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

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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.

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Abbreviations: ROI – reactive oxygen intermediate; GABA – γ-aminobutyric acid; К562 – K-lines of acute erythroid leucosis; МАО-А – monoaminooxidase А; cAMP – cyclic adenosine monophosphate; CNS – central nervous system; A375 – human melanoma cell line; A375, 501mel – unpigmented melanoma cell lines; ADAMTS8, ADAMTS9 – a disintegrin-like and metalloprotease with thrombospondin type 1 motif 8, 9; BDNF – brain-derived neurotrophic factor; CaMK-IV – calcium/calmodulin-dependent protein kinase; cAMP – cyclic adenosine monophosphate; CLL – chronic lymphocytic leukemia cell line; COX – cyclooxygenases; CREB – cAMP response element-binding protein; CUMS – chronic unpredictable mild stress; CXCL9, CXCL10, – C-X-C motif chemokine; CYP3a CYP2c – cytochromes; D273 – medulloblastoma cell line; GABA – γ-aminobutyric acid; HT-29 – colon adenocarcinoma cell line; HT22 – immortalised mouse hippocampal neuronal cell line; iNOS – inducible nitric oxide synthase; JAK1 – janus kinase 1; JEG-3 – choriocarcinoma cell line; K562 – acute erythroid leukemia cell line; МАО-А – monoamine oxidase А; MAPK – mitogen-activated protein kinase; MCF-7 – human breast cancer cell line; MEK – mitogen-activated protein kinase kinase; MG-63 osteosarcoma cell line; NGF – nerve growth factor; NMDAR – N-methyl-D-aspartate receptor; PC12 – pheochromocytoma cell line; PGE2 – prostaglandin E2; PI3K – phosphatidylinositol 3-kinase; PKB/Akt – protein kinase; RINm5F – insulinoma cell line; SCC – human squamous carcinoma cell line; SH-SY5Y – neuroblastoma cell line; TNFα – tumor necrosis factor α; TrkB – tropomyosin-related kinase B; TRPM2, TRPV1, TRPC6 – transient receptor potential cation channel; U937 – human acute myeloid leukemia cell line; UCT Mel-1 – pigmented melanoma cell line; β1-АR – β1-adrenergic receptors.


Despite the fact that Hypericum perforatum L. (St John’s wort) has been known for its medicinal properties for more than 2000 years, it has not yet lost its popularity and continues to be studied intensively by clinicians, pharmacologists, and chemists. The indicator of the active interest in H. perforatum is the number of reviews published over the last decade. They are devoted to both the general biological activity profile of its extracts and individual chemical components, as well as to specific types of activity, which are considered in the corresponding sections of this article.

Unlike many other medicinal plants, pharmacological studies of which are accompanied by the determination of the structures of certain new (or rediscovered) chemical compounds, modern research of H. perforatum is more focused on the mechanisms of its therapeutic action, and less on the identification of new components.

It is well known that among the secondary metabolites of St. John’s wort, there 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 hypericin, a photoreactive naphthodianthrone, and hyperforin — a phloroglucinol derivative, have been studied in most detail [1–5].

Today, H. perforatum is known primarily for its antidepressant-like properties, which have been confirmed by numerous preclinical studies and clinical trials. Still, there is no consensus on the effectiveness of St. John’s wort for severe or at least moderate depression (e.g. [2]).

And yet, the aforementioned beneficial properties of H. perforatum, as well as those yet unknown, continue to be studied with unceasing regularity, in different models and within different approaches. A brief (but by no means exhaustive) summary of such studies conducted over the past decade, is presented in this review.

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


To collect and analyze the information, electronic databases 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”.


Antidepressant activity

Despite St. John’s wort being a popular “mild” treatment choice for depression, its mechanism of action is not entirely known yet. According to current understanding, among its most active components аre the naphthodianthrone hypericin, the phloroglucinol derivatives hyperforin and adhyperforin, the biflavonoid amentoflavone, and other flavonoids [6–13].

According to a systematic review and a meta-analysis, which included 27 clinical trials, St. John’s wort is as effective in the patients with mild-to-moderate depression as are some of the most common synthetic antidepressants, at the same time being better tolerated [14–16]. H. perforatum is most effective in patients with mild and moderate depression [15–18], and in those experiencing pronounced somatization and gastrointestinal symptoms [19].

Standardized H. perforatum extracts WS 5572, LI 160, WS 5570, ZE 117 were found to be as effective for mild depression as sertraline and imipramine [20, 21]. In moderate depression, H. perforatum did not differ in effectiveness from citalopram [22] while surpassing paroxetine [23]. According to a retrospective observational study, IperiPlex®, a multi-fractionated H. perforatum extract, was significantly more effective in the patients with moderate depression than Nervaxon®, a mono-fractionated extract [24]. However, H. perforatum effectiveness in patients with moderate and severe depression remains somewhat unclear [25, 26].

A multicenter observational study showed the drugs Helarium® and Helarium-425®, both containing extracts of H. perforatum, to be well-tolerated by patients with mild to moderate depression [27]. However, H. perforatum treatment was associated with a greater frequency of some specific adverse events, including damage to the nervous system, reproductive organs, eyes, ears, liver, and kidneys [28]. A case of psychosis has been reported in a patient who self-administered H. perforatum as a herbal infusion [29].

H. perforatum extract potentiated yohimbine toxicity, and exhibited maximal antidepressive activity at 90 mg/kg [14]. Administered over time, both H. perforatum ethanolic extract and fluoxetine were found to affect hippocampal and hypothalamic gene expression in chronically stressed rats. Among those affected were genes coding for a number of biomolecules involved in neuroinflammatory and oxidative stress pathways, and some of those associated with Alzheimer’s disease [30].

In 2018, T. Herraiz et al. showed that in various dosage forms, H. perforatum inhibited monoamine oxidase А (МАО-А). Of all the identified plant constituents, quercetin (IC50= 3.4 μg/ml) and its glycosides were found to be the most active; hypericin (IC50 = 17.9 μg/ml) did not contribute significantly to the overall effect of the preparations, and hyperforin failed to show any activity throughout the studied concentration range. According to the authors, taking into account the average content of active ingredients in total preparations with H. perforatum, the observed MAO-A inhibition was most likely an additive effect [31].

When compared to venlafaxine, a serotonin and norepinephrine reuptake inhibitor, hypericin decreased blood corticosterone levels, prevented weight loss and anorexia, reduced anhedonia, and stimulated exploratory behaviour in rats with a chronic unpredictable mild stress (CUMS). Moreover, those effects had a shorter onset in the hypericin-treated group than in the venlafaxine-treated one. At the same time, hypericin affected the metabolism of norepinephrine, serotonin, and excitatory amino acids (glutamate and glutamine) [12]. Hypericin also inhibited calcium ion influx into hippocampal neurons, thus increasing an action potential duration, which could possibly play a role in enhancing a synaptic efficiency [32].

Pretreatment of glioblastoma cells with hyperforin and hyperoside hindered lateral mobility of β1-adrenergic receptors (β1-АR) and caused their internalization. The two compounds reduced cyclic adenosine monophosphate (cAMP) formation by 10% and 15%, respectively, and by 23% and 15% under subsequent cell stimulation with 5 μM dobutamine. Similar effects were observed when cells were pretreated with desipramine, a tricyclic antidepressant [7]. H. perforatum extract and hyperforin were found to increase presynaptic calcium concentrations and thus stimulate the release of the excitatory neurotransmitter glutamate [33].

B. Pochwat et al. found that hyperforin potentiated antidepressant-like activity of lanicemine, a N-methyl-D-aspartate receptor (NMDAR) antagonist, in chronic corticosterone-treated mice as well as in healthy controls. A combination of lanicemine and hyperforin increased the expression of synapsin I, a subunit of glutamate receptor A1, and neurotrophin BDNF (brain-derived neurotrophic factor) in frontal cortical neurons. Hyperforin also attenuated cognitive dysfunction caused by dizocilpine, a NMDAR antagonist having marked dissociative and psychedelic properties. Nonetheless, 0.3–10 μm hyperforin did not affect NMDAR electrical activity in vitro [13].

Much less is known about adhyperforin than about its parent compound, hyperforin. However, adhyperforin has also been shown to exert an antidepressant-like activity, stimulate exploratory behaviour, and reduce anhedonia and hypodynamia in rodents. It suppressed norepinephrine, serotonin and dopamine reuptake in vitro, and, just like hyperforin, antagonized reserpine-induced effects in vivo [8, 34].

Neuroprotective activities

An ethanolic extract of H. perforatum containing 6.0% of hyperforin stimulated neurite outgrowth in HT22 hippocampal cells, increased their resistance to glutamate toxicity, and inhibited the release of tumor necrosis factor α (TNFα) from macrophages [35].

Pretreatment of PC12 pheochromocytoma cells with an H. perforatum extract increased their viability at toxic concentrations of hydrogen peroxide, and prevented DNA fragmentation [36]. Another H. perforatum extract normalized lateral mobility of integral membrane proteins and phospholipids in glioblastoma cells, which made a more efficient transmembrane signal transduction possible [37]. Ethyl acetate, water, and methanolic extracts of H. perforatum inhibited acetyl- and butyrylcholinesterase; ethyl acetate and water extracts also inhibited tyrosinase [38].

An extract of H. perforatum reduced the severity of oxidative stress in leukocytes obtained from patients with multiple sclerosis. Cell apoptosis was largely prevented through the activation of antioxidant systems and normalization of intracellular calcium levels [39]. A similar effect associated with the blockade of calcium channels by H. perforatum was also observed in rat dorsal root ganglion neurons [40]. Later, some of the active constituents of H. perforatum were found to inhibit TRPM2 and TRPV1 channels, which mediate calcium ion influx under oxidative stress conditions [41].

A hyperforin-enriched (6.0%) extract (4 mg/kg/d×45 d) effectively prevented degeneration of nigral neurons induced in rats by a chronic exposure to rotenone. Quite on the contrary, an extract containing only 0.2% hyperforin and pure quercetin both exhibited significantly lower activity when administered by the same route and at the same doses [42]. The rats treated with an ethanolic extract of H. perforatum (200 mg/kg/d) for 1 week before and 1 week after the administration of 6-hydroxydopamine showed an increase in survival rates of nigral neurons, as well as an attenuation of astrogliosis, inflammation, oxidative stress, and motor dysfunction as compared to control animals [43]. Both St. John’s wort extract and pure hyperforin alleviated the symptoms of experimental autoimmune encephalomyelitis, a common model of multiple sclerosis, in mice [44, 45]. An ethanolic extract of St. John’s wort also prevented apoptosis of neurons and attenuated oxaliplatin-induced neurotoxicity in rats [46].

In the study by S. Valvassori et al., an H. perforatum extract (300 mg/kg /d × 28 d) significantly impaired memory acquisition and object recognition, and decreased the levels of the transcription factors BDNF and NGF (nerve growth factor) in rat hippocampi [47].

In an ex vivo experiment in isolated hippocampal neurons, hyperforin (0.3 μM, 24 h) promoted the formation of stubby dendritic spines and, at the same time, decreased the proportion of thin spines [48]. Interestingly, similar alterations in spine morphology have been observed for classical antidepressant agents such as fluoxetine [49], imipramine, and rolipram [50], but in those cases, they had a significantly slower onset, and most probably differed in nature [48].

Hyperforin activated MEK (mitogen-activated protein kinase), MAPK (mitogen-activated protein kinase), phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/Akt), and calcium/calmodulin-dependent protein kinase (CaMK-IV) in PC-12 pheochromocytoma cells and hippocampal neurons [51]. These changes culminated in the phosphorylation and activation of the transcription factor CREB (cAMP response element-binding protein), which is considered to be a promising therapeutic target for the treatment of Alzheimer’s disease [52–54]. Moreover, the therapeutic effect of H. perforatum in Alzheimer’s disease was seemingly independent of hyperforin concentration in the preparation [55]. Hyperforin was confirmed to exert neuroprotective effects against aluminum maltolate-induced toxicity in PC12 and SH-SY5Y cells [56].

Hyperforin stimulated CREB phosphorylation, induced TRPC6 calcium channel and TrkB BDNF receptor expression in embryonic mouse cortical neurons [57]. The extract of H. perforatum reduced a β-amyloid accumulation and increased levels of P-glycoprotein in the brain tissue of transgenic mice with Alzheimer’s disease. However, another study found an H. perforatum extract, hyperforin, and high concentrations of quercetin to inhibit P-glycoprotein activity in brain capillary endothelial cells [59]. A methanolic extract of H. perforatum inhibited acetylcholinesterase and reduced glutamate levels, at the same time potentiating noradrenergic and dopaminergic neurotransmission in an aluminum chloride-induced rat model of Alzheimer’s disease. The extract caused a decrease in β-amyloid deposition rates and ameliorated oxidative stress in treatment groups [60]. A 28 days-long H. perforatum treatment course inhibited neuroinflammation, lipid peroxidation, and lowered blood proinflammatory cytokines levels in rats subjected to mechanic sciatic nerve injury [61].

An intracerebroventricular administration of hyperforin to rats subjected to middle cerebral artery occlusion, significantly reduced infarct volume and post-stroke neurological deficit. Hyperforin inhibited the calpain-mediated TRPC6 channel degradation, thus maintaining normal CREB activity and, ultimately, increasing neuron viability following ischemia [62].

TRPC6 activation is thought to be a non-essential or, at the very least, not the only mechanism of a hyperforin action [9, 34]. For instance, a complete absence of TRPC6 had no effect on inward membrane ion currents in microglial cells treated with a hyperforin solution. Its molecule being highly lipophilic, and its properties depending heavily on pH of the medium, it was suggested that hyperforin acted as a protonophore and induced a transmembrane proton transfer in a channel-independent fashion [34]. However, in an in vivo experiment in mice, its neurotropic activity was blocked completely by a prior administration of either larixyl acetate or MK 2206, which inhibited TRPC6 and PKB, respectively [13].

Amentoflavone and hypericin are thought to have an opposite effect on a MAPK pathway activity compared to hyperforin [63–65]. Amentoflavone protected HT22 hippocampal neurons against glutamate-induced excitotoxic injury. Besides maintaining the activity of some of the most important antioxidant enzymes and inhibiting reactive oxygen species generation, it inhibited MAPK phosphorylation [66].

Amentoflavone has been shown to exert a direct effect on cholinergic neurotransmission in the central nervous system. It significantly attenuated scopolamine-induced retrograde amnesia through inhibition of acetylcholinesterase and enhancement of antioxidant enzymes activity, thus perpetuating long-term spatial memory [67].

Nootropic activity

A 2016 meta-analysis confirmed H. perforatum to possess a significant nootropic activity independent of its antidepressant-like activity. The authors suggested that the modulation of 5-HT2 serotonin receptor activity, dopaminergic, glutamatergic, and γ-aminobutyric acid (GABA)-mediated neurotransmission was among the possible mechanisms of H. perforatum nootropic action [68]. Long-term H. perforatum treatment has been shown to inhibit the release of adrenocorticotropin and, as a result, that of the glucocorticoid corticosterone, which is the main hormonal mediator of chronic stress response in rodents [68, 69]. An H. perforatum extract (125, 250 or 500 mg/kg/d × 30 d) prevented an increase in corticosterone and TNF-α levels in blood and hippocampus in bilateral ovariectomized rats [70].

The nootropic effects of H. perforatum preparations have been confirmed experimentally using acute [71] and chronic restraint stress models [72], and a model of cognitive deficit associated with diabetes mellitus [73].

H. perforatum preparations have been demonstrated to have a beneficial effect on neuronal synaptic plasticity in animal [74, 75] and human studies [76]. A single dose of 250 mg of H. perforatum tabletted dry extract (Remotiv®) improved short-term verbal and spatial memory in healthy volunteers. Quite surprisingly, no nootropic effect was observed at the dose of 500 mg, although both doses improved the patients’ mood and emotional stability. Similarities to and differences from some other neurotropic agents such as citalopram, bromocriptine, and sulpiride, as well as the inverse dose-dependency of H. perforatum effects suggest that its primary mechanism of action could involve the augmentation of dopaminergic transmission [77].

The effectiveness of H. perforatum for the treatment of autism spectrum disorder is limited. St. John’s wort modestly improved irritability, stereotypy and abnormal speech patterns, while clinician ratings on several symptom assessment scales remained unchanged [78].

Antiepileptic activity

Amentoflavone exhibited antiepileptic properties in a number of in vitro and in vivo studies. It attenuated oxidative stress, inhibited neuroinflammation, and increased GABA binding affinity to GABAA receptors [79–81]. An ether extract of H. perforatum lowered the seizure threshold and increased the after-discharge duration, while n-butanolic and water extracts, on the contrary, inhibited epileptogenesis [82]. A methanolic extract of H. perforatum reduced seizure duration and mortality in a mouse model of picrotoxin-induced epilepsy [83].

Anxiolytic activity

Anxiolytic properties of H. perforatum are related to its nootropic, neuroprotective and antidepressant-like kinds of activity, and are thought to be mediated by its effects on monoaminergic transmission and neuroinflammatory processes [71, 74].

The anxiolytic effect of amentoflavone (25 mg/kg), observed in mice following a single administration, was reduced by pretreatment with flumazenil, a benzodiazepine receptor antagonist. This fact suggested that amentoflavone exerted its anxiolytic effect through the interaction with the benzodiazepine-binding site of the GABAA receptor [84]. This mechanism of action was subsequently confirmed by radioligand binding assays [85].

Crupi et al. revealed that three-week treatment with an H. perforatum methanolic extract decreased anxiety in mice with chronic corticosterone-induced stress [74]. Extract-treated (50 or 100 mg/kg/d × 5 d) mice exhibited higher levels of exploratory activity and were less anxious following six hours of acute restraint stress, although those parameters still fell outside normal ranges [71]. An H. perforatum extract (100 or 200 mg/kg/d × 14 d) ameliorated anxiety and depression in streptozotocin-induced type II diabetic rats [86].

Antimicrobial, antiviral and antiprotozoal activity

Antibacterial activity of H. perforatum has been reviewed by Z. Saddiqe et al. in 2010 [87]. The antibacterial activity of individual compounds and extracts of St. John’s wort is somewhat unclear. Aerial parts macerated with olive oil showed little overall activity, and only a few samples were active against Trypanosoma brucei rhodesiense and Staphylococcus aureus [88]; hyperforin (but not hypericin) also moderately inhibited Staphylococcus aureus growth [89]. The aqueous fraction of an ethanolic extract of St. John’s wort suppressed Streptococcus sobrinus and Lactobacillus plantarum growth [90], and an alcoholic extract and hypericin were active against Lactobacillus acidophilus, allowing to consider them as potential oral disinfectants [91]. Photoactivated hypericin inhibited Candida albicans, C. parapsilosis, C. krusei [92], and Staphylococcus aureus growth, but did not affect that of Escherichia coli [93]. Hyperforin and a methanolic extract of the aerial parts of the plant were active against Mycobacterium JLS, although hypericin and pseudohypericin were not [94]. An ethyl acetate extract of H. perforatum exhibited antiviral activity against infectious bronchitis virus in vitro and in vivo (IBV strain M41) [95], human influenza virus A/PR/8/34 H1N1 [96], influenza A virus [97], and hepatitis B virus [98].

Antitumor and cytotoxic properties

An overview summarizing existing knowledge on the anticancer activity of Hypericum species was published in 2017 [99]. It was established that ultraviolet radiation increased the antiproliferative activity of a water/alcohol extract in human melanoma A375 cell line [100]. Investigations are underway to assess the cytotoxic activity of H. perforatum components in photodynamic therapy. For instance, hyperforin and aristofolin (a synthetic derivative of hyperforin) induced apoptosis of HT-29 colon adenocarcinoma cells subjected to hypericin-mediated photodynamic therapy [101], and death of both unpigmented (A375 and 501mel) and pigmented (UCT Mel-1) melanoma cells [102]1. Photoactivated hypericin decreased the viability of RINm5F insulinoma cells, human squamous carcinoma cells (SCC) [104], D273 medulloblastoma cells [105], and was effective against anaplastic thyroid cancer [106]. A flower extract inhibited growth and induced apoptosis of K562 (acute erythroid leukemia) cells [107], an ethanolic extract blocked proliferation and induced apoptosis of MCF-7 human breast cancer cells [108], and hyperforin induced death of CLL (chronic lymphocytic leukemia) cells ex vivo [109]. Hypericin exerted a cytotoxic effect on MCF-7 cells [110], promoted expression of genes coding for metalloproteinase family enzymes ADAMTS9 and ADAMTS8 having anti-angiogenic and antitumor properties in MCF-7 cells [111]. Hyperforin induced apoptosis of U937 (human acute myeloid leukemia) cells line [112]. An essential oil showed anti-angiogenic properties [113].

Analgesic, anti-inflammatory and wound-healing properties

There has been published a number of reviews focused on the anti-inflammatory and analgesic properties of H. perforatum extracts and their components [114–118]. A dry extract relieved neuropathic pain in an experimental study [119]. Hypericin inhibited the pro-inflammatory enzyme janus kinase 1 (JAK1) in silico, which could explain its anti-inflammatory properties [120].

Hyperforin inhibited the activity of cyclooxygenases (COX) 1 and 2 and microsomal prostaglandin synthase PGE2, which play key roles in inflammation and tumorigenesis [121]. Over the past decade, the investigations of anti-inflammatory properties of the four-component fraction of H. perforatum ethanolic extract containing amentoflavone, quercetin, chlorogenic acid and pseudohypericin, have been continued [122, 123]. The extract was found to be devoid of anti-inflammatory activity, in contrast with the four compounds [124]. H. perforatum flowering tops extract suppressed the expression of proinflammatory factors and stimulated that of anti-inflammatory ones in cultured adipocytes [125].

An extract facilitated wound healing properties in a clinical trial [126], and was effective for the treatment of psoriasis, lowering TNFα levels in dermis, endothelial, and dendrite cells [127]. An ethanolic extract prevented lipid peroxidation in neutrophils of patients with Behcet’s syndrome [128]. An oil extract was effective for the prevention and treatment of pressure sores [129]. Wound-healing properties of H. perforatum extracts were confirmed in different models [130–133] including diabetic animals [134–136]. An oil extract prevented the narrowing of the oesophageal lumen caused by burn injuries [137], and had anti-inflammatory, anti-angiogenic, and anti-fibroblastic effects when applied after corneal alkali burns [138]. Hyperforin reduced the migration of fibroblasts in 2D and 3D models of artificial skin and was proposed for the treatment of hypertrophic scars [139].

Hypolipidaemic and hypoglycaemic properties

Hypolipidaemic and hypoglycaemic properties have been discovered for extracts of the aerial parts of H. perforatum [141–143]. A hydroalcoholic (50%) extract of the whole plant at the doses of 100 and 200 mg/kg of body weight per day for 15 days exhibited hypocholesterolaemic properties [144], and similar effects were observed for an aqueous extract of the aerial parts at the dose of 300 mg/kg for 60 days [145]. A methanolic extract and hyperforin prevented pancreatic β-cells from damage by the cytokines iNOS, CXCL9, CXCL10, and COX2, which is associated with the development of type I diabetes [146]. It was found that excessive intake of H. perforatum flower extract, hypericin, and hyperforin could aggravate diabetes and obesity by inhibiting the differentiation of preadipocytes and inducing insulin resistance in mature fat cells [147].

Effects of H. perforatum in genitourinary system disorders

A powder of shoots at the dose of 200 mg/kg (8 weeks) in diabetic nephropathy showed a nephroprotective effect [147]. A methanolic extract of the aerial parts of H. perforatum, hypericin, and hyperforin exhibited spasmolytic activity and modulated detrusor contractile activity in isolated urinary bladder; for hypericin, this effect was associated with an increase in plasma membrane depolarization, and for hyperforin, with a stimulatory effect on the cholinergic system [149]. A hydroalcoholic extract of leaves reduced the size and number of ethylene glycol-induced renal calculi [150].

Clinical trials found out that a powder of St. John’s wort given at the doses of 270–330 μg for 2 months reduced hot flashes, menopausal symptoms, and depression [151], and the extract was effective for the treatment of premenstrual syndrome [152]. In an in vitro experiment, the extract (25 μg/mL) and hypericin (7.5 and 75 ng/mL) increased calcium concentration in JEG-3 placental cells [153]. The extract intake (100 mg/kg and 300 mg/kg) from mating till delivery prolonged foetal development and damaged foetal liver due to oxidative stress [154]; at the same doses, the extract worsened ovarian function and decreased fertility [155].

Effects of H. perforatum in maxillofacial injuries

An aqueous extract of the aerial parts activated a bone tissue regeneration in the orthopaedically expanded premaxillary suture, which is performed in orthognathic surgery [156]. Another experiment proved a standardized methanolic extract to restore mandible bone tissue in a stress model [157]; an ethanolic extract activated dental pulp regeneration [158]), and an oil extract improved bone healing after xenograft implantation [159].

Other effects

Several H. perforatum extracts prevented acetaminophen-induced liver injury [160, 161], a petroleum ether leaf extract had protective effects in a hepatic ischaemia-reperfusion model [162], and another extract accelerated hepatic clearance of technetium-99 [163]. Certain fractions of a water/ethanol extract of the aerial parts of H. perforatum had spasmolytic, bronchodilator, vasorelaxant and cardiotropic activities [164]; H. perforatum polysaccharides and a methanolic seed extract showed antioxidant properties [165, 166]. It is assumed that the antioxidant properties underly the photoprotective and anti-inflammatory effects of hyperforin on skin tissues [167]. At the doses of 250 and 500 mg/kg, a H. perforatum dry extract reduced binge eating episode frequency [168]. A leaf extract had antimutagenic properties [169]; the effects of hyperforin were described as antigenotoxic [170] and DNA-protective [171] in different in vitro models. An ethanolic extract of H. perforatum stimulated human osteoblast-like MG-63 cell proliferation in osteoporosis induced by ovariectomy [172]. A hydroalcoholic extract (110 mg/kg for 2 weeks) enhanced cellular immunity [173], and a methanolic extract of the aerial parts, dissolved in olive oil, prevented the development of myringosclerosis after myringotomy [174]. The β-diketone 2,6,9-trimethyl-8-decene-3,5-dione, hyperforatins B, D, and F, 15-epi-hyperforatin D, and 32-epi-hyperforatin E inhibited an acetylcholinesterase activity [175, 176], and a methanolic extract stimulated hepatic and renal activities of the cytochromes CYP3a and CYP2c [177].


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.


The study was carried out within the framework of the institutional research project N АААА-А19-119031290052-1 (Vascular plants of Eurasia: systematic, flora, plant resources) of the Komarov Botanical Institute of the Russian Academy of Sciences.


A.L. Budantsev – writing Introduction and Antibacterial, antiviral, antiprotozoal activity, Antitumor and cytotoxic properties, Analgesic, anti-inflammatory and wound-healing properties, compiling the list of references; I.V. Varganova – compiling of Antibacterial, antiviral, antiprotozoal activity, Antitumor and cytotoxic properties, Analgesic, anti-inflammatory and wound healing properties, Hypolipidemic and hypoglycemic properties, other effects, translation of the text into English, compiling the list of references; V.A. Prikhodko – compiling of Antidepressant activity, Neuroprotective activity, Nootropic activity, Antiepileptic activity, Anxiolytic activity, Effects of H. perforatum in genitourinary system disorders, Effects of H. perforatum in maxillofacial injuries, translation of the text into English, compiling the list of references; S.V. Okovity – compiling of Antidepressant activity, Neuroprotective activity, Nootropic activity, Antiepileptic activity, Anxiolytic activity, Effects of H. perforatum in maxillofacial injuries, Effects of H. perforatum in maxillofacial injuries.


The authors declare no conflict of interest


1 It was reported that the cytotoxicity of photodynamic hypericin was higher for amelanotic A375 melanoma cells in comparison with pigmented Mel-1 cells; in this regard, melanin was suggested to play a role in the chemoresistance of melanoma cells (Sharma, Davids, 2012b).


About the authors

Andrey L. Budantsev

Komarov Botanical Institute of the Russian Academy of Sciences

Author for correspondence.
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

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

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

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


  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.

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