Search

With an escalating global epidemic of obesity, the prevalence of obesity among reproductive women continues to rise. It has been widely reported that maternal obesity has profound effects on female reproduction. Of them, oocyte quality has been a major concern. In recent years, emerging evidence on maternal obesity has shown that meiosis damage, mitochondrial and endoplasmic reticulum dysfunction, and epigenetic modification changes occur in oocytes, and mechanisms are also being reported. Here we review the recent researches on the effects of maternal obesity on oocyte and embryo development, and propose the potential intervention targets and pathways to improve egg quality and reproductive outcome.

It has been widely reported that obesity adversely impacts reproductive performance of females. However, the effects of maternal obesity on fetal germ cells remain poorly understood. In the present study, by employing a high‐fat diet (HFD)‐based mouse model, it is discovered that maternal obesity disrupts the chromosomal synapsis and homologous recombination during fetal oogenesis. Moreover, transcriptomic profiling reveales the potential molecular network controlling this process. Of note, the global hypermethylation of genomic DNA in fetal oocytes from obese mouse is detected. Importantly, time‐restricted feeding (TRF) of obese mice not only ameliorate the meiotic defects, but also partly restore the epigenetic remodeling in fetal oocytes. In sum, the evidence are provided showing the deficit fetal oogenesis in obese mother, implicating a mechanism underlying the intergenerational effects of environmental insults. TRF may represent a potentially effective approach for mitigating fertility issues in obese patients. [ABSTRACT FROM AUTHOR]

Investigation of the roots of Lotus polyphyllos Clarke resulted in the isolation of two new isoflavone derivatives; 4′- O -methylerythrinin C ( 3 ) and 4′- O -methyl-2′′-hydroxydihydroalpinumisoflavone ( 4 ). In addition, the three known isoflavone derivatives 4′- O -methylalpinumisoflavone ( 1 ) lupinalbin F ( 5 ), 4′,7-dimethoxy-5-hydroxyisoflavone ( 6 ), and the phenylpropanoid ester tetracosyl p -coumarate ( 2 ) were also identified. The structures were determined from spectroscopic data. [ABSTRACT FROM AUTHOR]

Abstract: p27Kip1 (p27) binds and inhibits the cyclin E- or cyclin A-associated cyclin-dependent kinases (CDKs)2 and other CDKs, and negatively regulates G1–G2 cell cycle progression. To develop specific CDK inhibitors, we have modeled the interaction between p27 and cyclin A-CDK2, and designed a novel compound that mimics p27 binding to cyclin A-CDK2. The chemically synthesized inhibitor exhibited high potency and selective inhibition towards cyclin E/cyclin A-CDK2 kinase in vitro but not other kinases. To facilitate permeability of the inhibitor, a cell penetrating peptide (CPP) was conjugated to the inhibitor to examine its effect in several cancer cell lines. The CPP-conjugated inhibitor significantly inhibited the proliferation of cancer cells. The treatment of the inhibitor resulted in the increased accumulation of p27 and p21Cip1/Waf1 (p21) and hypo-phosphorylation of retinoblastoma protein (Rb). The degradation of p27, mediated through the phosphorylation of threonine-187 in p27, was also inhibited. Consequently, exposure of cells to the inhibitor caused cell cycle arrest and apoptosis. We conclude that specific cyclinE/cyclin A-CDK2 inhibitors can be developed based on the interaction between p27 and cyclin/CDK to block cell cycle progression to prevent tumor growth and survival. [Copyright &y& Elsevier]

Mycotoxin cyclochlorotine ( 1 ) and structurally related astins are cyclic pentapeptides containing unique nonproteinogenic amino acids, such as β-phenylalanine, l- allo -threonine, and 3,4-dichloroproline. Herein, we report the biosynthetic pathway for 1 , which involves intriguing tailoring processes mediated by DUF3328 proteins, including stereo- and regiospecific chlorination and hydroxylation and intramolecular O , N -transacylation. Our findings demonstrate that DUF3328 proteins, which are known to be involved in oxidative cyclization of fungal ribosomal peptides, have much higher functional diversity than previously expected.

The first total synthesis of the potent anti-tuberculosis cyclopeptide natural products ilamycins E 1 and F was achieved. This highly convergent strategy consists of the synthesis of the two units 10 and 11 and linking them together to form the macrocyclic lactam 31. The upper unit 10 was prepared from tryptophan in five steps, and the lower unit 11 was prepared from glutamic acid in thirteen steps. Conversion of ilamycin F, the most abundant of the cyclopeptides, into the more active congener, ilamycin E 1 , was also accomplished. This would provide sufficient material of ilamycin E 1 for more extensive biological studies.

The important anticancer drug Taxol (paclitaxel, PTX) owes its unique activity to its ability to bind to tubulin in a stoichiometric ratio and promote its assembly into microtubules. The conformation of the microtubule-bound drug has been the focus of numerous research efforts, since the inability of polymerized tubulin to form crystals precludes structure proof by X-ray crystallography. Likewise, although the alpha,beta-tubulin dimer structure has been solved by electron crystallography, the 3.7 A resolution is too low to permit direct determination of either ligand conformation or binding pose. In this article, we present experimental results from 2H{19F} REDOR NMR that provide direct confirmation that paclitaxel adopts a T-shaped conformation when it is bound to tubulin.