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41.
Despite great advances in the field of vaccination, there are still needs for novel and effective vaccines because still no effective vaccines have been produced for some diseases such as malaria, acquired immune deficiency syndrome (AIDS), and tuberculosis. Furthermore, many of the existing vaccines have disadvantages such as failure to stimulate completely the immune system, in vivo instability, high toxicity, the need for cold chain, and multiple administrations. Nanotechnology has been raised as a powerful tool for solving these problems in this regard. Generally, nanovaccines are a new generation of vaccines using nanoparticles (NPs) as carriers and/or adjuvants. Due to the similar scale (size) between the NPs and pathogens, the immune system can be stimulated well, resulting in triggered cellular and humoral immunity responses. Other benefits of the nanovaccines include their better stability in blood flow to increase the shelf life in blood, enhanced immune system stimulation, no need for booster doses, no need to maintain the cold chain, and ability to create active targeting. In addition, nanovaccines have raised the hope to treat diseases such as rheumatoid arthritis, AIDS, malaria, and chronic autoimmune, and so forth. 相似文献
42.
《Bioorganic & medicinal chemistry》2014,22(19):5234-5240
Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300 mg/kg, ip) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380. 相似文献
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45.
Ilia Fishbein Scott P. Forbes Richard F. Adamo Michael Chorny Robert J. Levy Ivan S. Alferiev 《Journal of visualized experiments : JoVE》2014,(90)
In-stent restenosis presents a major complication of stent-based revascularization procedures widely used to re-establish blood flow through critically narrowed segments of coronary and peripheral arteries. Endovascular stents capable of tunable release of genes with anti-restenotic activity may present an alternative strategy to presently used drug-eluting stents. In order to attain clinical translation, gene-eluting stents must exhibit predictable kinetics of stent-immobilized gene vector release and site-specific transduction of vasculature, while avoiding an excessive inflammatory response typically associated with the polymer coatings used for physical entrapment of the vector. This paper describes a detailed methodology for coatless tethering of adenoviral gene vectors to stents based on a reversible binding of the adenoviral particles to polyallylamine bisphosphonate (PABT)-modified stainless steel surface via hydrolysable cross-linkers (HC). A family of bifunctional (amine- and thiol-reactive) HC with an average t1/2 of the in-chain ester hydrolysis ranging between 5 and 50 days were used to link the vector with the stent. The vector immobilization procedure is typically carried out within 9 hr and consists of several steps: 1) incubation of the metal samples in an aqueous solution of PABT (4 hr); 2) deprotection of thiol groups installed in PABT with tris(2-carboxyethyl) phosphine (20 min); 3) expansion of thiol reactive capacity of the metal surface by reacting the samples with polyethyleneimine derivatized with pyridyldithio (PDT) groups (2 hr); 4) conversion of PDT groups to thiols with dithiothreitol (10 min); 5) modification of adenoviruses with HC (1 hr); 6) purification of modified adenoviral particles by size-exclusion column chromatography (15 min) and 7) immobilization of thiol-reactive adenoviral particles on the thiolated steel surface (1 hr). This technique has wide potential applicability beyond stents, by facilitating surface engineering of bioprosthetic devices to enhance their biocompatibility through the substrate-mediated gene delivery to the cells interfacing the implanted foreign material. 相似文献
46.
摘要 目的:探讨肺癌合并肺部感染患者病原菌分布、耐药性分析及血清炎性因子检测的临床意义。方法:选取我院于2018年6月~2020年3月期间收治的肺癌合并肺部感染患者90例为感染组,选取同期我院收治的肺癌未合并肺部感染患者100例为肺癌组,选取同期于我院进行体检的健康志愿者60例为对照组,对肺癌合并肺部感染患者的感染病原菌类型进行总结分析,分析常见病原菌药敏试验结果,统计病原菌耐药率。对比三组受试者的炎性因子水平。结果:90例肺癌合并肺部感染患者的送检痰液标本共检出100株病原菌,100株病原菌中以革兰阴性菌为主,其次为革兰阳性菌、真菌,分别占比63.00%、22.00%、15.00%。肺炎克雷伯菌、鲍氏不动杆菌、铜绿假单胞菌对亚胺培南的耐药率较低,对氨苄西林、甲氨苄啶的耐药率均较高。凝固酶阴性葡萄球菌、金黄色葡萄球菌对万古霉素的耐药率较高,对左氧氟沙星的耐药率较低。白色念珠菌、热带念珠菌对两性霉素B、氟康唑、酮康唑、伊曲康唑的耐药率均较低。感染组、肺癌组的血清白介素-6(IL-6)、降钙素原(PCT)、肿瘤坏死因子-α(TNF-α)水平均高于对照组,且感染组以上指标水平高于肺癌组(P<0.05)。结论:肺癌合并肺部感染患者体内病原菌种类繁多,对常见抗菌药物的耐药性存在差异,且患者体内存在较强的炎性反应,临床应根据药敏结果合理应用抗菌药物 。 相似文献
47.
Carol W. Hunja Holger Unger Pedro E. Ferreira Richard Lumsden Sheila Morris Rashid Aman Claire Alexander Toshihiro Mita Richard Culleton 《International journal for parasitology》2013
There is growing evidence that Plasmodium falciparum parasites in southeastern Asia have developed resistance to artemisinin combination therapy. The resistance phenotype has recently been shown to be associated with four single nucleotide polymorphisms in the parasite’s genome. We assessed the prevalence of two of these single nucleotide polymorphisms in P. falciparum parasites imported into Scotland between 2009 and 2012, and in additional field samples from six countries in southeastern Asia. We analysed 28 samples from 11 African countries, and 25 samples from nine countries in Asia/southeastern Asia/Oceania. Single nucleotide polymorphisms associated with artemisinin combination therapy resistance were not observed outside Thailand and Cambodia. 相似文献
48.
Limor Avrahami Avital Licht-Murava Miriam Eisenstein Hagit Eldar-Finkelman 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(7):1410-1414
Inhibiting glycogen synthase kinase-3 (GSK-3) activity has become an attractive approach for treatment of neurodegenerative and psychiatric disorders. Diverse GSK-3 inhibitors have been reported and used in cellular and in vivo models. A major challenge, however, is achieving selectivity. In addition, it is increasingly recognized that a moderate inhibition of a cellular target, particularly for long-term treatment, provides more favorable outcome than complete inhibition. Substrate competitive inhibitors can fulfill the requirement for selectivity and allow fine tuning of the degree of inhibition. Here we describe the therapeutic potential of GSK-3 inhibitors and highlight our progress in the development of substrate competitive inhibitors. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). 相似文献
49.
Targeting of extracellular protein–protein interactions (PPI) is emerging as a major application for de novo discovered macrocyclic peptides. Modern discovery platforms can routinely identify macrocyclic peptide ligands capable of highly selective modulation of extracellular signaling pathways; amenability to chemical synthesis and natural modularity of peptides additionally provides an avenue for their further structural elaboration, while the challenge of cell internalization can be minimized. Here, we discuss the recent progress in targeting extracellular PPIs with macrocyclic peptides by focusing on a number of recent case studies. We analyze the scope and potential limitations of the discovery systems in identifying functional macrocyclic ligands. We also highlight the recent technical advancements allowing for a more streamlined discovery pipeline and our brief perspective in this field. 相似文献
50.
《Bioorganic & medicinal chemistry letters》2014,24(18):4529-4532
The trans-sialidase of Trypanosoma cruzi (TcTS) is a surface enzyme that modifies the parasite glycocalyx covering it with sialic acid. This process is essential to adhesion and invasion mechanisms in life cycle of the protozoan in the human host, making TcTS a very attractive molecular target for drug design. Using the TcTS substrate 3′-sialyllactose as prototype, d-galactose-derived potential inhibitors of TcTS were designed using strategies of molecular modification. Ten new aryl galactosides modified at carbon-3 were synthesized employing classical carbohydrate chemistry and dibutyltin oxide method for regioselective 3-O-alkylations and evaluated against TcTS by spectrofluorimetry. The 4-methoxycarbonyl-2-nitrophenyl 3-O-carboxymethyl-β-d-galactopyranoside was the most active compound inhibiting 21% of TcTS enzymatic activity at 1 mM. 相似文献