Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma.

Circadian rhythm genes were reported to be strongly associated with the development and prognosis of circadian rhythm disorders related to stomach adenocarcinoma (STAD), which is one of the most prevalent cancers. This study aimed to identify a circadian rhythm-related gene signature that could help predict STAD outcome. Using bioinformatics analysis approaches, 105 genes were examined in 350 patients with STAD. Overall, six hub-type circadian rhythm-associated genes (GNA11, PER1, SOX14, EZH2, MAGED1, and NR1D1) were identified using univariate and multivariate Cox regression analyses. These genes were then used to build a genetic predictive model, which was further validated using a publicly available dataset (GSE26899). Overall, genes associated with the circadian rhythm were found to be substantially correlated with the characteristics of the STAD patients (grade, sex, and M stage). In addition, the circadian rhythm-related gene signature was significantly associated with the MAPK and Notch signaling pathways, which are known risk factors for poorer STAD outcome. Taken together, these findings suggest that the herein proposed prognostic model based on six circadian rhythm-associated genes may have predictive value and potential application for clinical decision-making and for personalized treatment of STAD.

Ginsenoside Contents in Ginseng: Quality by Design-Coupled Two-Dimensional Liquid Chromatography Technique.

Red ginseng and white ginseng, with different chemical constituents, exhibit different antioxidative, anticancer, antiasthmatic and immunomodulatory properties. The aim of this study was to determine the amount of ginsenoside contents (Rg1, Re, Rb1, Rb2, Rc, Rd and Ro) in red and white ginseng. A rapid and comprehensive method was developed using the quality-by-design (QbD) and heart-cutting two-dimensional liquid chromatography (2D-LC) techniques. The temperature (25°C), mobile phase constituent (0.1%H3PO4), flow rate (0.35 mL/min) and concentrations of the final (45%) and initial (19.5%) organic solvents were optimized to efficient chromatography-based isolation method. The gradient program was optimized by QbD Fusion AE system. A selective column (Thermo Acclaim RSLC Polar Advantage II 2.2 µm, 100 × 2.1 mm) was used for the studies. The ginsenoside Rb1, Rc and Ro exhibiting poor separation resolution were separated using the heart-cutting 2D-LC technique. The average Rb1, Rb2 and Rc contents in red ginseng were significantly higher than the average Rb1, Rb2 and Rc contents in white ginseng. Ginsenoside Ro can be potentially used as a marker to evaluate the qualities of white and red ginseng. This comprehensive and rapid method can be potentially used to screen the quality of the markers in the future.

Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology.

Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented. We use this approach to design compounds that both antagonize the A2A adenosine receptor and activate the D2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure-based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual-target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.

[Analysis of difficult problems on European Union laws and regulations of traditional herbal medicinal products].

Registration of Chinese patent medicine in European Union (EU) is of great significance to the internationalization of traditional Chinese medicine as EU market acts as an important position in the global botanical market. In retrospect, the domestic studies on EU regulations of traditional herbal medicinal products have been conducted for more than 10 years, but there is still some cognitive bias and lack of research. In this paper, a review of the relevant research progress and the main misunderstanding problems about Directive 2004/24/EC, like the centralized and decentralized supervision system of traditional herbal medicinal products in the EU, marketing authorization procedures for traditional herbal medicinal products, Community Herbal Monograph and List Entries, would be systematically analyzed, so as to provide reference for the registration of Chinese patent medicine in EU.

Xiaoxianggou attenuates atherosclerotic plaque formation in endogenous high Ang II ApoE(-/-) mice via the inhibition of miR-203 on the expression of Ets-2 in endothelial cells.

BACKGROUND: Atherosclerosis is a chronic immune-inflammatory disorder and one of the leading causes responsible for cardiovascular morbidity and mortality. Traditional Chinese medicine treatment with multi-targets has shown prospects for the therapeutic effect on atherosclerosis. Thus, this study aims to investigate whether xiaoxianggou has benefit for reducing the atherosclerotic plaque area in endogenous high Ang II ApoE(-/-) mice and investigated the underlying mechanisms. METHODS: Endogenous high Ang II ApoE(-/-) mice model was generated by using two kidney one clip (2K1C). All mice were treated by intragastric administration with xiaoxianggou two times a week for 16 weeks. En face plaque area was analyzed by oil-red O staining. Serum anti-OxLDL antibodies were measured by ELISA assay. Expression of miR-203 and Ets-2 were evaluated using qRT-RCR and western blotting analysis, respectively. RESULTS: This study revealed that xiaoxianggou treatment dose-dependently reduced the atherosclerotic plaque area and serum autoantibodies against oxLDL, elevated miR-203 expression and reduced Ets-2 expression in endogenous high Ang II ApoE(-/-) mice. In primary arterial ECs, Xiaoxianggou reverses the reduced miR-203 expression and the elevated Ets-2 expression induced by AngII, which was further recovered by miR-203 inhibitor. Additionally, miR-203 regulated the expression of Ets-2 by targeting Ets-2-3' UTR. Moreover, miR-203 inhibitor reversed the reduction of atherosclerotic lesion area induced by Xiaoxianggou. CONCLUSIONS: These findings present that xiaoxianggou plays an anti-atherosclerotic role in endogenous high Ang II ApoE(-/-) mice model, which is partly due to its antioxidant actions against atherosclerosis and the inhibition of miR-203 on the expression of Ets-2 in endothelial cells.

Neuropeptidomics of mouse hypothalamus after imipramine treatment reveal somatostatin as a potential mediator of antidepressant effects.

Excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with numerous diseases, including depression, and the tricyclic antidepressant imipramine has been shown to suppress activity of the HPA axis. Central hypothalamic control of the HPA axis is complex and involves a number of neuropeptides released from multiple hypothalamic subnuclei. The present study was therefore designed to determine the effects of imipramine administration on the mouse hypothalamus using a peptidomics approach. Among the factors found to be downregulated after acute (one day) or chronic (21 days) imipramine administration were peptides derived from secretogranin 1 (chromogranin B) as well as peptides derived from cerebellin precursors. In contrast, peptides SRIF-14 and SRIF-28 (1-11) derived from somatostatin (SRIF, somatotropin release inhibiting factor) were significantly upregulated by imipramine in the hypothalamus. Because diminished SRIF levels have long been known to occur in depression, a second part of the study investigated the roles of individual SRIF receptors in mediating potential antidepressant effects. SRA880, an antagonist of the somatostatin-1 autoreceptor (sst1) which positively modulates release of endogenous SRIF, was found to synergize with imipramine in causing antidepressant-like effects in the tail suspension test. Furthermore, chronic co-administration of SRA880 and imipramine synergistically increased BDNF mRNA expression in the cerebral cortex. Application of SRIF or L054264, an sst2 receptor agonist, but not L803807, an sst4 receptor agonist, increased phosphorylation of CaMKII and GluR1 in cerebrocortical slices. Our present experiments thus provide evidence for antidepressant-induced upregulation of SRIF in the brain, and strengthen the notion that augmented SRIF expression and signaling may counter depressive-like symptoms. This article is part of a Special Issue entitled 'Anxiety and Depression'.

A role for p11 in the antidepressant action of brain-derived neurotrophic factor.

BACKGROUND: The protein p11 (also called S100A10) is downregulated in human and rodent depressive-like states. Considerable experimental evidence also implicates p11 in the mechanism of action of antidepressant drugs and electroconvulsive seizures, in part due to its interaction with specific serotonin receptors. Brain-derived neurotrophic factor (BDNF) has been linked to the therapeutic activity of antidepressants in rodent models and humans. In the current study, we investigated whether BDNF regulates p11 in vitro and in vivo. METHODS: We utilized primary neuronal cultures, in vivo analyses of transgenic mice, and behavioral techniques to assess the effects of BDNF on p11. RESULTS: Results indicate that BDNF stimulates p11 expression through tropomyosin-related kinase B (trkB) receptors and via the mitogen-activated protein kinase signaling pathway. Brain-derived neurotrophic factor-induced changes in p11 in vivo correlate with changes in ligand binding to the 5-hydroxytryptamine receptor 1B, the subcellular localization of which is known to be regulated by p11. Behavioral studies demonstrate that p11 knockout mice are insensitive to the antidepressant actions of BDNF. CONCLUSIONS: Taken together, our data demonstrate that p11 levels are regulated by BDNF in vitro and in vivo and that the antidepressant-like effect of BDNF in two well-established behavioral models requires p11. These data support a role for p11 in the antidepressant activity of neurotrophins.