Hyperatins A-D, highly oxidized polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum L. with hypoglycemic potential in liver cells.

Hyperatins A-D (1-4), four previously undescribed polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum perforatum L. (St. John's wort). Compound 1 possessed a unique octahydroindeno[1,7a-b]oxirene ring system with a rare 2,7-dioxabicyclo[2.2.1]heptane fragment. Compounds 2-4 had an uncommon decahydrospiro[furan-3,7'-indeno[7,1-bc]furan] ring system. Their structures were established by spectroscopic analyses and X-ray crystallography. Plausible biosynthetic pathways of 1-4 were also proposed. Compounds 1 and 2 exerted promising hypoglycemic activity by inhibiting glycogen synthase kinase 3 expression in liver cells.

Hypericum perforatum L. protects against renal function decline in ovariectomy rat model by regulating expressions of NOS3 and AKT1 in AGE-RAGE pathway.

BACKGROUND: Hypericum perforatum L. (HPL) is a potential traditional Chinese medicine. It could promotes menopausal 'kidney-yin deficiency syndrome' that characterized by renal function decline. However, its potential pharmacological effect and mechanism remains unknown. OBJECTIVE: The aim of this study was to investigate whether HPL can improve menopausal renal function decline and to explore its mechanism of action. METHODS: The mainly ingredients of HPL were identified using UPLC-Q-TOF-MS/MS approach, and the potential therapeutic targets of HPL for renal function decline were chose via network pharmacology technique. The key therapeutic metabolites were selected through non-targeted metabolomic and chemometric methods. Then, the network were constructed and the key targets and metabolites were screened. At last, the validation experiments and mechanism exploring were adopted by using Immunofluorescence, enzyme-linked immunosorbent assay (ELISA), real-time PCR (RT-PCR), and western blotting assays. RESULTS: mainly ingredients of HPL were identified and determined 17 compounds and 29 targets were chose as mainly active compounds and potential therapeutic targets. Based on OVX induced renal decline rat model, after chemometric analysis, 59 endo-metabolites were selected as key therapeutic metabolites, and AGE-RAGE signal pathway in diabetes complications was enriched as the key pathway. By constructing a "disease-component-target" network, Hyperoside, Quercetrin, and quinic were selected as the key therapeutic compounds, and the AKT1 and NOS3 were selected as the key therapeutic targets. The results of ELISA, RT-PCR and western blot experiments indicated that HPL could rescue the abnormal expressions both of AKT1 and NOS3, as well as their related metabolites distortion. CONCLUSION: Our findings indicated that HPL regulated expression of AKT1 and NOS3 through modulating AGE-RAGE signaling pathway in OVX stimulated rats` renal dysfunction, implicating the potential values of HPL in menopause syndromes therapy.

Antibacterial activity of Hypericum perforatum L. (St. John's wort) extracts against Gram-positive bacteria and characterisation of its secondary metabolites.

This study aimed to determine the secondary metabolite profiles and antibacterial activity of H. perforatum L extracts against Gram-positive clinical isolates. The plant materials (Sample A and Sample B) were macerated with n-hexane, ethyl acetate and methanol (MeOH). The antibacterial activitiy of plant extracts and routinely used antibiotics were tested against Gram-positive bacteria. The secondary metabolite profiles of Sample A were determined by LC-Q-TOF-MS. The MIC values for n-hexane and ethyl acetate extracts of Sample A were lower than the susceptibility breakpoints of most broad-spectrum antibiotics (e.g. vancomycin, teicoplanin and linezolid) in a certain proportion of Gram-positive bacteria. The n-hexane extract of Sample A showed good antibacterial activity with MICs lower than the susceptibility breakpoint of teicoplanin in 58% of coagulase-negative staphylococci. The n-hexane and ethyl acetate extracts of Sample A had rich phloroglucinol constituents. The n-hexane and ethyl acetate extracts of Sample A could be alternative antibacterial agents against Gram-positive bacteria.

Emulsion Electrospinning of PLLA/PVA/Chitosan with Hypericum perforatum L. as an Antibacterial Nanofibrous Wound Dressing.

Chronic wounds are one of the most severe health problems that affect millions of people worldwide. These types of injuries impair healing and lead to life-threatening complications. Therefore, suitable wound dressing materials are essential to prevent the risk of infection and to provide an excellent healing environment. The present research reports the development of an electrospun Poly (L-lactic acid) (PLLA)/Poly (vinyl alcohol) (PVA)/Chitosan (CS) wound dressing material, produced via emulsion electrospinning in a single step using homogeneous gel-like suspensions of two different and incompatible polymer solutions. The electrospun PLLA/PVA/CS fiber mats were loaded with two different amounts of Hypericum perforatum L. (HP) (2.5% and 5.0% owf). The results revealed that the produced electrospun PLLA/PVA/CS fiber mats displayed ideal properties as a wound dressing due to a total porosity, wettability, water vapor transmission rate (WVTR), and swelling properties similar to those reported for the extracellular matrix (ECM) of the skin, mainly when 2.5% owf HP was incorporated. Moreover, the electrospun PLLA/PVA/CS fiber mats containing HP were able to prevent the growth of gram-positive bacterium Staphylococcus aureus (S. aureus) without causing cytotoxicity to normal human dermal fibroblasts (NHDF). These findings suggest that these electrospun dressing mats are helpful for preventing wound infections as well as an appropriate support and microenvironment for wound healing.

Case study of clinical improvement of atopic dermatitis in a patient treated with herbal-based parapharmaceuticals.

OBJECTIVES: Atopic dermatitis (AD) is a chronic inflammatory skin disorder that has the immunoallergological characteristics of atopy and is characterised by itchy dermatitis with a recurrent-relapsing course and skin hyperreactivity. Official therapy involves topical anti-inflammatory and antimicrobial drugs for the skin but, as it is a recurrent and relapsing disease, the use of systemic anti-inflammatory and immunosuppressive drugs is eventually necessary to control the disease and prevent clinical exacerbation. However, systemic treatment may have a major impact on the patient, induce adverse reactions and not resolve the disease. The aim of the study is to establish whether the use of plant extracts may play a role in improving the quality of life of AD patients. CASE PRESENTATION: We describe the clinical case of a 27-year old Caucasian woman with dry, lichenified, slightly reddened and scaly skin lesions (EASI score 1.6), with anamnesis of atopy and multiple allergies, who was treated with an alternative therapeutic strategy to her previous ones, with three herbal-based parapharmaceuticals (Ribes nigrum L. buds, Piper longum L. fruits, Perilla frutescens L. Britton leaves and seeds in LUXFITOAL; Arctium lappa L. radix, Helychrisum italicum (Roth.) G. Don. flos, Viola tricolor L. herba cum floribus in LUXDERM; Trigonella foenum grecum seed extract, Hypericum perforatum extract in LUXTRIGONELLA cream). Two weeks after taking the drops and applying the cream the dry, lichenified skin lesions were no longer present and an eudermic state of the skin is restored (EASI score 0). Furthermore, six months after the beginning of the therapy, the good condition of the skin was maintained. The patient has never had such a long lapse of time without dermatitis reappearing on the anatomical sites observed at the first follow-up. After nine months, the patient was treated again for a dermatitis that had developed at another anatomical site, spreading frontally at the border between the lower margin of the neck and the upper margin of the thorax and at the chin (EASI value 3.2), achieving a marked improvement and a return of the eudermic state after two days (EASI value 0). CONCLUSIONS: The patient was satisfied with the "clean hands" with no inflammation, with the resolution of the dermatitis in the other body sites and stated that the therapy has improved her perceived quality of life. These botanicals may be effective and play a role in improving the quality of life of a person with AD.

Cytotoxic and Antioxidant Activity of Hypericum perforatum L. Extracts against Human Melanoma Cells from Different Stages of Cancer Progression, Cultured under Normoxia and Hypoxia.

Oxidative stress and the hypoxic microenvironment play a key role in the progression of human melanoma, one of the most aggressive skin cancers. The aim of our study was to evaluate the effect of Hypericum perforatum extracts of different origins (both commercially available (HpEx2) and laboratory-prepared from wild grown (HpEx12) and in vitro cultured (HpEx13) plants) and hyperforin salt on WM115 primary and WM266-4 lymph node metastatic human melanoma cells cultured under normoxic and hypoxic conditions. The polyphenol content, radical scavenging activity, and hyperforin concentration were determined in the extracts, while cell viability, apoptosis, ROS production, and expression of NRF2 and HO-1, important oxidative stress-related factors, were analyzed after 24 h of cell stimulation with HpExs and hyperforin salt. We found that cytotoxic, pro-apoptotic and antioxidant effects depend on the extract composition, the stage of melanoma progression, and the oxygen level. Hyperforin salt showed lower activity than H. perforatum extracts. Our study for the first time showed that the anticancer activity of H. perforatum extracts differs in normoxia and hypoxia. Importantly, the composition of extracts of various origins, including in vitro cultured, resulting in their unique properties, may be important in the selection of plants for therapeutic application.

Evaluating the antioxidant activity of secondary metabolites of endophytic fungi from Hypericum perforatum L. by an electrochemical biosensor based on AuNPs/AC@CS composite.

Due to the variety and activity of secondary metabolites of endophytic fungi (SMEF) from medicinal plants, and the operation cumbersome of existing methods for evaluating the activity, there is urgent to establish a simple, efficient and sensitive evaluation and screening technology. In this study, the prepared chitosan functionalized activated carbon (AC@CS) composite as the electrode substrate material was used to modify glassy carbon electrode (GCE), and the gold nanoparticles (AuNPs) was deposited on AC@CS/GCE by cyclic voltammetry (CV). A ds-DNA/AuNPs/AC@CS/GCE electrochemical biosensor for evaluating the antioxidant activity of SMEF from Hypericum perforatum L. (HP L.) was fabricated using the method of layer by layer assembly. The experimental conditions affecting the evaluation results of the biosensor were optimized by square wave voltammetry (SWV) using Ru(NH3)63+ as the probe, and the antioxidant activity of various SMEF from HP L. was evaluated by the proposed biosensor. Meanwhile, the results of the biosensor were also verified by UV-vis. According to the optimized experimental results, the biosensors had a high levels of oxidative DNA damage at pH 6.0 and Fenton solution system with Fe2+ to OH- ratio of 1:3 for 30 min. Among the crude extracts of SMEF from roots, stems and leaves of HP L., the crude extracts from stems presents a high antioxidant activity, but it was weaker than l-ascorbic acid. This result was consistent with the evaluation results of UV-vis spectrophotometric method, also the fabricated biosensor presents high stability and sensitivity. This study not only provides a novel, convenient and efficient way for rapid evaluating the antioxidant activity of a wide variety of SMEF from HP L., but also provides a novel evaluation strategy for the SMEF from medicinal plants.

Hypericum perforatum L. Nanoemulsion Mitigates Cisplatin-Induced Chemobrain via Reducing Neurobehavioral Alterations, Oxidative Stress, Neuroinflammation, and Apoptosis in Adult Rats.

Cisplatin (Cis) is a potent chemotherapeutic agent; however, it is linked with oxidative stress, inflammation, and apoptosis, which may harmfully affect the brain. Hypericum perforatum L. (HP L.) is a strong medicinal plant, but its hydrophobic polyphenolic compounds limit its activity. Therefore, our study aimed to investigate the neuroprotective action of HP L. and its nanoemulsion (NE) against Cis-induced neurotoxicity. The prepared HP.NE was subjected to characterization. The droplet size distribution, surface charge, and morphology were evaluated. In addition, an in vitro dissolution study was conducted. Compared to Cis-intoxicated rats, HP L. and HP.NE-treated rats displayed improved motor activity and spatial working memory. They also showed an increase in their antioxidant defense system and a reduction in the levels of pro-inflammatory cytokines in the brain. Moreover, they showed an increase in the expression levels of the PON-3 and GPX genes, which are associated with a reduction in the brain levels of COX-2 and TP-53. These findings were confirmed by reducing the immunohistochemical expression of nuclear factor kappa (NF-ƘB) and enhanced Ki-67 levels. In conclusion, HP L. is a promising herb and could be used as an adjuvant candidate to ameliorate chemotherapeutic-induced neurotoxicity. Moreover, HP.NE has superior activity in lessening Cis-induced oxidative stress, inflammation, and apoptosis in brain tissue.

Rapid screening of α-glucosidase inhibitors in Hypericum perforatum L. using bio-affinity chromatography coupled with UPLC/MS.

α-glucosidase inhibitors (AGIs) are widely used for the treatment of type 2 diabetes, but their side effects have made it to develop novel and alternative AGIs immediately. In this study, the extract of Hypericum perforatum L. (HPE) has been confirmed to have α-glucosidase inhibitory activity in vitro and in vivo. Seven active compounds, rutin, hyperoside, isoquercitrin, avicularin, quercitrin, quercetin, and biapigenin, were screened based on a bio-affinity chromatography column with α-glucosidase enzyme-conjugated solid phase and UPLC/MS, which exhibited excellent α-glycosidase inhibitory effects by the determined IC50 values. The mechanism of α-glycosidase inhibitory activity of biapigenin was studied for the first time. The results showed that biapigenin was a high-potential, reversible, and mixed enzyme inhibitor. Analysis by molecular docking further revealed that hydrophobic interactions were generated by interactions between biapigenin and amino acid residues LYS156, PHE303, PHE314, and LEU313. In addition, hydrogen bonding occurred between biapigenin and α-glucosidase amino acid residues ASP307, SER241, and LYS156. This research identified that biapigenin could be a novel AGI and further applied to the development of potential anti-diabetic drugs. Furthermore, our studies established a rapid in vitro screening method for AGIs from plants.

Hypericum perforatum L. extract exerts insulinotropic effects and inhibits gluconeogenesis in diabetic rats by regulating AMPK expression and PKCε concentration.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum perforatum L., commonly known as St. John's Wort (SJW), represents one of the best-known and most thoroughly researched medicinal plant species. The ethnobotanical usage and bioactivities related to H. perforatum include treatment of skin diseases, wounds and burns, gastrointestinal problems, urogenital diseases and psychiatric disorders, particularly depression. In the last decade, many studies focused on the bioactive constituents responsible for the antihyperglycemic and antidiabetic activity of SJW extracts. However, the mechanism by which H. perforatum extract exhibits these properties is still unclear. Hence, the current study was designed to gain insight into the underlying biochemical and molecular mechanisms by which wildly growing H. perforatum exerts its antihyperglycemic and antidiabetic activities. MATERIAL AND METHODS: Plant material of H. perforatum was harvested from a natural population in the Republic of North Macedonia during full flowering season. Methanol (80% v/v) was used to extract bioactive components from HH powder. The dissolved HH dry extract (in 0.3% CMC) was given daily as a single treatment (200 mg/kg bw) during 14 days both in healthy and streptozotocin-induced diabetic rats. As a positive control, we applied glibenclamide. The activity of key enzymes involved in carbohydrate methabolisam in the liver were assessed, along with substrate concentration, as well as AMPK mRNA levels, PKCε concentration, plasma insulin level and pancreatic PARP activity. RESULTS: Compared to diabetic rats, treatment of diabetic rats with HH extract resulted with decreased activity of hepatic enzymes glucose-6-phospatase and fructose-1,6-bisphosphatase, increased liver glycogen and glucose-6-phosphate content, which resulted with reduced blood glucose concentration up to normoglycaemia. Non-significant changes were observed in the activity of hexokinase, glycogen phosphorylase and glucose-6-phospahte dehydrogenase. HH-treatment also caused an increase in plasma insulin concentration and increase in pancreatic PARP activity. Finally, HH treatment of diabetic rats showed significant increase in AMPK expression and decrease of PKCε concentration. CONCLUSION: We present in vivo evidence that HH- extract exert insulinotropic effects and regulate endogenous glucose production mostly by suppressing liver gluconeogenesis. The HH-treatment did not effected glycogenolysys and glycolysis. Finally, we confirm the antihyperglycemic and antidiabetic effect of HH-extract and the mechanism of this effect involves amelioration of AMPK and PKCε changes in the liver.

Enhancing the efficacy of Hypericum perforatum in the treatment of an experimental model of multiple sclerosis using gold nanoparticles: an in vivo study.

Objective: Hypericum perforatum is a herbal medicine used in traditional medicine for the treatment of depression due to its antidepressant and anti-inflammatory activities. Therefore, we evaluated the therapeutic efficacy of H. perforatum extract (HPE) in combination with gold nanoparticles (HPE-GNP) against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Materials and Methods: EAE was induced in C57BL/6 mice with subcutaneous injection of MOG35-55 emulsified in complete Freund's adjuvant, and intraperitoneal pertussis toxin. Mice were treated with drugs in free (HPE) and nano-form (HPE-GNP) preparations. Splenocytes were isolated from all mice and the level of inflammatory and anti-inflammatory cytokines were evaluated by ELISA. The expression of T cells' transcription factors was also assessed using Real-Time PCR. Results: Clinical score was reduced after HPE-GNP treatment. This change was associated with a decrease in the incidence and infiltration of inflammatory cells into the central nervous system. Additionally, treatment with HPE-GNP decreased the level of pro-inflammatory cytokines (IFN-γ, IL-17A and IL-6) and increased anti-inflammatory cytokines (TGF-ß, IL-10 and IL-4). The real-time analysis revealed a decrease in the level of T-bet and ROR-γt but an increase in FoxP3 and GATA3 expression. Conclusion: The current study demonstrated that HPE-GNP could potentially reduce clinical and pathological complications of EAE, but laboratory data showed that HPE-GNP was significantly more effective than HPE in the treatment of EAE.

Green Synthesis of Silver Nanoparticles Using Hypericum perforatum L. Aqueous Extract with the Evaluation of Its Antibacterial Activity against Clinical and Food Pathogens.

The rapid development of nanotechnology and its applications in medicine has provided the perfect solution against a wide range of different microbes, especially antibiotic-resistant ones. In this study, a one-step approach was used in preparing silver nanoparticles (AgNPs) by mixing silver nitrate with hot Hypericum perforatum (St. John's wort) aqueous extract under high stirring to prevent agglomeration. The formation of silver nanoparticles was monitored by continuous measurement of the surface plasma resonance spectra (UV-VIS). The effect of St. John's wort aqueous extract on the formation of silver nanoparticles was evaluated and fully characterized by using different physicochemical techniques. The obtained silver nanoparticles were spherical, monodisperse, face-centered cubic (fcc) crystal structures, and the size ranges between 20 to 40 nm. They were covered with a capping layer of organic compounds considered as a nano dimension protective layer that prevents agglomeration and sedimentation. AgNPs revealed antibacterial activity against both tested Gram-positive and Gram-negative bacterial strains causing the formation of 13-32 mm inhibition zones with MIC 6.25-12.5 µg/mL; Escherichia coli strains were resistant to tested AgNPs. The specific growth rate of S. aureus was significantly reduced due to tested AgNPs at concentrations ≥½ MIC. AgNPs did not affect wound migration in fibroblast cell lines compared to control. Our results highlighted the potential use of AgNPs capped with plant extracts in the pharmaceutical and food industries to control bacterial pathogens' growth; however, further studies are required to confirm their wound healing capability and their health impact must be critically evaluated.

(±)-Hyperpyran A: Terpenoid-based bicyclic dihydropyran enantiomers with hypoglycemic activity from Hypericum perforatum (St. John's wort).

(±)-Hyperpyran A (1a/1b), a pair of new terpenoid-based bicyclic dihydropyran enantiomers, were isolated from the aerial parts of Hypericum perforatum (St. John's wort). Their structures and absolute configurations were elucidated by NMR spectroscopic analyses, ECD comparison, and X-ray crystal diffraction. Compounds 1a/1b possess hexahydrocyclopenta[c]pyran ring system and a plausible biosynthetic pathway was also proposed. In addition, compound 1a exhibited a moderate promotion of glucose uptake activity in hepatocytes.

Hyperforin and Myrtucommulone Derivatives Act as Natural Modulators of Wnt/ß-Catenin Signaling in HCT116 Colon Cancer Cells.

The therapeutic activities of natural plant extracts have been well known for centuries. Many of them, in addition to antiviral and antibiotic effects, turned out to have anti-tumor activities by targeting different signaling pathways. The canonical Wnt pathway represents a major tumorigenic pathway deregulated in numerous tumor entities, including colon cancer. Here, we investigated the acylphloroglucinols hyperforin (HF) from St. John's wort (Hypericum perforatum L.) and myrtucommulone A (MC A) from myrtle (Myrtus communis) and semi-synthetic derivatives thereof (HM 177, HM 297, HM298) for their effects on Wnt/ß-catenin signaling. None of these substances revealed major cytotoxicity on STF293 embryonic kidney and HCT116 colon carcinoma cells at concentrations up to 10 µM. At this concentration, HF and HM 177 showed the strongest effect on cell proliferation, whereas MC A and HM 177 most prominently inhibited anchorage-independent growth of HCT116 cells. Western blot analyses of active ß-catenin and ß-catenin/TCF reporter gene assays in STF293 cells revealed inhibitory activities of HF, MC A and HM 177. In line with this, the expression of endogenous Wnt target genes, Axin and Sp5, in HCT116 cells was significantly reduced. Our data suggest that the acylphloroglucinols hyperforin, myrtucommulone A and its derivative HM 177 represent potential new therapeutic agents to inhibit Wnt/ß-catenin signaling in colon cancer.

Development of new and validated HPTLC methods for the qualitative and quantitative analysis of hyperforin, hypericin and hyperoside contents in Hypericum species.

PURPOSE: Hypericum perforatum L. (St. John's wort) is a medicinally important member of Hypericaceae. Many pharmacological activities have been mostly attributed to its hyperforin, hypericin and/or hyperoside contents. Therefore, qualitative and quantitative determinations of these ingredients are essential to justify the beneficial effects of St. John's wort on health. In the European Pharmacopoeia, the TLC and HPLC methods were given for this purpose. High performance thin layer chromatography (HPTLC) has recently become increasingly used as a suitable technique for analysing herbal drugs. This study aims to develop new and validated HPTLC methods to analyse these active components in different Hypericum spp. to find other suitable species to replace the official plant. METHODS: Three different mobile phases were developed: n-hexane-ethyl acetate (8:2) for hyperforin analysis, toluene-chloroform-ethyl acetate-formic acid (8:5:3.5:0.6) for hypericin analysis and ethyl acetate-formic acid-acetic acid-water (15:2:2:1) for hyperoside analysis. These newly developed and validated HPTLC systems were further applied to determine their concentrations in different Hypericum species. RESULTS: Hyperforin concentration was found between 6.40 to 26.40 mg/g only in H. triquetrifolium, H. scabrum and two H. perforatum samples; hypericin was detected between 0.81 and 1.41 mg/g only in H. bithynicum, H. perfoliatum, H. triquetrifolium and two H. perforatum samples; and hyperoside was identified in all tested specimens ranging from 1.01 to 9.73 mg/g. The new HPTLC methods developed and validated in the present study may ensure reliable results for the qualification and quantification of hyperforin, hypericin and hyperoside contents in Hypericum species.

Decoupling of Plant Growth and Accumulation of Biologically Active Compounds in Leaves, Roots, and Root Exudates of Hypericum perforatum L. by the Combination of Jasmonate and Far-Red Lighting.

The plant hormone jasmonic acid (JA) fine tunes the growth-defense dilemma by inhibiting plant growth and stimulating the accumulation of secondary compounds. We investigated the interactions between JA and phytochrome B signaling on growth and the accumulation of selected secondary metabolites in Hypericum perforatum L., a medically important plant, by spraying plants with methyl jasmonate (MeJA) and by adding far-red (FR) lighting. MeJA inhibited plant growth, decreased fructose concentration, and enhanced the accumulation of most secondary metabolites. FR enhanced plant growth and starch accumulation and did not decrease the accumulation of most secondary metabolites. MeJA and FR acted mostly independently with no observable interactions on plant growth or secondary metabolite levels. The accumulation of different compounds (e.g., hypericin, flavonols, flavan-3-ols, and phenolic acid) in shoots, roots, and root exudates showed different responses to the two treatments. These findings indicate that the relationship between growth and secondary compound accumulation is specific and depends on the classes of compounds and/or their organ location. The combined application of MeJA and FR enhanced the accumulation of most secondary compounds without compromising plant growth. Thus, the negative correlations between biomass and the content of secondary compounds predicted by the growth-defense dilemma were overcome.

Hypericum perforatum L. prevents the acquisition of and promotes resilience against stress-induced reinstatement of the conditioned place preference induced by cocaine.

Cocaine use disorder is a serious problem worldwide, and there are no approved medications for its treatment. A novel approach to the treatment of drug addiction is the use of natural products, and, in this context, preclinical evidence suggests that Hypericum perforatum L. (Hypericum) is effective against alcohol and other substance use disorders. We hypothesised that Hypericum could also be useful as a treatment for cocaine use disorder, and so we set out to test its effectiveness in a mice model of cocaine addiction. In the first experiment we evaluated its effects on the acquisition of cocaine-induced conditioned place preference (CPP). Adult male mice were conditioned with cocaine (25 mg/kg), cocaine with Hypericum (75, 150 or 300 mg/kg) or the plant extract alone (300 mg/kg). In the second experiment, we tested the effects of Hypericum on stress-induced reinstatement of cocaine CPP. All the mice were conditioned with cocaine (25 mg/kg) and, after extinction of CPP, the reinstating effects of social defeat (alone or with 75, 150 or 300 mg/kg of Hypericum) were evaluated. All the doses of Hypericum prevented the acquisition of cocaine-induced CPP. Furthermore, the plant extract dose-dependently reduced the reinstating effects of social defeat. Therefore, Hypericum is effective in reducing the rewarding effects of cocaine and prevents the stress-induced reinstatement of cocaine CPP in mice. The mechanisms underlying these positive effects of Hypericum perforatum L. need to be determined by future research. Our results endorse Hypericum as a natural treatment for cocaine dependence.

Plant Extracts Rich in Polyphenols as Potent Modulators in the Growth of Probiotic and Pathogenic Intestinal Microorganisms.

Medicinal plants and their extracts contain substantial quantities of polyphenols. As metabolically active plant metabolites, polyphenols are food components with a wide range of biological activities. Given their poor absorbability in the digestive tract their activity toward the human host is typically mediated through interaction with intestinal microbes. As a result, polyphenols comprise a novel group of prebiotics. In this study, we tested the effect of five polyphenol-rich extracts from four medicinal herbs on the growth of probiotic and pathogenic microbes. The studied medicinal herbs were Gentiana asclepiadea L. (willow gentian), Hypericum perforatum L. (St. John's wort), Satureja montana L. (winter savory), and Achillea millefolium L. (yarrow). All these plants are traditionally used for the treatment of digestive problems. Extracts were prepared using safe solvent combinations. We tested the impact of addition of plant extracts on the growth of three probiotic lactobacilli and probiotic yeast Saccharomyces boulardii. The effect of addition of plant extracts to liquid media (concentration range 0.25-10 mg/mL) on the growth of probiotics, was tested in vitro. The antimicrobial activity of the extracts was tested against several opportunistic bacteria and yeast. St. John's wort, winter savory, and willow gentian extracts showed a stimulative effect on probiotic yeast growth, while the highest growth-stimulating effect was achieved when microwave-assisted yarrow extract was used in the concentration of 0.5 mg/mL. Under these conditions growth of S. boulardii was increased 130-fold. In addition, the yarrow extract stimulated the growth of Lactiplantibacillus plantarum 299v. The growth of two Lacticasibacillus rhamnosus strains was not stimulated by the addition of any extracts. Our results show that plant polyphenol-rich extracts can influence the growth of microorganisms that are typical members of the intestinal microbiota. For the first time we demonstrate that probiotic yeast growth can be stimulated by extracts of medicinal herbs, which when accompanied by suppression of Candida yeasts suggests a potential benefit of the treatment in diseases that are associated with fungal dysbiosis.

Evaluation of the chemopreventive effects of Hypericum perforatum L on DMBA-applied rat oral mucosa.

OBJECTIVE: Hypericum perforatum L also known as St. John's wort is known to have many beneficial properties for the organism including its antioxidant and anticancer activities. It is also known to have shown antiproliferative and cytotoxic effects against various cancer cell lines. The purpose of this study was to investigate the effects of Hypericum perforatum L on 7,12-dimethylbenz(a)anthracene-induced rat oral squamous cell carcinoma model. DESIGN: The in vitro antioxidant properties of Hypericum perforatum L was determined and an extract was prepared. Thirty Wistar male rats were divided randomly into 4 groups (Control group, DMBA group, HP + DMBA group, HP group). The antioxidant defense mechanisms in tissue and blood samples were evaluated biochemically and immunohistochemically, the carcinomatous changes in connective tissue were investigated immunohistochemically and epithelial changes in the tissue samples were evaluated histopathologically. RESULTS: The extract revealed inhibitory effects on some antioxidant enzymes (catalase, glutathione peroxidase). Immunohistochemical evaluations revealed no invasive changes in the connective tissue. Hypericum perforatum L demonstrated chemopreventive effects although it did not prevent carcinomatous changes altogether. CONCLUSIONS: Hypericum perforatum L is a promising chemopreventive agent and further studies are needed in order to evaluate the full potential of this plant.

Improvements in estrogen deficiency-induced hypercholesterolemia by Hypericum perforatum L. extract are associated with gut microbiota and related metabolites in ovariectomized (OVX) rats.

Hypericum perforatum L. (HP), a well-known natural medicine, has a potential effect on menopausal hypercholesterolemia. However, the effect of HP extract on gut microbiota and related metabolites, which play vital roles in metabolic disease occurrence, in the context of estrogen deficiency have not yet been reported. The aims of the present study were to investigate the effects of HP extract on gut microbial composition and related metabolite profiles in ovariectomized (OVX) rats and reveal the relationships between pathological indicators and alterations in both gut microbial composition at the genus level and metabolites. Body weight, serum parameters, liver lipids and histomorphology were determined. Microbial composition was analyzed using 16S rRNA sequencing. Fecal short-chain fatty acids (SCFAs) and serum bile acids were quantitatively measured. Correlations between pathological indicators and alteration in gut microbiota and metabolites were investigated using Spearman's rank correlation test. Gene expression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7α-hydroxylase (CYP7A1) and cholesterol 27-hydroxylase (CYP27A1) in the liver and G protein-coupled receptors (GPCRs; GPR43 and GPR41), ZO-1 and occludin in the cecum were determined by PCR. Microbial composition and metabolite profiles were significantly changed in OVX rats compared with sham rats. Twelve bacterial genera, 5 SCFAs and 12 bile acids were identified as differential biomarkers. Differential genera, SCFAs and bile acids were closely associated with weight, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). In OVX rats, HP administration can significantly reverse the pathological symptoms of body weight gain, serum lipid disorders and hepatic steatosis, at the meanwhile, reestablish gut microbial composition and metabolite profiles. Moreover, HP administration significantly upregulated the levels of CYP7A1, GPR43 and GPR41. In conclusion, HP can ameliorate estrogen deficiency-induced hypercholesterolemia. The underlying mechanism may be associated with improvements in gut microbiota composition and the profile of related metabolites as well as increases in bile acid secretion.