A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual,SPR and NMR screening

NDM-1 can hydrolyze nearly all available β-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of ¹⁵N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.     

Reaction profile of the last step in cytochrome P-450 catalysis revealed by studies of model complexes

 A series of oxoiron(IV) porphyrin cation radical complexes was investigated as compound I analogs of cytochrome P-450. Both the spectroscopic features and the reactivities of the complexes in oxygen atom transfer to olefins were examined as a function of only one variable, the axial ligand trans to the oxoiron(IV) bond. The results disclosed two important kinetic steps – electron transfer from olefin to oxoiron(IV) and intramolecular electron transfer from metal to porphyrin radical – which are affected differently by the axial ligands. The large kinetic barrier of the latter step in the reaction of olefins with the perchlorato-bound oxoiron(IV) porphyrin cation radical complex enabled the trapping of a reaction intermediate in which the metal, but not the porphyrin radical, is reduced. The first electron transfer step is probably followed by σ-bond formation, which readily accounts for formation of isomerized organic products at low temperatures. It is finally postulated that part of the enhanced oxygenation activities of cytochrome P-450 monooxygenases and chloroperoxidases is due to a lowering of the energy barrier for the second electron transfer step via participation of their redox-active cysteinate ligand. Received: 16 January 1997 / Accepted: 24 May 1997     

Immunolocalization of the Na,K-ATPase in photoreceptor cells of the moth Manduca sexta-evidence for Na,K-ATPase on both the nonmicrovillar and the microvillar domains of the plasma membrane

Immunohistochemical and physiological studies on various insect photoreceptors have demonstrated that the Na,K-ATPase (sodium pump) is restricted to the nonreceptive nonmicrovillar area of the plasma membrane. Here, we examined the distribution of the Na,K-ATPase in photoreceptor cells of the superposition-type compound eye in the moth Manduca sexta. Using immunofluorescent and immunogold cytochemistry, we show that the Na,K-ATPase is localized to both the nonmicrovillar and the microvillar parts of the plasma membrane. Manduca photoreceptors thus deviate from the common concept that the sodium pump and the molecular components of the photoreceptive machinery reside on different domains of the plasma membrane.     

复方丹参滴丸联合阿司匹林治疗冠心病的疗效及对患者血脂水平的影响

目的:探讨复方丹参滴丸联合阿司匹林治疗冠心病患者的疗效及其对血脂水平的影响。方法:选取2015年1月至2016年1月我院收治的冠心病患者86例,按照随机数字表法将其分为对照组和实验组,各43例,两组均给予常规治疗,对照组在常规治疗基础上联用阿司匹林,实验组在常规治疗基础上联用阿司匹林和复方丹参滴丸。治疗8周后,对比两组患者临床疗效、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平;并对比两组患者的不良反应发生情况。结果:实验组总有效率为86.05%,显著高于对照组的37.21%(P0.05);治疗8周后,实验组TC、TG以及LDL-C较治疗前下降,HDL-C较治疗前升高,差异均有统计学意义(P0.05);治疗8周后,实验组患者血脂TC、TG、LHL均较对照组降低,HDL较对照组升高(P0.05)。治疗期间,实验组不良反应发生率为4.65%,对照组为6.98%,两组患者不良反应发生率无统计学差异(P0.05)。结论:冠心病患者采用复方丹参滴丸联合阿司匹林治疗具有较好的疗效,并能有效改善患者血脂水平,且安全性较高,具备临床推广价值。     

复合负压吸引的外固定钢板治疗四肢开放性骨折的应用价值

目的:探讨复合负压吸引的外固定钢板治疗四肢开放性骨折的应用价值。方法:选择2014年1月到2017年1月到我院诊治的胫腓骨中下段开放性骨折患者共68例为研究对象,根据随机信封抽签原则分为观察组与对照组,每组34例。对照组给予负压封闭引流(vacuum sealing drainage,VSD)的常规外固定钢板治疗,观察组给予复合负压吸引的外固定钢板治疗,记录和比较围手术期严重并发症的发生情况、手术时间、骨折愈合时间、临床疗效和创口愈合情况。结果:两组患者都完成手术,围手术期并无严重并发症发生。观察组的手术时间与骨折愈合时间分别为38.24±8.16 min和8.83±1.01周,均明显少于对照组(49.50±9.87min和12.23±0.91周)(P0.05)。术后3个月,观察组和对照组的疗效优良率分别是97.1%、82.4%,观察组明显高于对照组(P0.05);观察组的创口甲级愈合28例,乙级愈合6例,丙级愈合0例;对照组甲级愈合21例,乙级愈合8例,丙级愈合5例,观察组创口愈合情况明细优于对照组(P0.05)。结论:复合负压吸引的外固定钢板治疗四肢开放性骨折能明显缩短手术时间,促进骨折愈合,提高创口愈合质量,提高临床疗效。     

复方丹参滴丸联合阿司匹林对冠心病患者血小板聚集功能及血脂水平的影响

目的:探讨复方丹参滴丸联合阿司匹林对冠心病(CHD)患者血小板聚集功能及血脂水平的影响。方法:选取2011年10月到2016年12月在我院接受治疗的CHD患者320例作为本次研究对象,采用乱数表法将所有患者分为对照组和观察组各160例,两组患者均采用扩冠、抗凝和降压药物等常规内科治疗,在此基础上对照组给予阿司匹林治疗,观察组给予复方丹参滴丸联合阿司匹林治疗,两组均治疗6个月。对比两组临床疗效、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL)及高密度脂蛋白(HDL)、血栓素B2(TXB2)水平,记录血小板最大聚集率(PAGM)及不良事件发生率。结果:治疗后观察组的总有效率为93.13%,显著高于对照组的68.75%(P0.05)。治疗6个月后观察组HDL水平高于治疗前和对照组,LDL、TC、TG水平低于治疗前和对照组(P0.05)。治疗6个月后两组患者PAGM、TXB2水平均有明显下降,且观察组PAGM、TXB2水平低于对照组(P0.05)。观察组不良事件发生率为2.50%,显著低于对照组的18.13%(P0.05)。结论:复方丹参滴丸与阿司匹林联合治疗CHD临床疗效较好,可以有效抑制血小板凝聚,调节血脂,降低不良事件发生率,值得在临床上推广。     

Similarities and differences between the responses induced in human phagocytes through activation of the medium chain fatty acid receptor GPR84 and the short chain fatty acid receptor FFA2R

GPR84 is a recently de-orphanized member of the G-protein coupled receptor (GPCR) family recognizing medium chain fatty acids, and has been suggested to play important roles in inflammation. Due to the lack of potent and selective GPR84 ligands, the basic knowledge related to GPR84 functions is very limited. In this study, we have characterized the GPR84 activation profile and regulation mechanism in human phagocytes, using two recently developed small molecules that specifically target GPR84 agonistically (ZQ16) and antagonistically (GLPG1205), respectively. Compared to our earlier characterization of the short chain fatty acid receptor FFA2R which is functionally expressed in neutrophils but not in monocytes, GPR84 is expressed in both cell types and in monocyte-derived macrophages. In neutrophils, the GPR84 agonist had an activation profile very similar to that of FFA2R. The GPR84-mediated superoxide release was low in naïve cells, but the response could be significantly primed by TNFα and by the actin cytoskeleton disrupting agent Latrunculin A. Similar to that of FFA2R, a desensitization mechanism bypassing the actin cytoskeleton was utilized by GPR84. All ZQ16-mediated cellular responses were sensitive to GLPG1205, confirming the GPR84-dependency. Finally, our data of in vivo transmigrated tissue neutrophils indicate that both GPR84 and FFA2R are involved in neutrophil recruitment processes in vivo.In summary, we show functional similarities but also some important differences between GPR84 and FFA2R in human phagocytes, thus providing some mechanistic insights into GPR84 regulation in blood neutrophils and cells recruited to an aseptic inflammatory site in vivo.     

赤霉素产生菌的激光,化学复合诱变育种研究

采用激光和氯化锂复合诱变赤霉菌,对其产生的赤霉素中活性最高的ＧＡ３含量作为效价测定。结果表明与出发菌株相比,激光诱变,ＬｉＣｌ诱变,复合诱变效价分别提高为１１３．７％,４０．２％,１８９．６％。展示激光复合诱变是遗传育种的一种有效方法。     

Comparative study of spectral and antioxidant properties of pigments from the eyes of two Mysis relicta (Crustacea, Mysidacea) populations, with different light damage resistance

Retinal visual and screening pigments of two populations (one marine and the other freshwater) of the opossum shrimp Mysis relicta Lovén (Crustacea, Mysidacea), which have different ocular tolerance to light, was investigated. Visual pigments were extracted by detergent and their bleaching difference spectra were determined. The difference between the visual pigment absorption maximum of the two populations correlated with their difference in spectral sensitivity. Using buffer or neutral methanol, a yellow pigment was extracted which had absorption maxima at 440 nm and 325 nm and bright blue fluorescence (λ_max 415 nm). A screening pigment (ommochrome) with maximum at 525 nm was extracted by acid methanol, and was probably related to the group of ommines. The eyes of the lake population had 1.8–2.7 times less of this pigment than the eyes of the sea population. The sea population is more resistant to photo-induced accumulation of thiobarbituric acid-reactive substances in eye tissues. This resistance may be due to the higher ommochrome content. Accepted: 8 December 1998     

重金属复合污染对土壤植物系统的生态效应Ⅱ.对作物、苜蓿、树木吸收元素的影响

研究Cd、Pb、Cu、Zn、As 5元素复合污染对农作物、苜蓿、树木吸收元素的影响,供试污染物浓度以接近国内外土壤环境标准值作为高剂量处理,结果表明,5种元素间存在交互作用,可提高作物对Cd、Pb、Zn吸收系数,籽实超出粮食卫生标准的超标率在低剂量处理时Cd为16.6～42.85%,高剂量时达16.6～71.42%.苜蓿茎叶中Cd、Pb含量超出饲料卫生标准,树叶中含量也有所增加,在中、酸性土壤上尤甚.