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Plants in the genus Hypericum (Hypericaceae), include more than 500 species worldwide, and many are valued for their medicinal properties, and are used as traditional herbal medicines. However, only H. perforatum is officially recognized as herbal drug in several pharmacopoeias, and used as an antidepressant clinically. Hypericum perforatum had been used as an herbal medicine since the Han Dynasty (206 B.C. -220 A.D.) in China. It taxonomically belongs to the section Hypericum in the genus Hypericum. There are about 42 species in the section Hypericum , with six species occurring in China. All six are recorded as traditional herbal medicines for treating aliments, including hepatitis, malaria, traumatic hemorrhage, irregular menstruation, wounds, and bruises. The study aimed to characterize the chemical profiles of five phylogenetically related Hypericum species, and compare their metabolites with three H. perforatum products. Informed by ethnobotanical use, the extracts prepared from the five species were further investigated into anticancer, anti-inflammatory and antiplasmodial activity. This study tested the hypothesis that systematic metabolomic and bioactivity characterization of species in section Hypericum will help to validate their phytotherapeutic use and reveal potential drug lead compounds. Targeted and non-targeted metabolic analyses coupled with chemometrics were conducted on H. perforatum and four medicinal species, H. attenuatum , H. enshiense , H. erectum , and H. faberi , native to China from section Hypericum. UPLC-QTOF-MS/MS and UPLC-TQD-MS/MS were used for non-targeted and targeted metabolic analyses, respectively. Cytotoxicity bioassays on four cancer cell lines, anti-inflammation tests and anti-plasmodial activity on Plasmodium falciparum 3D7, selected based on traditional medicinal use, were evaluated on extracts from Hypericum species. Progenesis QI and EZinfo were used for chemometrics analysis to link the chemical profile and bioassay activity to aid in the identification of bioactive compounds. In total, 58 compounds were identified from the five species, including compounds with well-characterized bioactivity. Hypericum attenuatum , H. erectum , and H. perforatum , displayed the highest cytotoxicity, and contain the cytotoxic compounds petiolin A, prolificin A, and hypercohin G, respectively. Hypericum faberi and H. perforatum showed the highest anti-inflammatory activity, with pseudohypericin, quercetin and chlorogenic acid being observed at higher concentrations. Hypericum perforatum and H. erectum showed anti-plasmodial activity, with higher hyperforin and xanthones in these species that may account for the anti-plasmodial activity. This study characterized the chemical differences among five Hypericum species using metabolomics. These ethnomedically important species were tested for their biological activities in three distinct in vitro assays. The ethnobotanical data were useful for identifying bioactive Hypericum species. Hypericum attenuatum , H. erectum and H. faberi are promising phytotherapeutic species, although they are much less studied than H. perforatum , St. John's wort. Combining ethnobotanical surveys with chemometric analyses and bioactivity screening can greatly enhance the discovery of promising active constituents. [Display omitted] • Profiled five Hypericum species with non-targeted and targeted chemometrics. • Identified 58 representative compounds from five species that drive chemotaxonomy. • Described Hypericum cytotoxicity, anti-inflammatory, and anti-plasmodial activity. • Employed chemometrics to aid in the identification of bioactive compounds. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The leaves of Phaleria nisidai Kaneh. (Thymelaeaceae) are brewed into a tea commonly used as a tonic, strengthening beverage and immune enhancer in Palau, Micronesia. Recently, the leaves of P. nisidai have been shown to contain toxic daphnane diterpene esters which may pose a public health threat to Palauans. Aims of the study This project documents the use frequency, preparation and side effects of P. nisidai . The content of daphnane diterpene esters in aqueous and methanol extracts and infusions prepared by healers in Palau is compared to assess the risk of daphnane ingestion associated with traditional consumption. Quantitative results are correlated with an in vitro assessment of the immunomodulating activity of the extracts. Materials and methods Research participants, comprising traditional healers and laypeople, were interviewed concerning use patterns and side effects of P. nisidai . Several traditional healers prepared and provided boiled tea samples for chemical analysis. Leaves were collected and methanolic and aqueous extractions were prepared in the laboratory. Peripheral blood mononuclear cells (PBMCs) were cultured with various concentrations of methanol and aqueous leaf extracts and their output of IFNγ was measured using ELISA. Cell proliferation was also assessed using the MTT assay. The concentration of selected daphnane diterpene esters in healer-prepared infusions, lab methanol and lab aqueous extracts was quantified using ultraperformance liquid chromatography-mass spectrometry-triple quadrupole detection (UPLC-MS-TQD). Results Through structured interviews it was determined that P. nisidai tea was used frequently, with many participants drinking it daily. The reported side effects were mild, and with the exception of diarrhea ( n =2), no side effect was mentioned more than once. Methanol extracts contained 4.0 μg simplexin, 17.6 μg acetoxyhuratoxin and 2.3 μg huratoxin per g dry leaf material. In traditional water infusions provided by healers and in standardized lab-prepared aqueous extracts all three compounds were below the limit of detection (16.3 ng/mL) using our UPLC-MS-TQD method. Methanol and aqueous extracts increased the release of IFNγ by PBMCs ( p <0.05); however, methanol extracts were significantly more active than aqueous extracts ( p <0.05). Methanol and aqueous extracts significantly increased proliferation of PBMCs, causing at least 60% more cell proliferation than negative control ( p <0.05). Conclusions The presence of daphnane diterpene esters in a frequently consumed traditional beverage was initially viewed as a public health concern, though interview data reveal that Palauans do not observe toxicity or side effects associated with their use of P. nisidai tea. Concurrently, daphnanes are present in methanolic extracts but not detected in aqueous preparations indicating that the traditional method of preparation avoids the extraction of these potentially toxic compounds, while still maintaining immunostimulant activity. [ABSTRACT FROM AUTHOR]