Four New Polyprenylated Acylphloroglucinols from Hypericum perforatum L.

Hyperforatums A-D (1-4), four new polyprenylated acylphloroglucinols, together with 13 known compounds were isolated and identified from the aerial parts of Hypericum perforatum L. (St. John's wort). Their structures were confirmed with a comprehensive analysis comprising spectroscopic methods, including 1D and 2D NMR, HRESIMS, and electronic circular dichroism (ECD) calculations. Hyperforatum A featured an unusual chromene-1,4-dione bicyclic system, and hyperforatums B and C were two rare monocyclic PPAPs with five-membered furanone cores. Compound 1 exhibited a moderate inhibition effect on NO production in BV-2 microglial cells stimulated by LPS.

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.

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.

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.

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.

Hypericum perforatum L.: a medicinal plant with potential as a curative agent against obesity-associated complications.

Obesity is a low-grade inflammatory disease that is getting increasingly common among adults and children and causes different complications. Insulin resistance, Type II diabetes, atherosclerosis, metabolic syndrome and hypertension are among the major health problems, that are associated with obesity. Some medications are used to treat obese individuals and metabolic surgery is recommended, if appropriate, for individuals with a BMI ≥ 40. Due to the fact that medications and metabolic surgery are not tolerated by all, researchers focus on alternative therapies. Medicinal plants comprise the most important group of these alternative treatments. Hypericum perforatum L. is the medicinal plant, which we focused on in this study. Hypericum perforatum L. has been recognized as a medicinally valuable plant for over 2000 years. It has been used for generations to treat anxiety, depression, insomnia, gastritis, hemorrhoids, wounds, and burns. Recent studies have indeed shown promising effects for the treatment of obesity. In this study, 3T3-L1 adipocytes were used to mimic the adipocyte differentiation associated with obesity in cellular terms. Lipoprotein lipase (Lpl), Diacylglycerol-O-acyltransferase 1 (Dgat1), Fatty acid synthase (Fasn) markers were used to study the lipid accumulation, and Collagen V (ColV) was used to study cell elasticity to investigate the relationship of the effects of the administration of Hypericum perforatum L. with obesity.

Medicinal plants as therapeutic options for topical treatment in canine dermatology? A systematic review.

BACKGROUND: Medicinal plants have been used traditionally since centuries for wound care and treatment of skin diseases both in human and animals. Skin diseases are one of the most common reasons for owners to take their dog to the veterinarian. The demands for treatment and prophylaxis of these diseases are broad. A wide range of bacteria including antibiotic-resistant bacteria can be involved, making the treatment challenging and bear an anthropo-zoonotic potential. The aim of this review is to systematically evaluate based on recent scientific literature, the potential of four medicinal plants to enrich the therapeutic options in pyoderma, canine atopic dermatitis, otitis externa, wounds and dermatophytosis in dogs. RESULTS: Based on four books and a survey among veterinarians specialized in phytotherapy, four medicinal plants were chosen as the subject of this systematic review: Calendula officinalis L. (Marigold), Hypericum perforatum L. agg. (St. John's Wort), Matricaria chamomilla L. (syn. Matricaria recutita L., Chamomile) and Salvia officinalis L. (Sage). According to the PRISMA statement through literature research on two online databases a total of 8295 publications was screened and narrowed down to a final 138 publications for which full-text documents were analyzed for its content resulting in a total of 145 references (21 clinical, 24 in vivo and 100 in vitro references). CONCLUSIONS: All four plants were proven to have antibacterial and antifungal effects of a rather broad spectrum including antibiotic-resistant bacteria. This makes them an interesting new option for the treatment of pyoderma, otitis externa, infected wounds and dermatophytosis. Marigold, St. John's Wort and Chamomile showed wound-healing properties and are thus promising candidates in line to fill the therapeutic gap in canine wound-healing agents. St. John's Wort and Chamomile also showed anti-inflammatory and other beneficial effects on healthy skin. Due to the wide range of beneficial effects of these medicinal plants, they should be taken into account for the treatment of dermatologic diseases in dogs at least in future clinical research.

The Effects of Hypericum perforatum L. on the Proliferation, Osteogenic Differentiation, and Inflammatory Response of Mesenchymal Stem Cells from Different Niches.

The aim of this study is to demonstrate and compare the differentiation, proliferation, migration and inflammatory behavior of dental pulp- and bone marrow-derived mesenchymal stem cells (DP-MSCs and BM-MSCs) in response to a Hypericum perforatum ethanol extract. Using xCELLigence, a real-time monitoring system, a dose of 10 µg/mL was found to be the most efficient concentration for vitality. The IC50 values and doubling time were calculated. The results showed that H. perforatum L. was able to accelerate osteogenic differentiation in DP-MSCs, but calcium granulation was impaired in BM-MSCs. H. perforatum L.-induced migration increased when compared to the TNF-α-induced migration in a Transwell migration assay, and the IL-6 cytokine levels between cells also differed. It can be suggested that tissue memory is an important factor in MSCs, and that they differ in their response to external factors. In conclusion, H. perforatum L. can be considered an excellent osteoinductive agent for DP-MSCs but should not be used for BM-MSCs. Tissue-specific osteoinductive agents should be discussed in future studies.

Effects of Hypericum perforatum extract on oxaliplatin-induced neurotoxicity: in vitro evaluations.

Hypericum perforatum L. has been used for centuries as a natural remedy for the treatment of many disorders. Neuropathic pain is a common side effect of oxaliplatin-based chemotherapy and often the cause of therapy discontinuation. Thanks to its anti-inflammatory and analgesic effects, the use of H. perforatum may be a novel therapeutic strategy for neuropathy. The aim of this paper was to evaluate the effect of H. perforatum hydrophilic extract on an in vitro model of oxaliplatin-induced neurotoxicity. The antioxidant potential of extract was first evaluated in cell-free models by the thiobarbituric acid-reactive substances assay and nitro blue tetrazolium oxidation test; the ability of H. perforatum extract to reduce oxaliplatin-induced caspase-3 activity in rat astrocytes and its potential interference with the cytotoxic effects of oxaliplatin in a colorectal cancer in vitro model (HT-29 cells) were also evaluated. The extract showed a significant antioxidant effect and was able to reduce caspase-3 activity in rat astrocytes. Of note, the extract alone exerted a cytotoxic effect in HT-29 cells and did not reduce the cytotoxicity of oxaliplatin in HT-29 cells. These data suggest that H. perforatum could be used as a novel therapeutic strategy for counteracting chemotherapy-induced neuropathy.

Hypericum Perforatum Hydroalcoholic Extract Mitigates Motor Dysfunction and is Neuroprotective in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

Parkinson's disease is the second most common neurodegenerative disorder with selective and progressive decline of nigral dopaminergic neurons. Hypericum perforatum L. (H. perforatum, St. John's wort) has been traditionally used for management of different disorders, especially mild-to-moderate depression. This study was conducted to evaluate the effect of H. perforatum extract against unilateral striatal 6-hydroxydopamine (6-OHDA) toxicity and to unmask some involved mechanisms. Intrastriatal 6-OHDA-lesioned rats were treated with H. perforatum hydroalcoholic extract at a dose of 200 mg/kg/day started 1 week pre-surgery for 1 week post-surgery. The extract attenuated apomorphine-induced rotational behavior, decreased the latency to initiate and the total time on the narrow beam task, lowered striatal level of malondialdehyde and enhanced striatal catalase activity and reduced glutathione content, normalized striatal expression of glial fibrillary acidic protein, tumor necrosis factor α with no significant effect on mitogen-activated protein kinase, lowered nigral DNA fragmentation, and prevented damage of nigral dopaminergic neurons with a higher striatal tyrosine hydroxylase immunoreactivity. These findings reveal the beneficial effect of H. perforatum via attenuation of DNA fragmentation, astrogliosis, inflammation, and oxidative stress.

Effect of Hypericum perforatum L. extract on insulin resistance and lipid metabolic disorder in high-fat-diet induced obese mice.

Natural product Hypericum perforatum L. has been used in folk medicine to improve mental performance. However, the effect of H. perforatum L. on metabolism is still unknown. In order to test whether H. perforatum L. extract (EHP) has an effect on metabolic syndrome, we treated diet induced obese (DIO) C57BL/6J mice with the extract. The chemical characters of EHP were investigated with thin-layer chromatography, ultraviolet, high-performance liquid chromatography (HPLC), and HPLC-mass spectrometry fingerprint analysis. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and the glucose infusion rate (GIR) in hyperinsulinemic-euglycemic clamp test were performed to evaluate the glucose metabolism and insulin sensitivity. Skeletal muscle was examined for lipid metabolism. The results suggest that EHP can significantly improve the glucose and lipid metabolism in DIO mice. In vitro, EHP inhibited the catalytic activity of recombinant human protein tyrosine phosphatase 1B (PTP1B) and reduced the protein and mRNA levels of PTP1B in the skeletal muscle. Moreover, expressions of genes related to fatty acid uptake and oxidation were changed by EHP in the skeletal muscle. These results suggest that EHP may improve insulin resistance and lipid metabolism in DIO mice.

Hypericum perforatum L. preparations for menopause: a meta-analysis of efficacy and safety.

OBJECTIVE: To compare by meta-analysis the efficacy and adverse events of Hypericum perforatum L. (St. John's Wort), or its combinations, and placebo for menopausal women. DESIGN: A systematic review and meta-analysis were carried out by searching in Pubmed, Cochrane Library, Embase and the Web of Science database. RESULTS: Extracts of Hypericum perforatum L. and its combination with herbs were significantly superior to placebo (standard mean difference = -1.08; 95% confidence interval -1.38 to -0.77); extracts of Hypericum perforatum L. proved to be more effective than placebo in the treatment of menopause. Adverse events occurred in 53 (17.4%) patients on Hypericum perforatum L. preparations and 45 (15.4%) patients on placebo (relative risk = 1.16; 95% confidence interval 0.81-1.66). CONCLUSION: Extracts of Hypericum perforatum L. have possibly fewer side-effects than placebo for the treatment of menopausal women.

Hyperguanyes A and B, two new PPAPs from the branches and leaves of Hypericum perforatum L. with anti-cholinesterase activities.

Two new polycyclic polyprenylated acylphloroglucinols, hyperguanyes A and B (1-2) together with eight known compounds (3-10), were isolated from Hypericum perforatum L. Their structures were determined by using comprehensive spectroscopic techniques and quantum chemical calculation. The in vitro anti-cholinesterase activity of all compounds were studied. Among them, compounds 1-4, 8 and 9 exhibited anti-AchE and anti-BchE effects with IC50 ranging from 0.34 ± 0.04 to 15.68 ± 0.54 µM.

UPLC-Q-TOF-MS/MS combined with machine learning methods for screening quality indicators of Hypericum perforatum L.

Hypericum perforatum L. (HPL), also known as St. John's wort, is one of the extensively researched domestically and internationally as a medicinal plant. In this study, non-targeted metabolomics combined with machine learning methods were used to identify reasonable quality indicators for the holistic quality control of HPL. First, the high-resolution MS data from different samples of HPL were collected, and visualized the chemical compounds through the MS molecular network. A total of 122 compounds were identified. Then, the orthogonal partial least squares-discriminant analysis (OPLS-DA) model was established for comparing the differences in metabolite expression between flower, leaf, and branches. A total of 46 differential metabolites were screened out. Subsequently, analyzing the pharmacological activities of these differential metabolites based on protein-protein interaction (PPI) network. A total of 25 compounds associated with 473 gene targets were retrieved. Among them, 13 highly active compounds were selected as potential quality markers, and five compounds were ultimately selected as quality control markers for HPL. Finally, three different classifiers (support vector machine (SVM), random forest (RF), and K-nearest neighbor (KNN)) were used to validate whether the selected quality control markers are qualified. When the feature count is set to 122 and 46, the RF model demonstrates optimal performance. As the number of variables decreases, the performance of the RF model degrades. The KNN model and the SVM model also exhibit a decrease in performance but still manage to satisfy the intended requirements. The strategy can be applied to the quality control of HPL and can provide a reference for the quality control of other herbal medicines.

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.

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. attenuates depression by regulating Akkermansia muciniphila, tryptophan metabolism and NFκB-NLRP2-Caspase1-IL1ß pathway.

BACKGROUND: Gut microbiota dysbiosis significantly contributes to progression of depression. Hypericum perforatum L. (HPL) is traditionally used in Europe for treating depression. However, its mechanism remains largely underexplored. PURPOSE: This study aims to investigate the pivotal gut microbiota species and microbial signaling metabolites associated with the antidepressant effects of HPL. METHODS: Fecal microbiota transplantation was used to assess whether HPL mitigates depression through alterations in gut microbiota. Microbiota and metabolic profiling of control, chronic restraint stress (CRS)-induced depression, and HPL-treated CRS mice were examined using 16S rRNA gene sequencing and metabolomics analysis. The influence of gut microbiota on HPL's antidepressant effects was assessed by metabolite and bacterial intervention experiments. RESULTS: HPL significantly alleviated depression symptoms in a manner dependent on gut microbiota and restored gut microbial composition by enriching Akkermansia muciniphila (AKK). Metabolomic analysis indicated that HPL regulated tryptophan metabolism, reducing kynurenine (KYN) levels derived from microbiota and increasing 5-hydroxytryptophan (5-HTP) levels. Notably, supplementation with KYN activated the NFκB-NLRP2-Caspase1-IL1ß pathway and increased proinflammatory IL1ß in the hippocampus of mice with depression. Interestingly, mono-colonization with AKK notably increased 5-hydroxytryptamine (5-HT) and decreased KYN levels, ameliorating depression symptoms through modulation of the NFκB-NLRP2-Caspase1-IL1ß pathway. CONCLUSIONS: The promising therapeutic role of HPL in treating depression is primarily attributed to its regulation of the NFκB-NLRP2-Caspase1-IL1ß pathway, specifically by targeting AKK and tryptophan metabolites.

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.

Hyperipersions A-C, three new acylphloroglucinols from the branches and leaves of Hypericum perforatum L. with antiangiogenic activities.

Three new acylphloroglucinols were isolated from the branches and leaves of Hypericum perforatum L., named as hyperipersions A-C (1-3), together with three known compounds which were identified as elegaphenone (4), 2,6-dihydroxy-3,4-dimethylbenzoic acid methyl ester (5) and 2,3-methylenedioxyxanthone (6), respectively. The structures of isolated compounds were determined by UV, IR, HR-ESI-MS, NMR analysis. Their antiangiogenic activities were studied against HUVECs. The IC50 value of compound 3 was 2.39 ± 0.21 µM against HUVECs, which was stronger than vatalanib, and other compounds had moderate antiangiogenic activity.

Two new constituents from the endophyte of Alternaria alternata and its anti-neuroinflammatory activity guided by molecular docking.

Two new compounds, 3-hydroxy-1-(3-hydroxy-5-methoxyphenyl)-2-methyl propan-1-one (1) and 1,2,6-trihydroxy-8-methoxy-2,3,3a,9b-tetrahydrocyclopenta[c] isochromen-5(1H)-one (2), along with nine known compounds 3-11, involving pyranones, phenylpropenoids and alkaloids, were obtained from Alternaria alternata, an endophyte isolated from Hypericum perforatum L. The structures were elucidated by extensive spectroscopic analyses, including 1D NMR, 2D NMR, HRESIMS, IR, UV spectroscopy. The absolute configuration was established via spectroscopy techniques and X-ray crystallisation method. Furthermore, guided by molecular docking, compounds 1 and 3 exhibited promising anti-neuroinflammatory activity in LPS-induced BV-2 microglial cells, with IC50 values of 0.9 ± 0.3 µM and 3.0 ± 0.4 µM respectively. Moreover, they effectively attenuated the LPS-induced elevation of NO, TNF-α, IL-6, and IL-1ß production in BV-2 microglial cells. These findings diversify the metabolite of A. alternata and highlight their potential as leading compounds against neuroinflammatory-related diseases.