Hepialiamides A-C: Aminated Fusaric Acid Derivatives and Related Metabolites with Anti-Inflammatory Activity from the Deep-Sea-Derived Fungus Samsoniella hepiali W7.

A systematic investigation combined with a Global Natural Products Social (GNPS) molecular networking approach, was conducted on the metabolites of the deep-sea-derived fungus Samsoniella hepiali W7, leading to the isolation of three new fusaric acid derivatives, hepialiamides A-C (1-3) and one novel hybrid polyketide hepialide (4), together with 18 known miscellaneous compounds (5-22). The structures of the new compounds were elucidated through detailed spectroscopic analysis. as well as TD-DFT-based ECD calculation. All isolates were tested for anti-inflammatory activity in vitro. Under a concentration of 1 µM, compounds 8, 11, 13, 21, and 22 showed potent inhibitory activity against nitric oxide production in lipopolysaccharide (LPS)-activated BV-2 microglia cells, with inhibition rates of 34.2%, 30.7%, 32.9%, 38.6%, and 58.2%, respectively. Of particularly note is compound 22, which exhibited the most remarkable inhibitory activity, with an IC50 value of 426.2 nM.

Chemical Constituents of the Deep-Sea-Derived Penicillium citreonigrum MCCC 3A00169 and Their Antiproliferative Effects.

Six new citreoviridins (citreoviridins J-O, 1-6) and twenty-two known compounds (7-28) were isolated from the deep-sea-derived Penicillium citreonigrum MCCC 3A00169. The structures of the new compounds were determined by spectroscopic methods, including the HRESIMS, NMR, ECD calculations, and dimolybdenum tetraacetate-induced CD (ICD) experiments. Citreoviridins J-O (1-6) are diastereomers of 6,7-epoxycitreoviridin with different chiral centers at C-2-C-7. Pyrenocine A (7), terrein (14), and citreoviridin (20) significantly induced apoptosis for HeLa cells with IC50 values of 5.4 µM, 11.3 µM, and 0.7 µM, respectively. To be specific, pyrenocine A could induce S phase arrest, while terrein and citreoviridin could obviously induce G0-G1 phase arrest. Citreoviridin could inhibit mTOR activity in HeLa cells.

Growth inhibition and metabolomic analysis of Xanthomonas oryzae pv. oryzae treated with resveratrol.

BACKGROUND: Xanthomonas oryzae pv. oryzae (Xoo) can cause destructive bacterial blight in rice. As an antibacterial, resveratrol may inhibit Xoo growth. This study focused on the potential structural-activity relationship of resveratrol and its derivatives against Xoo growth, and 1H-NMR-based metabolomic analysis was applied to investigate the global metabolite changes in Xoo after resveratrol treatment. RESULTS: Resveratrol showed the strongest inhibitory effects on Xoo growth compared with its derivatives, which lacked double bonds (compounds 4-6) or hydroxyls were substituted with methoxyls (compounds 7-9). The IC50 of resveratrol against Xoo growth was 11.67 ± 0.58 µg/mL. Results indicated that the double bond of resveratrol contributed to its inhibitory effects on Xoo growth, and hydroxyls were vital for this inhibition. Interestingly, resveratrol also significantly inhibited Xoo flagellum growth. Based on 1H-NMR global metabolic analysis, a total of 30 Xoo metabolites were identified, the changes in the metabolic profile indicated that resveratrol could cause oxidative stress as well as disturb energy, purine, amino acid, and NAD+ metabolism in Xoo, resulting in the observed inhibitory effects on growth. CONCLUSIONS: This study showed that the double bond of resveratrol contributed to its inhibitory effects on Xoo growth, and hydroxyls were also the important active groups. Resveratrol could cause oxidative stress of Xoo cells, and disturb the metabolism of energy, purine, amino acid and NAD +, thus inhibit Xoo growth.

Synergistic combination of DT-13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC-823 cells via NM IIA/EGFR/HK II axis.

DT-13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT-13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis-related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non-muscle myosin IIA (NM IIA)-induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT-13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (-)002Dblebbistatin or MYH-9 shRNA, the synergistic inhibition effect of DT-13 and TPT on aerobic glycolysis was eliminated in BGC-823 cells. Immunohistochemical analysis revealed selective up-regulation of NM IIA while specific down-regulation of p-CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.

Alkaloids from the Branches and Leaves of Elaeocarpus angustifolius.

Nine new alkaloids, (+)-1, (-)-1, 2, (+)-3, (-)-3, and 4-7, along with five known compounds (8-12), were obtained from the branches and leaves of Elaeocarpus angustifolius. The alkaloids were structurally characterized by NMR and MS data. The absolute configurations of (+)-1, (-)-1, (+)-3, and (-)-3 were determined by comparing their experimental and computed electronic circular dichroism spectra. (±)-8,9-Dehydroelaeocarpine (5), (±)-9-epielaeocarpine cis-N-oxide trifluoroacetate (6), and (±)-elaeocarpine trifluoroacetate (9) exerted weak inhibitory activities against butyrylcholinesterase with IC50 values of 39, 29, and 35 µM, respectively, while that of tacrine, the positive control, was 0.07 ± 0.01 µM. This is the first report of the cholinesterase inhibitory activities of Elaeocarpus alkaloids.

Metabolomic analysis of quorum sensing inhibitor hordenine on Pseudomonas aeruginosa.

Proton magnetic resonance-based metabolomics analysis was performed to determine the global metabolite changes in pathogenic bacterium Pseudomonas aeruginosa PAO1 following exposure to quorum sensing (QS) inhibitor hordenine. Pyocyanin inhibition assay confirmed that hordenine exhibited potent QS inhibitory activity. A total of 40 metabolites were assigned by PMR spectra. Hordenine treatment resulted in the destruction of QS system in P. aeruginosa PAO1 by downregulating the expressions of genes involved in QS. The synthesis of antioxidant enzymes was repressed and the oxidative stress was enhanced due to the dysfunctional QS system of P. aeruginosa PAO1. The enhanced oxidative stress induced by the dysfunctional QS system of P. aeruginosa PAO1 altered the membrane components, enhanced membrane permeability, and disturbed energy metabolism, amino acid metabolism, and nucleotide metabolism, and would ultimately attenuate the pathogenicity of P. aeruginosa PAO1. Hordenine may have promising potential for controlling nosocomial pathogens.

Anti-Cancer Effects of Emodin on HepG2 Cells as Revealed by 1H NMR Based Metabolic Profiling.

Hepatic carcinoma is one of the most common cancers in the world, with a high incidence. Emodin is an anthraquinone derived from Polygonum multiflorum Thunb, possessing anti-cancer activity. The purpose of this study is to investigate the anti-cancer effect of different dosages of emodin on HepG2 cells using a 1H NMR based metabolic approach complemented with qRT-PCR and flow cytometry to identify potential markers and discover the targets to explore the underlying mechanism. Emodin can dose-dependently inhibit the growth of HepG2 cells, perturb cell cycle progression, down-regulate the expression of genes and proteins related to glycolysis, and trigger intracellular ROS generation. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) and correlation network analysis of the 1H NMR data showed significant changes in many endogenous metabolites after emodin exposure concerning oxidative stress and disturbances in amino acid and energy metabolism. These findings are helpful to understand the anti-cancer mechanism of emodin and provide a theoretical basis for its future application and development.

Metabolomic Investigations on Nesterenkonia flava Revealed Significant Differences between Marine and Terrestrial Actinomycetes.

Marine microorganisms are an important source of natural products with potent bioactivities. Unlike the land, the ocean, especially the deep-sea, is characterized by high pressure, high salinity, low nutrition, and no light among others. Therefore, the biodiversity of marine microorganisms is supposed to be very different from that of the terrestrial ones. Yet, many marine microorganisms can find their counterparts in terrestrial environments. To evaluate their differences, a comparative metabolomics investigation was performed on four strains of Nesterenkonia flava isolated from terrestrial and marine environments. As a result, marine strains were clearly distinguished from terrestrial ones on the principal components analysis (PCA) score plot. Furthermore, by partial least squares discrimination analysis (PLS-DA) and univariate analysis, the characteristic metabolites were figured out and found to be involved in osmotic regulation, redox balancing, and energy metabolism. Our results demonstrated that marine actinomycetes could produce novel secondary metabolites different from their terrestrial relatives because they have special metabolic patterns closely related to the unique features of their living environment.

Acute psychoactive and toxic effects of D. metel on mice explained by 1H NMR based metabolomics approach.

Datura metel L. (D. metel) is one well-known folk medical herb with wide application and also the most abused plants all over the world, mainly for spiritual or religious purpose, over-dosing of which often produces poisonous effects. In this study, mice were orally administered with the extract of D. metel once a day at doses for 10 mg/kg and 40 mg/kg for consecutive 4 days, 1H NMR based metabolomics approach aided with histopathological inspection and biochemical assays were used for the first time to study the psychoactive and toxic effects of D. metel. Histopathological inspection revealed obvious hypertrophy of hepatocytes, karyolysis and karyorrhexis in livers as well as distinct nerve cell edema, chromatolysis and lower nuclear density in brains. The increased tissue level of methane dicarboxylic aldehyde (MDA) and superoxide dismutase (SOD), decreased tissue level of glutathione (GSH) along with increased serum level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) suggested brain and liver injury induced by D. metel. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis revealed significant altered metabolites and related pathway that contributed to oxidative stress, energy metabolism disturbances, neurotransmitter imbalance and amino acid metabolism disorders.

(1)H-Nuclear Magnetic Resonance-Based Plasma Metabolic Profiling of Dairy Cows with Fatty Liver.

Fatty liver is a common metabolic disorder of dairy cows during the transition period. Historically, the diagnosis of fatty liver has involved liver biopsy, biochemical or histological examination of liver specimens, and ultrasonographic imaging of the liver. However, more convenient and noninvasive methods would be beneficial for the diagnosis of fatty liver in dairy cows. The plasma metabolic profiles of dairy cows with fatty liver and normal (control) cows were investigated to identify new biomarkers using (1)H nuclear magnetic resonance. Compared with the control group, the primary differences in the fatty liver group included increases in ß-hydroxybutyric acid, acetone, glycine, valine, trimethylamine-N-oxide, citrulline, and isobutyrate, and decreases in alanine, asparagine, glucose, γ-aminobutyric acid glycerol, and creatinine. This analysis revealed a global profile of endogenous metabolites, which may present potential biomarkers for the diagnosis of fatty liver in dairy cows.

[A new biflavone from needles of Taxus canadensis].

The presentstudy is to investigate the chemical constituents of needles of Taxus canadensis. The constituent was isolated by various chromatographic methods, and the chemical structure was elucidated on the basis of spectral analysis. A new biflavone was isolated and identified as 3"'-hydroxy-4"', 7-dimethylamentoflavone.

(+)- and (-)-liriodenol, a pair of novel enantiomeric lignans from Liriodendron hybrid.

(+)- and (-)-liriodenol, a pair of unprecedented enantiomeric lignans bearing a 1,1-disubstituted olefinic group, were isolated from the barks of Liriodendron hybrid. The structure and relative configurations were determined by comprehensive analysis of MS and NMR spectroscopy. The cytotoxicity of these three lignans ((±)-, (+)-, and (-)-liriodenol) was evaluated in vitro against four selected human tumor cell lines, where (+)-liriodenol showed more significant cytotoxic effects than the (±)- and (-)-liriodenol enantiomers.

Cytotoxic dammarane-type triterpenoids from the stem bark of Dysoxylum binecteriferum.

Fourteen new dammarane-type triterpenoids (1-14) and 11 known analogues were isolated from the stem bark of Dysoxylum binecteriferum. The absolute configurations were established by comparison with the literature or by Mo2(OAc)4-induced electronic circular dichroism data. All isolates were evaluated for their cytotoxicities against three human cancer cell lines as well as their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. Compounds 4 and 8 displayed moderate cytotoxicities against HepG2 with IC50 values of 6.5 and 8.0 µM, respectively.

Tabercarpamines A-J, apoptosis-inducing indole alkaloids from the leaves of Tabernaemontana corymbosa.

A total of 10 new indole alkaloids, tabercarpamines A-J (1-10), were isolated from the leaves of Tabernaemontana corymbosa. Tabercarpamines C-F (3-6) are rare C-14/C-15-seco-tabersonine-type monoterpenoid indole alkaloids, and 5 and 6 are the first examples with a lactone linkage between C-14 and C-20. The structures of these alkaloids were elucidated using spectroscopic methods, and the absolute configurations of 1 and 2 were determined using the ECD exciton chirality method. In addition, an MTT assay was used to examine the growth-inhibitory effects of all new isolates and of two known isolates on MCF-7, HepG2, and SMMC-7721 cells; 1 exhibited significant inhibitory effects against these three human cancer cell lines with IC50 values of 8.54, 3.31, and 6.76 µM, respectively. Additionally, the results from the annexin-V/PI double-staining assay indicated that 1 might inhibit the proliferation of HepG2 cells by inducing apoptosis.

Absolute configuration study of a new dimeric indole alkaloid from the leaves and twigs of Psychotria henryi.

From the leaves and twigs of Psychotria henryi, a new dimeric indole alkaloid, named psychohenin, was isolated, whose structure was elucidated on the basis of extensive spectroscopic analysis. The absolute configuration of psychohenin was determined by a single-crystal X-ray diffraction study using a mirror Cu Kα radiation.

[Research progress of chemical composition of taxane in Taxus canadensis and medicine source crisis solution].

Taxus canadensis distributed mainly in North America, such as northern Minnesota, Newfoundland, south to Wisconsin and Pennsylvania. Its composition has been shown to be very different from other species, and in recent years, some new skeletons also have been found in Canada yew. Through analysis of the taxanes content on various Taxus plants containing taxanes, the results showed a higher content of taxol in T. canadensis. Based on the current research on T. canadensis (from the research results of the author in recent years, as well as from studies of scholars in the field), the paper outlined the research progress in recent years on the chemical constituents of taxane of T. canadensis and the spectral characteristics of various types of compounds. Besides, this paper analyzed the present research about solutions for the taxol drug source crisis.

Total cucurbitacins from Herpetospermum pedunculosum pericarp do better than Hu-lu-su-pian (HLSP) in its safety and hepatoprotective efficacy.

The pericarp of Herpetospermum pedunculosum (HPP) has traditionally been used for treating jaundice and hepatitis. However, the specific hepatoprotective components and their safety/efficacy profiles remain unclear. This study aimed to characterize the total cucurbitacins (TCs) extracted from HPP and evaluate their hepatoprotective potential. As a reference, Hu-lu-su-pian (HLSP), a known hepatoprotective drug containing cucurbitacins, was used for comparison of chemical composition, effects, and safety. Molecular networking based on UHPLC-MS/MS identified cucurbitacin B, isocucurbitacin B, and cucurbitacin E as the major components in TCs, comprising 70.3%, 26.1%, and 3.6% as determined by RP-HPLC, respectively. TCs treatment significantly reversed CCl4-induced metabolic changes associated with liver damage in a dose-dependent manner, impacting pathways including energy metabolism, oxidative stress and phenylalanine metabolism, and showed superior efficacy to HLSP. Safety evaluation also showed that TCs were safe, with higher LD50 and no observable adverse effect level (NOAEL) values than HLSP. The median lethal dose (LD50) and NOAEL values of TCs were 36.21 and 15 mg/kg body weight (BW), respectively, while the LD50 of HLSP was 14 mg/kg BW. In summary, TCs extracted from HPP demonstrated promising potential as a natural hepatoprotective agent, warranting further investigation into synergistic effects of individual cucurbitacin components.

Bioactive terpenoids from the fruits of Aphanamixis grandifolia.

From the fruits of the tropical tree Aphanamixis grandifolia, five new evodulone-type limonoids, aphanalides I-M (1-5), one new apo-tirucallane-type triterpenoid, polystanin E (6), and three new chain-like diterpenoids, nemoralisins A-C (7-9), along with 12 known compounds were identified. The absolute configurations were determined by a combination of single-crystal X-ray diffraction studies, Mo2(OAc)4-induced electronic circular dichroism (ECD) data, the Mosher ester method, and calculated ECD data. The cytotoxicities of all the isolates and the insecticidal activities of the limonoids were evaluated.

Chemical constituents from Trichilia connaroides and their nitric oxide production and α-glucosidase inhibitory activities.

Phytochemical investigation of the stem and bark of Trichilia connaroides led to the isolation of eight new nortriterpenoids (1-8), along with fifteen known compounds (9-23). Their structures were established based on extensive spectroscopic analysis. The absolute configuration of 2 was confirmed by X-ray crystallographic study. The nitric oxide production and α-glucosidase inhibitory effects for these isolates were evaluated: moderate to strong nitric oxide production inhibitory activities were found for 5, 6, and 11-15, with IC50 values ranging from 7.5 to 26.3 µM; marked α-glucosidase inhibitory effects were observed for 22 and 23, with IC50 values of 2.3 and 0.4 µM, respectively.

Polystanins A-D, four new protolimonoids from the fruits of Aphanamixis polystachya.

Two new apo-tirucallane triterpenoids with six-membered hemiketal, polystanins A (1) and B (2), and two new tirucallane triterpenoids, polystanins C (3) and D (4) were isolated from the fruits of Aphanamixis polystachya. They were elucidated on the basis of detailed spectroscopic analysis including IR, high resolution-electrospray ionization (HR-ESI)-MS, 1 dimensional (1D)- and 2D-NMR. Their absolute configurations were determined by a combination of modified Mosher's method, and electronic circular dichroism (ECD) calculation.