Design, synthesis, and bioavailability evaluation of coumarin-based prodrug of meptazinol

Based on the known coumarin-based prodrug system, a new meptazinol (Z)-3-[2-(propionyloxy) phenyl]-2-propenoic ester (3) was designed and synthesized as prodrug to minimize the first-pass effect of meptazinol (1) and improve the oral bioavailability. The prodrug (3) showed a 4-fold increase in oral bioavailability over the parent drug meptazinol in rats.     

Breastfeeding in China: a review

This review aims to describe changes in breastfeeding and summarise the breastfeeding rates, duration and reasons of discontinuing 'any breastfeeding' or 'exclusive breastfeeding' in P.R. China. Breastfeeding rates in China fell during the 1970s when the use of breast milk substitutes became widespread, and reached the lowest point in the 1980s. As a result many efforts were introduced to promote breastfeeding. The breastfeeding rate in China started to increase in the 1990s, and since the mid-1990s 'any breastfeeding' rates in the majority of cities and provinces, including minority areas, have been above 80% at four months. But most cities and provinces did not reach the national target of 'exclusive breastfeeding' of 80%. The 'exclusive breastfeeding' rates in minority areas were relatively lower than comparable inland provinces. The mean duration of 'any breastfeeding' in the majority of cities or provinces was between seven and nine months. The common reasons for ceasing breastfeeding, or introducing water or other infant food before four months, were perceived breast milk insufficiency, mother going to work, maternal and child illness and breast problems. Incorrect traditional perceptions have a strong adverse influence on 'exclusive breastfeeding' in less developed areas or rural areas. China is a huge country, geographically and in population size, and there is considerable ethnic diversity. Therefore breastfeeding rates in different parts of China can vary considerably.     

Monomeric midkine induces tumor cell proliferation in the absence of cell-surface proteoglycan binding

Midkine (MK), a retinoic acid-inducible heparin-binding protein, is a mitogen which initiates a cascade of intracellular protein tyrosine phosphorylation mediated by the JAK/STAT pathway after binding to its high affinity p200(+)/MKR cell surface receptor in the G401 cell line [Ratovitski, E. A. (1998) J. Biol. Chem. 273, 3654-3660]. In this study, we determined the biophysical characteristics of purified recombinant murine MK and analyzed the requirements for ligand multimerization and cell surface proteoglycan binding for the G401 cell mitogenic activity of MK. Our studies indicate that the secreted form of MK (M = 13 kDa) exists in solution as an asymmetric monomer with a frictional coefficient of 1. 48 and a Stokes radius of 23.7 A. By constructing bead models of MK using the program AtoB and the program HYDRO to predict the hydrodynamic properties of each model, our data suggest that MK has a dumb-bell shape in solution composed of independent N- and C-terminal domains separated by an extended linker. This asymmetric MK monomer is a biologically active ligand with mitogenic activity on G401 cells in vitro. Neither heparin-induced formation of noncovalent MK multimers nor tissue transglutaminase II covalent multimerization of MK enhanced MK mitogenic activity in this system. Since neither heparin competition nor cell treatment with chondroitinase ABC or heparinase III abolished the mitogenic effects of MK on G401 cells, cell-surface proteoglycan binding by MK does not appear to be a requirement for its observed mitogenic effects. These results provide strong evidence that the MK-specific p200(+)/MKR has distinctive biochemical properties which distinguish it from the receptor tyrosine phosphatase cell-surface proteoglycan PTPzeta/RPTPbeta and support the hypothesis that the diverse biological effects of MK are mediated by multiple cell-specific signal transduction receptors.     

Chaperonin CCT-Mediated AIB1 Folding Promotes the Growth of ERα-Positive Breast Cancer Cells on Hard Substrates

Clinical observations have revealed a strong association between estrogen receptor alpha (ERα)-positive tumors and the development of bone metastases, however, the mechanism underlying this association remains unknown. We cultured MCF-7 (ERα-positive) on different rigidity substrates. Compared with cells grown on more rigid substrates (100 kPa), cells grown on soft substrates (10 kPa) exhibited reduced spreading ability, a lower ratio of cells in the S and G2/M cell cycle phases, and a decreased proliferation rate. Using stable isotope labeling by amino acids (SILAC), we further compared the whole proteome of MCF-7 cells grown on substrates of different rigidity (10 and 100 kPa), and found that the expression of eight members of chaperonin CCT increased by at least 2-fold in the harder substrate. CCT folding activity was increased in the hard substrate compared with the soft substrates. Amplified in breast cancer 1 (AIB1), was identified in CCT immunoprecipitates. CCT folding ability of AIB1 increased on 100-kPa substrate compared with 10- and 30-kPa substrates. Moreover, using mammalian two-hybrid protein-protein interaction assays, we found that the polyglutamine repeat sequence of the AIB1 protein was essential for interaction between CCTζ and AIB1. CCTζ-mediated AIB1 folding affects the cell area spreading, growth rate, and cell cycle. The expressions of the c-myc, cyclin D1, and PgR genes were higher on hard substrates than on soft substrate in both MCF-7 and T47D cells. ERα and AIB1 could up-regulate the mRNA and protein expression levels of the c-myc, cyclin D1, and PgR genes, and that 17 β-estradiol could enhance this effects. Conversely, 4-hydroxytamoxifen, could inhibit these effects. Taken together, our studies demonstrate that some ERα-positive breast cancer cells preferentially grow on more rigid substrates. CCT-mediated AIB1 folding appears to be involved in the rigidity response of breast cancer cells, which provides novel insight into the mechanisms of bone metastasis.     

The Combination of RAD001 and MK-2206 Exerts Synergistic Cytotoxic Effects against PTEN Mutant Gastric Cancer Cells: Involvement of MAPK-Dependent Autophagic,but Not Apoptotic Cell Death Pathway

In the current study, we showed that the combination of mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and Akt inhibitor MK-2206 exerted synergistic cytotoxic effects against low-phosphatase and tensin homolog (PTEN) gastric cancer cells (HGC-27 and SNU-601 lines). In HGC-27 cells, RAD001 and MK-2206 synergistically induced G1/S cell cycle arrest, growth inhibition, cell death but not apoptosis. RAD001 and MK-2206 synergistically induced light chain 3B (LC3B) and beclin-1 expression, two important autophagy indicators. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) and chloroquine inhibited the cytotoxic effects by RAD001 and MK-2206, suggesting that autophagic, but not apoptotic cell death was important for the cytotoxic effects by the co-administration. We observed that the combination of RAD001 and MK-2206 exerted enhanced effects on Akt/mTOR inhibition, cyclin D1 down-regulation and ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinases) activation. Intriguingly, MEK/ERK inhibitors PD98059 and U0126 suppressed RAD001 plus MK-2206-induced beclin-1 expression, autophagy induction and cytotoxicity in HGC-27 cells. In conclusion, these results suggested that the synergistic anti-gastric cancer cells ability by RAD001 and MK-2206 involves ERK-dependent autophagic cell death pathway.     

有机氯农药在大滨鹬和红腹滨鹬体内的富集程度

为探讨东亚-澳大利西亚迁徙路线上的鸻鹬类体内有机氯农药的含量及来源,本研究以该迁徙路线上的大滨鹬(Calidris tenuirostris)和红腹滨鹬(C.canutus)为研究对象,用索氏提取法对这两种鸟的胸肌和皮下脂肪中的有机污染物进行萃取,并用气相色谱法对19种有机氯农药进行检测。结果表明,HCHs、DDTs、硫丹Ⅱ等14种有机氯农药在大滨鹬和红腹滨鹬的组织中均有不同程度的检出,所有样品中的含量最高值达1 573.5 ng/g脂重;在检出的14种有机氯农药中,α-HCH、β-HCH、γ-HCH、p,p′-DDE、硫丹Ⅱ、硫丹硫酸酯和/或p,p′-DDT的检出率达100%;在大滨鹬的肌肉组织、红腹滨鹬的肌肉和脂肪组织中,p,p′-DDE的残留量最高;而在大滨鹬的脂肪组织中硫丹硫酸酯和/或p,p′-DDT的含量最高;目标物中的艾氏剂、异狄氏剂、七氯、反式氯丹等未达检出限或含量较低。我们对比了不同物种及不同组织样本中有机氯农药的富集程度,红腹滨鹬的肌肉组织中HCHs的沉积量显著高于大滨鹬,而大滨鹬的脂肪组织中硫丹硫酸酯和/或p,p′-DDT的含量显著高于红腹滨鹬。此外,分别对比两个物种的肌肉组织和脂肪组织中有机氯农药沉积量,部分有机氯农药在脂肪组织中的沉积量显著高于肌肉组织,说明相比于肌肉组织,有机氯农药可能更易于在脂肪组织中累积。     

兴安落叶松种群的稳定性与火干扰关系的研究

从种群生态学和干扰生态学的角度出发,采用火史重建的方法,研究了大兴安岭北部兴安落叶松种群的稳定性与火干扰的关系。结果表明：研究区内历史上火干扰频繁,平均间隔期为２８．９年,火烧强度较低。兴安落叶松依靠较强的耐火力、火力恢复力及自我恢复力具一定的稳定性。种群耐火力与长期火状况密切相关,表现为：低频类〈中频类〈高频类,高强类〈中强类〈低强类。火后恢复力与自我恢复力和最近一次火烧强度及距今时间密切相关：     

An efficient synthesis of methyl tetra-o-hexyl gentiooctaoside, an octaosyl analogue of ANP receptor antagonist HS-142-1

Methyl

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, a 3-O hexyl analogue of the octaosyl component of fungal lipooligosaccharide HS-142-1, was stereo- and regioselectively synthesized as a potent antagonist for the tetrameric atrial natriuretic peptide (ANP) receptors.