Synthesis and Antitumor Activity Evaluation of Novel 2-Amino-5-Ethylpyrimidine Derivatives

Russian Journal of Bioorganic Chemistry - In order to discover novel high efficiency and low toxic anticancer drugs, a series of novel 2-amino-5-ethylpyrimidine derivatives (XIIa–x) were...     

Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway

Abnormal HDL metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis. ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are increased in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein. We previously reported that unsaturated fatty acids destabilize ABCA1 in murine macrophages and ABCA1-transfected baby hamster kidney cells by increasing its serine phosphorylation through a phospholipase D (PLD) pathway. Here, we examined the cellular pathway downstream of PLD that mediates the ABCA1-destabilizing effects of unsaturated fatty acids. The protein kinase C delta (PKCdelta)-specific inhibitor rottlerin and PKCdelta small interfering RNA completely abolished the ability of unsaturated fatty acids to inhibit lipid transport activity, to reduce protein levels, and to increase serine phosphorylation of ABCA1, implicating a role for PKCdelta in the ABCA1-destabilizing effects of fatty acids. These data indicate that unsaturated fatty acids destabilize ABCA1 by activating a PKCdelta pathway that phosphorylates ABCA1 serines.     

When a G protein-coupled receptor does not couple to a G protein

Classically, G protein-coupled receptors (GPCRs) relay signals by directly activating heterotrimeric guanine nucleotide-binding proteins (G proteins). Increasing evidence indicates that GPCRs may also signal through G protein-independent pathways. JAK/STATs, Src-family tyrosine kinases, GRKs/beta-arrestins, and PDZ domain-containing proteins have been suggested to directly relay signals from GPCRs independent of G proteins. In addition, our laboratory recently reported that the beta(2) adrenergic receptor (beta(2)AR) could switch from G protein-coupled to G protein-independent ERK (extracellular signal-regulated kinase) activation in an agonist dosage-dependent manner. This finding provides a novel mechanism for G protein-independent GPCR signaling. This review focuses on recent progress in understanding the mechanisms by which G protein-independent GPCR signaling occurs.     

血红素加氧酶-1在中枢神经系统疾病中的作用

血红素加氧酶-1(heme oxygenase-1,HO-1)是一种应激蛋白,可将血红素降解为胆绿素、游离铁和一氧化碳。目前,国内外普遍认为HO-1在神经系统损伤后的应激反应中有至关重要的作用,其表达量与神经元凋亡和神经变性密切相关。本文对近年来HO-1在神经系统损伤性疾病中的现有研究结果进行了总结分析,旨在为相关研究的发展提供新的思路和方向。     

Cardiac Microvascular Barrier Function Mediates the Protection of Tongxinluo against Myocardial Ischemia/Reperfusion Injury

Objective

Tongxinluo (TXL) has been shown to decrease myocardial necrosis after ischemia/reperfusion (I/R) by simulating ischemia preconditioning (IPC). However, the core mechanism of TXL remains unclear. This study was designed to investigate the key targets of TXL against I/R injury (IRI) among the cardiac structure-function network.

Materials and Methods

To evaluate the severity of lethal IRI, a mathematical model was established according to the relationship between myocardial no-reflow size and necrosis size. A total of 168 mini-swine were employed in myocardial I/R experiment. IRI severity among different interventions was compared and IPC and CCB groups were identified as the mildest and severest groups, respectively. Principal component analysis was applied to further determine 9 key targets of IPC in cardioprotection. Then, the key targets of TXL in cardioprotection were confirmed.

Results

Necrosis size and no-reflow size fit well with the Sigmoid Emax model. Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R²=0.92, R²=0.57, P<0.01, respectively). Functional and structural indices correlate positively with NRS (R²=0.64, R²=0.62, P<0.01, respectively). TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, β-catenin, γ-catenin and P-selectin with a trend toward the sham group. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group. Among the above nine indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI.

Conclusions

Our study underlines the lethal IRI as one of the causes of myocardial necrosis. Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC.     

冻融季帽儿山森林改变有机碳输入方式对土壤活性氮含量的影响

根系与凋落物有机碳输入变化对土壤碳氮循环的影响已成为当前学界关注的热点,但冻融季不同有机碳输入方式将对土壤活性氮含量产生何种影响尚不明确。为此在春季具有明显冻融作用的温带森林设立凋落物去除、根系去除处理以代表仅根系有机碳输入方式、仅凋落物有机碳输入方式,并设置自然条件有机碳输入方式即保留根系及凋落物作为对照,多角度探究土壤微生物量氮、矿质氮动态变化。结果表明：(1)有机碳输入方式对土壤活性氮含量有重要影响：与自然条件下有机碳输入方式相比,仅根系输入处理使土壤微生物氮、总矿质氮含量升高10.5%、12.3%。(2)输入时长改变了有机碳输入方式对土壤活性氮含量的作用效果：长期单一有机碳输入使土壤微生物量氮含量下降,反应率值为0.451、0.422。(3)季节差异是影响有机碳输入方式对土壤活性氮含量作用效果的关键因素：仅根系有机碳输入在冻融季使总矿质氮含量上升,反应率值为0.404,生长季相反,呈下降趋势,其值为0.121。以上结果表明,有机碳输入方式对土壤活性氮含量有重要调控作用,且作用效果会受季节、输入时长等因素影响。     

细胞凋亡的分子机制

多细胞生物在发生、发展过程中,为了保持正常的生理机能,一部分的细胞发生自发性细胞死亡,这种细胞死亡是被细胞内一系列相关的分子所调控,并伴随有典型的形态学改变,这种现象被称为细胞凋亡（ａｐｏｐｔｏｓｉｓ）［１］。作为一种积极排除生物体内的过剩细胞和有害细胞的机制在个体形态形成、形态改变等发生过程中,成体的恒常性的维持以及生物体的防御等方面发挥作用。此外在许多病理状态下也存在着细胞凋亡。近年的研...