Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists.

Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 µM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 µM) and guggulsterone (IC50 = 45.9 ± 1.1 µM). Docking of A-11 in FXR's ligand-binding domain was also studied.

Therapy Management of Metabolic Disorder Comorbidity With Depression.

Depression is a common disease that seriously endangers the physical and mental health of human beings, and it often coexists with other metabolic disorders such as diabetes and cancer. There have been endless reports on the mechanism, prevention, and cure of comorbidity because of its high incidence and poor prognosis and the increased burden on the family and society. There may be a specific comorbid basis and causal relationship between depression and metabolic diseases. Depression in patients with metabolic disorders can be effectively alleviated through psychotherapy and medication. The timely and effective treatment of depression can significantly improve the quality of life of patients with metabolic disorders, reduce their psychological burden, and promote the effective treatment of metabolic diseases. This study reorganized the research progress on the management of metabolic disorder comorbidity with depression.

Population pharmacokinetic modeling and clinical application of vancomycin in Chinese patients hospitalized in intensive care units.

Management of vancomycin administration for intensive care units (ICU) patients remains a challenge. The aim of this study was to describe a population pharmacokinetic model of vancomycin for optimizing the dose regimen for ICU patients. We prospectively enrolled 466 vancomycin-treated patients hospitalized in the ICU, collected trough or approach peak blood samples of vancomycin and recorded corresponding clinical information from July 2015 to December 2017 at Tai Zhou Hospital of Zhejiang Province. The pharmacokinetics of vancomycin was analyzed by nonlinear mixed effects modeling with Kinetica software. Internal and external validation was evaluated by the maximum likelihood method. Then, the individual dosing regimens of the 92 patients hospitalized in the ICU whose steady state trough concentrations exceeded the target range (10-20 µg/ml) were adjusted by the Bayes feedback method. The final population pharmacokinetic model show that clearance rate (CL) of vancomycin will be raised under the conditions of dopamine combined treatment, severe burn status (Burn-S) and increased total body weight (TBW), but reduced under the conditions of increased serum creatinine (Cr) and continuous renal replacement therapy status; Meanwhile, the apparent distribution volume (V) of vancomycin will be enhanced under the terms of increased TBW, however decreased under the terms of increased age and Cr. The population pharmacokinetic parameters (CL and V) according to the final model were 3.16 (95%CI 2.83, 3.40) L/h and 60.71 (95%CI 53.15, 67.46). The mean absolute prediction error for external validation by the final model was 12.61% (95CI 8.77%, 16.45%). Finally, the prediction accuracy of 90.21% of the patients' detected trough concentrations that were distributed in the target range of 10-20 µg/ml after dosing adjustment was found to be adequate. There is significant heterogeneity in the CL and V of vancomycin in ICU patients. The constructed model is sufficiently precise for the Bayesian dose prediction of vancomycin concentrations for the population of ICU Chinese patients.

Short- and long-term outcomes of laparoscopic versus open surgery for rectal cancer: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: The present meta-analysis aimed to evaluate the short- and long-term outcomes of laparoscopic surgery (LS) versus open surgery (OS) for rectal cancer. METHODS: PubMed, Web of Science, and Cochrane Library, were searched for eligible randomized controlled trials (RCTs) published up to June 2017. Operation related index, postoperative complication, and long-term survival rate and disease-free survival rate were evaluated by meta-analytical techniques. RESULT: Nine RCTs enrolling 4126 patients were included in the present meta-analysis. Compared to OS, LS had similar positive circumferential resection margin (CRM) and number of lymph nodes extracted (LNE) as well as long term 5 years survival rate and disease-free survival rate, but of which the risk tendency was higher in LS group. The short-term outcomes of major and total postoperative complication were lower in LS group. CONCLUSIONS: LS for rectal cancer was as safe and effective as OS in terms of long-term outcomes, but with lower postoperative complication.

Glucocorticoid-induced leucine zipper may play an important role in icariin by suppressing osteogenesis inhibition induced by glucocorticoids in osteoblasts.

BACKGROUND AND PURPOSE: Icariin is a potent stimulator of osteogenic differentiation; however, the mechanism underlying its osteogenic effect remains unclear. The osteogenic effect of icariin is related to the upstream glucocorticoid-induced leucine zipper (GILZ) signaling pathway, and antagonism with dexamethasone-induced osteoblast inhibition was noted. METHODS: MC3T3-E1 cells were cultured in induced medium treated with icariin with or without dexamethasone. After short interfering RNA (siRNA) were used to silence GILZ expression, the degree of mineralization, proliferation, and GILZ expression as well as the levels of osteogenic (OPG, RANKL, ALP, OC and RUNX2) markers were tested. RESULTS: Dexamethasone inhibited, while icariin increased, osteogenic activity, as indicated by ALP activity and calcium nodules. Meanwhile, dexamethasone dose-dependently (10-6M-10-4M) increased GILZ and RANKL expression and reduced ALP, OPG and OC, but the pattern of mRNA expression was reversed when icariin was added. Furthermore, GILZ (dexamethasone-induced) inhibition caused by icariin or moderately silenced by GILZ siRNA abolished the osteogenesis inhibition effect of dexamethasone, as indicated by the changes in the GILZ, ALP, OPG and RANKL expression levels; ALP activity; and calcium nodule. CONCLUSIONS: These results indicate that the GILZ-mediated osteogenic signal pathway is involved in the osteogenic effect induced by icariin.