Annexin A5: shifting from a diagnostic towards a therapeutic realm

The surge in apoptosis research and the discovery of the phosphatidylserine binding properties of annexin A5 have propelled a tremendous interest in cell death detection technologies. In the past years, annexin A5 has evolved from an efficient assay for detection of apoptotic cells in vitro to an in vivo molecular imaging technology with potential clinical use. A second key discovery, the specific internalization properties of annexin A5, has opened the opportunity to use annexin A5 for therapeutic applications. Annexin A5-mediated internalization creates a novel therapeutic platform for targeted drug delivery and cell entry to treat various diseases, including cancer and cardiovascular disease. Received 29 June 2007; received after revision 19 July 2007; accepted 15 August 2007     

Moving towards a paradigm: common mechanisms of chemotactic signaling in Dictyostelium and mammalian leukocytes

Chemotaxis, or directed migration of cells along a chemical gradient, is a highly coordinated process that involves gradient sensing, motility, and polarity. Most of our understanding of chemotaxis comes from studies of cells undergoing amoeboid-type migration, in particular the social amoeba Dictyostelium discoideum and leukocytes. In these amoeboid cells the molecular events leading to directed migration can be conceptually divided into four interacting networks: receptor/G protein, signal transduction, cytoskeleton, and polarity. The signal transduction network occupies a central position in this scheme as it receives direct input from the receptor/G protein network, as well as feedback from the cytoskeletal and polarity networks. Multiple overlapping modules within the signal transduction network transmit the signals to the actin cytoskeleton network leading to biased pseudopod protrusion in the direction of the gradient. The overall architecture of the networks, as well as the individual signaling modules, is remarkably conserved between Dictyostelium and mammalian leukocytes, and the similarities and differences between the two systems are the subject of this review.     

Antiviral strategies against influenza virus: towards new therapeutic approaches

Influenza viruses are major human pathogens responsible for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need annual updating and give limited protection. Only two classes of drugs are currently approved for the treatment of influenza: M2 ion channel blockers and neuraminidase inhibitors. However, they are often associated with limited efficacy and adverse side effects. In addition, the currently available drugs suffer from rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Several new classes of antiviral agents targeting viral replication mechanisms or cellular proteins/processes are under development. This review gives an overview of novel strategies targeting the virus and/or the host cell for counteracting influenza virus infection.     

RNA and protein-dependent mechanisms in tauopathies: consequences for therapeutic strategies

Tauopathies are a group of neurodegenerative diseases characterised by intracellular deposits of the microtubule-associated protein tau. The most typical example of a tauopathy is Alzheimer’s disease. The importance of tau in neuronal dysfunction and degeneration has been demonstrated by the discovery of dominant mutations in the MAPT gene, encoding tau, in some rare dementias. Recent developments have shed light on the significance of tau phosphorylation and aggregation in pathogenesis. Furthermore, emerging evidence reveals the central role played by tau pre-mRNA processing in tauopathies. The present review focuses on the current understanding of tau-dependent pathogenic mechanisms and how realistic therapies for tauopathies can be developed. Received 3 December 2006; received after revision 23 February 2007; accepted 20 March 2007     

Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications

Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that salvage polyamines from diet and intestinal microorganisms, as well as stepwise degradation and efflux. Investigations using polyamine biosynthetic inhibitors indicate that alterations in cellular polyamine levels modulate normal and cancer cell growth. Studies using transgenic mice overexpressing polyamine biosynthetic enzymes support a role of polyamines in carcinogenesis. Many, if not all, signal transduction pathways intersect with polyamine biosynthetic pathways and the regulation of intracellular polyamine levels. Direct binding of polyamines to DNA and their ability to modulate DNA-protein interactions appear to be important in the molecular mechanisms of polyamine action in cell proliferation. Consistent with the role of polyamines as facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, polyamines also have a role in facilitating cell death. The basis of these diverse cellular responses is currently not known. Cell death response might be partly mediated by the production of hydrogen peroxide during polyamine catabolism. In addition, the ability of polyamines to alter DNA-protein and protein-protein interactions might be disruptive to cellular functions, when abnormally high levels are accumulated due to defects in polyamine catabolic or efflux pathways. A large body of data indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthesis, polyamine analogues as well as oligonucleotide/polyamine analogue combinations are promising drug candidates for chemoprevention and/or treatment of cancer.     

Tumor cell membrane-targeting cationic antimicrobial peptides: novel insights into mechanisms of action and therapeutic prospects

There is an ongoing need for effective and targeted cancer treatments that can overcome the detrimental side effects presented by current treatment options. One class of novel anticancer molecules with therapeutic potential currently under investigation are cationic antimicrobial peptides (CAPs). CAPs are small innate immunity peptides found ubiquitously throughout nature that are typically membrane-active against a wide range of pathogenic microbes. A number of CAPs can also target mammalian cells and often display selective activity towards tumor cells, making them attractive candidates as novel anticancer agents warranting further investigation. This current and comprehensive review describes key examples of naturally occurring membrane-targeting CAPs and their modified derivatives that have demonstrated anticancer activity, across multiple species of origin and structural subfamilies. In addition, we address recent advances made in the field and the ongoing challenges faced in translating experimental findings into clinically relevant treatments.     

HLA-G in organ transplantation: towards clinical applications

HLA-G plays a particular role during pregnancy in which its expression at the feto–maternal barrier participates into the tolerance of the allogenic foetus. HLA-G has also been demonstrated to be expressed in some transplanted patients, suggesting that it regulates the allogenic response. In vitro data indicate that HLA-G modulates NK cells, T cells, and DC maturation through its interactions with various inhibitory receptors. In this paper, we will review the data reporting the HLA-G involvement of HLA-G in human organ transplantation, then factors that can modulate HLA-G, and finally the use of HLA-G as a therapeutic tool in organ transplantation.     

Incredulity towards Lyotard: a critique of a postmodernist account of science and knowledge

Philosophers of science have paid little attention, positive or negative, to Lyotard’s book The postmodern condition, even though it has been popular in other fields. We set out some of the reasons for this neglect. Lyotard thought that sciences could be justified by non-scientific narratives (a position he later abandoned). We show why this is unacceptable, and why many of Lyotard’s characterisations of science are either implausible or are narrowly positivist. One of Lyotard’s themes is that the nature of knowledge has changed and thereby so has society itself. However much of what Lyotard says muddles epistemological matters about the definition of ‘knowledge’ with sociological claims about how information circulates in modern society. We distinguish two kinds of legitimation of science: epistemic and socio-political. In proclaiming ‘incredulity towards metanarratives’ Lyotard has nothing to say about how epistemic and methodological principles are to be justified (legitimated). He also gives a bad argument as to why there can be no epistemic legitimation, which is based on an act/content confusion, and a confusion between making an agreement and the content of what is agreed to. As for socio-political legitimation, Lyotard’s discussion remains at the abstract level of science as a whole rather than at the level of the particular applications of sciences. Moreover his positive points can be accepted without taking on board any of his postmodernist account of science. Finally we argue that Lyotard’s account of paralogy, which is meant to provide a ‘postmodern’ style of justification, is a failure.     

Recombinant G protein-coupled receptors from expression to renaturation: a challenge towards structure

G protein-coupled receptors (GPCRS) represent a class of integral membrane proteins involved in many biological processes and pathologies. Fifty percent of all modern drugs and almost 25% of the top 200 bestselling drugs are estimated to target GPCRs. Despite these crucial biological implications, very little is known, at atomic resolution, about the detailed molecular mechanisms by which these membrane proteins are able to recognize their extra-cellular stimuli and transmit the associated messages. Obviously, our understanding of GPCR functioning would be greatly facilitated by the availability of high-resolution three-dimensional (3D) structural data. However, expression, solubilization and purification of these membrane proteins are not easy to achieve, and at present, only one 3D structure has been determined, that of bovine rhodopsin. This review presents and compares the different successful strategies which have been applied to solubilize and purify recombinant GPCRs in the perspective of structural biology experiments. Received 21 November 2005; received after revision 20 January 2006; accepted 2 February 2006 An erratum to this article is available at .     

The therapeutic potential of GPR43: a novel role in modulating metabolic health

GPR43 is a receptor for short-chain fatty acids. Preliminary data suggest a putative role for GPR43 in regulating systemic health via processes including inflammation, carcinogenesis, gastrointestinal function, and adipogenesis. GPR43 is involved in secretion of gastrointestinal peptides, which regulate appetite and gastrointestinal motility. This suggests GPR43 may have a role in weight control. Moreover, GPR43 regulates plasma lipid profile and inflammatory processes, which further indicates that GPR43 could have the ability to modulate the etiology and pathogenesis of metabolic diseases such as obesity, type 2 diabetes mellitus, and cardiovascular disease. This review summarizes the current evidence regarding the ability of GPR43 to mediate both systemic and tissue specific functions and how GPR43 may be modulated in the treatment of metabolic disease.     

Multiple catalytically active thioredoxin folds: a winning strategy for many functions

The Thioredoxin (Trx) fold is a versatile protein scaffold consisting of a four-stranded β-sheet surrounded by three α-helices. Various insertions are possible on this structural theme originating different proteins, which show a variety of functions and specificities. During evolution, the assembly of different Trx fold domains has been used many times to build new multi-domain proteins able to perform a large number of catalytic functions. To clarify the interaction mode of the different Trx domains within a multi-domain structure and how their combination can affect catalytic performances, in this review, we report on a structural and functional analysis of the most representative proteins containing more than one catalytically active Trx domain: the eukaryotic protein disulfide isomerases (PDIs), the thermophilic protein disulfide oxidoreductases (PDOs) and the hybrid peroxiredoxins (Prxs).     

Signal transduction mechanisms in plants: an overview

This article provides an overview on recent advances in some of the basic signalling mechanisms that participate in a wide variety of stimulus-response pathways. The mechanisms include calcium-based signalling, G-protein-mediated-signalling and signalling involving inositol phospholipids, with discussion on the role of protein kinases and phosphatases interspersed. As a further defining feature, the article highlights recent exciting findings on three extracellular components that have not been given coverage in previous reviews of signal transduction in plants, extracellular calmodulin, extracellular ATP, and integrin-like receptors, all of which affect plant growth and development.