Discovery of selective farnesoid X receptor agonists for the treatment of hyperlipidemia from traditional Chinese medicine based on virtual screening and in vitro validation

Abstract

Farnesoid X receptor (FXR), a bile acid receptor, has important roles in maintaining bile acid and cholesterol homeostasis, which is an attractive target for hyperlipidemia. Present study aimed to discover potential selective FXR agonists over G-protein coupled bile acid receptor 1 (GPBAR1, TGR5) from traditional Chinese medicine (TCM) by using virtual screening, in vitro studies and molecular dynamics simulation (MD). Ligand-based pharmacophore model for FXR was firstly built to screen FXR agonists from the Traditional Chinese Medicine Database (TCMD). Then, 21 FXR crystal structures were clustered in two types and two representative structures (PDB ID: 3OMM and 3P89) were, respectively, used to carry out molecular docking to refine the screened result. Moreover, the pharmacophore model for GPBAR1 was built to screen selective FXR agonists with no activity on GPBAR1. A set of 24 candidate selective FXR agonists which fitvalue of FXR pharmacophore model and docking score of 3OMM and 3P89 were in the top 100 and cannot match the pharmacophore model for GPBAR1 were obtained. By the lipid-lowering activity test in HepG2 cell lines, Arctigenin was identified to be potential selective FXR agonist with the activity of 20?μmol·L^?1. After down-regulating FXR, Arctigenin could increase the mRNA of FXR while exerted no effect on the mRNA of GPBAR1. MD was further used to interpret the mechanism of Arctigenin with the representative structures. This research provided a new screening procedure for finding selective candidate compounds and appropriate docking models of a target by considering the structure diversity of PDB structures, which was applied to discovery novel selective FXR agonists to treat hyperlipidemia.

Communicated by Ramaswamy H. Sarma     

Diversity and selective pressures of anticoagulants in three medicinal leeches (Hirudinida: Hirudinidae,Macrobdellidae)

Although medicinal leeches have long been used as treatment for various ailments because of their potent anticoagulation factors, neither the full diversity of salivary components that inhibit coagulation, nor the evolutionary selection acting on them has been thoroughly investigated. Here, we constructed expressed sequence tag libraries from salivary glands of two species of medicinal hirudinoid leeches, Hirudo verbana and Aliolimnatis fenestrata, and identified anticoagulant‐orthologs through BLASTx searches. The data set then was augmented by the addition of a previously constructed EST library from the macrobdelloid leech Macrobdella decora. The identified orthologs then were compared and contrasted with well‐characterized anticoagulants from a variety of leeches with different feeding habits, including non‐sanguivorous species. Moreover, four different statistical methods for predicting signatures of positive and negative evolutionary pressures were used for 10 rounds each to assess the level and type of selection acting on the molecules as a whole and on specific sites. In total, sequences showing putative BLASTx‐orthology with five and three anticoagulant‐families were recovered in the A. fenestrata and H. verbana EST libraries respectively. Selection pressure analyses predicted high levels of purifying selection across the anticoagulant diversity, although a few isolated sites showed signatures of positive selection. This study represents a first attempt at mapping the anticoagulant repertoires in a comparative fashion across several leech families.     

弥散张量成像对脑室周围白质软化患儿术后脑白质恢复的评估作用

目的:研究弥散张量成像(DTI)对脑室周围白质软化(PVL)患儿选择性脊神经后根切除术(SPR)后脑白质恢复的评估价值。方法:选取从2014年1月至2015年8月在新疆医科大学二附院脑瘫中心择期行SPR手术治疗的PVL患儿40例作为观察组,另选同期磁共振成像(MRI)检查正常儿童40例作为对照组,两组分别在手术前后进行DTI检查,比较两组不同部位的部分各向异性值(FA)及表观弥散系数(ADC)。结果:术前观察组不同部位的FA值均显著低于对照组,胼胝体压部的ADC值显著高于对照组,差异均有统计学意义(P0.05)。与术前比较,术后观察组不同部位的FA值均上升,胼胝体压部的ADC值下降,差异均有统计学意义(P0.05),且与对照组之间的差异无统计学意义(P0.05)。结论:SPR术能够明显控制PVL患儿的病情,且采用DTI成像技术能够客观地反应PVL患儿SPR术后脑白质恢复情况,对辅助临床治疗和预后评估具有重要作用。     

Chemistry and selection

Life is the product of chemistry, which obeys deterministic laws, and of natural selection, which operates on variants offered to it by chance, but may, in a number of cases, have been provided with a sufficiently extensive array of variants to be optimizing. Thus, the origin and evolution of life have been largely shaped by the contingency of environmental conditions. The possibility remaining open for consideration is that certain critical conditions are sufficiently reproducible for life to arise and even to evolve into conscious, intelligent beings elsewhere in the universe.     

Expansion of the scaffold diversity for the development of highly selective butyrylcholinesterase (BChE) inhibitors: Discovery of new hits through the pharmacophore model generation,virtual screening and molecular dynamics simulation

Butyrylcholinesterase (BChE) is recently considered as a new target for the treatment of Alzheimer’s disease (AD). There is an increasing interest in the development of BChE inhibitors. In the present study, a set of pharmacophore models for BChE was developed and validated. Based on the models, virtual screening was performed on five compound collections, from which seventeen potential hits were retained for biological investigation. In total, eight of these seventeen potential hits showed selective BChE inhibitory activity. Moreover, four compounds displayed IC₅₀ values in sub-micromolar range on eqBChE and three displayed IC₅₀ values < 2 μM on huBChE. The diverse scaffolds of the active compounds provided good starting point further development of selective BChE inhibitors. As far as we concerned, here we disclose the first selective pharmacophore model targeting BChE. The high rate of the model in the identification of active hits indicates it is a valuable tool for the development of selective BChE inhibitors, which may benefit the treatment of AD.     

Kinetics improvement of high-grade sulphides bioleaching by effects separation

Abstract: The kinetics of bioleaching of sulphide concentrates by Thiobacillus ferrooxidans can be improved by performing separately the two operations relating the two effects involved in the indirect contact mechanism, (1) chemical leaching and (2) biological oxidation of the Fe2+ produced in the chemical stage (IBES: Indirect Bioleaching with Effects Separation). This scheme permits the separate enhancement of each stage. On the one hand, the chemical attack of the ferric iron to sulphides can be performed at a higher temperature. On the other hand, the biological oxidation stage is more effective when biofilm models are applied. At the same time, inhibitory phenomena produced as a result of the bacterial breaking caused by the abrasion of the solid particles on microorganisms are prevented. In this work the 1BES process has been applied to a Spanish copper-zinc and a copper sulphide concentrate. The objective has been to selectively dissolve zinc, which may be recovered by solvent exraction, the remaining residue being a copper concentrate suitable for pyrometallurgical treatment. The attributes of moderate temperature, atmospheric pressure, low cost of the leaching agent, flexibility and effectiveness make the process very attractive from an economic point of view.     

天然林不同强度择伐后林分空间结构变化动态

基于长期跟踪复测数据,利用混交度、大小比数和角尺度3个结构参数,研究了4种不同强度择伐(弱度13.O％、中度29.1％、强度45.8％、极强度67.1％)后天然林林分空间结构的变化动态.结果表明:弱度和中度择伐后林分平均混交度和大小比数呈增长趋势,强度和极强度择伐则呈下降趋势;择伐并未改变林木的空间分布格局,各样地林分均为聚集分布,中度择伐处于随机分布状态的林木数大幅增加.总的来说,弱度和中度择伐后林分空间结构正趋向优化.     

Studies of mercurated derivatives of acetylacetone and ethyl acetoacetate by solid state nuclear magnetic resonance and vibrational spectroscopies

Seven new mono- and/or dimercurated compounds involving acetylacetone (2,4-pentanedione) or ethyl acetoacetate (3-ethyl ketobutanoate) were synthesized in aqueous medium. In all cases, mercuration occurred at methylene carbon atoms. All compounds were carefully analyzed by solid state carbon-13 nuclear magnetic resonance. Assignments were confirmed by using selective sequences, which allowed a total editing of the spectra. It was shown that deshielding of ¹³C mercurated sites occurred when the rate of mercuration increased. It was also possible to measure direct ¹J(¹⁹⁹Hg¹³C) coupling constants. The main bands of the vibrational spectra (infrared and Raman) were assigned. It was proved that v(C = O) and δ(C(γ)-H) could be directly related to the mercuration rate of molecules.     

Efficient synthesis of a 6-deoxytalose tetrasaccharide related to the antigenic O-polysaccharide produced by Aggregatibacter actinomycetemcomitans serotype c

Concise synthesis of a 6-deoxy-α-l-talose tetrasaccharide, 6-deoxy-α-l-Talp-(1→3)-6-deoxy-α-l-Talp-(1→2)-6-deoxy-α-l-Talp-(1→3)-6-deoxy-α-l-Talp, the dimer of the disaccharide repeating unit of the OPS from Aggregatibacter actinomycetemcomitans serotype c, has been accomplished through suitable protecting group manipulations and stereoselective glycosylation starting from commercially available l-rhamnose. The target oligosaccharide in the form of its p-methoxyphenyl glycoside is suitable for further glycoconjugate formation via selective cleavage of this group.     

Brain cooling maintenance with cooling cap following induction with intracarotid cold saline infusion: a quantitative model

Intracarotid cold saline infusion (ICSI) is potentially much faster than whole-body cooling and more effective than cooling caps in inducing therapeutic brain cooling. One drawback of ICSI is hemodilution and volume loading. We hypothesized that cooling caps could enhance brain cooling with ICSI and minimize hemodilution and volume loading. Six-hour-long simulations were performed in a 3D mathematical brain model. The Pennes bioheat equation was used to propagate brain temperature. Convective heat transfer through jugular venous return and the circle of Willis was simulated. Hemodilution and volume loading were modeled using a two-compartment saline infusion model. A feedback method of local brain temperature control was developed where ICSI flow rate was varied based on the rate of temperature change and the deviation of temperature to a target (32 °C) within a voxel in the treated region of brain. The simulations confirmed the inability of cooling caps alone to induce hypothermia. In the ICSI and the combination models (ICSI and cap), the control algorithm guided ICSI to quickly achieve and maintain the target temperature. The combination model had lower ICSI flow rates than the ICSI model resulting in a 55% reduction of infusion volume over a 6 h period and higher hematocrit values compared to the ICSI model. Moreover, in the combination model, the ICSI flow rate decreased to zero after 4 h, and hypothermia was subsequently maintained solely by the cooling cap. This is the first study supporting a role of cooling caps in therapeutic hypothermia in adults.