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Herbal medicines are frequently used for the prevention and treatment of obesity and obesity-related disorders. Our preliminary screening showed that St. John's Wort (SJW) displayed potent inhibition on pancreatic lipase (PL), a key hydrolase responsible for lipid digestion and absorption in mammals. Herein, the inhibition potentials and inhibitory mechanism of SJW extract and its major constituents on PL were fully investigated by a set of in vitro and in silico studies. The results clearly demonstrated that the naphthodianthrones, biflavones and most of flavonoids in SJW displayed strong to moderate inhibition on PL. Among all tested natural compounds, two naphthodianthrones (hypericin and pseudohypericin) and one biflavone (I3,II8-biapigenin) isolated from SJW exhibited potent PL inhibition activity, with the IC 50 values of <1 μM. Inhibition kinetics analyses showed that hypericin, pseudohypericin and I3,II8-biapigenin inhibited PL via a mixed manner, while molecular dynamics simulations revealed that three newly identified PL inhibitors could bind on PL at both the catalytic cavity and the interface between colipase and the C-terminal domain of PL. Collectively, our findings suggested that part of major constituents in SJW displayed potent PL inhibition activities, which could be used as lead compounds for the development of novel PL inhibitors. • The inhibitory effects of St. John's wort extract and its major constituents on pancreatic lipase (PL) are assayed. • Hypericin, pseudohypericin and I3,II8-biapigenin display potent inhibition on PL, with the IC 50 values of <1 μM. • Hypericin, pseudohypericin and I3,II8-biapigenin are mixed inhibitors of PL. • Hypericin, pseudohypericin and I3,II8-biapigeninc could bind on PL at two distinct ligand-binding sites. [ABSTRACT FROM AUTHOR]

St. John's wort has attracted particular attention because of its beneficial effects as an antidepressant, antiviral, and anticancer agent. A method for the combination of integrated expanded bed adsorption chromatography and countercurrent chromatography for the simultaneous extraction and purification of pseudohypericin and hypericin from the herb is presented in this paper. Firstly, the constituents were extracted and directly adsorbed by expanded bed adsorption chromatography under optimal conditions. The stepwise elution was then performed by expanded bed adsorption chromatography that enriched the targets with higher purities and recoveries compared to other methods. Secondly, the eluent fractions from expanded bed adsorption chromatography were further separated by two-step high-speed countercurrent chromatography. A two-step high-speed countercurrent chromatography method with a biphasic solvent system composed of n-hexane/ethyl acetate/methanol/water with a volume ratio of 1:2:1:2 was performed by stepwise changing the flow rate of the mobile phase. Consequently, 5.6 mg of pseudohypericin and 2.2 mg of hypericin with purities of 95.5 and 95.0%, respectively, were successfully obtained from 40 mg of crude sample. [ABSTRACT FROM AUTHOR]

This study reports the first quantification study of pseudohypericin (PsHyp) and hypericin (Hyp) inHypericum undulatumSchousb. ex Willdin vitrocultures developed by a Portuguese company. Both compounds were quantified by high-performance liquid chromatography and their levels were compared with those in commercial samples ofHypericum perforatum. PsHyp was found to be the major naphthodianthrone ofH. undulatum,with an average ratio of 3.73:1 compared to Hyp. Significant statistical differences were found between the content of Hyp and PsHyp inH. undulatumregenerated shoots compared toin vivosamples. The mean concentration of total Hyps varied from 178.41 to 358.93 µg g−1dry extract inH. undulatumregenerated shoots, which is on average two to three times less than naphthodianthrone levels found inH. undulatum in vivoandH. perforatumcommercial samples. However, none of the analysed samples presented the levels of Hyps required by the European and United States Pharmacopoeias. [ABSTRACT FROM PUBLISHER]

Abstract: Hypericum perforatum extracts have been used to treat diseases, including mild-to-moderate depression and inflammatory conditions. It is particularly important to identify which constituents present in the H. perforatum extracts are responsible for its anti-inflammatory activity since consumers are taking H. perforatum preparations to treat inflammation. We used a combination of four putative bioactive constituents, called the 4-component-system that interacted synergistically to explain the light-activated anti-inflammatory activity of an H. perforatum fraction in RAW 264.7 mouse macrophages. We also combined the constituents at concentrations detected in the fraction to identify key molecular targets. LPS was used to model an inflammatory response, and the 4-component-system and H. perforatum fraction were used as treatments that inhibited LPS-induced prostaglandin E2 (PGE2) production in RAW 264.7 mouse macrophages in the studies of gene expression profiles. We used Affymetrix genechips, statistical analysis, and quantitative real-time PCR to identify key gene targets of the 4-component-system and the sub-fraction from an H. perforatum ethanol extract. The H. perforatum sub-fraction, with or without LPS stimulation, affected far more genes than the 4-component-system with and without LPS. Genes involved in Janus kinase, as well as a signal transducer and activator of transcription (JAK–STAT) and eicosanoid pathways were identified that could account for the reduction in PGE2 observed with both treatments in LPS-stimulated macrophages. Ten genes may be particularly important targets for activity of the 4-component-system and the fraction with LPS stimulation and these genes were involved in inflammatory signaling pathways, namely the JAK–STAT and eicosanoid pathways. [Copyright &y& Elsevier]

Abstract: Water stress is known to increase the secondary metabolites concentration in plant tissues and severe water stress conditions may cause oxidative stress due to the formation of reactive oxygen species and photoinhibitory damage. Current study was undertaken to evaluate the changes in the physiological status especially the photosynthetic efficiency and the biochemical profile of the leaf tissues of St. John''s wort (Hypericum perforatum) plants exposed to water stress. The net photosynthetic rates of the leaves of plants grown under a water stress condition were significantly low compared with those of the control. The maximal quantum efficiency of PSII photochemistry () of the dark adopted leaves was similar for both wilted and recovered plants although these values were significantly low compared with those of the control. The leaf tissues of the plants under a water stress condition had a significantly higher capacity to detoxify oxygen radicals with an about 2.5-fold increase over the antioxidant potential of the leaves of non-treated (control) or recovered plants. In the leaf tissues of plants grown under a water stress condition, both hypericin and pseudohypericin concentrations reduced with time and on Day 12 of the treatment, the concentration was significantly lower than that of the control; in contrast, the hyperforin concentration increased significantly and the value was nearly double after 12 days of the treatment. Under a water stress condition, the hyperforin concentration was about 70-fold higher than the total hypericins concentration in the leaf tissues; in case of control it was only 10–12 times higher. The results also indicate that the major secondary metabolite, hyperforin concentration of 62-day-old plants was three- to four-fold higher than the previously reported values for 1–2-year-old field-grown plants. [Copyright &y& Elsevier]

Phytochemical profiles and DNA fingerprints were obtained from 11 species and cultivars of Hypericum (H. androsaemum, H. calycinum, H. frondosum var. "Sunbrust", H. grandiflorum, H. inodorum, H. moseranum, H. olympicum, H. patulum vat. "Sungold", H. perforatum, H. pelforatum var. "Anthos", and H. perforatum vat. "Topas"). Accessions were identified using amplified fragment length polymorphism (AFLP) and DNA fingerprints. Although each accession had a distinctive DNA fingerprint, correlations between structurally similar plants and their DNA profiles were apparent. DNA banding patterns between each accession genetic distances were analyzed and quantified using a dendogram software program. High performance liquid chromatography (HPLC) was used to quantify the content of chlorogenic acid, hypertbrin, hypericin, pseudohypericin, and rutin in methanolic extracts of each Hypericum accession. Hypericum perforatum accessions and H. inodorum contained the highest concentration of marker phytochemicals, while H. calycimon, H. grandiflorum, and H. olympicunt contained the lowest concentration. AFLP profiles of the plants were correlated with their levels of marker phytochemicals enabling true to type identification and marker-assisted breeding programs. [ABSTRACT FROM AUTHOR]

Abstract: Several major constituents in St. John''s wort were determined for a homogenized plant sample. Three extraction techniques were evaluated: Soxhlet extraction, pressurized-fluid extraction (PFE), and sonication extraction. Levels of nine constituents (chlorogenic acid, rutin, hyperoside, isoquercitrin, quercitrin, quercetin, amentoflavone, pseudohypericin, and hypericin) were measured using liquid chromatography with ultraviolet/visible absorbance, mass spectrometric, and fluorescence detection. Levels of total naphthodianthrones determined by liquid chromatography (LC) with absorbance detection at 590nm were compared with levels determined by direct spectrophotometry at the same wavelength. Additionally, the methods described in this paper were applied to several brands of St. John''s wort finished products. [Copyright &y& Elsevier]

Abstract: Seedlings of Hypericum perforatum were grown with 0.01 and 0.1 mM of chromium added to the nutrient media. A treatment with 0.01 mM Cr(VI) for seven days resulted in an increased production of protopseudohypericin (+135%), hypericin (+38%) and pseudohypericin (+5%). Treatment with 0.1 mM Cr(VI) for two days also caused an increase of protopseudohypericin (+167%), hypericin (25%) and pseudohypericin (+5%). The greatest effect of chromium treatment was observed at a concentration of 0.1 mM for seven days: protopseudohypericin increased +404% and pseudohypericin to +379%. Hypericin was not affected by this treatment. [Copyright &y& Elsevier]

Abstract: Temperature stress is known to cause many physiological, biochemical and molecular changes in plant metabolism and possibly alter the secondary metabolite production in plants. The hypothesis of the current study was that temperature stress can increase the secondary metabolite concentrations in St. John''s wort. Plants were grown under controlled environments with artificial light using cool white fluorescent lamps and CO2 enrichment and 70-day-old plants were subjected for 15 days to different temperature treatments of 15, 20, 25, 30 and 35 °C before harvested. Major aim of the study was to increase the major secondary metabolites in St. John''s wort by applying temperature stress and to evaluate the physiological status of the plant especially the photosynthetic efficiency and peroxidase activity of the leaf tissues exposed to different temperatures under precisely controlled environmental factors. Results revealed that relatively high (35 °C) or low (15 °C) temperatures reduced the photosynthetic efficiency of the leaves of St. John''s wort plants and resulted in low CO2 assimilation. Net photosynthetic rates and the maximal quantum efficiency of PSII photochemistry of the dark adopted leaves (ϕp max) decreased significantly in the leaves of plants grown under 35 or 15 °C temperature treatments. High temperature (35 °C) treatment increased the leaf total peroxidase activity and also increased the hypericin, pseudohypericin and hyperforin concentrations in the shoot tissues. These results provide the first indication that temperature is an important environmental factor to optimize the secondary metabolite production in St. John''s wort and controlled environment technology can allow the precise application of such specific stresses. [Copyright &y& Elsevier]

Hypericum perforatum L. (St. John’s wort) is a traditional medicinal plant that has been used for the treatment of neurological disorders and depression. To investigate a large-scale in vitro growth system for St. John’s wort cv ‘New Stem’, six different culture systems, balloon type bubble bioreactor, temporary immersion bioreactor, temporary root zone immersion bioreactor, Erlenmeyer flask, large vessel with gelled medium under forced ventilation (LFV system), and Magenta vessel, were compared with greenhouse-grown plants for biomass production efficiency and accumulation of the selected bioactive molecules, hypericin, pseudohypericin, and hyperforin. After 25 days in culture, significantly more plant fresh mass was observed in a balloon type bubble (BB) bioreactor system than in other in vitro culture systems or in the greenhouse system. Plant dry mass was at a similar level in BB bioreactor, LFV system, and greenhouse. Chlorophylls a and b were highest in the leaves of plantlets grown in either large vessels with forced ventilation or temporary root zone immersion bioreactors. In general, levels of hypericin, pseudohypericin and hyperforin of the plantlets grown in the LFV system and levels of hypericin and pseudohypericin in the Magenta vessel were greater or similar to those in greenhouse-grown plants. Gelled medium (LFV system and Magenta vessel) had higher concentrations of hypericin and pseudohypericin than those grown in liquid medium. Together these results show that St. John’s wort can be efficiently produced in a variety of in vitro culture systems for aseptic production of bioactive compounds. [Copyright &y& Elsevier]

St. John''s wort (Hypericum perforatum L.) is widely used for the treatment of mild to moderately severe depression. However, the nature of its active principles and the exact mode of antidepressant action are still unknown. It has been suggested repeatedly in preclinical and clinical studies that the content of the acylphloroglucinol hyperforin decisively contributes to the antidepressant efficacy of St. John''s wort extracts. Experimental studies in vivo also indicate that the naphthodianthrone hypericin may reduce the activity of the hypothalamic–pituitary–adrenal axis. Exacerbated hypothalamic–pituitary–adrenal activity has often been associated with depressive states in patients. Corticotropin-releasing factor (CRF) seems to be a major determinant in the regulation of the hypothalamic–pituitary–adrenal activity via activation of CRF1 receptors. In the present study, we investigated the CRF1 receptor antagonist activity of three main constituents of St. John''s wort (hypericin, pseudohypericin and hyperforin) by measuring their effect on CRF-stimulated cAMP formation in recombinant Chinese hamster ovary (CHO) cells. As a selectivity test, the compounds were also tested against calcitonin in the same cells. Of the three compounds tested, only pseudohypericin selectively antagonised CRF (KB 0.76 μM). Hypericin and hyperforin affected both CRF and calcitonin with similar potencies and the same type of behaviour (competitive antagonism for hypericin, noncompetitive for hyperforin). It is concluded that pseudohypericin is the only real CRF1 receptor antagonist of the three constituents tested. In addition, evidence is provided that beside hyperforin, both pseudohypericin and hypericin are implicated in the antidepressant efficacy of St. John''s wort. [Copyright &y& Elsevier]

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