凯时联合甲钴铵治疗32例糖尿病患者勃起功能障碍

目的:观察脂化前列腺素1(凯时)与甲钴胺联合应用治疗糖尿病患者勃起功能障碍(ED)的疗效。方法:将32例勃起功能障碍的糖尿病患者给予凯时与甲钴胺联合治疗,治疗前后根据国际勃起功能指数表(IIEF-5)患者进行自我评分。结果:32例患者接受凯时与甲钴铵治疗后,患者IIEF-5总评分和各问题的评分均显著高于治疗前(P<0.05或0.01)。结论:凯时联合甲钴铵治疗糖尿病合并ED具有良好的效果。     

基于CONVEF的四阶各向异性扩散及图像去噪

偏微分方程在图像去噪中有广泛的应用。传统的二阶偏微分方程虽然具有较好的去噪效果,但是处理得到的结果容易产生阶梯效应,这种现象会引起后续图像处理的误判断。You和Kaveh提出了四阶偏微分方程,该模型可以有效的去除阶梯效应,但由于该算法是一个各向同性的滤波算法,因此图像的边缘保护能力有所降低,使去噪结果中边缘和纹理等细节信息丢失。针对以上缺点,提出了基于卷积虚拟电子场(CONVEF)的四阶偏微分方程。新的模型降低了图像在边缘方向的扩散,得到一个有效的各向异性扩散模型,从而在去噪的同时可以更好的保护图像的边缘、纹理等细节特征。     

The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways

Cyclic adenosine 3', 5'-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs) but also activates certain ion channels and guanine nucleotide exchange factors (Epacs). Metabolism of cAMP is catalysed by phosphodiesterases (PDEs). Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.     

新型1,5-二芳基咪唑类选择性COX-2抑制剂的抗炎构效关系

采用PM5半经验量子化学方法对29个新型1,5-二芳基咪唑类选择性环氧合酶(COX-2)抑制剂的结构进行了全优化，从数据库搜寻或计算了它们的430种结构参数，利用遗传算法和逐步回归方法，建立了经典结构-活性关系(2D-QSAR)。抑制剂结构优化表明活性1，5-二芳基咪唑类选择性环氧合酶(COX-2)抑制剂具有类似塞来昔布等三环类环氧合酶-2选择性抑制剂的立体结构，但构效关系研究则表明该类抑制剂具有不同于塞来昔布等传统COX-2选择性抑制剂的新型构效关系。     

Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter

At most synapses, chemical signalling is terminated by a rapid reaccumulation of neurotransmitter into presynaptic terminals. Uptake systems for the biogenic amines are the initial site of action for therapeutic antidepressants and drugs such as cocaine and the amphetamines. We have isolated a complementary DNA clone encoding a human noradrenaline transporter. The cDNA sequence predicts a protein of 617 amino acids, with 12-13 highly hydrophobic regions compatible with membrane-spanning domains. Expression of the cDNA clone in transfected HeLa cells indicates that noradrenaline transport activity is sodium-dependent and sensitive to selective noradrenaline transport inhibitors. Transporter RNA is localized to the brainstem and the adrenal gland. The predicted protein sequence demonstrates significant amino-acid identity with the Na+/gamma-aminobutyric acid transporter, thus identifying a new gene family for neurotransmitter transporter proteins. Analysis of its structure and function may lead to structure-based drug design for the treatment of human depression and could help determine whether transporter abnormalities underlie affective disorders.     

环(L-脯-L-苯丙)二肽——潜在的磷酸二酯酶抑制剂

利用海藻来源的黄曲霉中提取到的次级代谢产物筛选GPR41的激动剂,发现环二肽类化合物环(L-脯-L-苯丙)二肽(17号)可在多种(G41-CHO,G12-CHO,Mock-CHO,SH-sy5y和HEK293)细胞中引起细胞内cAMP水平升高.实验结果表明,17号化合物引起cAMP升高不依赖于GPCR的激活,且腺苷酸环化酶激活剂forskolin与17号化合物共处理组比fsk单独处理组cAMP进一步增加.实验结果提示,17号化合物可能是通过抑制cAMP水解,从而引起cAMP水平的持续升高.17号化合物与已知的PDE抑制剂具有相似的结构特征,可能是潜在的磷酸二酯酶抑制剂.这是首次发现环(L-脯-L-苯丙)二肽具有在多种细胞内提高cAMP浓度的作用.     

新型1,5-二芳基咪唑类制剂的分子对接研究

采用PM5半经验量子化学方法对29个新型1,5-二芳基咪唑类选择性环氧合酶(COX-2)抑制剂的结构进行了全优化,将这些优化结构与COX-2的活性位点进行了分子对接。对接研究表明：活性1,5－二芳基咪唑类COX-2抑制剂具有类似塞来昔布等三环类环氧合酶-2选择性抑制剂的立体结构,对接自由能与抑制剂活性有较好的相关性。     

Enhanced urease inhibition activity of Ag nanomaterials capped with N-substituted methyl 5-acetamido-β-resorcylate

Medically, bacterial ureases are important virulent factors and are used for treatment of peptic ulcers and urinary tones. Reported urease inhibitors are associated with various side effects including antibiotic resistance as a major one. Still there is an urgent need to synthesize new urease inhibitors. In this context we have synthesized new urease inhibitor i.e. AgL that is composed of Ag nanomaterials capped with N-substituted methyl 5-acetamido-β-resorcylate(L). The conjugation of L to silver was confirmed through FTIR, UV–vis and TEM analysis.Bare silver nanomaterials(Ag) were also prepared. The stability of AgL nanostructures was determined against various parameters(temperature, high salt concentration, pH) and found to be stable. The in vitro antimicrobial(antibacterial, antifungal), enzyme inhibition(xanthine oxidase, urease, carbonic anhydrase, α-chymotrypsin,cholinesterase) and antioxidant activities of AgL were investigated and compared with Ag, L and standard drugs.In comparison to other bioactivities, AgL shows statistically enhanced selective enzyme inhibition activity against urease enzyme. Urease inhibition activity of AgL was significantly greater than standard drug(thiourea),L and Ag. On a per weight basis, AgL required about 11–18 times less amount of L for inhibition of urease enzyme.     

Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants

The potential impact of pandemic influenza makes effective measures to limit the spread and morbidity of virus infection a public health priority. Antiviral drugs are seen as essential requirements for control of initial influenza outbreaks caused by a new virus, and in pre-pandemic plans there is a heavy reliance on drug stockpiles. The principal target for these drugs is a virus surface glycoprotein, neuraminidase, which facilitates the release of nascent virus and thus the spread of infection. Oseltamivir (Tamiflu) and zanamivir (Relenza) are two currently used neuraminidase inhibitors that were developed using knowledge of the enzyme structure. It has been proposed that the closer such inhibitors resemble the natural substrate, the less likely they are to select drug-resistant mutant viruses that retain viability. However, there have been reports of drug-resistant mutant selection in vitro and from infected humans. We report here the enzymatic properties and crystal structures of neuraminidase mutants from H5N1-infected patients that explain the molecular basis of resistance. Our results show that these mutants are resistant to oseltamivir but still strongly inhibited by zanamivir owing to an altered hydrophobic pocket in the active site of the enzyme required for oseltamivir binding. Together with recent reports of the viability and pathogenesis of H5N1 (ref. 7) and H1N1 (ref. 8) viruses with neuraminidases carrying these mutations, our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir.     

Phosphodiesterase 4 and compartmentalization of cyclic AMP signaling

Cyclic AMP (cAMP), as a second messenger, plays a critical role in cellular signaling transduction. However, it is not clear how this apparently identical cAMP signal induces divergent physiological re- sponses. The potential explanation that cAMP signaling is compartmentalized was proposed by Buxton and Brunton twenty years ago. Compartmentalization of cAMP signaling allows spatially distinct pools of protein kinase A (PKA) to be differently activated. Research on cAMP signaling has regained impetus in many fields of life sciences due to the progress in understanding cAMP signaling complexity and functional diversity. The cAMP/PKA signaling compartments are maintained by A-kinase anchoring proteins (AKAPs) which bind PKA and other signaling proteins, and by PDEs which hydrolyse cAMP and thus terminate PKA activity. PDE4 enzymes belong to PDE superfamily and stand at a crossroad that allows them to integrate various signaling pathways with that of cAMP in spatially distinct com- partments. In the current review, the nomenclature, taxonomy and gene expression of PDE4, and the system and region of its effect are described. In addition, the idiographic molecules, mechanisms, and regulation models of PDE4 are summarized. Furthermore, the important roles PDE4 plays in the matu- ration of rat granulosa cells and cAMP signaling compartmentalization are discussed.     

天然产物活性化合物抗SARS-CoV研究

针对系统综合征冠状病毒 2 (SARS-CoV-2),在全球范围大流行并呈指数级传播,迫切需要有 效的抗病毒药物和疫苗来控制和预防 SARS-CoV-2 疫情,寻找与开发有效、价格低廉的治疗 SARS-CoV-2 药物,是全世界面临的挑战;结合国内外最新文献,介绍了冠状病毒的起源、种类、人类感染的危害与应对措 施,发现药用植物与其它天然产物,其活性化合物抗 SARS-CoV 和增强免疫力廉价、可行,中医临床也证实 天然药物治疗 SARS-CoV 的有效性;天然产物包括药用植物、真菌和海洋生物的活性成分,可能成为 SARS- CoV-2 抑制剂研究与开发的新前沿。     

Structural determinants for regulation of phosphodiesterase by a G protein at 2.0 A

A multitude of heptahelical receptors use heterotrimeric G proteins to transduce signals to specific effector target molecules. The G protein transducin, Gt, couples photon-activated rhodopsin with the effector cyclic GMP phosophodiesterase (PDE) in the vertebrate phototransduction cascade. The interactions of the Gt alpha-subunit (alpha(t)) with the inhibitory PDE gamma-subunit (PDEgamma) are central to effector activation, and also enhance visual recovery in cooperation with the GTPase-activating protein regulator of G-protein signalling (RGS)-9 (refs 1-3). Here we describe the crystal structure at 2.0 A of rod transducin alpha x GDP x AlF4- in complex with the effector molecule PDEgamma and the GTPase-activating protein RGS9. In addition, we present the independently solved crystal structures of the RGS9 RGS domain both alone and in complex with alpha(t/i1) x GDP x AlF4-. These structures reveal insights into effector activation, synergistic GTPase acceleration, RGS9 specificity and RGS activity. Effector binding to a nucleotide-dependent site on alpha(t) sequesters PDEgamma residues implicated in PDE inhibition, and potentiates recruitment of RGS9 for hydrolytic transition state stabilization and concomitant signal termination.     

A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells.

Human cytomegalovirus (HCMV) is a major pathogen in immunosuppressed individuals, including patients with acquired immune deficiency syndrome. The nucleoside analogue ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl)-guanine) is one of the few drugs available to treat HCMV infections, but resistant virus is a growing problem in the clinic and there is a critical need for new drugs. The study of ganciclovir-resistant mutants has indicated that the selective action of ganciclovir depends largely on virus-controlled phosphorylation in HCMV-infected cells. The enzyme(s) responsible have not been identified. Here we report that the HCMV gene UL97, whose predicted product shares regions of homology with protein kinases, guanylyl cyclase and bacterial phosphotransferases, controls phosphorylation of ganciclovir in HCMV-infected cells. A four-amino-acid deletion of UL97 in a conserved region, which in cyclic AMP-dependent protein kinase participates in substrate recognition, causes impaired ganciclovir phosphorylation. The implications of these results for antiviral drug development and drug resistance are discussed.     

[2 + 2 + 1]反应合成2,3,5-三取代噻吩衍生物

噻吩骨架存在于替诺立定、西他生坦、莫他匹酮等生物碱中，可用作抗炎药、降压药、PDE3抑制剂. 对该骨架的修饰，一直是有机合成的热点. 在碱促进下，1,4-二羰衍生物和硫氰基芳酮经[2 + 2 + 1]反应，构建了噻吩骨架，同时实现了C-2位和C-5位的双芳酰基化、C-3位的芳基化. 分别从红外、核磁、质谱和单晶不同角度证实了产物的结构. 该反应机制涉及[3 + 2]环加成、原位开环、互变异构、S_N2反应等过程.      

新型Atorvastatin类HMGR抑制剂的3D-QSAR和分子对接

羟甲基戊二酰辅酶A还原酶(HMGR)是内源性胆固醇合成的重要催化限速酶,通过抑制HMGR的活性可以降低内源性胆固醇的合成.HMGR抑制剂(他汀类)是治疗心血管疾病的最佳药物之一.运用计算机辅助药物设计(CADD)方法,综合三维定量构效关系(3D-QSAR)和分子对接分析研究已合成的HMGR抑制剂的结构与抑制活性之间的关系.根据最优3D-QSAR模型,再结合分子对接分析,设计出新型活性高的HMGR抑制剂分子.     

非甾体类抗炎药的临床应用研究

目的阐述非甾体抗炎药物的临床应用.方法通过对国内外文献的比较分析,概述非甾体抗炎药作用机制、发展进程及发展趋势.结果非甾体抗炎药物是通过抑制花生四烯酸代谢而发挥作用,但对花生四烯酸代谢酶的选择性差异造成其严重的不良反应,使非甾体抗炎药临床应用受限.结论为了降低药物的不良反应,选择性COX-2/5-LO双重抑制剂及一氧化氮释放型非甾体抗炎药是临床用药的发展趋势.     

流向变换反应器方程组模型解的大时间性态研究

对流向变换反应器周期操作的非线性反应-对流-扩散偏微分方程组数学模型解的大时间性态进行了分析，定义了对应于此方程组模型的循环定态问题的弱解，在比较符合实际情况的假设条件下，证明了对应的循环定态问题的弱解存在，且时间趋于无穷时模型的解趋于此循环定态问题的弱解。     

振雄展势丹对勃起障碍大鼠壮阳作用的研究

探讨专利中药复方振雄展势丹对勃起功能障碍的动物模型的改善作用,并初步探讨其补肾壮阳的作用机理.70只雄性大鼠随机分为7组.除正常组,其余60只雄性大鼠建立勃起功能障碍的去势动物模型,分别灌胃给予振雄展势丹(4,2,1 g/kg),男宝胶囊(200 mg/kg)和丙酸睾酮注射液(2 mg/kg),连续给药21 d.不同剂量振雄展势丹组与模型组相比,勃起潜伏期显著下降.血清睾酮在中、高剂量组的水平明显升高,LH和LSH水平显著降低,且包皮腺,精囊和提肛肌指数明显增加.结果表明,振雄展势丹具有良好的改善勃起功能障碍及补肾壮阳的作用,其作用机理与促进雄性激素分泌,同化激素活性,促进睾丸间质细胞增殖有关.     

一类奇异半线性偏微分方程的上下解方法

利用变分方法，讨论了一类奇异半线性偏微分方程的一般上下解方法．作为应用．证明了含有正负指数项的一个重要的奇异半线性偏微分方程的解存在性．     

Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase

In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.