Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia.

A series of tryptamine derivatives has been designed and synthesized as novel GluN2B subunit-containing NMDA receptor (GluN2B-NMDAR) antagonists, which could simultaneously manifest the receptor-ligand interactions of representative GluN2B-NMDAR antagonists ifenprodil (1) and EVT-101 (3). In the present study, the neuroprotective potential of these compounds was explored through chemical synthesis and pharmacological characterization. Compound Z25 with significantly better neuroprotective activity than the positive control drug (percentage of protection: 55.8 ± 0.6% vs. 41.0 ± 2.7%) was considered to be an effective antagonist of the human GluN2B-NMDA receptor. Judging from in vitro pharmacological profiling, Z25 could downregulate NMDA-induced increased intracellular Ca2+ concentration, and Z25 could also upregulate NMDA-induced decreased intracellular p-ERK 1/2 expression, which suggested that Z25 is an antagonist of the GluN2B-NMDA receptor. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound Z25 showed remarkable plasma stability. Based on in vivo pharmacokinetic and pharmacodynamic studies in C57 mice, compound Z25 exhibited a relatively short half-life and a low F value (3.12 ± 0.01%), while administration of Z25 substantially improved the cognitive performance of mice in a series of tests of cerebral ischemic injury. Overall, these results support the further development of compound Z25 as a potential lead compound to treat the cerebral ischemic injury by antagonizing GluN2B-NMDA receptor.

Identification and in silicon binding study of a novel NR2B selective NMDAR antagonist.

Alzheimer's disease (AD) is a major group of diseases that threaten human health, and the search for drugs and treatments for it has never stopped. Research and development of NMDA receptor antagonists as potential therapeutic targets have also been ongoing. Our group designed and synthesized 22 new tetrahydropyrrolo[2,1-b]quinazolines based on NR2B-NMDARs targets and evaluated them for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, A21 exhibited excellent neuroprotective activity. Subsequently, the structure-activity relationships and inhibitor binding modes of the tetrahydropyrrolo[2,1-b]quinazolines were further analyzed by molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The results showed that A21 could match the two binding pockets of NR2B-NMDARs. The research results of this project will lay a certain foundation for the research of novel NR2B-NMDA receptor antagonists and also provide new ideas for the subsequent research and development of this target.

Excessive weight gain during pregnancy and risk of macrosomia: a meta-analysis.

PURPOSE: This meta-analysis aimed to estimate the relation between excessive gestational weight gain and macrosomia. METHODS: We performed a meta-analysis by searching PubMed, EMBASE and the Cochrane library for English-language literature from inception to 1 October 2014. Studies assessing the relationship between excessive gestational weight gain and macrosomia were included. Characteristics including study design, country, sample size, definition of macrosomia, adjusted odds ratios, CIs and adjustment factors were extracted independently by two reviewers. Summary odds ratios were calculated by using a random-effects model meta-analysis. RESULTS: 15 relevant articles were eligible for the meta-analysis. Incorporated by random-effect model before the heterogeneity tests, the value of OR was 2.35 (95 % CI: 1.95, 2.85). Stratified analysis showed no differences regarding different study design, definition of macrosomia and location of study. There was no indication of a publication bias either from the result of Egger's test (P = 0.572) or Begg's test (P = 0.572). CONCLUSIONS: Our meta-analysis indicated that excessive gestational weight gain might increase the risk of macrosomia.

[Influence of sedentary behavior on weight retention among postpartum women within one year after childbirth].

OBJECTIVE: To identify the risk factors that affect the postpartum weight retention among women and provide evidence for the prevention of obesity and metabolic disorders due to childbirth. METHODS: The baseline data were collected from 1 220 postpartum women who had given childbirth 42 days ago in Hefei Maternal and Child Health Care Center, Anhui province. Their pre-pregnancy weight, weight gain during pregnancy and childbirth information were obtained from local maternal information management system, and the follow up for the women were conducted at 3, 6, 9, and 12 months after childbirth. The sedentary behaviors of the women were observed. The relationship between postpartum weight retention and sedentary behavior of the women were analyzed by mixed-effects model analysis and repeated measures analysis of variance. RESULTS: The pre-pregnancy average body weight (kg) of the women was (53.22 ± 6.88), and their postpartum average body weight retention was (7.85 ± 5.11), (7.51 ± 5.40), (5.79 ± 5.18), (4.42 ± 4.91) and (3.26 ± 4.65) at 42 days, 3, 6, 9, 12 months later after childbirth, respectively. The differences in body weight retention at different times after childbirth indicated by repeated measures analysis of variance were statistical significant (P < 0.001). Mixed-effects model analysis showed the postpartum sedentary behavior and postpartum body weight retention was statistically associated after adjusting for pre-pregnancy BMI, feeding pattern, delivery mode and other confounding factors (P < 0.001), Mixed-effects model analysis results tended to be stable after step by step adjustment for confounding factors. CONCLUSION: The results of this study suggested that postpartum sedentary behavior is one of the important factors influencing postpartum weight retention.

Is gestational diabetes mellitus an independent risk factor for macrosomia: a meta-analysis?

PURPOSE: The aim of our meta-analysis was to explore whether gestational diabetes mellitus (GDM) is an independent risk factor for macrosomia or not. METHODS: Three databases were systematically reviewed and reference lists of relevant articles were checked. Meta-analysis of published epidemiological studies (cohort and case-control studies) comparing whether GDM was associated with macrosomia. Calculations of pooled estimates were conducted in random-effect models. Heterogeneity was tested by using Chi square test and I (2) statistics. Publication bias was estimated from Egger's test (linear regression method) and Begg's test (rank correlation method). RESULTS: Twelve studies met the inclusion criteria, including five cohort studies and seven case-control studies. The meta-analysis showed that GDM was associated with macrosomia independent of other risk factors. The adjusted odds ratio was 1.71, 95% CI (1.52, 1.94) in random-effect model, stratified analyses showed no differences regarding different study design, quality grade, definition of macrosomia, location of study and number of confounding factors adjusted for. There was no indication of a publication bias either from the result of Egger's test or Begg's test. CONCLUSION: Our findings indicate that GDM should be considered as an independent risk factor for newborn macrosomia. To adequately evaluate the clinical evolution of GDM need to be carefully assessed and monitored.

The association between gestational weight gain and substantial weight retention 1-year postpartum.

PURPOSE: Postpartum weight retention contributes to obesity development of women in their reproductive age. The studies about the association between gestational weight gain (GWG) and substantial weight retention are lacking. This study examined the association between GWG and substantial postpartum weight retention (SPPWR). METHODS: The participants (n = 1,122) in the study were healthy, mature and fed their infants whose ages were 3, 6, 9, 12 months (2010-2012), respectively. They self-reported their socio-demographic, clinical prenatal and behaviors characteristics via questionnaires. We collected their weight data including pre-pregnancy and prior to delivery, as well as weight at 3, 6, 9, and 12 months postpartum. The major outcomes included weight retention and substantial weight gain 1 year postpartum. RESULTS: Of the 1,122 women, the median weight retention was 3.0 (IQR = 5.5) kg 12 months postpartum. 35.7 % of them reported substantial weight retention (≥4.55 kg). GWG categories were established as follows: inadequate weight gain (n = 366, 33 %), adequate weight gain (n = 596, 53 %), and excessive weight gain (n = 160, 14 %). Adjusted odds ratios of SPPWR were 0.59 (95 % CI 0.43, 0.81) for inadequate weight gain and 4.05 (95 % CI 2.75, 5.95) for excessive weight gain versus adequate weight gain (P < 0.001). CONCLUSIONS: Excessive GWG would increase the risk of substantial weight retention 1-year postpartum. The interventions to prevent postpartum obesity should consider the strategies how to attain optimal maternal GWG.

Composition of transgenic soybean seeds with higher γ-linolenic acid content is equivalent to that of conventional control.

γ-Linolenic acid (GLA) has been used as a general nutraceutical for pharmacologic applications, particularly in the treatment of skin conditions such as eczema. Four transgenic soybean lines that produce GLA at high yields (4.21% of total fatty acids, up to 1002-fold) were generated through the stable insertion of the Delta-6-fatty acid desaturase gene isolated from Borago officinalis into the genome of a conventional soybean cultivar. As part of the safety assessment of genetically engineered crops, the transgenic soybean seeds were compared with their parental soybean seeds (nontransgenic) by applying the principle of substantial equivalence. Compositional analyses were conducted by measuring the fatty acids, proximate analysis (moisture, crude protein, crude fat, carbohydrates, TDF, and ash contents), amino acids, lectins, and trypsin inhibitor activity. The present results showed that the specific transgenic cultivar studied was similar to the conventional control.