纳米药物载体靶向治疗脑胶质瘤的现状及前景展望

脑胶质瘤在成人原发脑肿瘤中居首位,目前的治疗手段疗效较差,手术切除后复发率高,而化疗药物不能有效的穿透血脑屏障并聚集在肿瘤部位。纳米材料作为载药体为其治疗开辟了新的思路,纳米材料在保持药物稳定性,增加其血液循环时间方面有明显优势。但目前纳米材料还存在着一些亟待解决的问题,如穿透血脑屏障(BBB)、准确靶向于脑胶质瘤细胞等。本文简略论述了纳米材料载药的特性及优势,重点就目前纳米材料载药所面临的问题进行综述,总结了纳米药物穿透血脑屏障的多种策略及纳米药物靶向于脑胶质瘤的不同方式,并详细讨论了目前纳米材料载药多重靶向策略,对其未来的发展进行展望。     

Modeling of Menkes disease via human induced pluripotent stem cells

Menkes disease (MD) is a copper-deficient neurodegenerative disorder that manifests severe neurologic symptoms such as seizures, lethargic states, and hypotonia. Menkes disease is due to a dysfunction of ATP7A, but the pathophysiology of neurologic manifestation is poorly understood during embryonic development. To understand the pathophysiology of neurologic symptoms, molecular and cellular phenotypes were investigated in Menkes disease-derived induced pluripotent stem cells (MD-iPSCs). MD-iPSCs were generated from fibroblasts of a Menkes disease patient. Abnormal reticular distribution of ATP7A was observed in MD-fibroblasts and MD-iPSCs, respectively. MD-iPSCs showed abnormal morphology in appearance during embryoid body (EB) formation as compared with wild type (WT)-iPSCs. Intriguingly, aberrant switch of E-cadherin (E-cad) to N-cadherin (N-cad) and impaired neural rosette formation were shown in MD-iPSCs during early differentiation. When extracellular copper was chelated in WT-iPSCs by treatment with bathocuprione sulfate, aberrant switch of E-cad to N-cad and impaired neuronal differentiation were observed, like in MD-iPSCs. Our results suggest that neurological defects in Menkes disease patients may be responsible for aberrant cadherin transition and impaired neuronal differentiation during early developmental stage.     

A synergistic approach to protein crystallization: Combination of a fixed‐arm carrier with surface entropy reduction

Protein crystallographers are often confronted with recalcitrant proteins not readily crystallizable, or which crystallize in problematic forms. A variety of techniques have been used to surmount such obstacles: crystallization using carrier proteins or antibody complexes, chemical modification, surface entropy reduction, proteolytic digestion, and additive screening. Here we present a synergistic approach for successful crystallization of proteins that do not form diffraction quality crystals using conventional methods. This approach combines favorable aspects of carrier‐driven crystallization with surface entropy reduction. We have generated a series of maltose binding protein (MBP) fusion constructs containing different surface mutations designed to reduce surface entropy and encourage crystal lattice formation. The MBP advantageously increases protein expression and solubility, and provides a streamlined purification protocol. Using this technique, we have successfully solved the structures of three unrelated proteins that were previously unattainable. This crystallization technique represents a valuable rescue strategy for protein structure solution when conventional methods fail.     

类弹性蛋白多肽及其在生物医学材料的应用

类弹性蛋白多肽是一种人造基因工程蛋白质聚合物,其结构主要由五肽重复串连序列单元 (GVGXP) 的这一肽段单元重复组成。由于具有可逆相变特征,并可进行高通量生产,加之良好的生物相容性及生物可降解性,使其在新型生物医学材料方面展示了广阔的应用前景。概括了类弹性蛋白多肽的相变机理、合成方法及在生物医学材料上的应用,重点阐述了类弹性蛋白多肽在组织工程、靶向肿瘤、构造药物载体微粒的应用。     

Interaction between CFTR and prestin (SLC26A5)

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel that is present in a variety of epithelial cell types, and usually expressed in the luminal membrane. In contrast, prestin (SLC26A5) is a voltage-dependent motor protein, which is present in the basolateral membrane of cochlear outer hair cells (OHCs), and plays an important role in the frequency selectivity and sensitivity of mammalian hearing. By using in situ hybridization and immunofluorescence, we found that both mRNA and protein of CFTR are present in OHCs, and that CFTR localizes in both the apical and the lateral membranes. CFTR was not detected in the lateral membrane of inner hair cells (IHCs) or in that of OHCs derived from prestin-knockout mice, i.e., in instances where prestin is not expressed. These results suggest that prestin may interact physically with CFTR in the lateral membrane of OHCs. Immunoprecipitation experiments confirmed a prestin-CFTR interaction. Because chloride is important for prestin function and for the efferent-mediated inhibition of cochlear output, the prestin-directed localization of CFTR to the lateral membrane of OHCs has a potential physiological significance. Aside from its role as a chloride channel, CFTR is known as a regulator of multiple protein functions, including those of the solute carrier family 26 (SLC26). Because prestin is in the SLC26 family, several members of which interact with CFTR, we explored the potential modulatory relationship associated with a direct, physical interaction between prestin and CFTR. Electrophysiological experiments demonstrated that cAMP-activated CFTR is capable of enhancing voltage-dependent charge displacement, a signature of OHC motility, whereas prestin does not affect the chloride conductance of CFTR.     

Characterization of two different acyl carrier proteins in complex I from Yarrowia lipolytica

Acyl carrier proteins of mitochondria (ACPMs) are small (∼ 10 kDa) acidic proteins that are homologous to the corresponding central components of prokaryotic fatty acid synthase complexes. Genomic deletions of the two genes ACPM1 and ACPM2 in the strictly aerobic yeast Yarrowia lipolytica resulted in strains that were not viable or retained only trace amounts of assembled mitochondrial complex I, respectively. This suggested different functions for the two proteins that despite high similarity could not be complemented by the respective other homolog still expressed in the deletion strains. Remarkably, the same phenotypes were observed if just the conserved serine carrying the phosphopantethein moiety was exchanged with alanine. Although this suggested a functional link to the lipid metabolism of mitochondria, no changes in the lipid composition of the organelles were found. Proteomic analysis revealed that both ACPMs were tightly bound to purified mitochondrial complex I. Western blot analysis revealed that the affinity tagged ACPM1 and ACPM2 proteins were exclusively detectable in mitochondrial membranes but not in the mitochondrial matrix as reported for other organisms. Hence we conclude that the ACPMs can serve all their possible functions in mitochondrial lipid metabolism and complex I assembly and stabilization as subunits bound to complex I.     

乙型肝炎病毒核心蛋白作为表位疫苗载体的应用

乙型肝炎病毒核心蛋白(Hepatitis B viruscore protein,HBc)可以形成二十面体对称的颗粒样结构,由于其N端、C端和主要免疫显性区域(Major immunodominant region,MIR)允许一定程度的缺失和外源插入,并且能够将外源序列重复且高密度地暴露在颗粒的表面,诱发强烈的外源序列特异的体液和细胞免疫反应,从上世纪80年代中期就开始被运用于表位疫苗的研究。以下主要从影响HBc作为表位疫苗载体的因素,包括HBc长度、外源插入位点和表位序列的性质等来介绍HBc作为表位疫苗载体的应用。