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.

Hyparillums A and B: polycyclic polyprenylated acylphloroglucinols from Hypericum patulum.

Hyparillums A (1) and B (2), two previously unidentified polycyclic polyprenylated acylphloroglucinols (PPAPs) with intricate architectures, were isolated from Hypericum patulum Thunb. Hyparillum A was the first PPAP with eight-carbon rings based on an unprecedented 6/6/5/6/6/5/6/4 octocyclic system featuring a rare heptacyclo[10.8.1.11,10.03,8.08,21.012,19.014,17]docosane core. In contrast, hyparillum B featured a novel heptacyclic architecture (6/6/5/6/6/5/5) based on a hexacyclo[9.6.1.11,9.03,7.07,18.011,16]nonadecane motif. Furthermore, hyparillums A and B demonstrated promising inhibitory effects on the proliferation of murine splenocytes stimulated by anti-CD3/anti-CD28 monoclonal antibodies and lipopolysaccharide, exhibiting half-maximal inhibitory concentration (IC50) values ranging from 6.13 ± 0.86 to 12.69 ± 1.31 µmol·L-1.

Discovery of bioactive polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons from Hypericum wilsonii.

In this work, nine previous undescribed polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons, cumilcinols A-I (1-9), along with six known analogues, were isolated and identified from the stems, leaves and flowers of Hypericum wilsonii. Their structures were determined by HRESIMS, NMR spectroscopic analysis, single-crystal X-ray crystallography as well as electronic circular dichroism calculations and comparisons. Compound 2 formed a unique furan ring bearing a rare acetal functionality. In bioassays, hyperacmosin G (13) could significantly inhibit the production of NO in LPS-stimulated RAW264.7 cell (IC50 = 4.350 ± 1.146 µM), and increased expression of related transcription factors at the gene level, inhibit the nuclear translocation of NF-κBp65, and reduce the protein expression of COX-2. Additionally, compound 5 showed significant inhibitory activity on Con A-induced T-lymphocyte proliferation (IC50 = 4.803 ± 3.149 µM), and treatment of 5 could reduce the increased ratio of CD4 and CD8 subpopulations induced by Con A in vitro. Those results indicated 13 possesses potential anti-inflammatory activity, and 5 exhibits a certain degree of immunosuppressive activity.

Three new Furano-lactones from the endophytic fungus Aspergillus nidulans.

Three new furano-lactones, asperilactones A-C (1-3), and two known compounds silvaticol (4) and violaceic acid (5) were isolated from an ethanol extract of Aspergillus nidulans, a fungus isolated from the Annelida Whitmania pigra Whitman (Haemopidae). Their structures were elucidated by a combination of spectroscopy, ECD calculations, comparing optical rotation values, and single-crystal X-ray diffraction analyses. Asperilactone A (1) represented the first example of furano-lactone with an unusual 2-thia-6-oxabicyclo[3.3.0]octane ring system. Asperilactones A and B showed weak toxicity against the HL-60 and RKO.

Prenyllongnols A-D, New Prenylated Acylphloroglucinols that Fight Concanavalin A-Induced Autoimmune Hepatitis.

Autoimmune hepatitis is a serious hepatic disorder with unknown nosogenesis, and natural products have been deemed to be one of the most significant sources of new drugs against this disease. Prenyllongnols A-D (1-4), four undescribed prenylated acylphloroglucinols, were isolated from Hypericum longistylum. Compounds 1-4 exhibited remarkable immunosuppressive activities in murine splenocyte proliferation under the induction of concanavalin A (Con A), and IC50 values ranged from 2.98 ± 0.21 to 6.34 ± 0.72 µM. Furthermore, in a Con A-challenged autoimmune hepatitis mouse model, the mice in the group that were pretreated with isolate 2 significantly ameliorated liver injury and decreased proinflammatory cytokine production. Notably, natural product 2 was the first prenylated acylphloroglucinol to protect against concanavalin A-induced autoimmune hepatitis. This finding underscores the potential of prenylated acylphloroglucinol-type metabolites as promising candidates for designing novel immunosuppressors in the quest for new antiautoimmune hepatitis drugs.

Polyketides with Anti-Inflammatory Activity from Trichoderma koningiopsis, a Rhizosphere Fungus from the Medicinal Plant Polygonum paleaceum.

Twelve new fungal polyketides, koningiopisins I-P (1-8) and trichoketides C-F (9-12), together with six known congeners (13-18), were isolated from Trichoderma koningiopsis, a rhizosphere fungus obtained from the medicinal plant Polygonum paleaceum. Their structures and absolute configurations were established by spectroscopic analysis, single-crystal X-ray diffraction, the modified Mosher's method, chemical derivatization, the octant rule, and 13C NMR and ECD calculations. Compounds 1-5 are tricyclic polyketides possessing an octahydrochromene framework with a 6,8-dioxabicyclo[3.2.1]octane core. Compounds 7 and 8 contain a unique ketone carbonyl group at C-7 and differ from other members of this group of compounds with the ketone carbonyl group at C-1. Compounds 1, 2, and 13 showed inhibitory activity on LPS-induced BV-2 cells on NO production with IC50 values of 14 ± 1, 3.0 ± 0.5, and 8.9 ± 2.7 µM, respectively.

Anti-inflammatory effect of dictamnine on allergic rhinitis via suppression of the LYN kinase-mediated molecular signaling pathway during mast cell activation.

Mast cells (MCs) are important therapeutic targets for allergic diseases. High-affinity immunoglobulin E (IgE) Fc receptors (FcεRI) trigger abnormal activation of MCs. Allergic rhinitis (AR) is an IgE-mediated antigen inhalation reaction that occurs in the nasal mucosa. MC aggravation and dysfunction were observed during the early stages of AR pathogenesis. Herb-derived dictamnine exhibits anti-inflammatory effects. Here, we investigated the pharmacological effects of herb-derived dictamnine on IgE-induced activation of MCs and an ovalbumin (OVA)-induced murine AR model. The results indicated that dictamnine attenuated OVA-induced local allergic reactions and reduced body temperature in OVA-challenged mice with active systemic anaphylaxis. Additionally, dictamnine decreased the frequency of nasal rubbing and sneezing in an OVA-induced murine AR model. Moreover, dictamnine inhibited FcεRI-activated MC activation in a dose-dependent manner without causing cytotoxicity, reduced the activation of the tyrosine kinase LYN in LAD2 cells, and downregulated the phosphorylation of PLCγ1, IP3R, PKC, Erk1/2, and Akt, which are downstream of LYN. In conclusion, dictamnine suppressed the OVA-stimulated murine model of AR and activated IgE-induced MCs via the LYN kinase-mediated molecular signaling pathway, suggesting that dictamnine may be a promising treatment for AR.

Trichodermatides A-D, four new polyketides from Trichoderma sp. XM-3.

Four new polyketides named trichodermatides A-D (1-4), along with five known analogues (5-9), were isolated from the fungus Trichoderma sp. XM-3. Their structures were elucidated on the basis of HRESIMS and NMR analyses, and their absolute configurations were determined by ECD comparison, 1H and 13C NMR calculation, DP4+ analysis, modified Mosher's method, and X-ray crystallography. Trichodermaketone D (9) showed mild antibacterial activity against Pseudomonas aeruginosa.

Alpha-linolenic acid improves nasal mucosa epithelial barrier function in allergic rhinitis by arresting CD4+ T cell differentiation via IL-4Rα-JAK2-STAT3 pathway.

BACKGROUND: Allergic rhinitis (AR) defined as inflammation and tissue remodeling of the nasal mucosa in atopic individuals after allergen exposure. Alpha-linolenic acid [cis-9, cis-12, cis-15-octadecatrienoic acid (18:3)] (ALA) as dietary supplementation can reduce inflammation and allergic symptoms. OBJECTIVE: To evaluate the potential therapeutic effect and mechanism of ALA in AR mouse model. METHODS: Ovalbumin sensitized AR mouse model were challenged with oral ALA administration. Nasal symptoms, tissue pathology, immune cell infiltration and goblet cell hyperplasia were investigated. Levels of IgE, TNF-ß, IFN-γ, IL-2, IL-4, IL-5, IL-12, IL-13 and IL-25 were determined by ELISA in serum and nasal fluid. Quantitative RT-PCR and immunofluorescence were performed for occludin and zonula occludens-1 expression. CD3+CD4+ T-cells from peripheral blood and splenic lymphocytes were isolated and Th1/Th2 ratio were determined. Mouse naive CD4+ T cell were isolated and Th1/Th2 ratio, IL-4Rα expression, and IL5/IL13 secretion were determined. IL-4Rα-JAK2-STAT3 pathway change in AR mice were performed by western blot. RESULTS: Ovalbumin induced AR, nasal symptoms, pathological performance, IgE, and cytokine production. ALA treated mice showed reduced nasal symptoms, nasal inflammation, nasal septum thickening, goblet cell hyperplasia, and eosinophil infiltration. In serum and nasal fluid of ovalbumin challenged mice, ALA decreased IgE, IL-4 levels, and the increase of Th2-cells. ALA prevented the disruption of the epithelial cell barrier in ovalbumin-challenged AR mice. Simultaneously, ALA prevents IL-4 induced barrier disruption. ALA treatment of AR by affecting the differentiation stage of CD4+T cells and block IL-4Rα-JAK2-STAT3 pathway. CONCLUSION: This study suggests that ALA has the potential therapeutic effect to ovalbumin-induced AR. ALA can affect the differentiation stage of CD4+T cells and improve epithelial barrier functions through IL-4Rα-JAK2-STAT3 pathways. CLINICAL IMPLICATION: ALA might be considered as drug candidate for improving epithelial barrier function through Th1/Th2 ratio recovery in AR.

Kinsenoside alleviates oxidative stress-induced blood-brain barrier dysfunction via promoting Nrf2/HO-1 pathway in ischemic stroke.

An ischemic stroke usually causes blood-brain barrier (BBB) damage and excessive oxidative stress (OS) levels. Kinsenoside (KD), a major effective compound extracted in Chinese herbal medicine Anoectochilus roxburghii (Orchidaceae), has anti-OS effects. The present study focused on exploring KD's protection against OS-mediated cerebral endothelial cell damage and BBB damage within the mouse model. Intracerebroventricular administration of KD upon reperfusion after 1 h ischemia decreased infarct volumes, neurological deficit, brain edema, neuronal loss, and apoptosis 72 h post-ischemic stroke. KD improved BBB structure and function, as evidenced by a lower 18F-fluorodeoxyglucose pass rate of the BBB and upregulation of tight junction (TJ) proteins such as occludin, claudin-5, and zonula occludens-1 (ZO-1). KD protected bEnd.3 endothelial cells from oxygen and glucose deprivation/reoxygenation (OGD/R) injury in an in-vitro study. Meanwhile, OGD/R reduced transepithelial electronic resistance, whereas KD significantly increased TJ protein levels. Furthermore, based on in-vivo and in-vitro research, KD alleviated OS in endothelial cells, which is related to nuclear factor, erythroid 2 like 2 (Nrf2) nuclear translocation as well as Nrf2/haem oxygenase 1 signaling protein stimulation. Our findings demonstrated that KD might serve as a potential compound for treating ischemic stroke involving antioxidant mechanisms.

Geranylated or prenylated flavonoids from Cajanus volubilis.

Five new flavonoid derivatives, cajavolubones A-E (1-5), along with six known analogues (6-11) were isolated from Cajanus volubilis, and their structures were elucidated by spectroscopic analysis and quantum chemical calculations. Cajavolubones A and B (1 and 2) were identified as two geranylated chalcones. Cajavolubone C (3) was a prenylated flavone, while cajavolubones D and E (4 and 5) were two prenylated isoflavanones. Compounds 3, 8, 9 and 11 displayed cytotoxicity against HCT-116 cancer cell line.

Silibinin attenuated pseudo-allergic reactions and mast cell degranulation via PLCγ and PI3K/Akt signaling pathway.

Anaphylaxis is a type of potentially fatal hypersensitivity reaction resulting from the activation of mast cells. Many endogenous or exogenous factors could cause this reaction. Silibinin is the main chemical component of silymarin and has been reported to have pharmacological activities. However, the anti-allergic reaction effect of silibinin has not yet been investigated. This study aimed to evaluate the effect of silibinin to attenuate pseudo-allergic reactions in vivo and to investigate the underlying mechanism in vitro. In this study, calcium imaging was used to assess Ca2+ mobilization. The levels of cytokines and chemokines, released by stimulated mast cells, were measured using enzyme immunoassay kits. The activity of silibinin was evaluated in a mouse model of passive cutaneous anaphylaxis (PCA). Western blotting was used to explore the related molecular signaling pathways. In results, silibinin markedly inhibited mast cell degranulation, calcium mobilization, and preventing the release of cytokines and chemokines in a dose-dependent manner via the PLCγ and PI3K/Akt signaling pathway. Silibinin also attenuated PCA in a dose-dependent manner. In summary, silibinin has an anti-pseudo-allergic pharmacological activity, which makes it a potential candidate for the development of a novel agent to arrest pseudo-allergic reactions.

Myricetin alleviated immunologic contact urticaria and mast cell degranulation via the PI3K/Akt/NF-κB pathway.

Immunologic contact urticaria (ICU) is characterized by the wheal and flare reaction from direct contact with a chemical or protein agent, which involves a type I hypersensitivity mediated by allergen-specific immunoglobulin E (sIgE). Myricetin (Myr), a bioactive flavonoid, exhibits antiinflammatory activities. Our results showed that treatment with Myr could alleviate ICU symptoms, including a decrease in the number of wheals and scratching, and inhibit ear swelling in the IgE/DNFB-induced mice. The serum level of IgE, histamine, interleukin (IL)-4, TNF-α, and MCP-1 were reduced in Myr-treated mice. Myr also attenuated mast cells (MCs) degranulation and H-PGDS, TSLP, IL-33, PI3K, Akt, and NF-κB mRNA levels in ICU model. The IgE-mediated anaphylaxis mouse models demonstrated anti-allergic effects of Myr. In vitro analysis showed that Myr reduced IgE-induced calcium (Ca2+ ) influx, suppressed degranulation, and chemokine release in LAD2 cells (human primary mast cells). Myr can significantly inhibited PLCγ1, Akt, NF-κB, and p38 phosphorylation. In conclusion, the study demonstrated that Myr alleviate ICU symptoms and inhibit mast cell activation via PI3K/Akt/NF-κB signal pathway.

A new diketopiperazine-type alkaloid from the endophytic fungus Penicillium expansum.

A chemical investigation on an endophytic fungus Penicillium expansum isolated from the medicinal plant Plantago depressa Willd. (Plantaginaceae) afforded one new diketopiperazine-type alkaloid, namely penicimine A (1), as well as two known congeners (2 and 3). Their structures were elucidated by widespread spectroscopic data, and the absolute configurations of 1 and 2 were further confirmed by single-crystal X-ray diffraction analyses. Compound 1 represented the first example of benzyl-containing diketopiperazine-type alkaloid bearing a methyl group attached at C-15 position. Compound 1 showed anti-inflammatory activity against LPS-induced nitric oxide (NO) production in RAW264.7 mouse macrophages with an IC50 value of 25.65 µM.

Effects of light source and inter-species mixed culture on the growth of microalgae and bacteria for nutrient recycling and microalgae harvesting using black odorous water as the medium.

To achieve the sustainable and effective removal efficiency of nutrients in black odorous water, light source, inter-species microalgae mixed culture, and the harvesting effect were all explored. The results showed that under a LED light source, the addition of interspecific soluble algal products (SAP) promoted the growth of Haematococcus pluvialis (H. pluvialis) M1, and its maximum specific growth rate was 1.76 times that of H. pluvialis cultivated alone. That was due to the hormesis effect between the two kinds of microalgae, the SAP produced by Scenedesmus could stimulate the growth of H. pluvialis. The algae and bacteria symbiotic system with black odorous water as the medium showed excellent performance to treat nutrients, where the concentration of ammonia nitrogen (NH3-N) and total phosphorus (TP) (0.84, 0.23 mg/L) met the requirements of landscape water. The microbial diversity analysis revealed that the introduction of microalgae changed the dominant species of the bacterial community from Bacteroidota to Proteobacteria. Furthermore, timely microalgae harvesting could prevent water quality from deteriorating and was conducive to microalgae growth and resource recycling. The higher harvest efficiency (98.1%) of H. pluvialis was obtained when an inoculation size of 20% and 0.16 g/L FeCl3 were provided.

An unprecedented ergostane with a 6/6/5 tricyclic 13(14 → 8)abeo-8,14-seco skeleton from Talaromyces adpressus.

Talasterone A (1), an unprecedented 6/6/5 tricyclic 13(14 â†’ 8)abeo-8,14-seco-ergostane steroid, together with two known congeners dankasterone B (2) and (14ß,22E)-9,14-dihydroxyergosta-4,7,22-triene-3,6-dione (3), were characterized from Talaromyces adpressus. The structure of 1 with absolute configuration was elucidated based on NMR spectroscopic data and ECD calculation. Compound 2 belongs to a class of unconventional 13(14 â†’ 8)abeo-ergostanes, which have been renewed via the 1,2-migration of C-13-C-14 bond to C-8. In addition, compound 1 represents the first example of ergostane with a tricyclic 13(14 â†’ 8)abeo-8,14-seco-ergostane skeleton. The proposed biosynthetic pathway was established with the support of the coisolation of the known congeners from the producing organism. It is especially noteworthy that compound 1 exhibited potent anti-inflammatory activity with an IC50 value of 8.73 ± 0.66 µM, inhibiting the NF-κB pathway and thus reducing the production of proinflammatory cytokines.

Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-κB/NLRP3 signaling pathway.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) has replaced viral hepatitis as the main driver of the rising morbidity and mortality associated with cirrhosis and liver cancer worldwide, while no FDA-approved therapies are currently known. Kinsenoside (KD), naturally isolated from Anoectochilus roxburghii, possesses multiple biological activities, including lipolysis, anti-inflammation, and hepatoprotection. However, the effects of KD on NASH remain unclear. PURPOSE: This study aimed to explore the roles of KD in NASH and its engaged mechanisms. METHODS: Two typical animal models of NASH, mice fed a methionine-choline-deficient (MCD) diet (representing non-obese NASH) and mice fed a high-fat and -fructose diet (HFFD) (representing obese NASH), were used to investigate the effect of KD on NASH in vivo. Transcriptome sequencing was performed to elucidate the underlying mechanisms of KD. Lipopolysaccharide (LPS)-stimulated THP-1 cells and transforming growth factor ß1 (TGF-ß1)-activated LX-2 cells were applied to further explore the effects and mechanisms of KD in vitro. RESULTS: The intragastric administration of KD remarkably alleviated MCD/HFFD-induced murine NASH almost in a dose-dependent manner. Specifically, KD reduced lipid accumulation, inflammation, and fibrosis in the liver of NASH mice. KD ameliorated alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), and malondialdehyde (MDA) abnormalities. In addition, it decreased the level of serum proinflammatory factors (IL-12p70, IL-6, TNF-α, MCP-1, IFN-γ) and the hepatic expression of typical fibrosis-related molecules (α-SMA, Col-I, TIMP-1). Mechanically, KD attenuated the MCD/HFFD-induced NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Consistently, KD reduced inflammation stimulated by LPS in THP-1 cells via suppressing the NF-κB/NLRP3 pathway. Furthermore, it prevented the activation of LX-2 cells directly, by inhibiting the proliferation stimulated by TGF-ß1, and indirectly, by inactivating the NLRP3 inflammasome in macrophages. CONCLUSION: For the first time, the practical improvement of NASH by KD was revealed. Our study found that KD exerted its alleviative effects on NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Given its hepatoprotective and nontoxic properties, KD has the potential to be a novel and effective drug to treat NASH.

(±)-Walskiiglucinol A, a pair of rearranged acylphloroglucinol derivative enantiomers from Hypericum przewalskii.

(±)-Walskiiglucinol A (1a/1b), a pair of rearranged acylphloroglucinol derivatives with a new carbon skeleton, was obtained from Hypericum przewalskii. Compounds 1a/1b were the first examples of naturally occurring acylphloroglucinol derivatives possessing a unique 1-oxaspiro[4.4]nonane core bearing a new 5/5 ring system. Their planar and relative structures were identified by extensive spectroscopic analysis and NMR chemical shift calculations with DP4+ probability analysis, and their absolute configurations were determined by electronic circular dichroism (ECD) calculations. A plausible biogenetic pathway of 1a/1b was proposed in which the breakage of the C-2/C-3 linkage via a retro-Claisen reaction and the cyclization between C-3 and C-1 were proposed as key steps. The isolates were evaluated for cytotoxic activities against a panel of cancer cell lines and anti-inflammatory activities against lipopolysaccharide (LPS)-induced NO production, and compounds 1a/1b showed moderate cytotoxic activities with IC50 values ranging from 9.72 to 36.75 µM.

Norprzewalsone A, a Rearranged Polycyclic Polyprenylated Acylphloroglucinol with a Spiro[cyclopentane-1,3'-tricyclo[7.4.0.01,6]tridecane] Core from Hypericum przewalskii.

Norprzewalsone A (1), a rearranged polyprenylated polycyclic acylphloroglucinol (PPAP) with a new carbon skeleton, along with a new congener, norprzewalsone B (2), were isolated from Hypericum przewalskii. Compound 1 possessed a new 5/6/5/6/6 pentacyclic ring system based on a spiro[cyclopentane-1,3'-tricyclo[7.4.0.01,6]tridecane] core, which might be derived from the common [3.3.1]-type bicyclic polyprenylated acylphloroglucinol (BPAP) via the key retro-Claisen, intramolecular cyclization, and Diels-Alder cyclization reactions. Their structures and absolute configurations were confirmed by spectroscopic data, calculated 1D NMR data with DP4+ probability analyses, and electronic circular dichroism calculations and comparison. More significantly, compound 1 exhibited a moderate inhibitory effect on NO production in lipopolysaccharide-stimulated RAW264.7 cells.

(±)-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.