Ectodomain shedding of the receptor for advanced glycation end products: a novel therapeutic target for Alzheimer’s disease

Receptor for advanced glycation end products (RAGE) mediates diverse physiological and pathological effects and is involved in the pathogenesis of Alzheimer’s disease (AD). RAGE is a receptor for amyloid β peptides (Aβ), mediates Aβ neurotoxicity and also promotes Aβ influx into the brain and contributes to Aβ aggregation. Soluble RAGE (sRAGE), a secreted RAGE isoform, acts as a decoy receptor to antagonize RAGE-mediated damages. Accumulating evidence has suggested that sRAGE represents a promising pharmaceutic against RAGE-mediated disorders. Recent studies revealed proteolysis of RAGE as a previously unappreciated means of sRAGE production. In this review we summarize these findings on the proteolytic cleavage of RAGE and discuss the underlying regulatory mechanisms of RAGE shedding. Furthermore, we propose a model in which proteolysis of RAGE could restrain AD development by reducing Aβ transport into the brain and Aβ production via BACE. Thus, the modulation of RAGE proteolysis provides a novel intervention strategy for AD.     

The effect of ligand on the kinetics of the sulfhydryl groups of human hemoglobin with p-mercuribenzoate

The rate of reaction of PMB with the masked sulfhydryls of human hemoglobin derivatives correlates well with the extent of dissociation for various ligands. It is suggested that the alpha1beta2 dimer of hemoglobin participates in the slow step of the reaction with PMB.     

Soluble proteins of chemical communication in the social wasp <Emphasis Type="Italic">Polistes dominulus</Emphasis>

Members of the odorant-binding protein (OBP) and chemosensory protein (CSP) families were identified and characterised in the sensory tissues of the social wasp Polistes dominulus (Hymenoptera: Vespidae). Unlike most insects so far investigated, OBPs were detected in antennae, legs and wings, while CSPs appeared to be preferentially expressed in the antennae. The OBP is very different from the homologous proteins of other Hymenopteran species, with around 20% of identical residues, while the CSP appears to be much better conserved. Both OBP and CSP, not showing other post-translational modifications apart from disulphide bridges, were expressed with high yields in a bacterial system. Cysteine pairing in the recombinant and native proteins follows the classical arrangements described for other members of these classes of proteins. OBPs isolated from the wings were found to be associated with a number of long-chain aliphatic amides and other small organic molecules. Binding of these ligands and other related compounds was measured for both recombinant OBP and CSP.Received 14 May 2003; received after revision 8 June 2003; accepted 12 June 2003     

The effect of ligand on the kinetics of the reaction of the sulfhydryl groups of human hemoglobin with p-mercuribenzoate

Summary The rate of reaction of PMB with the masked sulfhydryls of human hemoglobin derivatives correlates well with the extent of dissociation for various ligands. It is suggested that the ₁₂ dimer of hemoglobin participates in the slow step of the reaction with PMB.     

Glycolipids and phospholipids as natural CD1d-binding NKT cell ligands

Natural killer T (NKT) cells have been shown by a number of studies to play a protective role against cancers, autoimmune diseases and infectious diseases. Several glycolipids and phospholipids derived from mammalian, bacterial, protozoan and plant species have recently been identified as natural ligands (antigens) for NKT cells. Some of these glycolipid/phospholipid ligands have now been crystallized in forms bound to CD1d molecules, and the tertiary structure of these complexes has finally been revealed. This review is intended to list natural NKT cell ligands identified to date, and discuss how their structures relate to their propensity to bind CD1d molecules and, as a consequence, stimulate NKT cells. Received 14 February 2006; received after revision 31 March 2006; accepted 15 May 2006     

Substrate specificity of bacterial DD-peptidases (penicillin-binding proteins)

The DD-peptidase enzymes (penicillin-binding proteins) catalyze the final transpeptidation reaction of bacterial cell wall (peptidoglycan) biosynthesis. Although there is now much structural information available about these enzymes, studies of their activity as enzymes lag. It is now established that representatives of two low-molecular-mass classes of DD-peptidases recognize elements of peptidoglycan structure and rapidly react with substrates and inhibitors incorporating these elements. No members of other DD-peptidase classes, including the high-molecular-mass enzymes, essential for bacterial growth, appear to interact strongly with any particular elements of peptidoglycan structure. Rational design of inhibitors for these enzymes is therefore challenging.     

链霉素诱导的2型糖尿病大鼠模型的肾脏功能变化

目的通过观察链霉素诱导的2型糖尿病大鼠模型肾脏功能的变化,以探讨此种模型是否适用于糖尿病肾损害的研究。方法采用链脲佐菌素(streptozotocin,STZ)辅以高脂饮食建立2型糖尿病大鼠模型,筛选造模成功的大鼠为糖尿病组,并与正常大鼠比较,造模后8周观察两组大鼠血糖、血尿素氮(blood urea nitrogen,BUN)、血肌酐(creatinine,CR)、血糖基化终末产物(Advanced glycation end products,AGE)、尿微量白蛋白、肾重指数的变化以及AGE受体(Receptor of AGE,RAGE)、蛋白激酶C(protein kinase C,PKC)、蛋白激酶A(protein kinase A,PKA)在肾脏的表达变化。结果糖尿病组的血糖、血尿素氮、血肌酐、血AGE、尿微量白蛋白以及肾重指数均明显高于正常组(P0.05),RAGE、PKC的mRNA以及蛋白表达水平均较正常组高(P0.05),PKA的mRNA和蛋白表达水平则较正常组低(P0.05)。结论 STZ诱导的2型糖尿病大鼠模型在造模后第8周肾脏功能存在明显的损害,并且导致肾脏损害的上游重要介质RAGE、PKC、PKA在第8周都有着明显的变化。此种模型能够用于糖尿病肾损害的研究,并且是观察中早期糖尿病肾病的较好的模型。     

Generation of MHC class I ligands in the secretory and vesicular pathways

CD8⁺ T lymphocytes screen the surface of all cells in the body to detect pathogen infection or oncogenic transformation. They recognize peptides derived from cellular proteins displayed at the plasma membrane by major histocompatibility complex (MHC) class I molecules. Peptides are mostly by-products of cytosolic proteolytic enzymes. Peptidic ligands of MHC class I molecules are also generated in the secretory and vesicular pathways. Features of protein substrates, of proteases and of available MHC class I molecules for loading peptides in these compartments shape a singular collection of ligands that also contain different, longer, and lower affinity peptides than ligands produced in the cytosol. Especially in individuals who lack the transporters associated with antigen processing, TAP, and in infected and tumor cells where TAP is blocked, which thus have no supply of peptides derived from the cytosol, MHC class I ligands generated in the secretory and vesicular pathways contribute to shaping the CD8⁺ T lymphocyte response.     

Soluble proteins in insect chemical communication

Our understanding of the biochemical mechanisms that mediate chemoreception in insects has been greatly improved after the discovery of olfactory and taste receptor proteins. However, the presence of soluble polypeptides in high concentration around the dendrites of sensory neurons still poses unanswered questions. More than 2 decades after their discovery and despite the wealth of structural information available, the physiological function of odorant-binding proteins is not well understood. More recently, members of a second family of soluble polypeptides, the chemosensory proteins, were also discovered in the lymph of chemosensilla. Here we review the structural properties of both classes of soluble proteins, their affinity to small ligands, and their expression in the different parts of the insect body and subcellular localisation. Finally, we discuss current ideas and models of the role of such proteins in insect chemoreception. Received 27 December 2005; received after revision 6 March 2006; accepted 13 April 2006     

The neurosecretory cells of the cerebral ganglia and the nerve chain in the isopod crustacean Asellus aquaticus L. Cyclic variations in the beta type cells as a function of reproduction]

Asellus aquaticus L. cerebral ganglions and nervous cord contain seven types of neurosecretory cells; two of these are similar to Malacostraca beta and alpha cells. Female beta cells are the seat of cyclic acidophil variations which are connected to ovocyte growing; this acidophil secretion is superimposed on the basophil constant secretion in male and female beta pericaryons.     

Evidence of 5 alpha-androstane-3 beta, 6 alpha, 17 beta-triol and of 5 alpha-androstane-3 beta, 7 alpha, 17 beta-triol in the anterior pituitary of the prepuberal male rate]

Incubation of 3H-5 alpha-androstane-3 beta, 17 beta-diol with anterior pituitaries from immature male Rats led to the major production of polar radio-metabolites. Of these, 53 and 27% were identified with 5 alpha-androstane-3 beta, 6 alpha, 17 beta-triol and 5 alpha-androstane-3 beta, 7 alpha, 17 beta-triol, respectively. The formation of these trihydroxysteroids may be involved in the intracellular regulation of 5 alpha-androstane-3 beta, 17 beta-diol levels.     

Evidence for the extranuclear localization of thymosins in thymus.

A new radioimmunoassay has been developed for thymosin beta 4 by generating rabbit polyclonal antibodies against the synthetic N-terminal peptide fragment 1-15 coupled to KLH. The synthetic analogue [Tyr12]-thymosin beta 4 (1-15) was used as tracer. This radioimmunoassay, with a useful range of 10-1000 pmoles, showed cross-reactivity with the second homologous beta-thymosin of man and rat (thymosin beta 10) but not of calf (thymosin beta 9). This radioimmunoassay, together with an improved radioimmunoassay for the N-terminus of parathymosin alpha, was employed for the measurement of the levels of thymosin beta 4 and parathymosin alpha in nuclear and extranuclear extracts of calf thymus. The bulk of these polypeptides was found in the extranuclear material whereas only traces were observed in the nuclear environment, which indicates the extranuclear localisation of alpha- and beta-thymosins.     

Modeling the MHC class I pathway by combining predictions of proteasomal cleavage,TAP transport and MHC class I binding

Epitopes presented by major histocompatibility complex (MHC) class I molecules are selected by a multi-step process. Here we present the first computational prediction of this process based on in vitro experiments characterizing proteasomal cleavage, transport by the transporter associated with antigen processing (TAP) and MHC class I binding. Our novel prediction method for proteasomal cleavages outperforms existing methods when tested on in vitro cleavage data. The analysis of our predictions for a new dataset consisting of 390 endogenously processed MHC class I ligands from cells with known proteasome composition shows that the immunological advantage of switching from constitutive to immunoproteasomes is mainly to suppress the creation of peptides in the cytosol that TAP cannot transport. Furthermore, we show that proteasomes are unlikely to generate MHC class I ligands with a C-terminal lysine residue, suggesting processing of these ligands by a different protease that may be tripeptidyl-peptidase II (TPPII).Received 26 November 2004; received after revision 4 February 2005; accepted 4 March 2005S. Tenzer and B. Peters contributed equally to this work.     

Protein proteinase inhibitors from avian egg whites

Avian egg whites are a rich source of protein inhibitors of proteinases belonging to all four mechanistic classes. Ovomucoid and ovoinhibitor are multidomain Kazal-type inhibitors with each domain containing an actual or putative reactive site for a serine proteinase. Cystatin is a cysteine proteinase inhibitor, while ovostatin inhibits proteinases of all four mechanistic classes. In this review we have summarized the general features, isolation, inhibitory mechanism and evolutionary aspects of these inhibitors. Received 6 March 1996; received after revision 17 June 1996; accepted 10 July 1996     

Eisen(III)-Komplexe mit 3 ungepaarten Elektronen

Summary Magnetic measurements on iron(III)-complexes of amino acids show that in these compounds, as also in Ferritin, there are 3 unpaired electrons for each iron atom. From this it follows that, according to the Pauling theory, there is a square-planar arrangement of the 4 ligands.     

S100A6 protein: functional roles

S100A6 protein belongs to the A group of the S100 protein family of Ca²⁺-binding proteins. It is expressed in a limited number of cell types in adult normal tissues and in several tumor cell types. As an intracellular protein, S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors. S100A6 can be secreted/released by certain cell types which points to extracellular effects of the protein. RAGE (receptor for advanced glycation endproducts) and integrin β1 transduce some extracellular S100A6’s effects. Dosage of serum S100A6 might aid in diagnosis in oncology.     

Purification, cloning and characterisation of odorant- and pheromone-binding proteins from pig nasal epithelium

Two distinct classes of lipocalin isoforms (OBP-IIs and OBP-IIIs) were purified and identified from porcine nasal mucosa of male and female individuals. Using primers designed on their N-terminal sequence, the complete primary structures of the mature polypeptides were determined. Mass spectrometry analysis confirmed the identity of the cDNA-derived sequences and provided information regarding their post-translational modifications. These species strongly resemble a lipocalin expressed by von Ebner's gland and salivary lipocalins carrying sex-specific pheromones secreted only by the boar's submaxillary glands. Both OBP-IIs and OBP-IIIs present two cysteines paired in a disulphide bond; the remaining residues occur in a reduced form. In addition, OBP-IIIs are heavily glycosylated and markedly different in their glycan moiety from the salivary lipocalins. A three-dimensional model is proposed based on protein species with known structure. Like salivary lipocalins, OBP-IIIs bind a number of odorant molecules, with highest affinity for the specific pheromone 5alpha-androst-16-en-3-one. The high similarity between OBPs from the nasal area and lipocalins from secretory glands suggests a common function in binding the same pheromonal ligands, the latter carrying chemical messages into the environment the former delivering them to specific receptors.