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New Targets (new + target)
Selected AbstractsPotential Role of NKG2D and Its Ligands in Organ Transplantation: New Target for ImmunointerventionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2009B. Suárez-Álvarez NKG2D is one of the best characterized activating receptors on Natural Killer (NK) and CD8+ T cells. This receptor recognizes several different ligands (MICA/MICB and ULBPs) induced by cellular stress and infection. In addition to the role described in cancer surveillance, recent data highlight the importance of NKG2D and its ligands in organ transplantation. Allografts show evidence of MICA and MICB expression in both acute and chronic rejection. The presence of anti-MICA antibodies has been correlated with incidence of graft rejection. Furthermore, NKG2D-ligand engagement activates NK cells, which provides T-cell costimulation, and enhances antigen specific CTL-mediated cytotoxicity. Activated NK cells may function as a bridge between innate and adaptive immunity associated with transplantation. Activated NK cells in response to IL-15 can also trigger organ rejection through NKG2D and affect the maturation of both donor and recipient antigen presenting cells (APCs) and ultimately the T-cell allogeneic response. Regulatory T cells, which modulate T-cell responses in organ transplantation and infections, were reduced in numbers by NK cells exposed to intracellular pathogens, possibly via interaction with one NK2GD receptor. Blockage of NKG2D-NKG2D-L interactions provides a novel pathway for development of inhibitors. These studies have important clinical and therapeutic implications in solid organ transplantation. [source] Cardiac Allograft Hypertrophy: A New Target for Therapy, a Surrogate Marker for Survival?AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009G. Torre-Amione Long-term heart transplant survival may not simply be limited by allograft vasculopathy, but also by diffuse myocardial injury in form of left ventricular hypertrophy. See also article by Raichlin et al in this issue on page 132. [source] Optimization of Repolarization during Biventricular Pacing: A New Target in Patients with Biventricular Devices?ANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 1 2010Cengizhan Türko, lu M.D. Background: Evaluation of repolarization during sequentional biventricular pacing. Methods: Patients with biventricular devices, and left ventricular leads placed to the basal part of lateral left ventricular wall were enrolled. QRS, QTc, JTc, and corrected Tpeak-Tend intervals were compared during sequentional biventricular, left ventricular, and right ventricular pacing. Results: Five patients with nonischemic and five with ischemic cardiomyopathy due to anterior myocardial infarction were enrolled. No correlation was observed between values of repolarization among patients. The optimal values of repolarization were significantly different from values of echocardiographically guided hemodynamic optimization. Two patients with biventricular pacing-induced ventricular fibrillation were successfully treated by reprogramming of V-V delay according to interventricular delay resulting in shorter Tpeak-Tend interval, although delayed effect of amiodarone in one of these patients cannot be ruled out. Conclusions: Patients with biventricular devices may be prone to development of ventricular arrhythmias depending on programmed V-V interval. We suggest that optimization of repolarization may be performed in patients with biventricular pacemakers in the absence of backup ICD and those with frequent episodes of ventricular tachyarrhythmias, although this finding deserves further study. Ann Noninvasive Electrocardiol 2010;15(1):36,42 [source] Structural Models and Binding Site Prediction of the C-terminal Domain of Human Hsp90: A New Target for Anticancer DrugsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2008Miriam Sgobba Heat shock protein 90 is a valuable target for anticancer drugs because of its role in the activation and stabilization of multiple oncogenic signalling proteins. While several compounds inhibit heat shock protein 90 by binding the N-terminal domain, recent studies have proved that the C-terminal domain is important for dimerization of the chaperone and contains an additional binding site for inhibitors. Heat shock protein 90 inhibition achieved with molecules binding to the C-terminal domain provides an additional and novel opportunity to design and develop drugs. Therefore, for the first time, we have investigated the structure and the dynamic behaviour of the C-terminal domain of human heat shock protein 90 with and without the small-middle domain, using homology modelling and molecular dynamics simulations. In addition, secondary structure predictions and peptide folding simulations proved useful to investigate a putative additional ,-helix located between H18 and ,20 of the C-terminal domain. Finally, we used the structural information to infer the location of the binding site located in the C-terminal domain by using a number of computational tools. The predicted pocket is formed by two grooves located between helix H18, the loop downstream of H18 and the loop connecting helices H20 and H21 of each monomer of the C-terminal domain, with only two amino acids contributing from each middle domain. [source] New targets for pulmonary hypertension: gene and stem cell therapyINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2007S. Gaine No abstract is available for this article. [source] A paradigm for the treatment of prostate cancer bone metastases based on an understanding of tumor cell,microenvironment interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Robert D. Loberg Abstract The pliability of cancer cells to mutate into several different phenotypes in an attempt to find one that will survive and colonize at the metastatic site is a tremendous "hurdle" to overcome in designing novel cancer therapeutics. New targets of therapy are essential if we are to effectively overcome the evasiveness of cancer. The interaction between the tumor cell and the surrounding microenvironment creates a vicious cycle that perpetuates disease survival and progression. The future of cancer therapy resides in the ability to focus on the recruited and exploited relationships of the cancer cell with the host environment. These therapies target cancer cell growth early and interrupt the vicious cycle that is created by the tumor cells interacting with bone components by inhibiting osteoclasts, osteoblasts, stromal cells, and endothelial cells. They alter the bone microenvironment, creating a hostile "soil" that prevents the "seed" from developing into bone metastases and represent a potential new platform for the development of prostate cancer therapeutics. © 2005 Wiley-Liss, Inc. [source] New targets of the PII signal transduction protein identified in cyanobacteriaMOLECULAR MICROBIOLOGY, Issue 5 2004Antonia Herrero First page of article [source] Role of orexin in the regulation of glucose homeostasisACTA PHYSIOLOGICA, Issue 3 2010H. Tsuneki Abstract Orexin-A (hypocretin-1) and orexin-B (hypocretin-2) are hypothalamic neuropeptides that play key roles in the regulation of wakefulness, feeding, reward, autonomic functions and energy homeostasis. To control these functions indispensable for survival, orexin-expressing neurones integrate peripheral metabolic signals, interact with many types of neurones in the brain and modulate their activities via the activation of orexin-1 receptor or orexin-2 receptor. In addition, a new functional role of orexin is emerging in the regulation of insulin and leptin sensitivities responsible for whole-body glucose metabolism. Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. In fact, the expression of orexin gene is known to be down-regulated by hyperglycaemia in the rodent model of diabetes, such as ob/ob and db/db mice. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycaemia due to insulin insensitivity during ageing or by habitual consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, thereby further exacerbating peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for possible future treatment of hyperglycaemia in patients with type 2 diabetes. [source] Adrenomedullin and diabetes mellitusDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2001Eva Ruzicska Abstract Adrenomedullin (AM) is a novel 52 amino acid peptide hormone, originally isolated from human pheochromocytoma. AM acts as a local autocrine and/or paracrine vasoactive hormone and has vasodilator and blood pressure lowering properties. AM as a vasodilative molecule protects the vascular wall but its exact role is still uncertain. AM is considered to play an important endocrine role in various tissues in maintaining electrolyte and fluid homeostasis. Its plasma concentration in healthy conditions is low. In hypertension, chronic renal failure and congestive heart failure its plasma concentration increases in a parallel manner with the severity of the disease. It is assumed that this peptide plays an important role in physiological and pathological conditions compensating the effects of vasoconstrictive molecules. Investigations have proven that in diabetic angiopathies the levels and production of vasoconstrictive factors and AM are increased, while other relaxing substances such as nitric oxide (NO) are decreased. It is still uncertain whether the increased release of AM is a compensatory mechanism or a coincidental event. Although the precise role of AM in the pathogenesis of diabetic complications is still to be elucidated, the altered concentration of AM in diabetes could indicate a certain interaction between AM induction and vascular function. Hence, the induction of vascular AM can be a new target of therapeutic approach to diabetic complications. Copyright © 2001 John Wiley & Sons, Ltd. [source] The brain angiotensin IV/AT4 receptor system as a new target for the treatment of Alzheimer's diseaseDRUG DEVELOPMENT RESEARCH, Issue 7 2009John W. Wright Abstract The brain renin-angiotensin system (RAS) regulates several physiologies including blood pressure, body sodium and water balance, cyclicity of reproductive hormones and related sexual behaviors, and the release of pituitary gland hormones. These physiologies are under the control of the angiotensin II (AngII)/AT1 receptor subtype system. The AngII/AT2 receptor subtype system is expressed during fetal development and is less abundant in the adult. This system appears to oppose growth responses facilitated by activation of the AT1 receptor. There is a growing list of nontraditional physiologies mediated by the most recently discovered angiotensin IV (AngIV)/AT4 receptor subtype system that include the regulation of blood flow, modulation of exploratory behaviors, involvement in stress responses and seizure, and a role in learning and memory acquisition. There is evidence to support an inhibitory influence by AngII, and a facilitory role by AngIV, on neuronal firing rate, long-term potentiation, and associative and spatial learning and memory. These findings suggest an important role for the RAS, and the AT4 receptor in particular, in normal cognitive processing and provide the stimulus for developing drugs that penetrate the blood-brain barrier to interact with this brain receptor in the treatment of dysfunctional memory. Drug Dev Res 70: 472,480, 2009. © 2009 Wiley-Liss, Inc. [source] Cytosolic protein-protein interactions that regulate the amyloid precursor proteinDRUG DEVELOPMENT RESEARCH, Issue 2 2002Shasta L. Sabo Abstract Alzheimer disease (AD), a progressive neurodegenerative disease, is the most common cause of dementia in the elderly and is among the leading causes of death in adults. AD is characterized by two major pathological hallmarks, amyloid plaques and neurofibrillary tangles. For a number of reasons, amyloid plaque accumulation is widely thought to be the probable cause of AD. The amyloid plaque core is largely composed of an approximately 4-kDa peptide referred to as A,. A, is derived from its precursor, the Alzheimer amyloid protein precursor (APP), by endoproteolytic processing. APP is a type I integral membrane protein, with a long extracellular domain, one transmembrane domain, and a short (,50 amino acid) cytoplasmic tail. Despite intense efforts to decipher the function of APP, its normal physiological role has remained elusive. The carboxy-terminus of APP contains the sequence YENPTY, which is absolutely conserved across APP homologues and across species. The YENPTY sequence is important for regulation of APP processing and trafficking. Given the importance of the cytoplasmic domain in APP physiology, a number of laboratories have hypothesized that proteins that bind to the YENPTY sequence in the cytoplasmic domain of APP might regulate APP processing, trafficking, and/or function. In this article, we will discuss data revealing which proteins bind to the cytoplasmic domain of APP, how these binding-proteins regulate APP metabolism and function, and why such protein-protein interactions provide an exciting new target for therapeutic intervention in AD. Drug Dev. Res. 56:228,241, 2002. © 2002 Wiley-Liss, Inc. [source] LOXL as a target to increase the elastin content in adult skin: a dill extract induces the LOXL gene expressionEXPERIMENTAL DERMATOLOGY, Issue 8 2006Valérie Cenizo Abstract:, The lysyl oxidases lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) are responsible for elastin cross-linking. It was shown recently that LOXL is essential for the elastic fibres homeostasis and for their maintenance at adult age. We first determined whether or not elastin, LOX and LOXL are less expressed during adulthood. The LOX and LOXL mRNA level, quantified by real-time reverse transcriptase-polymerase chain reaction decreased in adult skin fibroblasts compared with fibroblasts from children. In contrast, the elastin mRNA level remains stable at all ages. The goal of this study was to induce elastogenesis at the adult age. Therefore, both enzymes, and in particular LOXL, of which expression is the most affected by age, could be targeted to induce elastogenesis in adult skin. We screened a library of about 1000 active ingredients to find activators capable to stimulate specifically the LOXL gene expression in adult dermal fibroblasts. The positive effect of selected active ingredients was confirmed on fibroblasts grown on monolayers and on dermal and skin equivalent cultures. One extract, obtained from dill (LYS'LASTINE V, Engelhard, Lyon, France), stimulates the LOXL gene expression in dermal equivalents (+64% increase in the LOXL mRNA level when compared with control). At the same time, the elastin detection is increased in dermal equivalents and under the dermal,epidermal junction of skin equivalents, without increase of the elastin mRNA. In conclusion, LOXL can be considered as a new target to reinduce elastogenesis. Its stimulation by a dill extract is correlated with increased elastin detection, suggesting an increase in elastogenesis efficiency. [source] Evidence that the keratinocyte colony number is genetically controlledEXPERIMENTAL DERMATOLOGY, Issue 6 2002Natalia V. Popova Abstract: We tested five inbred strains and two outbred stocks of female mice in a quantitative assay for clonogenic keratinocytes from the cutaneous epithelium. We found three significantly different subsets of colony counts such that: C57BL/6 , C3H = DBA/2 = SENCAR = BALB/c > FVB = CD,1 in culture conditions optimized for CD,1 0. C57BL/6 and BALB/c, two inbred parental strains, were chosen for further analysis. The F1 generation of these two parental strains had an intermediate number of colonies. The keratinocyte colony number from the two backcross generations was significantly different, while the colony number in the F2 generation was intermediate between the two backcrosses. We conclude that the number of keratinocyte colonies represents a new genetically definable quantitative trait. Analysis suggests that this trait is multigenic where the genes have an additive but not necessarily equal effect. We have therefore laid the foundation for identifying these stem cell regulatory genes, which may provide a new perspective on the mechanism of carcinogenesis and a new target for gene therapy. [source] Structure,function relationship of novel X4 HIV-1 entry inhibitors , L- and D-arginine peptide-aminoglycoside conjugatesFEBS JOURNAL, Issue 24 2007Ravi Hegde We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers d - and l -arginine peptides (APACs). The d -APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective l -APACs. d -arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their l -arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1, (SDF-1,)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. d -APACs readily concentrate in the nucleus, whereas the l -APACs do not. 9-mer- d -arginine analogues are more efficient inhibitors than the 6-mer- d -arginine conjugates and the neomycin- d -polymers are better inhibitors than their respective neamine conjugates. This and further structure,function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors. [source] Insulin resistance, a new target for nitric oxide-delivery drugsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2002Stéphane Cook Abstract In the Western hemisphere, the incidence of insulin resistance and its complications has been growing rapidly and is reaching epidemic proportions. Over the past decade, evidence has accumulated, indicating that nitric oxide (NO) plays a key role in the regulation of metabolic and cardiovascular homeostasis. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes insulin resistance, arterial hypertension and dyslipidemia in mice, and characterizes insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction in mice, may also cause metabolic insulin resistance, suggesting a Yin,Yang effect of NO in the regulation of glucose homeostasis. Here, we will review the evidence for this novel concept, and thereby provide the conceptual framework for the use of NO-delivery drugs and pharmacological agents that modulate the bioavailability of endogenously produced NO for the treatment of insulin resistance. [source] CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis,HEPATOLOGY, Issue 4 2010Mirko Moreno Zaldivar Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4,/, and wild-type mice were subjected to two models of chronic liver injury (CCl4 and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus,induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl4 and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf -, [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4,/, mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8+ T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. Conclusion: The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies. (HEPATOLOGY 2010.) [source] Silencing MAT2A gene by RNA interference inhibited cell growth and induced apoptosis in human hepatoma cellsHEPATOLOGY RESEARCH, Issue 5 2007Quanyan Liu Aims:, A switch in gene expression from MAT1A to MAT2A was found in liver cancer, suggesting that MAT2A plays an important role in facilitating cancer growth. MAT2A is an interesting target for antineoplastic therapy. The molecular mechanisms of silencing MAT2A by RNA interference inhibited cell growth and induced apoptosis in hepatoma cells was studied. Methods:, We investigated the effects of MAT2A on S-adenosyl-methionine (SAM) production, cell growth and apoptotic cell death in hepatoma cell lines (Bel-7402, HepG2, and Hep3B) using an RNA interference approach. Results:, The treatment of three hepatoma cell lines with small interfering RNA (siRNA) targeting to the MAT2A gene resulted in reducing the MAT II activity, facilitating SAM production, increasing SAM : SAH ratio, inhibiting cell growth and inducing cell apoptosis in hepatoma cells. In addition, silencing MAT2A gene resulted in the stimulation of MAT1A mRNA production, which was blocked by 3-deazaadenosine and l -ethionine, but not d -ethionine, suggesting that such effect was specific and mediated by upregulation of SAM level and SAM : S-adenosylethionine (SAH) ratio. Conclusion:, Silencing MAT2A by sequence-specific small interfering RNA caused a switch of MAT gene expression from MAT2A to MAT1A, which led the content of SAM to change to a higher steady-state level that resulted in the inhibition of cell growth and the induction of apoptotic cell death in human hepatoma cells. These results also suggested that MAT2A may hold potential as a new target for liver cancer gene therapy. [source] Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patientsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Eriko Tokunaga Abstract Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy. © 2005 Wiley-Liss, Inc. [source] Aging well , the role of minimally invasive aesthetic dermatological procedures in women over 65JOURNAL OF COSMETIC DERMATOLOGY, Issue 1 2010Uwe Wollina MD Summary Background, The western world is getting older. Aging well has become the new target of preventative medicine. Aesthetic dermatology can contribute to this quest. Females over 65 represent an important and growing group of consumers of cosmetic procedures. In this group, there is a paucity of scientific evaluation of aesthetic procedures. Objective, To review the use of minimally invasive procedures for facial rejuvenation in women over 65. Methods, Drawing from both the literature and personal experience, the opportunities, modifications, and limitations of minimally invasive techniques for facial rejuvenation in older women are considered. Results, In this older age group, dermal fillers, chemical and laser peels, and nonablative photorejuvenation remain useful and can each be used as stand-alone treatments. In this age group, botulinum toxin (BTX) injections are more often used in combination with other procedures. Conclusions, With respect to aesthetic procedures, women over 65 are different from younger women. More scientific investigation is necessary to better meet needs of this growing part of the population. Available data suggest that aesthetic dermatology can make a major contribution to the complex matter of aging well. [source] Protein tyrosine phosphatase 1B: a new target for the treatment of obesity and associated co-morbiditiesJOURNAL OF INTERNAL MEDICINE, Issue 6 2002O. Ukkola Abstract.,Ukkola O, Santaniemi M (University of Oulu, Oulu, Finland). Protein tyrosine phosphatase 1B: a new target for the treatment of obesity and associated co-morbidities (Review). J Intern Med 2002; 251: 467,475. Impaired insulin action is important in the pathophysiology of multiple metabolic abnormalities such as obesity and type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is considered a negative regulator of insulin signalling. This is best evidenced by studies on knockout mice showing that lack of PTP1B is associated with increased insulin sensitivity as well as resistance to obesity and in vitro studies whilst studies in animals and humans have given contradictory results. However, several studies support the notion that insulin signalling can be enhanced by the inhibition of PTP1B providing an attractive target for therapy against type 2 diabetes and obesity. In addition, recent genetic studies support the association between PTP1B with insulin resistance. The development of PTP1B inhibitors has already begun although it has become clear that is not easy to find both a selective, safe and effective PTP1B inhibitor. The objective of this paper is to review the current evidence of PTP1B in the pathophysiology of obesity, type 2 diabetes and cancer as well as in the treatment of these disorders. [source] Cerebral ischemia/stroke and small ubiquitin-like modifier (SUMO) conjugation , a new target for therapeutic intervention?JOURNAL OF NEUROCHEMISTRY, Issue 3 2008Wei Yang Abstract Transient cerebral ischemia/stroke activates various post-translational protein modifications such as phosphorylation and ubiquitin conjugation that are believed to play a major role in the pathological process triggered by an interruption of blood supply and culminating in cell death. A new system of post-translational protein modification has been identified, termed as small ubiquitin-like modifier (SUMO) conjugation. Like ubiquitin, SUMO is conjugated to the lysine residue of target proteins in a complex process. This review summarizes observations from recent experiments focusing on the effect of cerebral ischemia on SUMO conjugation. Transient global and focal cerebral ischemia both induced a rapid, dramatic and long-lasting rise in levels of SUMO2/3 conjugation. After transient focal cerebral ischemia, SUMO conjugation was particularly prominent in neurons located at the border of the ischemic territory where SUMO-conjugated proteins translocated to the nucleus. Many SUMO conjugation target proteins are transcription factors and sumoylation has been shown to have a major impact on the activity, stability, and cellular localization of target proteins. The rise in levels of SUMO-conjugated proteins is therefore likely to have a major effect on the fate of post-ischemic neurons. The sumoylation process could provide an exciting new target for therapeutic intervention. [source] Two novel monoclonal antibodies to VWFA3 inhibit VWF-collagen and VWF-platelet interactionsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2007Y. ZHAO Summary.,Background:,The interaction of collagen-von Willebrand factor (VWF)-GPIb is essential for platelet adhesion, especially under high shear conditions. VWF, which acts as a bridge between platelets and exposed subendothelium, interacts with collagen through its A3 domain, which is a new target for the antithrombotic agent. Objective:,To develop functional blockers that specifically inhibit VWF-dependent adhesion of platelets to collagen under high shear stress. Methods:,To develop murine antihuman VWF A3 monoclonal antibodies (mAbs) by standard hybridoma technology, and characterize their abilities to block interactions between VWF A3 and collagen as well as platelet function. Results:,Thirty anti-VWF-A3 mAbs were obtained. Among them, two mAbs, designated as SZ-123 and SZ-125, were found to inhibit VWF-collagen type III interaction. SZ-123 and SZ-125 inhibited the binding of purified human VWF (1.5 or 3 ,g mL,1) to human placenta collagen type III (IC50 = 0.07 ± 0.02 and 0.15 ± 0.03 ,g mL,1, respectively) or to calf skin collagen type III (IC50 = 0.48 ± 0.06 and 0.51 ± 0.07 ,g mL,1, respectively) coated on plates. Under flow shear condition (1000 s,1), SZ-123 and SZ-125 inhibited platelet adhesion on human placenta collagen- or calf skin collagen-coated surfaces. Both mAbs also inhibited platelet aggregation induced by ristocetin, botrocetin or bovine plasma. Conclusions:,SZ-123 and SZ-125 inhibited VWF-collagen and VWF-platelet interactions. [source] Factor XIa as a possible new target of antithrombotic therapyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2006S. GOTO No abstract is available for this article. [source] On the origin of bladder sensing: Tr(i)ps in urology,NEUROUROLOGY AND URODYNAMICS, Issue 4 2008Wouter Everaerts Abstract The mammalian TRP family consists of 28 channels that can be subdivided into 6 different classes: TRPV (vanilloid), TRPC (canonical), TRPM (Melastatin), TRPP (Polycystin), TRPML (Mucolipin), and TRPA (Ankyrin). TRP channels are activated by a diversity of physical (voltage, heat, cold, mechanical stress) or chemical (pH, osmolality) stimuli and by binding of specific ligands, enabling them to act as multifunctional sensors at the cellular level. Currently, a lot of scientific research is devoted to these channels and their role in sensing mechanisms throughout the body. In urology, there's a growing conviction that disturbances in afferent (sensory) mechanisms are highly important in the pathogenesis of functional problems. Therefore, the TRP family forms an interesting new target to focus on. In this review we attempt to summarize the existing knowledge about TRP channels in the urogenital tract. So far, TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1 have been described in different parts of the urogenital tract. Although only TRPV1 (the vanilloid receptor) has been extensively studied so far, more evidence is slowly accumulating about the role of other TRP channels in the (patho)physiology of the urogenital tract. Neurourol. Urodynam. 27:264,273, 2008. © 2007 Wiley-Liss, Inc. [source] Tumor-associated macrophages infiltrate plasmacytomas and can serve as cell carriers for oncolytic measles virotherapy of disseminated myeloma,AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2009Kah-Whye Peng In multiple myeloma, some of the neoplastic plasma cells are diffusely dispersed among the normal bone marrow cells (bone marrow resident), whereas others are located in discrete, well-vascularized solid tumors (plasmacytomas) that may originate in bone or soft tissue. Interactions between bone marrow-resident myeloma cells and bone marrow stromal cells (BMSCs) are important determinants of myeloma pathogenesis. However, little is known of the factors sustaining myeloma growth and cell viability at the centers of expanding plasmacytomas, where there are no BMSCs. Histologic sections of 22 plasmacytomas from myeloma patients were examined after immunostaining. Abundant CD68+, CD163+, S100-negative macrophage infiltrates were identified in all tumors, accompanied by scattered collections of CD3+ T lymphocytes. The CD68+ tumor-associated macrophages (TAM) accounted for 2,12% of nucleated cells and were evenly distributed through the parenchyma. The TAM generally had dendritic morphology, and each dendrite was in close contact with multiple plasma cells. In some cases, the TAM were strikingly clustered around CD34+ blood vessels. To determine whether cells of the monocytic lineage might be exploitable as carriers for delivery of therapeutic agents to plasmacytomas, primary human CD14+ cells were infected with oncolytic measles virus and administered intravenously to mice bearing KAS6/1 human myeloma xenografts. The cell carriers localized to KAS6/1 tumors, where they transferred MV infection to myeloma cells and prolonged the survival of mice bearing disseminated human myeloma disease. Thus, TAM are a universal stromal component of the plasmacytomas of myeloma patients and may offer a promising new target for therapeutic exploitation. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Crystal structure of the Streptococcus pneumoniae mevalonate kinase in complex with diphosphomevalonatePROTEIN SCIENCE, Issue 5 2007John L. Andreassi II Abstract Streptococcuspneumoniae, a ubiquitous gram-positive pathogen with an alarming, steadily evolving resistance to frontline antimicrobials, poses a severe global health threat both in the community and in the clinic. The recent discovery that diphosphomevalonate (DPM), an essential intermediate in the isoprenoid biosynthetic pathway, potently and allosterically inhibits S. pneumoniae mevalonate kinase (SpMK) without affecting the human isozyme established a new target and lead compound for antimicrobial design. Here we present the crystal structure of the first S. pneumoniae mevalonate kinase, at a resolution of 2.5 Ĺ and in complex with DPM·Mg2+ in the active-site cleft. Structural comparison of SpMK with other members of the GHMP kinase family reveals that DPM functions as a partial bisubstrate analog (mevalonate linked to the pyrophosphoryl moiety of ATP) in that it elicits a ternary-complexlike form of the enzyme, except for localized disordering in a region that would otherwise interact with the missing portion of the nucleotide. Features of the SpMK-binding pockets are discussed in the context of established mechanistic findings and inherited human diseases linked to MK deficiency. [source] Generation and Evaluation of a Homology Model of PfGSK-3ARCHIV DER PHARMAZIE, Issue 6 2009Sebastian Kruggel Abstract Plasmodial GSK-3 is a potential new target for malaria therapy. For a structure-based design project, the three-dimensional information of the designated target is needed. Unfortunately, experimental structure data for plasmodial GSK-3 is not yet available. Homology building can be used to generate such three-dimensional structure data using structure information of a homologous protein. GSK-3 possesses a very flexible ATP-binding site, a fact reflected in the variety of X-ray structures of the human GSK-3, which are deposited in the protein data base and are crystallized with different ligands. We used ten different HsGSK-3, templates for the model building of plasmodial GSK-3 and generated 200 models for each template with different modeling protocols. The quality of the models was evaluated with different tools. The results of these evaluations were used to calculate a rank-by-rank consensus score. The top models of this were used to compile an ensemble of PfGSK-3 models that reflect the flexibility of the ATP-binding site and that will be used for the structure-based design of potential ATP-binding site inhibitors of PfGSK-3. [source] Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNKARTHRITIS & RHEUMATISM, Issue 9 2003Monisha Sundarrajan Objective The mitogen-activated protein (MAP) kinase JNK is a key regulator of interleukin-1 (IL-1),induced collagenase gene expression and joint destruction in arthritis. Two upstream kinases, MKK-4 and MKK-7, have been identified as potential activators of JNK. However, the role of MAP kinase kinases (MAPKKs) and their functional organization within fibroblast-like synoviocytes (FLS) have not been defined. We therefore evaluated the interactions between the various MAP kinase components and determined their subcellular localization. Methods MKKs were identified by immunohistochemistry of rheumatoid arthritis (RA) and osteoarthritis (OA) synovium. Western blotting was used to determine the expression of FLS. Immunoprecipitation experiments using antibodies specific for MKK-4, MKK-7, and JNK were performed. Phosphospecific antibodies and immunohistochemistry were used to evaluate the activation state of synovial MKK-4 and MKK-7. Confocal microscopy was used to determine the subcellular location of the kinases. Results Immunohistochemistry studies demonstrated abundant MKK-4 and MKK-7 in RA and OA synovium, but the levels of phosphorylated kinases were significantly higher in RA synovium. MKK-4 and MKK-7 were constitutively expressed by cultured RA and OA FLS, and IL-1 stimulation resulted in rapid phosphorylation of both kinases. JNK was detected in MKK-4 and MKK-7 immunoprecipitates. Furthermore, MKK-4 coprecipitated with MKK-7 and vice versa, indicating that the 3 kinases form a stable complex in FLS. Confocal microscopy confirmed that JNK, MKK-4, and MKK-7 colocalized in the cytoplasm, with JNK migrating to the nucleus after IL-1 stimulation. The signal complex containing MKK-4, MKK-7, and JNK was functionally active and able to phosphorylate c-Jun after IL-1 stimulation of FLS. Conclusion These studies demonstrate that JNK, MKK-4, and MKK-7 form an active signaling complex in FLS. This novel JNK signalsome is activated in response to IL-1 and migrates to the nucleus. The JNK signalsome represents a new target for therapeutic interventions designed to prevent joint destruction. [source] Structure of the methyltransferase domain from the Modoc virus, a flavivirus with no known vectorACTA CRYSTALLOGRAPHICA SECTION D, Issue 8 2009Anna M. Jansson The Modoc virus (MODV) is a flavivirus with no known vector (NKV). Evolutionary studies have shown that the viruses in the MODV group have evolved in association with mammals (bats, rodents) without transmission by an arthropod vector. MODV methyltransferase is the first enzyme from this evolutionary branch to be structurally characterized. The high-resolution structure of the methyltransferase domain of the MODV NS5 protein (MTaseMODV) was determined. The protein structure was solved in the apo form and in complex with its cofactor S -adenosyl- l -methionine (SAM). Although it belongs to a separate evolutionary branch, MTaseMODV shares structural characteristics with flaviviral MTases from the other branches. Its capping machinery is a relatively new target in flaviviral drug development and the observed structural conservation between the three flaviviral branches indicates that it may be possible to identify a drug that targets a range of flaviviruses. The structural conservation also supports the choice of MODV as a possible model for flavivirus studies. [source] Circuits and systems in stress.DEPRESSION AND ANXIETY, Issue 1 2002Abstract This paper follows the preclinical work on the effects of stress on neurobiological and neuroendocrine systems and provides a comprehensive working model for understanding the pathophysiology of posttraumatic stress disorder (PTSD). Studies of the neurobiology of PTSD in clinical populations are reviewed. Specific brain areas that play an important role in a variety of types of memory are also preferentially affected by stress, including hippocampus, amygdala, medial prefrontal cortex, and cingulate. This review indicates the involvement of these brain systems in the stress response, and in learning and memory. Affected systems in the neural circuitry of PTSD are reviewed (hypothalamic-pituitary-adrenal axis (HPA-axis), catecholaminergic and serotonergic systems, endogenous benzodiazepines, neuropeptides, hypothalamic-pituitary-thyroid axis (HPT-axis), and neuro-immunological alterations) as well as changes found with structural and functional neuroimaging methods. Converging evidence has emphasized the role of early-life trauma in the development of PTSD and other trauma-related disorders. Current and new targets for systems that play a role in the neural circuitry of PTSD are discussed. This material provides a basis for understanding the psychopathology of stress-related disorders, in particular PTSD. Depression and Anxiety 16:14,38, 2002. © 2002 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||