[Progress in study of selective ERß ligands].

Estrogen receptors (ERs) are members of nuclear receptors and related to several diseases such as cancer, inflammation and osteoporosis. ERs have two forms, ERα and ERß, which have different functions and organism distributions. Compounds selectively targeting ERß can regulate important physiological functions and avoid the side effects caused by targeting ERα. Therefore, selective ERß ligands have received considerable research interest in recent years. In this article, different kinds of selective ERß ligands were summarized and their structure-activity relationships were also analyzed.

The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway.

The acute-phase protein orosomucoid (ORM) exhibits a variety of activities in vitro and in vivo, notably modulation of immunity and transportation of drugs. We found in this study that mice lacking ORM1 displayed aberrant energy homeostasis characterized by increased body weight and fat mass. Further investigation found that ORM, predominantly ORM1, is significantly elevated in sera, liver, and adipose tissues from the mice with high-fat diet (HFD)-induced obesity and db/db mice that develop obesity spontaneously due to mutation in the leptin receptor (LepR). Intravenous or intraperitoneal administration of exogenous ORM decreased food intake in C57BL/6, HFD, and leptin-deficient ob/ob mice, which was absent in db/db mice and was significantly reduced in mice with arcuate nucleus (ARC) LepR knockdown, whereas enforced expression of ORM1 in ARC significantly decreased food intake, body weight, and serum insulin level. Furthermore, we found that ORM is able to bind directly to LepR and activate the receptor-mediated JAK2-STAT3 signaling in hypothalamus tissue and GT1-7 cells, which was derived from hypothalamic tumor. These data indicated that ORM could function through LepR to regulate food intake and energy homeostasis in response to nutrition status. Modulating the expression of ORM is a novel strategy for the management of obesity and related metabolic disorders.

Effects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates.

Structure-based prediction of sites of metabolism (SOMs) mediated by cytochrome P450s (CYPs) is of great interest in drug discovery and development. However, protein flexibility and active site water molecules remain a challenge for accurate SOM prediction. CYP2C19 is one of the major drug-metabolizing enzymes and has attracted considerable attention because of its polymorphism and capability of metabolizing ∼7% clinically used drugs. In this study, we systematically evaluated the effects of protein flexibility and active site water molecules on SOM prediction for CYP2C19 substrates. Multiple conformational sampling techniques including GOLD flexible residues sampling, molecular dynamics (MD) and tCONCOORD side-chain sampling were adopted for assessing the influence of protein flexibility on SOM prediction. The prediction accuracy could be significantly improved when protein flexibility was considered using the tCONCOORD sampling method, which indicated that the side-chain conformation was important for accurate prediction. However, the inclusion of the crystallographic or MD-derived water molecule(s) does not necessarily improve the prediction accuracy. Finally, a combination of docking results with SMARTCyp was found to be able to increase the SOM prediction accuracy.

[Thinking on current treatment situation of acupuncture foe functional defecation disorders].

In order to optimize acupuncture treatment protocol for functional defecation disorders, literature during past 20 years is reviewed, and factors which influences acupuncture therapeutic effect are analyzed from aspects of acupoint, acupuncture technique, etc. As for the selection of acupoint, more attention should be paid on the use of Baliao, especially Zhongliao (BL 33) and Xialiao (BL 34); when Baliao is deeply needled, it is essential to acquire scientific technique. The relationship between acupuncture parameter (including electroacupuncture waveform and frequency), acupuncture techniques (including reinforcing and reducing technique, quantity of stimulation, etc. ) and acupuncture efficacy is complicated, and the scientific values of present research conclusion are in need, of further improvement. The diagnosis and treatment awareness on types of functional defecation should be strengthened, and the mental health of the constipation patients should be concerned. The combination of acupuncture and biofeedback training can have a synergistic effect, which is benefit to achieve a better long-term effect. Based on this, acupuncture treatment protocol for functional defecation disorders can be optimized to further improve the efficacy.