电磁场的应用与研究进展

随着生物医学工程学发展,物理疗法已经成为当前疾病治疗一个重要手段,因此电磁场治疗及生物电磁的研究成为当前热点。特别是在骨病等相关领域的研究,研究发现电磁场能有效的治疗和预防骨质疏松症。因此本文就电磁场治疗以及机理研究方面进行综述。     

焦磷酸盐与血管钙化

血管钙化是指促钙化因子与抑钙化因子失衡导致钙磷在血管壁的异常沉积,与心血管疾病的高发病率与高死亡率密切相关。细胞外焦磷酸盐作为内源性羟磷灰石结晶形成的抑制剂,在血管钙化的发生中发挥重要的作用。近年来的研究发现,焦磷酸盐代谢异常是导致某些家族遗传性疾病及慢性肾病患者发生血管钙化的重要机制。本文着重对焦磷酸盐在体内的代谢、焦磷酸盐及其代谢相关酶在血管钙化发生中的作用进行综述。     

MORC家族蛋白的生物学功能研究进展

Microrchidia(MORC)是高度保守的核蛋白超家族,包括MORC1、MORC2、MORC3和MORC4。MORCs作为新的表观遗传调控因子,参与多种基本的生物学过程,包括DNA损伤修复、细胞增殖、细胞衰老和表观遗传调控。MORCs的调节异常与癌症、自身免疫疾病和骨病相关。对MORCs结构和功能的进一步研究将为开发治疗MORCs相关疾病的新方法奠定基础。该文将结合作者的研究工作,重点对MORCs在癌症和骨稳态调节中的作用进行综述,并讨论MORCs作为癌症、自身免疫疾病和骨病治疗的新药物靶点的可能应用前景。     

遗传性骨病致病基因及相关miRNA的相互作用分析

目的:筛选遗传性骨病相关的致病基因和其相关的mi RNA,并研究两者相互作用关系以及在遗传性骨病中的作用。方法:本研究应用生物信息学的方法,首先应用mirwalk和《国际遗传性骨病分类标准》分析遗传性骨病的致病基因,根据筛选出来的致病基因利用mirwalk的10个预测mirna搜索引擎功能,搜索致病基因的相关mi RNA,并应用excel工作表统计分析mirna的靶向致病基因;再应用Cytoscape软件分析致病基因和相关mirna之间的相互作用关系。结果:本研究中与遗传性骨病密切相关的基因可以分为四类:第一类为成骨不全类基因COL1A1、COL1A2等;第二类为骨密度降低类基因如ACVR1、ALX1等;第三类为骨密度增加类基因如CASR、DMTF1等;第四类为通过作用骨干参与骨密度增加的基因如TGFBR1、MYCN等。其中与成骨不全关系最为密切的mirna是hsa-miR-26b、hsa-miR-19、hsa-miR-200c;与骨密度降低关系最为密切的mirna是hsa-miR-138、hsa-miR-505;与骨密度增加关系最为密切的mirna是hsa-miR-196a、hsa-miR-200b、hsa-miR-19b。结论:mirna可通过调控遗传性骨病致病基因在其病理过程中起到重要作用,提示上述mirna可能是成为遗传性骨病产前筛查和临床药物治疗的新靶点。     

与钙化相关的骨基质蛋白研究的现状与展望

生物矿化（biomineralization）不仅包括正常情况下骨骼和牙齿的钙化也包括各种疾病时的钙化,如血管钙化、胎盘钙化,还包括珊瑚和贝类以及纳米细菌等不同物种的钙化。研究表明与骨骼钙化的相关的蛋白不仅发现于骨骼的钙化中,也同样发现于其他组织的钙化过程和其他物种的矿化过程中,因此本文就与骨骼钙化的相关蛋白做一综述,以期为进一步研究纳米细菌自身的矿化机制,探讨其引起的相关疾病的致病机制以及为进一步实验筛选合适的标志蛋白。     

《自然-化学》：新技术可精确分析蛋白分子折叠形状

来自美国俄亥俄州立大学、国立卫生研究所（NIH）信息技术中心的研究人员研发了一种新型的蛋白质结构分析技术,该技术可帮助研究人员精确分析生物分子的折叠形状,从而可以更好地了解这些分子在健康细胞中的关键功能及参与致病的机理。相关研究成果公布在《自然一化学》（Naturechemistry）杂志上。     

溶质转运蛋白超家族的功能及结构研究进展

溶质转运蛋白(solute carriers,SLC)超家族是人类细胞膜(含胞内膜)上最重要的膜转运蛋白家族之一,它参与了细胞间的物质运输、能量传递、营养代谢、信号传导等重要生理活动。SLC转运蛋白超家族包含52个亚家族,共有400多名成员。研究表明,人类基因突变所致SLC蛋白表达异常或功能缺陷与糖尿病、高血压、抑郁症等多种重大疾病密切相关,使得该家族蛋白的功能研究近年来备受关注。SLC转运家族蛋白三维结构的解析有助于阐述其底物选择性结合与转运的精确分子机制,为研究该家族功能相关疾病的分子机理以及针对理性药物研发奠定了精细的三维结构基础。本文对近年来溶质转运蛋白超家族的结构及功能研究进展进行了总结,试图对该家族的共性规律进行阐述。     

科研快讯

《自然-化学》:新技术可精确分析蛋白分子折叠形状来自美国俄亥俄州立大学、国立卫生研究所(NIH)信息技术中心的研究人员研发了一种新型的蛋白质结构分析技术,该技术可帮助研究人员精确分析生物分子的折叠形状,从而可以更好地了解这些分子在健康细胞中的关键功能及参与致病的机理。相关研究成果公布在《自然-化学》(Nature chemistry)杂志上。     

老年痴呆症的分子机制

老年痴呆症是一种多发于老年人群的神经退行性疾病,其发病机理十分复杂,目前主要认为与β-淀粉样蛋白的神经毒性和微管结合蛋白tau的异常修饰相关。将从β-淀粉样蛋白在神经突触功能失调、神经元凋亡、炎症反应中的作用,以及tau蛋白异常修饰的机理与神经损伤等方面阐述老年痴呆症发病的分子机理,并对相关诊断和治疗手段进行讨论。     

植物细胞核雄性不育基因研究进展

植物雄性不育既是研究植物生殖生物学重要的植物学性状也是研究作物杂种优势利用重要的农艺性状,在遗传和分子生物学中具有重要地位。以模式植物拟南芥和水稻为主,对植物雄性不育的控制基因和相关分子机理已有众多进展,按照花药发育时期和雄性败育的表现形式可以归纳为减数分裂异常、胼胝质代谢异常、绒毡层发育异常、花粉壁发育异常、花药开裂异常,以及其它类型的雄性不育。在不育相关基因中,导致胼胝质代谢异常、绒毡层发育异常和花粉壁发育异常的基因往往表现一因多效,一个相关基因的突变会产生复合表型。关于植物雄性不育相关基因的研究表明,雄性器官和小孢子形成过程中的任何相关基因的改变,均可导致雄性不育的产生。本文总结了植物核基因雄性不育的研究进展,以期促进不同物种间雄性不育基因的比较分析,使植物雄性不育研究更加深入。     

The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family

Protein inhibitors of proteolytic enzymes regulate proteolysis and prevent the pathological effects of excess endogenous or exogenous proteases. Cysteine proteases are a large family of enzymes found throughout the plant and animal kingdoms. Disturbance of the equilibrium between cysteine proteases and natural inhibitors is a key event in the pathogenesis of cancer, rheumatoid arthritis, osteoporosis, and emphysema. A family (I42) of cysteine protease inhibitors (http://merops.sanger.ac.uk) was discovered in protozoan parasites and recently found widely distributed in prokaryotes and eukaryotes. We report the 2.2 A crystal structure of the signature member of the I42 family, chagasin, in complex with a cysteine protease. Chagasin has a unique variant of the immunoglobulin fold with homology to human CD8alpha. Interactions of chagasin with a target protease are reminiscent of the cystatin family inhibitors. Protein inhibitors of cysteine proteases may have evolved more than once on nonhomologous scaffolds.     

Revisiting catalysis by chymotrypsin family serine proteases using peptide substrates and inhibitors with unnatural main chains.

Chymotrypsin family serine proteases play essential roles in key biological and pathological processes and are frequently targets of drug discovery efforts. This large enzyme family is also among the most advanced model systems for detailed studies of enzyme mechanism and structure/function relationships. Productive interactions between these enzymes and their substrates are widely believed to mimic the "canonical" interactions between serine proteases and "standard" inhibitors observed in numerous protease-inhibitor complexes. To test this central hypothesis we have synthesized and characterized a series of peptide analogs, based on model substrates and inhibitors of trypsin, that contain unnatural main chains. These results call into question a long accepted theory regarding the interaction of chymotrypsin family serine proteases with substrates and suggest that the canonical interactions observed between these enzymes and standard inhibitors may represent nonproductive rather than productive, substrate-like interactions.     

Evaluation of classical NSAIDs and COX-2 selective inhibitors on purified ovine enzymes and human whole blood.

Cyclooxygenase is the key enzyme in the biosynthesis of prostanoids, biologically active substances involved in several physiological processes and also in pathological conditions such as inflammation. It has been well known for 10 years that this enzyme exists under two forms: a constitutive (COX-1) and an inducible form (COX-2). Both enzymes are sensitive to inhibition by conventional non-steroidal anti-inflammatory drugs (NSAIDs). Observations were made that COX-1 was mainly involved in homeostatic processes, while the COX-2 expression was associated with pathological conditions leading to the development of COX-2 selective inhibitors. Several methods have been reported for the evaluation of the COX-1 and COX-2 inhibitory potency and selectivity of conventional or COX-2 selective NSAIDs. In this study, we evaluated the COXs inhibitory profile of both conventional NSAIDs and COX-2 selective inhibitors using two different in vitro methods: the first test was performed using purified enzymes while the second method consisted of a whole blood assay. The results obtained with reference drugs in these two assays will be discussed and compared in this article.     

Hydrolytic enzymes and their proteinaceous inhibitors in regulation of plant–pathogen interactions

This review considers the main groups of hydrolytic enzymes associated with plant pathogens, as well as proteinaceous inhibitors of these enzymes, acting as the components of plant defense system. The role of hydrolases is described in the development of a pathological process in plant tissues. Significance of hydrolase inhibitors in the development of plant resistance to pathogens is analyzed. It is proposed that specific interactions in the “host plant–pathogen” system, involving hydrolytic enzymes and their proteinaceous inhibitors, depend on the nutritional specialization of fungi.     

Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge

Zn-metalloproteinases are an important class of hydrolytic enzymes that are characterized by the presence of a catalytic zinc(II) atom in their active center which is fundamental for proteolytic activity. Metzincins, a superfamily of Zn-metalloproteinases with many structural and functional commonalities among its members, are responsible for the fine tuning of key physiological functions in mammals and the deregulation of their activity is directly connected to numerous inflammatory and degenerative diseases such as arthritis or cancer. Development of small-molecule exogenous inhibitors of metzincins able to re-establish normal proteolytic activity in pathological conditions has been a field of intense research effort for many years but applications in the clinic were not always successful. One of the main reasons for this failure is the uncontrolled action of these inhibitors on target as well as anti-target metzincin family members. Current medicinal efforts have been shifted to the discovery of target-specific inhibitors that will help to improve our understanding of metzincins biological function and provide the basis for the development of safer pharmaceutical agents. This review focuses on the cases of certain medicinally important metzincins [matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), ADAMs with thrombospondin motifs (ADAMTSs), and procollagen C-proteinase (PCP)] and summarizes the latest advances on the discovery of inhibitors of these enzymes that display improved selectivity profiles.     

Sphingosine 1-phosphate activation of ERM contributes to vascular calcification

Vascular calcification is the deposition of mineral in the artery wall by vascular smooth muscle cells (VSMCs) in response to pathological stimuli. The process is similar to bone formation and is an independent risk factor for cardiovascular disease. Given that ceramide and sphingosine 1-phosphate (S1P) are involved in cardiovascular pathophysiology and biomineralization, their role in VSMC matrix mineralization was investigated. During phosphate-induced VSMC mineralization, endogenous S1P levels increased accompanied by increased sphingosine kinase (SK) activity and increased mRNA expression of SK1 and SK2. Consistent with this, mineralization was increased by exogenous S1P, but decreased by C2-ceramide. Mechanistically, exogenous S1P stimulated ezrin-radixin-moesin (ERM) phosphorylation in VSMCs and ERM phosphorylation was increased concomitantly with endogenous S1P during mineralization. Moreover, inhibition of acid sphingomyelinase and ceramidase with desipramine prevented increased S1P levels, ERM activation, and mineralization. Finally, pharmacological inhibition of ERM phosphorylation with NSC663894 decreased mineralization induced by phosphate and exogenous S1P. Although further studies will be needed to verify these findings in vivo, this study defines a novel role for the SK-S1P-ERM pathways in phosphate-induced VSMC matrix mineralization and shows that blocking these pathways with pharmacological inhibitors reduces mineralization. These results may inform new therapeutic approaches to inhibit or delay vascular calcification.     

Inhibition of cysteine peptidase activity in ascitic fluid in pancreatic cancer patients

The work's objective is to answer the question whether there is any possibility of activity inhibition of cysteine peptidases inhibitors playing an important role in key processes accompanying cancer formation, including pancreas. There is a justified speculation that specific inhibitors of these enzymes may inhibit development of cancer processes by inhibiting their activity. In vitro studies confirmed that these enzymes in ascitic fluid were inhibited with egg whites inhibitors even to 90% of their original activity.     

Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization

We review here the Stenciling Principle for extracellular matrix mineralization that describes a double-negative process (inhibition of inhibitors) that promotes mineralization in bone and other mineralized tissues, whereas the default condition of inhibition alone prevents mineralization elsewhere in soft connective tissues. The stenciling principle acts across multiple levels from the macroscale (skeleton/dentition vs soft connective tissues), to the microscale (for example, entheses, and the tooth attachment complex where the soft periodontal ligament is situated between mineralized tooth cementum and mineralized alveolar bone), and to the mesoscale (mineral tessellation). It relates to both small-molecule (e.g. pyrophosphate) and protein (e.g. osteopontin) inhibitors of mineralization, and promoters (enzymes, e.g. TNAP, PHEX) that degrade the inhibitors to permit and regulate mineralization. In this process, an organizational motif for bone mineral arises that we call crossfibrillar mineral tessellation where mineral formations – called tesselles – geometrically approximate prolate ellipsoids and traverse multiple collagen fibrils (laterally). Tesselle growth is directed by the structural anisotropy of collagen, being spatially restrained in the shorter transverse tesselle dimensions (averaging 1.6 × 0.8 × 0.8 μm, aspect ratio 2, length range 1.5–2.5 μm). Temporo-spatially, the tesselles abut in 3D (close ellipsoid packing) to fill the volume of lamellar bone extracellular matrix. Poorly mineralized interfacial gaps between adjacent tesselles remain discernable even in mature lamellar bone. Tessellation of a same, small basic unit to form larger structural assemblies results in numerous 3D interfaces, allows dissipation of critical stresses, and enables fail-safe cyclic deformations. Incomplete tessellation in osteomalacia/odontomalacia may explain why soft osteomalacic bones buckle and deform under loading.     

Structure and function of the Mur enzymes: development of novel inhibitors

One of the biggest challenges for recent medical research is the continuous development of new antibiotics interacting with bacterial essential mechanisms. The machinery for peptidoglycan biosynthesis is a rich source of crucial targets for antibacterial chemotherapy. The cytoplasmic steps of the biosynthesis of peptidoglycan precursor, catalysed by a series of Mur enzymes, are excellent candidates for drug development. There has been growing interest in these bacterial enzymes over the last decade. Many studies attempted to understand the detailed mechanisms and structural features of the key enzymes MurA to MurF. Only MurA is inhibited by a known antibiotic, fosfomycin. Several attempts made to develop novel inhibitors of this pathway are discussed in this review. Three novel inhibitors of MurA were identified recently. 4-Thiazolidinone compounds were designed as MurB inhibitors. Many phosphinic acid derivatives and substrate analogues were identified as inhibitors of the MurC to MurF amino acid ligases.     

Matrix metalloproteinases and their expression in mammary gland

The matrix metalloproteinases (MMPs) are a family of zine-dependent endopeptidases that play a key role in both normal and pathological processes involving tissue remodeling events.The expression of these proteolytic enzymes is highly regulated by a balance between extracellular matrix (ECM) deposition and its degradation,and is controlled by growth factors,cytokines,hormones,as well as interactions with the ECM macromolecules.Furthermore,the activity of the MMPs is regulated by their natural endogenous inhibitors,which are members of the tissue inhibitor of metalloproteinases (TIMP) family.In the normal mammary gland,MMPs are expressed during ductal development,lobulo-alveolar development in pregnancy and involution after lactation.Under pathological conditions,such as tumorigenesis,the dysregulated expression of MMPs play a role in tumor initiation,progression and malignant conversion as well as facilitating invasion and metastasis of malignant cells through degradation of the ECM and basement membranes.