Altern. Med. 2013; 13: 97. doi: 10.1186/1472-6882-13-97.
  170. Imreova P, Feruszova J, Kyzek S, Bodnarova K, Zduriencikova M, Kozics K, Mucaji P, Galova E, Sevcovicova A, Miadokova E, Chalupa I. Hyperforin exhibits antigenotoxic activity on human and bacterial cells. Molecules. 2017; 22(1): Pii: E167. doi: 10.3390/molecules22010167.
  171. Ševčovičová A, Šemeláková M, Plšíková J, Loderer D, Imreová P, Gálová E, Kožurková M, Miadoková E, Fedoročko P. DNA-protective activities of hyperforin and aristoforin. Toxicol. In Vitro. 2015; 29(3): 631–637. doi: 10.1016/j.tiv.2015.01.016.
  172. You MK, Kim DW, Jeong KS, Bang MA, Kim HS, Rhuy J, Kim HA. St. John’s Wort (Hypericum perforatum) stimulates human osteoblastic MG-63 cell proliferation and attenuates trabecular bone loss induced by ovariectomy. Nutr. Res. Pract. 2015; 9(5): 459–465. doi: 10.4162/nrp.2015.9.5.459.
  173. Abtahi Froushani SM, Esmaili Gouvarchin Galee H, Khamisabadi M, Lotfallahzade B. Immunomudulatory effects of hydroalcoholic extract of Hypericum perforatum. Avicenna J. Phytomed. 2015; 5(1): 62–68.
  174. Eğilmez OK, Kökten N, Ekici AI, Kalcıoğlu MT, Yesilada E, Tekin M. The effect of Hypericum perforatum L. (St. John’s Wort) on prevention of myringosclerosis after myringotomy in a rat model. Int. J. Pediatr. Otorhinolaryngol. 2015; 79(7): 1128–1134. doi: 10.1016/j.ijporl.2015.05.009.
  175. Radulović NS, Genčić MS, Stojanović NM, Randjelović PJ, Baldovini N, Kurteva V. Prenylated β-diketones, two new additions to the family of biologically active Hypericum perforatum L. (Hypericaceae) secondary metabolites. Food Chem. Toxicol. 2018; 118: 505–513. doi: 10.1016/j.fct.2018.05.009.
  176. Guo Y, Zhang N, Sun W, Duan X, Zhang Q, Zhou Q, Chen C, Zhu H, Luo Z, Liu J, Li XN, Xue Y, Zhang Y. Bioactive polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum. Org. Biomol. Chem. 2018; 16(43): 8130–8143. doi: 10.1039/c8ob02067a.
  177. Yang JF, Liu YR, Huang CC, Ueng YF. The time-dependent effects of St John’s wort on cytochrome P450, uridine diphosphate-glucuronosyltransferase, glutathione S-transferase, and NAD(P)H-quinone oxidoreductase in mice. J. Food Drug. Anal. 2018; 26(1): 422–431. doi: 10.1016/j.jfda.2017.01.004.

Copyright (c) 2021 Budantsev A.L., Prikhodko V.A., Varganova I.V., Okovityi S.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
 

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies