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Therapeutic Candidates (therapeutic + candidate)
Selected AbstractsSIRT6 protects against pathological damage caused by diet-induced obesityAGING CELL, Issue 2 2010Yariv Kanfi Summary The NAD+-dependent SIRT6 deacetylase is a therapeutic candidate against the emerging metabolic syndrome epidemic. SIRT6, whose deficiency in mice results in premature aging phenotypes and metabolic defects, was implicated in a calorie restriction response that showed an opposite set of phenotypes from the metabolic syndrome. To explore the role of SIRT6 in metabolic stress, wild type and transgenic (TG) mice overexpressing SIRT6 were fed a high fat diet. In comparison to their wild-type littermates, SIRT6 TG mice accumulated significantly less visceral fat, LDL-cholesterol, and triglycerides. TG mice displayed enhanced glucose tolerance along with increased glucose-stimulated insulin secretion. Gene expression analysis of adipose tissue revealed that the positive effect of SIRT6 overexpression is associated with down regulation of a selective set of peroxisome proliferator-activated receptor-responsive genes, and genes associated with lipid storage, such as angiopoietin-like protein 4, adipocyte fatty acid-binding protein, and diacylglycerol acyltransferase 1, which were suggested as potential targets for drugs to control metabolic syndrome. These results demonstrate a protective role for SIRT6 against the metabolic consequences of diet-induced obesity and suggest a potentially beneficial effect of SIRT6 activation on age-related metabolic diseases. [source] Yeast apurinic/apyrimidinic endonuclease Apn1 protects mammalian neuronal cell line from oxidative stressJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Renee Ho Abstract Reactive oxygen species (ROS) have been implicated as one of the agents responsible for many neurodegenerative diseases. A critical target for ROS is DNA. Most oxidative stress-induced DNA damage in the nucleus and mitochondria is removed by the base excision repair pathway. Apn1 is a yeast enzyme in this pathway which possesses a wider substrate specificity and greater enzyme activity than its mammalian counterpart for removing DNA damage, making it a good therapeutic candidate. For this study we targeted Apn1 to mitochondria in a neuronal cell line derived from the substantia nigra by using a mitochondrial targeting signal (MTS) in an effort to hasten the removal of DNA damage and thereby protect these cells. We found that following oxidative stress, mitochondrial DNA (mtDNA) was repaired more efficiently in cells containing Apn1 with the MTS than controls. There was no difference in nuclear repair. However, cells that expressed Apn1 without the MTS showed enhanced repair of both nuclear and mtDNA. Both Apn1-expressing cells were more resistant to cell death following oxidative stress compared with controls. Therefore, these results reveal that the expression of Apn1 in neurons may be of potential therapeutic benefit for treating patients with specific neurodegenerative diseases. [source] Biological significance and development of practical synthesis of biotinMEDICINAL RESEARCH REVIEWS, Issue 4 2006Masahiko Seki Abstract Biotin (1), a water-soluble B series vitamin, distributes widely in microorganisms, plants, and animals. Biosynthesis of 1 involves five steps sequence starting from pimelic acid. The last step, a transformation from dethiobiotin (DTB) to 1, includes an iron clusters-mediated radical process. The compound 1 is a cofactor of carboxylation enzymes and plays crucial roles in the metabolism of fatty acids, sugars, and ,-amino acids. In addition to the increasing application to feed additives, recent reports have revealed that 1 enhances insulin secretion in animals, suggesting it for a promising therapeutic candidate for an anti-diabetes drug. The remarkably strong affinity of 1 with avidin and streptavidin has been extensively applied for such technologies as photoaffinity labeling. Among the number of approaches to 1 so far developed in 50 years, a synthesis using L -cysteine and thiolactone as a starting material and a key intermediate, respectively, represents one of the best routes leading to 1, because of short steps, high yield, use of inexpensive reagents, and ease of operation. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 4, 434,482, 2006 [source] Complement and fungal pathogens: an updateMYCOSES, Issue 6 2008Cornelia Speth Summary Fungal infections are a serious complication in immunocompromised patients such as human immunodeficiency virus-infected individuals, patients with organ transplantations or with haematological neoplasia. The lethality of opportunistic fungal infection is high despite a growing arsenal of antimycotic drugs, implying the urgent need for supportive immunological therapies to strengthen the current inefficient antimicrobial defences of the immunocompromised host. Therefore, increasing effort has been directed to investigating the interplay between fungi and the host immunity and thus to find starting points for additional therapeutic approaches. In this article, we review the actual state of the art concerning the role of complement in the pathogenesis of fungal infections. Important aspects include the activation of the complement system by the fungal pathogen, the efficiency of the complement-associated antimicrobial functions and the arsenal of immune evasion strategies applied by the fungi. The twin functions of complement as an interactive player of the innate immunity and at the same time as a modulator of the adaptive immunity make this defence weapon a particularly interesting therapeutic candidate to mobilise a more effective immune response and to strengthen in one fell swoop a broad spectrum of different immune reactions. However, we also mention the ,Yin-Yang' nature of the complement system in fungal infections, as growing evidence assigns to complement a contributory part in the pathogenesis of fungus-induced allergic manifestations. [source] Brief Communication: Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathyNEPHROLOGY, Issue 5 2010LIN-SHEN XIE ABSTRACT Immunoglobulin A nephropathy (IgAN), characterized by predominant or exclusive deposition of IgA1 in glomerular mesangium, is the most common primary glomerulonephritis worldwide. At present, the treatment is always limited due to the incomplete understanding of the pathogenesis of IgAN. Mesangial deposited IgA1 is the common final pathway leading to glomerulonephritis and renal injury. IgA1 protease, a proteolytic enzyme with strict substrate specificity for human IgA1, may be an effective therapeutic candidate for IgAN by removing the mesangial deposited IgA1. [source] Insulin like growth factor-1 and insulin like growth factor binding proteins in the cerebrospinal fluid and serum from patients with Alzheimer's diseaseBIOFACTORS, Issue 2 2008Zivar Salehi Insulin like growth factor-1 (IGF-1) is ubiquitously expressed growth factor that has profound effects on the growth and differentiation of many cell types and tissues, including cells of the central nervous system (CNS). IGF-1 is produced by a wide variety of cells and is found in many biological fluids including cerebrospinal fluid (CSF). IGF-1 plays important role during CNS development and repair. IGF-1 has broad range neuroprotective effects and is a therapeutic candidate for Huntington's disease (HD). IGF-1 protects striatal neurons from the toxicity of mutated Huntington in vitro and improves neuronal survival in vivo in a phenotypic model of HD. Alzheimer's disease (AD) is an age-dependent dementia characterized by progressive loss of cognitive functions and by characteristic pathological changes in the brain: the formation of aggregates extracellularly by ß-amyloid (AB) peptide and intracellularly by tau proteins. Since cerebrospinal fluid (CSF) is in contact with the extracellular space of the brain, biochemical brain modifications could be reflected in the CSF. IGFs in circulation and other physiological fluids are associated with a group of high-affinity binding proteins insulin like growth factor binding proteins (IGFBPs) that specifically bind and modulate their bioactivity at the cellular level. The aim of this study was to determine the level of CSF and serum IGF-1 and IGFBPs concentrations in the patients with AD. CSF was obtained by lumbar puncture. The presence of IGF-1 and IGFBPs in the CSF and serum samples was confirmed by Western blot using anti-IGF-1 and IGFBPs antibodies. Using enzyme linked immunosorbent assay (ELISA), it was shown that the concentration of CSF and serum IGF-1 and IGFBPs in the patients with AD is higher than in normal control. The data from this study indicate that IGF-1 is a constant component of human CSF. It is also concluded that high levels of CSF IGF-1 may be partly related to AD pathophysiology. [source] New prospects for immunotherapy at diagnosis of type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2009Paolo Pozzilli Immune intervention at diagnosis of type 1 diabetes (T1D) aims to prevent or reverse the disease by blocking autoimmunity, thereby preserving/restoring ,-cell mass and function. Recent clinical trials of non-specific and of antigen-specific immune therapies have demonstrated the feasibility of modulation of islet-specific autoimmunity in patients with partial prevention of loss of insulin secretion. In a series of review articles published in this issue of the journal, some of the most promising approaches of immune intervention in T1D are presented. Here we outline the rationale of such interventions and future prospects in this area. Copyright © 2009 John Wiley & Sons, Ltd. Insulin therapy in type 1 diabetes (T1D) rescues the patient from a certain death but not cure the disease. The goal of any therapeutic intervention in T1D is the preservation of insulin-secreting cells; this is achieved by the abrogation of pathogenic reactivity to beta cell autoantigens while preserving full capacity to generate a normal immune response against foreign antigens. Although several therapeutic candidates have been investigated in experimental models of T1D many of which showed promising results, a successful extrapolation of these findings to human T1D has proved to be difficult. In part, this failure results from the considerable disease heterogeneity associated with diverse genetic and non-genetic disease determinants and the spectrum of clinical phenotype at diagnosis. Thus, a younger age at onset is associated with stronger genetic susceptibility, more intense immune response to ,-cell antigens, shorter duration of symptoms, more severe metabolic derangement at diagnosis and a more rapid rate of ,-cell-destruction 1,3. Therefore, designing therapies that would be effective in all clinical settings is definitely challenging. In this issue five different approaches are discussed ranging from antigen-specific therapies [DiaPep277 and glutamic acid decarboxylase(GAD)], to non-antigen-specific immunoregulation (anti-CD3) and to anti-inflammatory (anti-IL1 receptor antagonist). These approaches are currently being tested in large international multicenter trials, and all of them use very similar outcome in terms of a beneficial effect (C-peptide secretion as evidence of a therapeutic effect on restoration of ,-cell function). The authors have been asked to follow a similar format in presenting their approaches so that the reader can easily compare them in terms of rationale and therapeutic goals. [source] Viral vectors as tools to model and treat neurodegenerative disordersTHE JOURNAL OF GENE MEDICINE, Issue 5 2005N. Déglon Abstract The identification of disease-causing genes in familial forms of neurodegenerative disorders and the development of genetic models closely replicating human central nervous system (CNS) pathologies have drastically changed our understanding of the molecular events leading to neuronal cell death. If these achievements open new opportunities of therapeutic interventions, including gene-based therapies, the presence of the blood-brain barrier and the post-mitotic and poor regenerative nature of the target cells constitute important challenges. Efficient delivery systems taking into account the specificity of the CNS are required to administer potential therapeutic candidates. In addition, genetic models in large animals that replicate the late stages of the diseases are in most cases not available for pre-clinical studies. The present review summarizes the potential of viral vectors as tools to create new genetic models of CNS disorders in various species including primates and the recent progress toward viral gene therapy clinical trials for the administration of therapeutic candidates into the brain. Copyright © 2005 John Wiley & Sons, Ltd. [source] Efficient suppression of murine arthritis by combined anticytokine small interfering RNA lipoplexesARTHRITIS & RHEUMATISM, Issue 8 2008Maroun Khoury Objective Blocking tumor necrosis factor (TNF) effectively inhibits inflammation and joint damage in rheumatoid arthritis (RA), but 40% of RA patients respond only transiently or not at all to the current anti-TNF biotherapies. The purpose of this study was to develop an alternative targeted therapy for this subgroup of RA patients. As proof of concept, we tested the efficiency of an RNA interference (RNAi),based intervention that targets proinflammatory cytokines in suppressing murine collagen-induced arthritis (CIA). Methods Two synthetic short interfering RNA (siRNA) sequences were designed for each of the proinflammatory cytokines interleukin-1 (IL-1), IL-6, and IL-18. Their silencing specificity was assessed according to lipopolysaccharide-induced messenger RNA expression in J774.1 mouse macrophages as compared with control siRNA. For in vivo administration, siRNA were formulated as lipoplexes with the RPR209120/DOPE liposome and a carrier DNA and were injected intravenously (0.5 mg/kg) into DBA/1 mice with CIA. Results Weekly injections of anti,IL-1, anti,IL-6, or anti,IL-18 siRNA-based lipoplexes significantly reduced the incidence and severity of arthritis, abrogating joint swelling and destruction of cartilage and bone, both in the preventative and the curative settings. The most striking therapeutic effect was observed when the 3 siRNA were delivered in combination. The siRNA lipoplex cocktail reduced all pathologic features of RA, including inflammation, joint destruction, and the Th1 response, and overall parameters of RA were improved as compared with anti-TNF siRNA lipoplex,based treatment. Conclusion Our results present a novel option for in vivo RNAi-based antiinflammatory immunotherapy. Our findings indicate that intravenous administration of a lipoplex cocktail containing several anticytokine siRNA is a promising novel antiinflammatory therapy for RA, as well as a useful and simple tool for understanding the pathophysiology of RA and for evaluating new therapeutic candidates. [source] Differentiation rather than aging of muscle stem cells abolishes their telomerase activityBIOTECHNOLOGY PROGRESS, Issue 4 2009Matthew S. O'Connor Abstract A general feature of stem cells is the ability to routinely proliferate to build, maintain, and repair organ systems. Accordingly, embryonic and germline, as well as some adult stem cells, produce the telomerase enzyme at various levels of expression. Our results show that, while muscle is a largely postmitotic tissue, the muscle stem cells (satellite cells) that maintain this biological system throughout adult life do indeed display robust telomerase activity. Conversely, primary myoblasts (the immediate progeny of satellite cells) quickly and dramatically downregulate telomerase activity. This work thus suggests that satellite cells, and early transient myoblasts, may be more promising therapeutic candidates for regenerative medicine than traditionally utilized myoblast cultures. Muscle atrophy accompanies human aging, and satellite cells endogenous to aged muscle can be triggered to regenerate old tissue by exogenous molecular cues. Therefore, we also examined whether these aged muscle stem cells would produce tissue that is "young" with respect to telomere maintenance. Interestingly, this work shows that the telomerase activity in muscle stem cells is largely retained into old age wintin inbred "long" telomere mice and in wild-derived short telomere mouse strains, and that age-specific telomere shortening is undetectable in the old differentiated muscle fibers of either strain. Summarily, this work establishes that young and old muscle stem cells, but not necessarily their progeny, myoblasts, are likely to produce tissue with normal telomere maintenance when used in molecular and regenerative medicine approaches for tissue repair. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 [source] Antagonistic lipopolysaccharides block E. coli lipopolysaccharide function at human TLR4 via interaction with the human MD-2 lipopolysaccharide binding siteCELLULAR MICROBIOLOGY, Issue 5 2007Stephen R. Coats Summary Lipopolysaccharides containing underacylated lipid A structures exhibit reduced abilities to activate the human (h) Toll-like receptor 4 (TLR4) signalling pathway and function as potent antagonists against lipopolysaccharides bearing canonical lipid A structures. Expression of underacylated lipopolysaccharides has emerged as a novel mechanism utilized by microbial pathogens to modulate host innate immune responses. Notably, antagonistic lipopolysaccharides are prime therapeutic candidates for combating Gram negative bacterial sepsis. Penta-acylated msbB and tetra-acylated Porphyromonas gingivalis lipopolysaccharides functionally antagonize hexa-acylated Escherichia coli lipopolysaccharide-dependent activation of hTLR4 through the coreceptor, hMD-2. Here, the molecular mechanism by which these antagonistic lipopolysaccharides act at hMD-2 is examined. We present evidence that both msbB and P. gingivalis lipopolysaccharides are capable of direct binding to hMD-2. These antagonistic lipopolysaccharides can utilize at least two distinct mechanisms to block E. coli lipopolysaccharide-dependent activation of hTLR4. The main mechanism consists of direct competition between the antagonistic lipopolysaccharides and E. coli lipopolysaccharide for the same binding site on hMD-2, while the secondary mechanism involves the ability of antagonistic lipopolysaccharide,hMD-2 complexes to inhibit E. coli lipopolysaccharide,hMD-2 complexes function at hTLR4. It is also shown that both hTLR4 and hMD-2 contribute to the species-specific recognition of msbB and P. gingivalis lipopolysaccharides as antagonists at the hTLR4 complex. [source] Multitasking by Multivalent Circular DNA AptamersCHEMBIOCHEM, Issue 3 2006Daniel A. Di Giusto Abstract Nucleic acid aptamers are finding increasing applications in biology, especially as therapeutic candidates and diagnostic components. An important characteristic in meeting the needs of these applications is improved stability in physiological fluids, which is most often accomplished with chemical modification or unnatural nucleotides. In an alternative approach we have specified the design of a multivalent circular DNA aptamer topology that encompasses a number of properties relevant to nucleic acid therapeutic candidates, especially the ability to multitask by combining different activities together within a modular structure. Improved stability in blood products, greater conformational stability, antidoting by complementary circular antiaptamers, heterovalency, transcription factor decoy activity and minimal unintended effects upon the cellular innate immune response are desirable properties that are described here. Multitasking by circular DNA aptamers could similarly find applications in diagnostics and biomaterials, where the combination of interchangeable modules might generate new functions, such as anticoagulation coupled with reversible cell capture as, described here. These results provide a platform for further exploration of multivalent circular aptamer properties, especially in novel combinations of nucleic acid therapeutic modes. [source] Neurotoxicity by microglia: Mechanisms and potential therapeutic strategyCLINICAL AND EXPERIMENTAL NEUROIMMUNOLOGY, Issue 1 2010Hideyuki Takeuchi Abstract Microgliosis (accumulation of activated microglia) around degenerative neurons is a common pathological feature of various neurological disorders. Glutamate released by activated microglia induces excito-neurotoxicity and most likely contributes to neurodegeneration in numerous neurological diseases including ischemia, inflammation, epilepsy and neurodegenerative diseases. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for activated microglia-mediated neurodegenerative diseases, clinical trials have been failed because of adverse effects. In the present review, the neurotoxic factors from activated microglia are examined, and how these factors disturb neuronal functions is discussed. The efforts to suppress neurotoxic mechanisms by microglia are also introduced. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759-1961.2009.00001.x, January 2010) [source] | ||||||||||||||||