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A versatile terpene synthase (LcTPS2) producing unconventional macrocyclic terpenoids was characterized from Leucosceptrum canum. Engineered E. coli and Nicotiana benthamiana expressing LcTPS2 produced six 18-/14-membered sesterterpenoids including five new ones and two 14-membered diterpenoids, representing the first macrocyclic sesterterpenoids from plants and the largest sesterterpenoid ring system identified to date. Surprisingly, none of these macrocyclic terpenoids were detected in L. canum. Two variants F516A and F516G producing approximately 3.3- and 2.5- folds respectively more sesterterpenoids than the wild type enzyme was engineered. Both 18- and 14-membered ring sesterterpenoids displayed significant inhibitory activity on the IL-2 and IFN-I³ production of T cells via inhibition of MAPK pathway. The findings will contribute to the development of efficient biocatalysts to create bioactive macrocyclic sesterterpenoids, and also herald a new potential in the well-trodden territory of plant terpenoid biosynthesis.

Background and purpose IL-1β produced by macrophages via the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, mediates the inflammatory crosstalk between macrophages and adipocytes. In our previous study, (16S,20S,24R)-12β-acetoxy-16,23-epoxy-24,25-dihydroxy-3β-(β-D-xylopyranosyloxy)-9,19-cyclolanost-22(23)-ene (AEDC), a cycloartane triterpenoid isolated from Actaea vaginata (Ranunculaceae), was found to possess anti-inflammatory effect on LPS-treated RAW264.7 macrophages. This study was designed to investigate whether AEDC modulates macrophage-adipocyte crosstalk to alleviate adipose tissue inflammation. Experimental approach The anti-inflammatory effect of AEDC was evaluated on LPS plus ATP-induced THP-1 macrophages and C57BL/6J mice. The expression of autophagy-related and NLRP3 inflammasome complex proteins was analysed by western blots, immunofluorescence staining and co-immunoprecipitation. The pro-inflammatory cytokines levels were determined by ELISA kits. The adipose tissue inflammation was evaluated by histological analysis and immunohistochemical staining. Key results AEDC (5 and 10 μM) activated autophagy, which in turn suppressed the NLRP3 inflammasome activation and IL-1β secretion in THP-1 macrophages. AEDC increased the expression of SIRT3 deacetylase and enhanced its deacetylating activity to reverse mitochondrial dysfunction and activate AMP-activated protein kinase, which together induced autophagy. Moreover, AEDC (10 μM) attenuated macrophage conditioned medium-induced inflammatory responses in adipocytes and blocked THP-1 macrophages migration towards 3T3-L1 adipocytes. In inflammation mice, AEDC (5 and 20 mg·kg-1 ) treatment reduced the levels of pro-inflammatory cytokines in serum and epididymal adipose tissue and reduced macrophage infiltration to alleviate adipose tissue inflammation. Conclusion and implications AEDC attenuated the inflammatory crosstalk between macrophages and adipocytes through SIRT3-autophagy-mediated NLRP3 inflammasome inhibition, which might used for the treatment of adipose tissue inflammation-related metabolic disorders.

Metastasis is one of the primary causes for high mortality in patients with squamous cell carcinoma of the head and neck (SCCHN). Our previous study showed that chemokine (C‐C motif) ligand 18 (CCL18), derived from tumour‐associated macrophages (TAMs), regulates SCCHN metastasis by promoting epithelial‐mesenchymal transition (EMT) and preserving stemness. However, the underlying mechanism needs to be further investigation. Interestingly, metadherin (MTDH) expression was induced when SCCHN cells were stimulated with recombinant CCL18 protein in this study. Suppressing MTDH expression reversed CCL18‐induced migration, invasion and EMT in SCCHN cells. Furthermore, the NF‐κB signalling pathway was involved in the MTDH knock‐down cells with CCL18 stimulation. We performed ELISA to evaluate the CCL18 levels in the serums of 132 treatment‐naive SCCHN patients, 25 patients with precancerous lesion and 32 healthy donors. Our results demonstrated that serum CCL18 levels were significantly higher in SCCHN patients than patients with precancerous lesion and healthy individuals. CCL18 levels were found to be significantly correlated with tumour classification, clinical stage, lymph node metastasis and histological grade in SCCHN patients. Thus, our findings suggest that CCL18 may serve as a potential biomarker for diagnosis of SCCHN and promote SCCHN invasion, migration and EMT by MTDH‐NF‐κB signalling pathway.

Four polycyclic norditerpenoids, cephalotanins A-D (1-4) representing three unprecedented carbon skeletons with highly rigid ring systems, were isolated from Cephalotaxus sinensis and structurally characterized by a combination of various methods. Compounds 1 and 2 are new skeletal norditerpenoid trilactones, while 3 and 4 are two norditerpenoids featuring different new carbon skeletons. Biosynthetic pathways for 1-4 were proposed by involving diverse and very fascinating chemical events with the coexisting cephalotane troponoids as the precursors. Compound 1 exhibited good NF-κB inhibition with an IC50 value of 4.12±0.61 μΜ.

Two pairs of new neolignan enantiomers, (±)-torreyayunan A (1a/1b) and (±)-torreyayunan B (2a/2b), featuring a rare C-8 − C-9′ linked skeleton, were isolated from leaves and twigs of Torreya yunnanensis. Their absolute configuration involving two chiral centers was determined by combined spectral and Density Functional Theory (DFT) calculation. This is the first report of the absolute configuration of this group of neolignans. Chirality 26:825–828, 2014. © 2014 Wiley Periodicals, Inc.

Two new cycloartane triterpenoids, (23R)-21,23:23,27-diepoxycycloarta-1,24-diene-3,27-dione (1) and (3α)-(α-L-arabinopyranosyloxy)-1α-hydroxy-23-oxocycloartan-28-oic acid (2), together with six known pentacyclic triterpenoids, 3–8, and five known C29 steroids, 9–13, were isolated from Kleinhovia hospita. The structures of these compounds were determined by analysis of their spectroscopic data. Moreover, the absolute configuration of 1 was confirmed by quantum-chemical TDDFT calculation of its ECD spectrum. All compounds were evaluated for their cytotoxic activities against human colon carcinoma (HCT116) and gastric carcinoma (SGC7901) cell lines, and compounds 6, 7, 8, 11, and 12 exhibited antiproliferative activities with IC50 values ranging from 23.0 to 91.8 μM.

Phytochemical study on the root tubers of Ophiopogon japonicus resulted in the isolation and identification of 13 homoisoflavonoids, including three new compounds, 8-formyl-7-hydroxy-5,4′-dimethoxy-6-methylhomoisoflavone (1), 6-formylisoophiopogonone B (2), and 8-formylophiopogonanone B (4), and the ten known homoisoflavonoids 3, and 5–13. The absolute configurations of 8-formylophiopogonanone B (4) and 8-formyl-7-hydroxy-5,4′-dimethoxy-6-methylhomoisoflavanone (5) were confirmed by time-dependent density-functional-theory (TD DFT) calculations of their theoretical electronic circular dichroism (ECD) spectra. The structure of the formerly reported ‘6-aldehydoisoophiopogonone B’ was revised to 8-formylophiopogonone B (3). All compounds were evaluated for their cytotoxic activities against the human-lung-tumor A549 cell line, and compounds 3, 9, 10, and 13 exhibited promising antiproliferative activities with IC50 values of 10.01, 6.40, 0.84, and 1.66 μM, respectively.

Two new polyketide derivatives, huaspenones C and D (1 and 2, resp.), were isolated from the cultures of an endophytic fungus Peyronellaea sp. HS-12, derived from the stems of Huperzia serrata. They share N-bearing furan-3(2H)-one backbone, and 2 has an unprecedented furo[3,2-c]pyridine skeleton. Their structures including the absolute configuration were elucidated by extensive spectroscopic analysis combined with quantum-chemical calculations. (2E,4E)-6-hydroxy-2-methylocta-2,4-dienoic acid (3), a key intermediate of the biosynthesis of 1 and 2, was also obtained from the endophyte.

Three new ent-kaurane diterpenoids, (4α)-19-nor-ent-kaurane-4,16,17-triol (1), (4α,16α)-17-(acetyloxy)-19-nor-ent-kaurane-4,16-diol (2), and 17-hydroxy-ent-kaur-15-en-19-al (3), together with 11 known compounds, were isolated from the stem bark of Annona squamosa L. The structures of 1–3 were identified by analysis of their spectroscopic data. All compounds were evaluated for cytotoxic activity against human lung cancer (95-D) and ovarian cancer (A2780) cell lines, and compounds 3, 5, 7, 11–14 exhibited promising antiproliferative activities with IC50 values ranging from 0.38 to 34.66 μM.

Chemical investigation into the minor constituents of Aphanamixis grandifolia yielded three new diterpenoid dimers, aphadilactones E-G (1-3) featuring a new carbon skeleton. Their structures and absolute configurations were fully established by comprehensive spectroscopic data analysis and ECD calculation. Discovery of another two new dimers (4 and 5) suggested the structure of recently reported aphanamene A to be re-investigated. Compounds 1-5 showed moderate antimalarial activities with low micromolar IC50 values.

Two new indolizidine alkaloids, (±)-3-oxoisoelaeocarpine (1) and (±)-elaeocarpine N-oxide (2), along with three known alkaloids, (±)-isoelaeocarpine (3), (±)-elaeocarpine (4), and (−)-isoelaeocarpiline (5), were isolated from an EtOH extract of the branches and leaves of Elaeocarpus sphaericus. The structures of these compounds were determined by spectroscopic and chemical methods. Furthermore, enantiomers of compounds 1 and 3 were separated on a chiral CD-Ph column, and their absolute configurations were determined by TD-DFT (=time-dependent density-functional theory) quantum-chemical calculations of their electronic circular dichroism (ECD) spectra.

An ultra-pressure LC (UPLC) method has been developed and validated for the quality evaluation of a traditional Chinese medicine (Radix Linderae) by chemical fingerprint analysis with chromatograms collected at two wavelengths (260 and 320 nm). Eleven characteristic peaks in the fingerprints were identified by comparing their retention times, UV spectra and ESI-MS/MS data with those of the reference substances or the data in the literatures. Both correlation coefficient of similarities in chromatograms and relative peak areas of common peaks were calculated for quality expression of the Radix Linderae samples collected from different areas in China. The results showed high variation of relative peak area and correlation coefficients among the samples collected from various habitats, which indicated that the quality consistency of Radix Linderae is still a problem worthy of serious concern.

Eight new cycloartane triterpenoids are isolated from the ethanol extract of the rhizomes of Beesia calthifolia along with six known compounds.

Seventeen Daphniphyllum alkaloids, including two new pentacyclic alkaloids, yuzuric acid (1) and daphnezomic acid (2), and 15 known ones, were isolated from the fruits of Daphniphyllum oldhamii. The structures and configuration of the two new alkaloids were determined on the basis of spectroscopic methods, especially 2D NMR techniques.

Three new alkaloids, N-hydroxypaxdaphnine B (1), 21-O-acetylpaxdaphnine B (2), and methyl 17-hydroxyhomodaphniphyllate (3), were isolated from the fresh fruits of Daphniphyllum macropodum, together with six known alkaloids. Their structures were established on the basis of extensive spectroscopic and mass-spectrometric analyses in combination with chemical transformations.

Three new natural products, the taraxastane-type triterpenoid 1, the azafluorene-based constituent 2-hydroxyonychine (2), and the diterpenoid nemoralisin (3) were isolated from the EtOH extract of Polyalthia nemoralis, along with five known compounds. The structures of the new compounds were established by in-depth spectroscopic and mass-spectrometric analyses, as well as by chemical transformation.

Two novel diterpenoids, jatrocurcadiones A (1) and B (2), possessing an unusual 10,11-seco-premyrsinane skeleton were isolated from the twigs of Jatropha curcas. Their structures were determined by combined spectroscopic and chemical methods, and the absolute configurations were elucidated by quantum chemical calculations and Rh2(OCOCF3)4-induced CD analysis. Jatrocurcadione A exhibited more potent inhibitory activity (IC50 = 10.0 μM) than the positive control (curcumin, IC50 = 25.0 μM) against thioredoxin reductase (TrxR), a potential target for cancer chemotherapy with redox balance and antioxidant functions.

isolation, structure elucidation and cytotoxic activities of new triterpenoids (I), (II) and six known pentacyclic triterpenoids

Logeracemin A (1), the first Daphniphyllum alkaloid dimer featuring an unprecedented carbon skeleton with a unique conjugated trispiro[4,5] decane backbone, was isolated from Daphniphyllum longeracemosum. Its structure and absolute configuration were established on the basis of spectroscopic data and X-ray crystallography. Logeracemin A showed significant anti-HIV activity with an EC50 of 4.5 ± 0.1 μM and a selectivity index of 6.2. The structure–activity relationship of the tested compounds was briefly discussed.

The effect of different oils on the absorption of carotenoids was investigated in mesenteric lymph duct cannulated rats. Sixteen treatment emulsions containing increasing concentrations of either lycopene (LYC) or astaxanthin (AST) (5, 10, 15, 20 micromol/L) were prepared with olive oil or corn oil and continuously infused into the duodenum of the rat. Absorption of carotenoids into the mesenteric lymph duct was determined. Absorption of LYC and AST from both oils increased with the amount infused into the duodenum. The average recovery of AST in the lymph from the olive oil emulsion was 20% but was decreased to 13% from emulsions containing corn oil. Lycopene was not as well absorbed as AST. The average recovery of LYC was 6% from olive oil emulsions but only 2.5% when infused with corn oil. The LYC used in this study was isolated from tomato paste and was primarily in the all-trans form. We did not observe any significant isomerization of all-trans LYC to 9-cis LYC during absorption. We conclude that the type of oil with which a carotenoid is consumed can influence its absorption.

The purpose of this study was to validate the use of the mesenteric lymph duct cannulated rat to study the absorption of carotenoids which do not have provitamin A activity. The absorption of two carotenoids, a hydrocarbon carotenoid (lycopene) and a xanthophyll carotenoid (canthaxanthin), were investigated. In the first experiment, lipid emulsions containing lycopene (LYC) or canthaxanthin (CTX) were continuously infused into the duodenum, and lymph was collected for analysis at 2-h intervals. The time course for absorption of carotenoids and triacylglycerol (TAG) was similar. Carotenoids and TAG reached steady-state concentrations in the lymph by 6 h. There was no evidence for a delayed release of either carotenoid from the intestine relative to TAG. During a second experiment, emulsions containing increasing concentrations of LYC or CTX (5, 10, 15, 20 mumol/L) were infused. The LYC and CTX in the lymph increased in a dose-dependent manner. The average efficiency of CTX absorption was 16% while the efficiency of LYC absorption averaged only 6%. Efficiency of carotenoid absorption was not related to concentration infused. Finally, to test whether LYC and CTX interact during absorption both were added to a lipid emulsion at equal concentrations (20 mumol/L) and infused. The carotenoids did not significantly affect each other's absorption. These results demonstrate the usefulness of the rat as an animal model to study the absorption of non-provitamin A carotenoids.

Two novel rearranged oleanane-type triterpenes, dysoxyhainanin A (1) possessing a unique 1,3-cyclo-2,3-seco A ring with a formamido-containing appendage and dysoxyhainanin B (2) featuring an unprecedented 1,2-dinor-3,10:9,10-bisseco skeleton, were isolated from Dysoxylum hainanense. Dysoxyhainanin A (1) exhibited significant antibacterial activity against Gram-positive bacteria.

A novel bisbenzylisoquinoline alkaloid, linderegatine (1), as well as two known isoquinoline alkaloids (+)-reticuline (2) and pallidine (3) were isolated from the roots of the Chinese medicinal pla...

Seventeen Daphniphyllum alkaloids, including two new pentacyclic alkaloids, yuzuric acid (1) and daphnezomic acid (2), and 15 known ones, were isolated from the fruits of Daphniphyllum oldhamii. The structures and configuration of the two new alkaloids were determined on the basis of spectroscopic methods, especially 2D NMR techniques.

Three new alkaloids, N-hydroxypaxdaphnine B (1), 21-O-acetylpaxdaphnine B (2), and methyl 17-hydroxyhomodaphniphyllate (3), were isolated from the fresh fruits of Daphniphyllum macropodum, together with six known alkaloids. Their structures were established on the basis of extensive spectroscopic and mass-spectrometric analyses in combination with chemical transformations.