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Centromere protein A (CENP-A) is a centromere-specific protein that determines kinetochore positioning and the accuracy of chromosome segregation. Despite its recognized importance in maintaining mitotic fidelity, the molecular details of CENP-A regulation in mitosis are still obscure. We performed a structure-activity relationship (SAR) study of the cell cycle-arresting indole terpenoid mimic JP18 and identified two more potent analogues, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin was identified as a potential protein target of these two halogenated analogues by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallographic analysis determined that (+)-6-Br-JP18 and (+)-6-Cl-JP18 bind to the colchicine-binding site of β-tubulin. We further found that treatment of cancer cells with microtubule-targeting agents (MTAs), including these two compounds, upregulated CENP-A by destabilizing Cdh1, an E3 ubiquitin ligase component. The mechanistic study revealed that Cdh1 mediates proteolysis of CENP-A in mitosis, specifying the role of Cdh1 in maintaining mitotic fidelity.

Objective: To construct a recombinant adenovirus with artificial microRNA targeting the epidermal growth factor receptor (EGFR) to inhibit the proliferation and induce the apoptosis of tumor cells. Methods: An artificial microRNA (amiR) targeting EGFR was designed and cloned into an adenovirus shuttle plasmid to obtain pDC312-SLPI (secretory leukoprotease inhibitor)-EGFR amiR-pA. Then it was co-transfected into 293 cells with the adenovirus backbone plasmid pBHGloxΔE1, 3Cre to pack the recombinant adenovirus Ad-SLPI-EGFR amiR. After the recombinant adenovirus infected Hep-2 cells by Ad-SLPI-EGFR amiR, a morphological change was observed, and an MTT assay was performed to assess the proliferation of the tumor cells. The expression of EGFR was determined by western blotting analyses to assess the effect of Ad-SLPI-EGFR amiR. Results: The sequence of artificial microRNA targeting EGFR was confirmed by DNA sequencing. Ad-SLPI-EGFR amiR significantly downregulated EGFR expression at the protein level and exerted an inhibitory effect on proliferation in Hep-2 cells. The transfected cells became round, shrunken, partly grape-like and floating under a lighted microscope. Conclusion: The recombinant adenovirus of Ad-SLPI-EGFR amiR was successfully constructed, and it was able to sufficiently decrease the expression of EGFR and inhibit the proliferation of Hep-2 cells.

The disruption of the MDM2-p53 interaction has been regarded as an attractive strategy for anticancer drug discovery. Here, the natural small-molecule SCY45 was identified as a potent MDM2-p53 interaction inhibitor based on fluorescence polarization and molecular modeling. SCY45 inhibited the MDM2-p53 interaction with an IC50 value of 4.93±0.08 μm. The structural modeling results showed that SCY45 not only had high structural similarity with nutlin-3a, a well-reported MDM2-P53 interaction inhibitor, but also bound to the p53 binding pocket of MDM2 with a binding mode similar to that of nutlin-3a. Moreover, SCY45 reduced the cell viability in cancer cells with MDM2 gene amplification. SCY45 showed the highest inhibition for SJSA-1 cells, which exhibit excessive MDM2 gene amplification, with an IC50 value of 7.54±0.29 μm, whereas SCY45 showed a weaker inhibition for 22Rv1 cells and A549 cells, which have a single copy of the MDM2 gene, with IC50 values of 18.47±0.75 μm and 31.62±1.96 μm, respectively.

Merrilliadione (1), a new diterpene with a unique isopropyl (1311)-abeo-9,11-seco-abietane skeleton, and two new abietane diterpenoids (2 and 3) were isolated from Illicium merrillianum. This is the first report of an isopropyl (1311)-abeo-9,11-seco abietane diterpenoid. The structures of 1–3 were established by comprehensive spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical computation of electronic circular dichroism (ECD) spectra.

Background: A number of studies have investigated the association between increased pretreatment serum C-reactive protein (CRP) levels and the prognosis of gastric cancer. However, due to the inconsistent results, whether the serum CRP level can be a prognostic factor in primary gastric cancer remains controversial. Methods: We searched Medline, PubMed, Embase and the Cochrane Central Register of Controlled Trials for relevant high-quality reports. A meta-analysis was carried out using the included studies to assess the association between pretreatment serum CRP level and overall survival (OS) in patients with gastric cancer. Correlation analyses were conducted to evaluate the relationship between serum CRP and tumor characteristics such as tumor node metastasis (TNM) stage and recurrence. Results: Twelve reports involving 2,597 patients with gastric cancer were included. Primary meta-analysis indicated a significant association between elevated CRP level and poor OS (HR 1.77, 95% CI 1.56-2.00). Subgroup analyses showed no single factor could alter the primary results when we divided the included studies by “number of patients”, “max follow-up period”, “TNM stage”, “treatment” and “cut-off value”. Correlation analyses showed that serum CRP level was significantly related to TNM stage (OR 2.96, 95% CI 2.22-3.93) and tumor recurrence (OR 1.81, 95% CI 1.21-2.71). Conclusions: We demonstrated that increased pretreatment serum CRP level (≥10mg/L) was significantly associated with poor prognosis in gastric cancer patients, either in early or advanced stages.

In the present study, the antidepressant-like effect of bacopaside I, a saponin compound present in the Bacopa monniera plant, was evaluated by behavioral and neurochemical methods. Bacopaside I (50, 15 and 5 mg/kg) was given to mice via oral gavage for 7 successive days. The treatment significantly decreased the immobility time in mouse models of despair tests, but it did not influence locomotor activity. Neurochemical assays suggested that treatment by bacopaside I (50, 15 and 5 mg/kg) improved brain antioxidant activity to varying degrees after the behavioral despair test. Bacopaside I (15 and 5 mg/kg) significantly reversed reserpine-induced depressive-like behaviors, including low temperature and ptosis. Conversely, bacopaside I did not affect either brain MAO-A or MAO-B activity after the behavioral despair test in mice. Additionally, 5-hydroxytryptophan (a precursor of 5-serotonin) was not involved in the antidepressant-like effect of bacopaside I. These findings indicated that the antidepressant-like effect of bacopaside I might be related to both antioxidant activation and noradrenergic activation, although the exact mechanism remains to be further elucidated.

The Th17 cell frequency in peripheral blood and levels of IL-17 showed significant differences between patients with laryngeal squamous cell carcinoma and those with vocal cords polyps. Serum levels of IL-17 were correlated with laryngocarcinoma staging.To investigate associations among the frequency of Th17 cells, levels of IL-17, and laryngeal squamous cell carcinoma.Eighty in-patients with laryngeal squamous cell carcinoma and 114 in-patients with polypus of the vocal cord were enrolled. Th17 cell frequencies in peripheral blood and serum levels of IL-17 were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. The tissue expression levels of IL-17 mRNA transcripts and protein were measured using quantitative RT-PCR or immunohistochemical detection, respectively.Th17 cell frequencies in peripheral blood and serum concentrations of IL-17 were significantly higher in patients with laryngocarcinoma compared with those in patients with polyps (p0.01 for both Th17 cells and IL-17 levels). Serum concentrations of IL-17 were significantly higher in patients with advanced laryngocarcinoma than in patients with early laryngocarcinoma (p0.01). The mRNA and protein levels of IL-17 were significantly higher in laryngocarcinoma tissues than in adjacent normal tissues (p0.01 for mRNA levels, p0.05 for protein levels).

Abiestetranes A (1) and B (2), two unique tetraterpenes formed by Diels-Alder cycloaddition between a lanostane triterpenoid and a monoterpenoid, were isolated from Abies fabri. Their structures were elucidated by extensive analysis of NMR data. The electronic circular dichroism was utilized to assign the absolute configuration of 1. Compounds 1 and 2 showed significant cytotoxic activities against ZR-75-30 tumor cell with IC50 values of 6.26 and 1.63 mu g/mL, respectively. (C) 2012 Elsevier Ltd. All rights reserved.

Nineteen natural compounds with diverse structures are identified as potential MMPIs using structure-based virtual screening from 4000 natural products. Hydroxycinnamic acid or analogs of natural products are important for potent inhibitory and selectivity against MMPs, and the solvent effect in the S1' pocket can affect the hydrophobic interactions and hydrogen bonds between MMPIs and MMPS, making MMPIs exhibit certain selectivity for a specific MMP isoenzyme. Furthermore, compound 5 can reduce the expression of both MMP-2 and active-MMP-9, and suppress the migration of MDA-MB-231 tumor cell in a wound healing assay, which may be further developed as an anticancer agent.

Phytochemical investigation of the aerial parts of Inula hupehensis Ling. led to the isolation and identification of 27 sesquiterpene lactones (1-27), including three new eudesmanolides (3-5), three new germacranolides (9-11), one new xanthanolide (16), two new carabrone derivatives (25-26), and 18 known sesquiterpene lactones. The structures were elucidated by extensive spectroscopic methods and comparison to previously reported spectroscopic data. All compounds were evaluated for their inhibitory effects against LPS-induced nitric oxide production in RAW264.7 macrophages, and compound 5 showed the strongest activity with the IC₅₀ value of 3.2 ± 0.4 µM.

A systematic phytochemical investigation on Abies forrestii afforded two new and 20 known compounds. Abieseconordines A and B (1 and 2) are the first two examples of norditerpenes with a novel 18-nor-5,10?:?9,10-disecoabietane skeleton. Their structures were established mainly by analysis of 1D- and 2D-NMR spectroscopic data. In addition, electronic circular-dichroism calculations and molecular-orbital analysis were utilized to confirm the absolute configuration of 1. Both compounds exhibited a potent effect in a bioassay inhibiting LPS-stimulated NO production in RAW264.7 macrophages.

A phytochemical investigation of Inula falconeri, a plant endemic to the Himalayas, afforded 10 new sesquiterpenoids and 26 known sesquiterpene lactones, including those bearing guaiane, pseudoguaiane, xanthane, eudesmane, germacrane, rare secocaryophyllane, chromolaevane, and carabrane frameworks. The structures were elucidated via spectroscopic analysis and compared with data from literature. All the isolates were assessed for their inhibitory effects against LPS-induced nitric oxide production in RAW264.7 macrophages. Compounds 4, 11, 24, and 31 showed stronger inhibitory activities than the positive control with IC(50) values of 0.13, 0.07, 0.11, and 0.11 μM, respectively. These studies also led to a better understanding of the structure-activity relationships for the sesquiterpene lactone family of compounds.

A novel trinorsesquiterpene (1), three new (2-4), and 10 known sesquiterpenes were isolated from the roots of Inula racemosa Hook. f. The structures and absolute configurations of the new sesquiterpenes were elucidated by extensive spectroscopic and computational methods. All compounds were evaluated for their inhibition of LPS-induced nitric oxide production in RAW264.7 macrophages, and the results indicated that compounds 9, 12, and 13 moderately inhibited nitric oxide production with IC50 values of 7.39 +/- 0.36, 6.35 +/- 0.26, and 5.39 +/- 0.18 mu M, respectively.

The phytochemical investigation of the ethanolic extract of the whole plants of Geum japonicum Thunb. var. chinense F. Bolle yielded four new compounds: 20 β,28-epoxy-28-hydroxytaraxasteran-3 β-ol (1), (7R,8R)-4-hydroxy-9'-O-(α-L-rhamnopyranosyl)-3,3',5'-trimethoxy-8-O-4'-neolignan (2), (7R,8S)-4-hydroxy-9'-O-(α-L-rhamnopyranosyl)-3,3',5'-trimethoxy-8-O-4'-neolignan (3), and (7S,8S)-5-methoxycupressoside A (4), as well as 40 other known compounds. Structures were elucidated by physical, chemical, and spectroscopic methods, including 1D and 2D NMR, HRESIMS, and CD experiments. The taraxasterane-type triterpene (1) and lignans (2- 6) are reported for the first time from the GEUM genus. Moreover, all compounds were evaluated for anti-inflammatory activities against NO production in RAW264.7 macrophages, and only moderate activities were detected.

Twenty-two new sesquiterpenes were isolated from the aerial parts of Inula japonica Thunb., together with fifteen known ones. Their structures were determined by detailed spectroscopic analysis, X-ray diffraction studies, and modified Mosher method. All 37 compounds were evaluated for the inhibition of LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, and most of isolates significantly inhibited the NO production with IC 50 values in the range of 3.5–20 μM. Besides, results obtained in our studies provided a structure–activity relationship that would be used to design anti-inflammatory agents in the future.

The isolation and structure elucidation of winolide A (Ia), B (Ib) and C (II) is described.

The cytotoxic activity of merrilliadione (I) is moderate against several human cancer cell lines.

γ-Hydroxynitrile glucosides (prinsepicyanosides A-E) were isolated alongside 11 known compounds from seeds of Prinsepia utilis Royle. Their structures were determined by detailed analysis of NMR and MS spectroscopic data. The relative configuration of prinsepicyanoside C was established by Cu-Kα X-ray crystallography. Prinsepicyanoside A, osmaronin, and 4-(hydroxylmethyl)-5H-furan-2-one exhibited borderline antibacterial activity against Salmonella gallinarum, Vibrio parahaemolyticus, and Vibrio cholera with MIC values of 30.1, 20.7, and 22.8μg/mL, respectively.

Four new sesquiterpenoid dimers (lineariifolianoids E-H, 1-4), five new sesquiterpenoids (5-9), and seven known sesquiterpenoids (10-16) were isolated from the aerial parts of Inula lineariifolia Turcz. Their structures were determined by spectroscopic data analysis and X-ray diffraction studies. The compounds were then evaluated for their in vitro cytotoxicity against two human breast cancer cell lines (MCF-7 and MDA-MB-231) and one normal breast cell line (MCF-10A). Lineariifolianoid E (1) showed IC50 values of 1.56 μM and 2.75 μM against MCF-7 and MDA-MB-231, respectively. However, lineariifolianoid E demonstrated low toxicity to MCF-10A cells, which indicated a selective cytotoxicity for tumor cells. Further studies also presented that lineariifolianoid E had significant, dose-dependent effects on cell cycle progression and apoptosis in breast cancer cells.

Eleven compounds were identified as estrogen receptor modulators from an in-house natural product database (NPD) by structure-based virtual screening for ERα and ERβ. Among them, 3 compounds were confirmed as ER agonists and 8 compounds were confirmed as ER antagonists by yeast two-hybrid (Y2H) assay, with EC50 values ranging from several micromolar to 100 micromolar. In this study, a novel series of cycloartane triterpenoids isolated from Schisandra glaucescens Diels was found to have ER antagonistic effect, the most potent antagonist of which exhibited activity with EC50 value of 2.55 and 4.68 μM for ERα and ERβ, respectively. Moreover, the types of modulation and subtype selectivity were also investigated through molecular docking simulation.

Compounds (I) and (II) demonstrate a promising inhibition of the LPS-stimulated NO production in RAW 264.7 macrophages.

A new acylated flavonoid, 3-O-rhamnocitrin-6-O-benzoyl-β-D-glucopyranoside (1), together with five known flavonoids, rhamnocitrin (2), pratensein (3), (3R)-7,3′-dihydroxy-2′,4′-dimethoxyisoflavan (4), (3R)-7,2′-dihydroxy-3′,4′-dimethoxyisoflavan (5) and isoliquiritigenin (6), was isolated from Oxytropis ochrocephala Bunge. The structural elucidation of the isolated compounds was primarily based on HRESIMS, IR and 1-D- and 2-D-NMR analyses.

Incarvilleatone (1), an unprecedented dimeric cyclohexylethanoid analog with a racemic nature, was isolated from the whole plant of Incarvillea younghusbandii. HPLC chiral separation of 1 gave two enantiomers (−)-incarvilleatone and (+)-incarvilleatone. The structure of 1 was established by spectroscopic methods and single crystal X-ray diffraction. The absolute configurations of enantiomers were determined by quantum mechanical calculation. (−)-Incarvilleatone exhibited a potent inhibitory effect against NO production in LPS-induced RAW264.7 macrophages.

Four new sesquiterpene lactones, (1 S,5 R,6 S,7 S,8 R,9 R,10 S,11 S)-6-acetoxy-9-hydroxy-4-oxo-pseudoguai-2(3)-en-12,8-olide, (1 S,2 R,5 R,6 S,7 R,8 S,10 R)-6-acetoxy-2-ethoxy-4-oxo-pseudoguai-11(13)-en-12,8-olide, (1 S,2 R,5 R,6 S,7 R,8 S,10 R)-6-acetoxy-2-hydroxy-4-oxo-pseudoguai-11(13)-en-12,8-olide, and 14-acetoxy-1 β,5 α,7 αH-4 β-hydroxy-guai-9(10),11(13)-dien-12,8 α-olide, along with 26 known sesquiterpene lactones, were isolated from the whole plants of Inula hookeri C. B. Clarke. Their structures were established based on spectroscopic methods including HRESIMS, 1D and 2D NMR, and CD techniques. All compounds were evaluated for their cytotoxic activities against HepG2, HeLa, PC-3, and MGC-803 cell lines by CCK-8 assay. Some of the isolates, especiallly pseudoguaianolides and guaianolides, exhibited significant cytotoxicities against these four examined cell lines.

Eight new pseudoguaianolides (1-8), two new guaianolides (9 and 10), and 14 known sesquiterpenes were isolated from the aerial parts of Inula hupehensis. The structures were elucidated using spectroscopic methods and circular dichroism analysis. All compounds were tested for inhibitory activities against LPS-induced nitric oxide production in RAW264.7 macrophages. Compounds 13 and 22 were found to inhibit nitric oxide production potently, with IC50 values of 0.9 and 0.6 μM, respectively. Preliminary structure-activity relationships for these compounds are proposed.

With the development of stem cells and regenerative medicine (treatment of various diseases using stem cells) research, the induction of differentiation of human stem cell technology has also made significant progress. The development of chemical biology offers a variety of small biological molecules for stem cell biology. This review focuses on how small molecule compounds (natural and synthetic) induce differentiation of stem cells.

Four new compounds: an abietane (1), two isopimarane (2 and 3) diterpenes, and a dihydrobenzofuran neolignan (5), together with a sesquiterpene glycoside (6) firstly isolated from a natural source, and a known phenol glycoside (4) were isolated from leaves of Platycladus orientalis. The structures and relative configurations of these compounds were assigned on the basis of MS, IR, 1D and 2D NMR data. The absolute configuration of compound 1 was determined via density functional theory calculations of its electronic circular dichroism. In addition, the results of bioassays indicated that compounds 4 and 6 showed a potent inhibitory effect on NO production with IC₅₀ values of 24.4 and 11.9 µM, respectively. Meanwhile, compounds 1, 2, and 3 moderately inhibited TNF- α release.

Winolides A–C (1–3), three bioactive sesquiterpene lactones with irregular 5,6-secoeudesmane frameworks, which probably arise from different dienol-benzene rearrangements, were isolated from Inula wissmanniana. Their structures and absolute configurations were established by extensive analysis of spectroscopic data, computational methods, and asymmetric synthesis.

Lineariifolianoids A–D (1–4), a rare class of unsymmetrical sesquiterpenoid dimers with xanthane and guaiane frameworks have been isolated for the first time from Inula lineariifolia. Notably, lineariifolianoid D (4) features the first exo-adduct of such dimers through a plausible Diels–Alderase catalyzed biogenetic pathway. Moreover, the absolute configuration of japonicone A (5) has been revised by the Flack method. The inhibitory effects of the new isolates on TNF-α-mediated L929 cytotoxicity have also been evaluated and only the exo-adduct lineariifolianoid D (4) displays the inhibitory property.

The potential drug target database (PDTD) was searched by the TarFisDock server, a reverse docking approach, to identify putative targets for a collection of 19 natural products derived from two medicinal plants Bacopa monnieri (L.) Wettst (BMW) and Daphne odora Thunb. var. marginata (DOT), which are both used for the treatment of diabetes and inflammation in Traditional Chinese Medicine (TCM). Out of the top 5% of target candidates, dipeptidyl peptidase IV (DPP-IV) was the most frequent potential target and the predicted results were subsequently confirmed by in vitroenzyme assay. As a result, five natural products show moderate inhibitory activities against DPP-IV with IC50 values ranging from 14.13 μM to 113.76 μM. Subsequently, thirteen analogues of active compounds out of our in-house natural products database (NPD) were also identified with inhibitory activity against DPP-IV, with IC50 values ranging from 26.92 μM to 87.72 μM. The results indicate that the computational chemical biology approach is a good complement to the experimental target identification strategies for elucidating the mechanism of the natural products, especially for those components without unambiguous binding targets whilst having some traditional efficacy in TCM.