Patumantanes A-D, seco-Polycyclic Polyprenylated Acylphloroglucinols with Diverse Carbon Skeletons from Hypericum patulum.

Patumantanes A-D (1-4), four new seco-polycyclic polyprenylated acylphloroglucinols (PPAPs) were isolated from Hypericum patulum. Patumantane A (1) was an unprecedented 1,2-seco-homoadamantane-type PPAP bearing a new 3,7-dioxatetracyclo[7.7.0.01,6.111,15]heptadecane architecture based on a 6/7/5/6 ring system. Patumantane B (2) was a unique 1,9-seco-adamantane-type PPAP with a tricyclo[4.4.4.0.02,12]tridecane core formed by a 6/6/6 carbon skeleton, and the further breakage between C-5 and C-9 decorated patumantane C (3) with the 9-nor-adamantane skeleton. More importantly, compounds 2 and 3 exhibited moderate immunosuppressive activity on Con A-induced T-lymphocyte proliferation in vitro, with IC50 values of 5.6 ± 1.2 and 11.2 ± 1.2 µM, respectively.

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.

SIVA-1 enhances acquired chemotherapeutic drug resistance of gastric cancer in vivo by regulating the ARF/MDM2/p53 pathway.

SIVA-1 has been shown to affect apoptotic processes in various different cell lines, and SIVA-1 significantly contributes to the decreased responsiveness of cancer cells to some chemotherapy agents. However, whether SIVA-1 has potential application in gastric cancer remains unknown. Therefore, the objective of this investigation was to clarify the distinct function of SIVA-1 in chemotherapeutic drug resistance within a living murine model with gastric malignancy, and initially elucidate the underlying mechanisms. In an established multidrug-resistant gastric cancer xenograft mouse model, lentivirus, named Lv-SIVA-1, was injected into xenograft tumors, and increased the mRNA and protein expression of endogenous SIVA-1 in tumors. Immunohistochemical assays of xenograft tumor showed that SIVA-1 was significantly upregulated, and the protein expression levels of SIVA-1 were highly increased, as detected by Western blotting. In addition, we detected the role of SIVA-1 in cell proliferation and cell apoptosis in gastric cancer cells by TUNEL and found that SIVA-1 decreased tumor cell apoptosis and promoted tumor growth in vivo. Using a TMT assay between tumor tissues of experimental and control groups, differentially expressed proteins were examined and three potential biomarkers of multidrug resistance (ARF, MDM2, and p53) were screened. We further investigated the molecular mechanism by which SIVA-1 played an efficient role against chemotherapies and found that overexpressed SIVA-1 leads to increased ARF and MDM2 expression and suppressed expression of p53 in tumor tissue. In conclusion, SIVA-1 plays a significant role in the multidrug resistance of gastric tumors. In addition, overexpressed SIVA-1 positively regulates cell proliferation, adjusts cycle progression, and reduces the response to drug treatment for gastric cancer in an ARF/MDM2/p53-dependent manner. This novel research provides a basis for chemical management of gastric cancer through regulation of SIVA-1 expression.

Discovery of adamantane-type polycyclic polyprenylated acylphloroglucinols that can prevent concanavalin A-induced autoimmune hepatitis in mice.

Hyperadamans A-G (1-7), seven new adamantane type polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from Hypericum wilsonii N. Robson. Structurally, 1-4 were the first adamantanes bearing an unusual 2,7-dioxabicyclo-[2.2.1]-heptane fragment, and compound 5 was the first adamantane with a rare 1,6-dioxaspiro[4.4]nonane section. Importantly, 1-7 exhibited significant immunosuppressive activity on Con A-induced T-lymphocyte proliferation in vitro, with IC50 values ranging from 3.97 ± 0.10 to 18.12 ± 1.07 µM. Pretreatment with 1 in Con A-challenged autoimmune hepatitis mice could dramatically ameliorate the levels of hepatic injury indexes (ALT and AST) and reduce the product of proinflammatory cytokines (COX-2, IL-6, IL-1ß, IL-18, IL-23A and TNF-α). Furthermore, the protective effect of 1 on the Con A-induced liver injury was corroborated by the histological analysis and the immunohistochemistry.

Maydistacins A-G, Terpestacin-type Sesterterpenoids with Anti-inflammatory Activity from the Phytopathogenic Fungus Bipolaris maydis.

Seven undescribed terpestacin-type sesterterpenoids, maydistacins A-G (1-7), along with two known congeners (8 and 9), were isolated from the phytopathogenic fungus Bipolaris maydis collected from the leaves of Hypericum longistylum. The structures of 1-7 were elucidated based on extensive spectroscopic analysis, chemical methods, NMR calculations with DP4+ probability analysis, and comparison of experimental and calculated electronic circular dichroism (ECD) calculations. In vitro anti-inflammatory effects of these compounds were tested in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Compound 1 exhibited inhibition of the production of nitric oxide in LPS-induced macrophages, with an IC50 value of 19 ± 2 µM. A dexamethasone control displayed an IC50 value of 6.7 ± 0.6 µM. Compound 1 is the first terpestacin-type sesterterpenoid reported to display anti-inflammatory activity and may provide a novel chemical scaffold for the discovery of new anti-inflammatory drugs.

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.

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.

Bioactive Indole Alkaloid from Aspergillus amoenus TJ507 That Ameliorates Hepatic Ischemia/Reperfusion Injury.

Hepatic ischemia/reperfusion injury (IRI) is a major factor contributing to the failure of hepatic resection and liver transplantation. As part of our ongoing investigation into bioactive compounds derived from fungi, we isolated eight indole alkaloids (1-8) from the endophytic fungus Aspergillus amoenus TJ507. Among these alkaloids, one previously undescribed compound, amoenamide D (1), was identified. The planar structure of 1 was elucidated by extensive spectroscopic analysis, including HRESIMS and NMR spectra. The absolute configuration of 1 was elucidated by using electronic circular dichroism calculations. Notably, in the CoCl2-induced hepatocyte damage model, notoamide Q (3) exhibited significant anti-hypoxia injury activity. Furthermore, in a murine hepatic ischemia/reperfusion injury model, treatment with 3 prevents IRI-induced liver damage and hepatocellular apoptosis. Consequently, 3 might serve as a potential lead compound to prevent hepatic ischemia/reperfusion injury.

Discovery of ergosterol derivative from Aspergillus sp. TJ507 that protects against hepatic ischemia/reperfusion injury.

Hepatic ischemia/reperfusion injury is a major cause of hypohepatia after surgical procedures such as hypovolemic shock, transplantation, and so on. In our continuous study of bioactive natural products from fungus, eight ergosterol-type sterides (1-8), including two undescribed compounds, sterolaspers A (1) and B (2), were isolated from Aspergillus sp. TJ507. Structure elucidation was accomplished by extensive spectroscopic analysis and comparison with the reported NMR data as well as X-Ray single crystal diffraction tests. Activity screen of these isolates showed 5α-stigmast-3,6-dione (3) possessing anti-hypoxia injury effects against CoCl2-induced hypoxia damage in hepatocytes. More importantly, compound 3 could improve liver function, alleviate liver damage, and restrain the hepatocellular apoptosis in hepatic ischemia/reperfusion injury murine model. As such, this ergosterol-type steride, 5α-stigmast-3,6-dione (3), might serve as lead structure for the development of novel hepatoprotective agents in the clinical treatment of hepatic ischemia/reperfusion injury.

ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T-Cell Metabolism.

Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T-cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft-infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK-specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine-treated mice show a decrease in the number and activation of allograft-infiltrated T cells. It is further confirmed that lycorine-treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine-treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen-activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T-cell activation and allograft rejection.

Interlayer Modulation of Layered Transition Metal Compounds for Energy Storage.

Layered transition metal compounds are one of the most important electrode materials for high-performance electrochemical energy storage devices, such as batteries and supercapacitors. Charge storage in these materials can be achieved via intercalation of ions into the interlayer channels between the layer slabs. With the development of lithium-beyond batteries, larger carrier ions require optimized interlayer space for the unrestricted diffusion in the two-dimensional channels and effectively shielded electrostatic interaction between the slabs and interlayer ions. Therefore, interlayer modulation has become an efficient and promising approach to overcome the problems of sluggish kinetics, structural distortion, irreversible phase transition, dissolution of some transition metal elements, and air instability faced by these materials and thus enhance the overall electrochemical performance. In this review, we focus on the interlayer modulation of layered transition metal compounds for various batteries and supercapacitors. Merits of interlayer modulation on the charge storage procedures of charge transfer, ion diffusion, and structural transformation are first discussed, with emphasis on the state-of-art strategies of intercalation and doping with foreign species. Following the obtained insights, applications of modified layered electrode materials in various batteries and supercapacitors are summarized, which may guide the future development of high-performance and low-cost electrode materials for energy storage.

TV-NARX and Coiflets WPT based time-frequency Granger causality with application to corticomuscular coupling in hand-grasping.

The study of the synchronous characteristics and functional connections between the functional cortex and muscles of hand-grasping movements is important in basic research, clinical disease diagnosis and rehabilitation evaluation. The electroencephalogram (EEG) and electromyographic signal (EMG) signals of 15 healthy participants were used to analyze the corticomuscular coupling under grasping movements by holding three different objects, namely, card, ball, and cup by using the time-frequency Granger causality method based on time-varying nonlinear autoregressive with exogenous input (TV-NARX) model and Coiflets wavelet packet transform. The results show that there is a bidirectional coupling between cortex and muscles under grasping movement, and it is mainly reflected in the beta and gamma frequency bands, in which there is a statistically significant difference (p < 0.05) among the different grasping actions during the movement execution period in the beta frequency band, and a statistically significant difference (p < 0.1) among the different grasping actions during the movement preparation period in the gamma frequency band. The results show that the proposed method can effectively characterize the EEG-EMG synchronization features and functional connections in different frequency bands during the movement preparation and execution phases in the time-frequency domain, and reveal the neural control mechanism of sensorimotor system to control the hand-grasping function achievement by regulating the intensity of neuronal synchronization oscillations.

Aureoterrolides B‒M: Eremophilane-type sesquiterpenoids isolated from Aspergillus aureoterreus and their cytotoxicity.

Uncovered by genome sequence analyses, twelve undescribed sesquiterpenoids designated aureoterrolides B‒M, were isolated from the culture broth of the fungus Aspergillus aureoterreus together with two known analogues. They are unusual eremophilanes with an oxidized C-4, of which aureoterrolide J is an unreported furanoeremophilane comprising a 3/6/6/5/3 pentacyclic architecture with a rare 3,6-spiro ring system. Their structures and absolute configurations were unambiguously assigned by extensive spectroscopic method and theoretical ECD calculation. All isolated compounds were evaluated their cytotoxicity, and aureoterrolides A, B, and I-K showed moderate cytotoxic activity against three human cancer cell lines (HL-60, HepG-2, and SKOV-3) with IC50 values ranging from 4.53 ± 0.05 to 24.71 ± 0.16 µM. Among them, aureoterrolide A exhibited activity such close to the positive control and apoptotic effect on HL-60 cells at a concentration of 5.0 µM.

Stabilizing Layered Structure in Aqueous Electrolyte via O2-Type Oxygen Stacking.

Despite the high energy density of O3-type layered cathode materials, the short cycle life in aqueous electrolyte hinders their practical applications in aqueous lithium-ion batteries (ALIBs). In this work, it is demonstrated that the structural stability of layered LiCoO2 in aqueous electrolyte can be remarkably improved by altering the oxygen stacking from O3 to O2. As compared to the O3-type LiCoO2 , the O2-type LiCoO2 exhibits significantly improved cycle performance in neutral aqueous electrolyte. It is found that the structural degradation caused by electrophilic attack of proton can be effectively mitigated in O2-type layered structure. With O2 stacking, CoO6 octahedra in LiCoO2 possess stronger CoO bonds while Co migration from Co layer to Li layer is strongly hampered, resulting in enhanced structural stability against proton attack and prolonged cycle life in aqueous electrolyte. The findings in this work reveal that regulating oxygen stacking sequence is an effective strategy to improve the structural stability of layered materials for ALIBs.

(±)-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.

Kiiacylphnols A-H, eight undescribed polycyclic polyprenylated acylphloroglucinols with anticancer activities from Hypericum przewalskii Maxim.

Kiiacylphnols A-H, eight previously undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs), along with two known congeners (hyperforcinol F and oxepahyperforin), were obtained from Hypericum przewalskii Maxim. The structures of these metabolites were confirmed by spectroscopic analyses, quantum-chemical 1H and 13C NMR calculations with DP4+ analyses, electronic circular dichroism (ECD) comparisons and calculations. Kiiacylphnols A and B were the first [3.3.1]-type PPAPs with an unusual octahydrooxireno[2,3-i]chromene scaffold bearing a rare 6/6/6/3 ring system. More significantly, kiiacylphnol A and oxepahyperforin displayed cytotoxicity against acute myeloid leukemia and diffuse large B-cell lymphoma cell lines by inducing cell apoptosis.

Discovery of Undescribed Monoterpenoid Polyprenylated Acylphloroglucinols with Immunosuppressive Activities from Hypericum longistylum.

Acylphlorostylums A-G (1-7), seven undescribed monoterpenoid polyprenylated acylphloroglucinols, were isolated and identified from Hypericum longistylum. Significantly, acylphlorostylums A and B were the first monoterpenoid polyprenylated acylphloroglucinols possessing a dodecahydro-1H-benzo [b]cyclopenta [e]oxepine moiety bearing a 6/7/5 fused tricyclic ring system that assembled by the attack from 4-OH to C-13. In addition, acylphlorostylums A-G exhibited moderate in vitro immunosuppressive activity in anti-CD3/anti-CD28 monoclonal antibodies, lipopolysaccharide and concanavalin A-induced murine splenocyte proliferation, with IC50 values ranging from 1.51 ± 0.12 to 18.49 ± 1.67 µM, underscoring those isolates as novel chemical templates in the development of novel immunosuppressors.

Two pairs of undescribed enantiomers isolated from the fungus Penicillium griseofulvum.

Two pairs of undescribed enantiomers including a 2,5-diketopiperazine namely (±)-janthinolide G and a related analogue (±)-janthinolide H, were isolated from the crude extract of the fungus Penicillium griseofulvum together with five known compounds. Both two structures were determined by spectroscopic method and HRESIMS, whereas absolute stereochemistry was elucidated by using theoretical NMR calculation and ECD calculation. Janthinolide G is the first example of 2,5-diketopiperazine enantiomers with a cleavage diketopiperazine ring and comprises a terminal oxime group rarely seen in natural products. Biological screening of selected compounds found that 4 and 7 both exhibited weak α-glucosidase inhibitory effects, and a potential correlation was afforded by docking studies of α-glucosidase protein (PDB: 3TOP) and bioactive molecules. The plausible biosynthetic pathways of two unreported isolates are proposed here.