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Biological Events (biological + event)
Selected AbstractsGeneral Method for the 11C-Labeling of 2-Arylpropionic Acids and Their Esters: Construction of a PET Tracer Library for a Study of Biological Events Involved in COXs ExpressionCHEMISTRY - A EUROPEAN JOURNAL, Issue 14 2010Misato Takashima-Hirano Abstract Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate 11C radionuclide into various 2-arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, we developed a novel 11C-radiolabeling methodology based on rapid C -[11C]methylation by the reaction of [11C]CH3I with enolate intermediates generated from the corresponding esters under basic conditions. One-pot hydrolysis of the above [11C]methylation products also allows the synthesis of desired 11C-incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [11C]Ibuprofen, [11C]Naproxen, [11C]Flurbiprofen, [11C]Fenoprofen, [11C]Ketoprofen, and [11C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)-induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [11C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general 11C-labeling of 2-arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression. [source] Mimicking biological delivery through feedback-controlled drug release systems based on molecular imprintingAICHE JOURNAL, Issue 6 2009David R. Kryscio Intelligent drug delivery systems (DDS) are able to rapidly detect a biological event and respond appropriately by releasing a therapeutic agent; thus, they are advantageous over their conventional counterparts. Molecular imprinting is a promising area that generates a polymeric network which can selectively recognize a desired analyte. This field has been studied for a variety of applications over a long period of time, but only recently has it been investigated for biomedical and pharmaceutical applications. Recent work in the area of molecularly imprinted polymers in drug delivery highlights the potential of these recognitive networks as environmentally responsive DDS that can ultimately lead to feedback controlled recognitive release systems. © 2009 American Institute of Chemical Engineers AIChE J, 2009. [source] 900 MHz modulated electromagnetic fields accelerate the clathrin-mediated endocytosis pathwayBIOELECTROMAGNETICS, Issue 3 2009Mihaela G. Moisescu Abstract We report new data regarding the molecular mechanisms of GSM-induced increase of cell endocytosis rate. Even though endocytosis represents an important physical and biological event for cell physiology, studies on modulated electromagnetic fields (EMF) effects on this process are scarce. In a previous article, we showed that fluid phase endocytosis rate increases when cultured cells are exposed to 900 MHz EMF similar to mobile phones' modulated GSM signals (217 Hz repetition frequency, 576 µs pulse width) and to electric pulses similar to the GSM electrical component. Trying to distinguish the mechanisms sustaining this endocytosis stimulation, we exposed murine melanoma cells to Lucifer Yellow (LY) or to GSM,EMF/electric pulses in the presence of drugs inhibiting the clathrin- or the caveolin-dependent endocytosis. Experiments were performed at a specific absorption rate (SAR) of 3.2 W/kg in a wire patch cell under homogeneously distributed EMF field and controlled temperature (in the range of 28.5,29.5 °C). Thus, the observed increase in LY uptake was not a thermal effect. Chlorpromazine and ethanol, but not Filipin, inhibited this increase. Therefore, the clathrin-dependent endocytosis is stimulated by the GSM,EMF, suggesting that the cellular mechanism affected by the modulated EMF involves vesicles that detach from the cell membrane, mainly clathrin-coated vesicles. Bioelectromagnetics 30:222,230, 2009. © 2008 Wiley-Liss, Inc. [source] Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazideDIABETES OBESITY & METABOLISM, Issue 2 2004J.-C. Mamputu Aim:, We have previously demonstrated that advanced glycation end products (AGEs) stimulate bovine retinal endothelial cell (BREC) proliferation through induction of vascular endothelial growth factor (VEGF) production by these cells. We have also shown that gliclazide, a sulfonylurea which decreases oxidative stress, inhibits this effect. The aim of the present study was to characterize the signalling pathways involved in AGE-induced BREC proliferation and VEGF production and mediating the inhibitory effect of gliclazide on these biological events. Methods:, BRECs were treated or not treated with AGEs in the presence or absence of gliclazide, antioxidants, protein kinase C (PKC), mitogen-activated protein kinase (MAPK) or nuclear factor-,B (NF-,B) inhibitors. BREC proliferation was assessed by measuring [3H]-thymidine incorporation into DNA. Activation of PKC, MAPK and NF-,B signal transduction pathways and determination of VEGF expression were assessed by Western blot analysis using specific antibodies. MAPK activity was also determined by an in vitro kinase assay. Results:, Treatment of BRECs with AGEs significantly increased cell proliferation and VEGF expression. AGEs induced PKC-, translocation, extracellular signal-regulated protein kinase 1/2 and NF-,B activation in these cells. Pharmacological inhibition of these signalling pathways abolished AGE effects on cell proliferation and VEGF expression. Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N -acetyl- l -cysteine resulted in a significant decrease in AGE-induced activation of PKC-, MAPK- and NF-,B-signalling pathways. Conclusions:, Our results demonstrate the involvement of PKC, MAPK and NF-,B in AGE-induced BREC proliferation and VEGF expression. Gliclazide inhibits BREC proliferation by interfering with these intracellular signal transduction pathways. [source] CONCORDANCE OF THE CIRCADIAN CLOCK WITH THE ENVIRONMENT IS NECESSARY TO MAXIMIZE FITNESS IN NATURAL POPULATIONSEVOLUTION, Issue 4 2008Kevin J. Emerson The ubiquity of endogenous, circadian (daily) clocks among eukaryotes has long been held as evidence that they serve an adaptive function, usually cited as the ability to properly time biological events in concordance with the daily cycling of the environment. Herein we test directly whether fitness is a function of the matching of the period of an organism's circadian clock with that of its environment. We find that fitness, measured as the per capita expectation of future offspring, a composite measure of fitness incorporating both survivorship and reproduction, is maximized in environments that are integral multiples of the period of the organism's circadian clock. Hence, we show that organisms require temporal concordance between their internal circadian clocks and their external environment to maximize fitness and thus the long-held assumption is true that, having evolved in a 24-h world, circadian clocks are adaptive. [source] Frontiers and controversies in the pathobiology of vitiligo: separating the wheat from the chaffEXPERIMENTAL DERMATOLOGY, Issue 7 2009Raymond E. Boissy Abstract:, The pathogenesis of vitiligo is complex and not well understood. Genes play a role in all aspects of vitiligo pathogenesis, and studies are ongoing to identify these genes and understand their biology. There is a body of interlocking, compelling evidence supporting an autoimmune basis for most or all cases of generalized vitiligo. The development of an autoimmune disease generally involves three components; the immune system, environmental triggers and other exogenous precipitating factors, and the target tissue. In vitiligo, precipitating factors could induce melanocyte damage in genetically susceptible individuals and consequent cell death, loss of tolerance, and induction of melanocyte-directed autoimmunity. Future research will more precisely define the multiple biological events that regulate development of vitiligo. [source] Molecular diagnosis in dermatopathology: What makes sense, and what doesn'tEXPERIMENTAL DERMATOLOGY, Issue 1 2009Markus Braun-Falco Abstract:, Molecular techniques have provided us with a wealth of information about biological events in healthy individual, and improved tremendously our understanding about the pathogenesis of a huge variety of cutaneous diseases. Those methods have originally been invented to support basic scientific investigations on a molecular level and are translated increasingly into sophisticated diagnostic tools changing the classic paradigm of diagnostic pathology; among them are immunohistochemistry (IHC), polymerase chain reaction (PCR), G-banding, loss of heterozygosity, fluorescence in situ hybridization (FISH), chromogen in situ hybridization (CISH), comparative genomic hybridization on chromosomes and microarray technology. Some of them such as IHC and PCR have already been standardized to a level that allows its utility in daily routine diagnostics for several dermatological diseases. For others like array-based technologies, their optimal indications await to be fully determined. These ancillary methods have the great potential to contribute important new information to challenging cases, and will help to improve diagnostic accuracy particularly in cases in which conventional histopathology is ambiguous. Thus, they will broaden our armamentarium for diagnostic pathology. Herein, some key techniques will be reviewed and their applicability towards the diagnosis of dermatological diseases critically discussed. [source] NUB1-mediated targeting of the ubiquitin precursor UbC1 for its C-terminal hydrolysisFEBS JOURNAL, Issue 5 2004Tomoaki Tanaka NEDD8 is a ubiquitin-like protein that controls vital biological events through its conjugation to target proteins. Previously, we identified a negative regulator of the NEDD8 conjugation system, NEDD8 ultimate buster-1 (NUB1), that recruits NEDD8 and its conjugates to the proteasome for degradation. Recently, we performed yeast two-hybrid screening with NUB1 as bait and isolated a ubiquitin precursor UbC1 that is composed of nine tandem repeats of a ubiquitin unit through ,-peptide bonds. Interestingly, NUB1 interacted with UbC1 through its UBA domain. Further study revealed that the UBA domain interacted with ,-peptide bond-linked polyubiquitin, but not with isopeptide bond-linked polyubiquitin, indicating that the UBA domain of NUB1 is a specific acceptor for the linear ubiquitin precursor. A functional study revealed that an unidentified protein that was immunoprecipitated with NUB1 served as a ubiquitin C-terminal hydrolase for UbC1. Thus, NUB1 seems to form a protein complex with the unidentified ubiquitin C-terminal hydrolase and recruit UbC1 to this complex. This might allow the ubiquitin C-terminal hydrolase to hydrolyze UbC1, in order to generate ubiquitin monomers. Northern blot analysis showed that the mRNAs of both NUB1 and UbC1 were enriched in the testis. Furthermore, in situ hybridization showed that both mRNAs were strongly expressed in seminiferous tubules of the testis. These results may imply that the UbC1 hydrolysis mediated by NUB1 is involved in cellular functions in the seminiferous tubules such as spermatogenesis. [source] Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathwaysGENES TO CELLS, Issue 8 2000Shigeaki Kato Oestrogen (E2) plays significant roles in variety of biological events such as the development and maintenance of female reproductive organs, bone and lipid metabolisms. More recently, from study of knock-out mice deficient in oestrogen receptor (ER) , and ER, it turned out that normal spermatogenesis requires the E2 actions. Furthermore, this female steroid hormone is also well known to be deeply involved in many pathophysiological events such as osteoporosis and cancer development in female reproductive organs. It is particularly well known that most breast cancer is dependent on E2 in its development. Such E2 actions are thought to be mediated through two subtypes of ERs. Growth factors have been shown to synergize in this E2 signalling pathway, although the actual molecular mechanism largely remains unknown. Recently, we found that the MAP kinase activated by growth factors phosphorylates the Ser118 residue of the human ER, A/B domain and this phosphorylation potentiates the N-terminal transactivation function (AF-1) of human ER,, indicating the possible molecular mechanism of a novel cross-talk between E2 and growth factor signalling pathways. More recently, we have identified a coactivator associating with the hER, AF-1 in a MAPK-mediated phosphorylation-dependent manner. In this review, the molecular mechanism of this cross-talk is discussed in terms of the transactivation function of ERs, and their coactivators. [source] Impacts of climate on prey abundance account for fluctuations in a population of a northern wader at the southern edge of its rangeGLOBAL CHANGE BIOLOGY, Issue 1 2010JAMES W. PEARCE-HIGGINS Abstract Understanding the mechanisms by which climate change will affect animal populations is vital for adaptive management. Many studies have described changes in the timing of biological events, which can produce phenological mismatch. Direct effects on prey abundance might also be important, but have rarely been studied. We examine the likely importance of variation in prey abundance in driving the demographics of a European golden plover (Pluvialis apricaria) population at its southern range margin. Previous studies have correlated plover productivity with the abundance of their adult cranefly (Tipulidae) prey, and modelled the phenology of both plover breeding and cranefly emergence in relation to temperature. Our analyses demonstrate that abundance of adult craneflies is correlated with August temperature in the previous year. Correspondingly, changes in the golden plover population are negatively correlated with August temperature 2 years earlier. Predictions of annual productivity, based on temperature-mediated reductions in prey abundance, closely match observed trends. Modelled variation in annual productivity for a future scenario of increasing August temperatures predicts a significant risk of extinction of the golden plover population over the next 100 years, depending upon the magnitude of warming. Direct effects of climate warming upon cranefly populations may therefore cause northward range contractions of golden plovers, as predicted by climate envelope modelling. Craneflies are an important food source for many northern and upland birds, and our results are likely to have wide relevance to these other species. Research into the potential for habitat management to improve the resilience of cranefly populations to high temperature should be an urgent priority. [source] Climatic trends and advancing spring flight of butterflies in lowland CaliforniaGLOBAL CHANGE BIOLOGY, Issue 7 2003MATTHEW L. FORISTER Abstract Many studies, largely from cool-temperate latitudes, have investigated the relationship between the timing of biological events and changes in climatic conditions during the past few decades. Relatively little is known about the response of plants and animals at lower latitudes. Here we show that the average first spring flight of 23 butterfly species in the Central Valley of California has advanced to an earlier date over the past 31 years. Among the species that have appeared significantly earlier, the average shift is 24 days. Climatic conditions (largely winter temperature and precipitation) are found to explain a large part of the variation in changing date of first flight. These results suggest a strong ecological influence of changing climatic conditions on a suite of animals from a mid-latitude, Mediterranean climate. [source] Relationship between UVA protection and skin response to UV light: proposal for labelling UVA protectionINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 4 2004M. Jean-Louis Refrégier Synopsis Definition and validation of a most relevant method to assess ultravoilet A (UVA) protection is a major concern for industry, authorities and consumers. However, due to the lack of knowledge about all the biological phenomena involved, the level of UVA protection needed, the ways to assess and label it, remain controversial. In order to overcome this situation, the paper deals with the outcomes of a mathematical model to calculate the distribution between ultravoilet B (UVB) and UVA components of skin responses to UV light. Mathematical calculations of UVB and UVA erythemal components of skin response to sunlight are developed from the well-known determination procedure to calculate the sunburn protection factor (SPF) of sunscreens. The model establishes the relationship between the UVA component of skin erythemal response to overall UV radiation received from sunlight and the ratio SPF/PFAe (erythemal protection factor) where SPF is the product and PFAe is related to the UVA part of the sunlight. Depending on the efficacy profile of sunscreens, the skin erythemal response may be mainly promoted by UVB rays as it normally occurs in unprotected skin or on contrary by UVA rays. Therefore, the efficacy profile of sunscreens defines the deepness where biological events induced by sunlight take place. This new relationship pinpoints the tremendous importance of the protection afforded by sunscreen products in the UVA range when erythema is taken as biological response. By extrapolation of the model to any other biological skin response it becomes possible to predict how to improve the efficiency of sunscreen products in the future. UVA protection afforded by sunscreens should be improved until reaching the same level as the SPF protection factor so that all UV-induced biological responses could be prevented or lowered at the same extend. To enforce this improvement, a proposal to classify sunscreen products in relation with their UVA protection is made. Résumé Bien que les méfaits du rayonnement UVA soient à présent reconnus et l'importance de s'en protéger au même titre que ceux du rayonnement UVB totalement admise, l'obtention d'un consensus au niveau international, sur les méthodes pour mesurer l'efficacité des produits solaires vis-à-vis des UVA et sur les niveaux d'efficacité souhaitables, semble impossible à atteindre. Afin de tenter de surmonter les obstacles actuels, nous présentons un modèle mathématique qui permet d'établir la relation qui dèfinit le poids relatif des rayonnements UVB et UVA dans l'initiation des phénomènes biologiques engendrés par le rayonnement solaire, en fonction des caractéristiques du produit solaire utilisé et en particulier de son efficacité protectrice vis-à-vis des UVA. Dans le cas de l'érythème nous établissons ainsi que la proportion des effets engendrés par le rayonnement UVA est définie par le rapport SPF/PFAe: le SPF étant le facteur de protection contre l'érythème vis-à-vis de l,ensemble du rayonnement UV, c'est l'indice de protection affiché sur les produits; et, PFAe étant le facteur de protection du produit vis-à-vis du seul rayonnement UVA. L'extrapolation possible de ce modèle à l'ensemble des phénomènes biologiques met en évidence que le facteur de proportionnalité entre la protection globale et celle apportée vis-à-vis des UVA (SPF/PFAe) permet d'établir une classification de la qualité des systèmes filtrants en fonction de leur aptitude à prèvenir l'ensemble des méfaits du rayonnement solaire. Ce modèle démontre l'importance d'évaluer l,efficacité protectrice des produits solaires vis-à-vis du rayonnement UVA et son enseignement plus pertinent que celle de seulement évaluer l'allure des spectres d'absorption. Nous jugeons que l'application directe de ce modèle, au même titre que les méthodes d'évaluation de l,allure des spectres d'absorption, n'est aujourd'hui pas souhaitable en raison des connaissances et donc de la validation insuffisantes des méthodes in vitro en particulier pour évaluer les produits non parfaitement photostables. En conséquence, nous proposons de mettre en place une qualification qui repose sur l'évaluation de la protection UVA par les mèthodes in vivo dûment étudiées et validées telles que les méthodes PPD ou PFA. La mise en place du système proposé de qualification des produits solaires, permettrait d'apporter rapidement aux consommateurs une meilleure information sur la qualité des produits et permettrait de créer une dynamique d'amélioration de la qualité de l'ensemble des produits commercialisés. [source] Carbon Monoxide Alleviates Salt-Induced Oxidative Damage in Wheat Seedling LeavesJOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 3 2006Ben-Kai Huang Abstract Carbon monoxide (CO), a by-product released during the degradation of heme by heme oxygenases (EC 1.14.99.3) in animals, is regarded as an important physiological messenger or bioactive molecule involved in many biological events that has been recently reported as playing a major role in mediating the cytoprotection against oxidant-induced lung injury. In the present study, we first determined the protective effect of exogenous CO against salt-induced oxidative damage in wheat seedling leaves. Wheat seedlings treated with 0.01 ,mol/L hematin as the CO donor demonstrated significant reversal of chlorophyll decay, dry weight, and water loss induced by 300 mmol/L NaCl stress. Interestingly, the increase in lipid peroxidation observed in salt-treated leaves was reversed by 0.01 nmol/L hematin treatment. Time-course analyses showed that application of 0.01 ,mol/L hematin enhanced guaiacol peroxidase, superoxide dismutase, ascorbate peroxidase and catalase activities in wheat seedling leaves subjected to salt stress. These effects are specific for CO because the CO scavenger hemoglobin (1.2 mg/L) blocked the actions of the CO donor hematin. However, higher concentration of the CO donor (1.0 ,mol/L) did not alleviate dry weight and water loss of salt-stressed wheat seedlings. These results suggest that exogenous application of low levels of a CO donor may be advantageous against salinity toxicity. (Managing editor: Ping He) [source] Enrichment of peptides from plasma for peptidome analysis using multiwalled carbon nanotubesJOURNAL OF SEPARATION SCIENCE, JSS, Issue 6 2007Xin Li Abstract Human plasma contains a complex matrix of proteolytically derived peptides (plasma peptidome) that may provide a correlate of biological events occurring in the entire organism. Analyzing these peptides from a small amount of serum/plasma is difficult due to the complexity of the sample and the low levels of these peptides. Here, we describe a novel peptidome analysis approach using multiwalled carbon nanotubes (MWCNTs) as an alternative adsorbent to capture endogenous peptides from human plasma. Harvested peptides were analyzed by using liquid chromatography-mass spectrometry as a means of detecting and assessing the adsorbed molecules. The improved sensitivity and resolution obtained by using liquid chromatography-mass spectrometry allowed detection of 2521 peptide features (m/z 300,1800 range) in about 50 ,L of plasma. 374 unique peptides were identified with high confidence by two-dimensional liquid chromatography system coupled to a nano-spray ionization linear ion trap-mass spectrometer. High recovery of BSA digest peptides enriched with MWCNTs, in both standard buffer and high abundance protein solution, was observed. Comparative studies showed that MWCNTs were superior to C18 and C8 for the capture of the smaller peptides. This approach could hold promise of routine plasma peptidome analysis. [source] A quantitative study of factors affecting in vivo bioluminescence imagingLUMINESCENCE: THE JOURNAL OF BIOLOGICAL AND CHEMICAL LUMINESCENCE, Issue 5 2008Kemi Cui Abstract In vivo bioluminescence imaging (BLI) has the advantages of high sensitivity and low background. By counting the number of photons emitted from a specimen, BLI can quantify biological events such as tumour growth, gene expression and drug response. The intensities and kinetics of the BL signal are affected by many factors and may confound the quantitative results acquired from consecutive imaging sessions or different specimens. We used three different mouse models of tumours to examine whether anaesthetics, positioning and tumour growth may affect the consistency of the BL signal. The results showed that BLI signal could be affected by different anaesthetics and repetitive positioning. Using the same anaesthetics produced consistent peak times, while other factors were held constant. However, as the tumours grew the peak times shifted and the time course of BL signals had different shapes, depending on the positioning of the mice. The data indicate that a carefully designed BLI experiment is required to generate optimal and consistent results. Copyright © 2008 John Wiley & Sons, Ltd. [source] Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospectsMEDICINAL RESEARCH REVIEWS, Issue 1 2006Brigitte Bauvois Abstract Aminopeptidase N (APN)/CD13 (EC 3.4.11.2) is a transmembrane protease present in a wide variety of human tissues and cell types (endothelial, epithelial, fibroblast, leukocyte). APN/CD13 expression is dysregulated in inflammatory diseases and in cancers (solid and hematologic tumors). APN/CD13 serves as a receptor for coronaviruses. Natural and synthetic inhibitors of APN activity have been characterized. These inhibitors have revealed that APN is able to modulate bioactive peptide responses (pain management, vasopressin release) and to influence immune functions and major biological events (cell proliferation, secretion, invasion, angiogenesis). Therefore, inhibition of APN/CD13 may lead to the development of anti-cancer and anti-inflammatory drugs. This review provides an update on the biological and pharmacological profiles of known natural and synthetic APN inhibitors. Current status on their potential use as therapeutic agents is discussed with regard to toxicity and specificity. © 2005 Wiley Periodicals, Inc. Med Res Rev [source] Galectin-9, a Novel Prognostic Factor with Antimetastatic Potential in Breast CancerTHE BREAST JOURNAL, Issue 2006Akira Yamauchi MD Abstract: Galectin-9, a member of the ,-galactoside-binding animal lectin family, is involved in various cellular biological events, including aggregation and apoptosis, adhesion of cancer cells, and dendritic cell maturation. We recently reported the relationship between galectin-9 expression in tumor tissue and distant metastasis in breast cancer. Tumors in 42 of the 84 patients were galectin-9-positive, and tumors in 19 of the 21 patients with distant metastasis were galectin-9-negative, assessed by immunohistochemistry. The cumulative distant metastasis-free survival ratio for galectin-9-positive patients was better than for the galectin-9-negative group (p < 0.0001). Multivariate analysis revealed that galectin-9 status influenced distant metastasis independent of and much more than lymph node metastasis. MCF-7 subclones with a high level of galectin-9 expression formed tight clusters during proliferation in vitro, whereas a subclone (K10) with the lowest level of galectin-9 expression did not. However, K10 cells stably transfected with a galectin-9 expression vector aggregated in nude mice as well as in culture. Ectopic expression of galectin-9 also reduced MCF-7 cell adhesion to extracellular matrix proteins., [source] Toward the development of new medicinal leads with selectivity for protein kinase C isozymesTHE CHEMICAL RECORD, Issue 4 2005Kazuhiro Irie Abstract Tumor promoters such as phorbol esters bind strongly to protein kinase C (PKC) isozymes to induce their activation. Since each PKC isozyme is involved in diverse biological events in addition to tumor promotion, the isozymes serve as promising therapeutic targets. Tumor promoters bind to the C1A and/or C1B domain of conventional (,, ,I, ,II, and ,) and novel PKC isozymes (,, ,, ,, and ,). As these C1 domains play differential roles in PKC activation and their translocation in cells, the development of agents with binding selectivity for individual C1 domains is a pressing need. For this purpose, we established a synthetic C1 peptide library of all PKC isozymes. The library enabled us to identify indolactam-V (1) as a promising lead compound. Our diverse structure,activity studies on 1 indicated that the position of the hydrophobic substituent on the indole ring dominates the PKC isozyme- and C1 domain-selective binding rather than conformation of the nine-membered lactam. Moreover, we suggested that the indole ring of 1 could be involved in the CH/, interaction with Pro-11 of the C1B domain of PKC,. This invaluable information will lead to the structural optimization of the PKC, ligand as exemplified by the design and synthesis of naphtholactam-V8 (21). © 2005 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 5: 185,195; 2005: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20044 [source] Intrinsic Toxicity of Hemoglobin: How to Counteract ItARTIFICIAL ORGANS, Issue 2 2009Jan Simoni Abstract The development of safe and effective blood substitutes is of great importance in both civilian and military medicine. The currently tested hemoglobin (Hb)-based oxygen carriers, however, have toxicity and efficacy problems. A number of unwanted effects have been observed in human trials, creating doubts about their clinical usefulness. In some subjects, vasoconstriction and decreased blood flow to the vital organs, heart attack, stroke, systemic inflammation, organ damage, and even death, have been attributed to the transfusion of these experimental products. Hb is a well-known pressor agent and strong oxidant, although the full understanding of its intrinsic toxicity is yet to be uncovered. In particular, the complete mechanism of Hb-induced vasoconstriction needs full elucidation. Knowledge of the biological events that trigger the induction of genes upon treatment with redox-active Hb, as well as its catabolism, is still incomplete. It seems that our limited knowledge of free Hb effects in vivo is the main reason for not yet having a viable substitute of human blood. The future for universal red cell substitutes is in the new-generation products that address all of Hb's intrinsic toxicity issues. [source] Incorporating Physiological and Biochemical Mechanisms into Pharmacokinetic,Pharmacodynamic Models: A Conceptual Framework,BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2010Svein G. Dahl In general, modelling of data has the purpose (1) to describe experimental data, (2a) to reduce the amount of data resulting from an experiment, e.g. a clinical trial and (2b) to obtain the most relevant parameters, (3) to test hypotheses and (4) to make predictions within the boundaries of experimental conditions, e.g. range of doses tested (interpolation) and out of the boundaries of the experimental conditions, e.g. to extrapolate from animal data to the situation in man. Describing the drug/xenobiotic-target interaction and the chain of biological events following the interaction is the first step to build a biologically based model. This is an approach to represent the underlying biological mechanisms in qualitative and also quantitative terms, thus being inherently connected in many aspects to systems biology. As the systems biology models may contain variables in the order of hundreds connected with differential equations, it is obvious that it is in most cases not possible to assign values to the variables resulting from experimental data. Reduction techniques may be used to create a manageable model which, however, captures the biologically meaningful events in qualitative and quantitative terms. Until now, some success has been obtained by applying empirical pharmacokinetic/pharmacodynamic models which describe direct and indirect relationships between the xenobiotic molecule and the effect, including tolerance. Some of the models may have physiological components built in the structure of the model and use parameter estimates from published data. In recent years, some progress toward semi-mechanistic models has been made, examples being chemotherapy-induced myelosuppression and glucose-endogenous insulin-antidiabetic drug interactions. We see a way forward by employing approaches to bridge the gap between systems biology and physiologically based kinetic and dynamic models. To be useful for decision making, the ,bridging' model should have a well founded mechanistic basis, but being reduced to the extent that its parameters can be deduced from experimental data, however capturing the biological/clinical essential details so that meaningful predictions and extrapolations can be made. [source] Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patientsBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2003Gian Matteo Rigolin Summary. The urokinase-type plasminogen activator (uPA) system, which consists of a proteinase (uPA), a receptor (uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration, tissue remodelling, angiogenesis and cell adhesion. Recent findings suggest that malignant plasma cells express uPA and uPAR. The expression of these factors could represent a process by which myeloma plasma cells interact with the bone marrow (BM) environment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing and, possibly, clinical evolution. We evaluated uPAR (CD87) and its soluble form (suPAR) in 49 multiple myeloma (MM) patients and correlated their expression and levels with clinico-biological characteristics of the disease. Flow cytometric analysis demonstrated that CD87 was expressed in all MM patients. High CD87 expression was associated with higher intensity of expression of CD56 (P = 0·038), CD38 (P = 0·058) and CD138 (P = 0·054) and CD45bright positivity (P = 0·014). suPAR levels correlated positively with soluble serum CD138 (P = 0·001), creatinine (P = 0·001), beta2 -microglobulin (P < 0·001), disease stage (P = 0·017) and extra-BM involvement (P = 0·002). In the 46 evaluable patients, multivariate analysis showed that high levels of suPAR (P = 0·0214) and disease stage (P = 0·0064) were predictive of extra-BM involvement. In multivariate Cox analysis, 13q deletion (P = 0·0278), high soluble serum CD138 (P = 0·0201) and high suPAR (P = 0·0229) were the only parameters that independently affected survival. We conclude that CD87 is expressed on myeloma plasma cells and that suPAR, which predicts extra-BM involvement and poor prognosis, possibly represents a molecule with a relevant role in the biology of MM. [source] Estrogen signaling pathway and its imaging in human breast cancerCANCER SCIENCE, Issue 10 2009Shin-ichi Hayashi Recent remarkable progress in hormonal therapy has provided great benefit to breast cancer patients, but it also evokes novel issues: how accurately can the efficacy of each hormonal therapy be predicted and how can hormonal therapy,resistant patients be treated? These clinically important issues must be closely related to the biological events in each cancer, such as the alteration of intracellular multiple estrogen signaling pathways and the estrogen-related cancer microenvironment, which has recently revealed by molecular biological studies on estrogen and its receptors. However, the estrogen signaling status in individual breast cancers has not been clarified yet. Here we present the context of these issues and introduce our study of new tools which enable the visualization of estrogen signals in individual cancers. The assessment of estrogen receptor (ER)-, activity in individual cancers or ER-activating ability of the cancer microenvironment in each breast cancer patient revealed several new findings and interesting observations. We hope that these approaches provide new clues about the estrogen-dependent mechanisms of breast cancer development, and will be useful to advance the diagnosis and treatment of breast cancer patients. (Cancer Sci 2009; 100: 1773,1778) [source] ADAMs in cancer cell proliferation and progressionCANCER SCIENCE, Issue 5 2007Satsuki Mochizuki A disintegrin and metalloproteinases (ADAMs) are a new gene family of proteins with sequence similarity to the reprolysin family of snake venomases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). They are structurally classified into two groups: the membrane-anchored ADAM and ADAM with thrombospondin motifs (ADAMTS). These molecules are involved in various biological events such as cell adhesion, cell fusion, cell migration, membrane protein shedding and proteolysis. Studies on the biochemical characteristics and biological functions of ADAMs are in progress, and accumulated lines of evidence have shown that some ADAMs are expressed in malignant tumors and participate in the pathology of cancers. The activities of ADAMs are regulated by gene expression, intracytoplasmic and pericellular regulation, activation of the zymogens and inhibition of activities by inhibitors. Many ADAM species, including ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19, ADAM28, ADAMTS1, ADAMTS4 and ADAMTS5, are expressed in human malignant tumors. Many of them are involved in the regulation of growth factor activities and integrin functions, leading to promotion of cell growth and invasion, although the precise mechanisms of these are not clear at the present time. In this article, we review recent information about ADAM family members and their implications for cancer cell proliferation and progression. (Cancer Sci 2007; 98: 621,628) [source] Technoreview: Focusing light on infection in four dimensionsCELLULAR MICROBIOLOGY, Issue 4 2004Pascal Roux Summary The fusion of cell biology with microbiology has bred a new discipline, cellular microbiology, in which the primary aim is to understand host,pathogen interactions at a tissue, cellular and molecular level. In this context, we require techniques allowing us to probe infection in situ and extrapolate quantitative information on its spatiotemporal dynamics. To these ends, fluorescent light-based imaging techniques offer a powerful tool, and the state-of-the-art is defined by paradigms using so-called multidimensional (multi-D) imaging microscopy. Multi-D imaging aims to visualize and quantify biological events through time and space and, more specifically, refers to combinations of: three (3D, volume), four (4D, time) and five (5D, multiwavelength)-dimensional recordings. Successful multi-D imaging depends upon understanding the available technologies and their limitations. This is especially true in the field of microbiology where visualization of infectious/pathogenic activities inside living host systems presents particular technical challenges. Thus, as multi-D imaging rapidly becomes a common bench tool to the cellular microbiologist, this review provides the new user with some of the necessary technical insight required to get the best from these methods. [source] Recent Progress in Strategies for the Creation of Protein-Based Fluorescent BiosensorsCHEMBIOCHEM, Issue 16 2009Hangxiang Wang Abstract The creation of novel bioanalytical tools for the detection and monitoring of a range of important target substances and biological events in vivo and in vitro is a great challenge in chemical biology and biotechnology. Protein-based fluorescent biosensors,integrated devices that convert a molecular-recognition event to a fluorescent signal,have recently emerged as a powerful tool. As the recognition units various proteins that can specifically recognize and bind a variety of molecules of biological significance with high affinity are employed. For the transducer, fluorescent proteins, such as green fluorescent protein (GFP) or synthetic fluorophores, are mostly adopted. Recent progress in protein engineering and organic synthesis allows us to manipulate proteins genetically and/or chemically, and a library of such protein scaffolds has been significantly expanded by genome projects. In this review, we briefly describe the recent progress of protein-based fluorescent biosensors on the basis of their platform and construction strategy, which are primarily divided into the genetically encoded fluorescent biosensors and chemically constructed biosensors. [source] Cornelia de Lange syndrome, cohesin, and beyondCLINICAL GENETICS, Issue 4 2009J Liu Cornelia de Lange syndrome (CdLS) (OMIM #122470, #300590 and #610759) is a dominant genetic disorder with multiple organ system abnormalities which is classically characterized by typical facial features, growth and mental retardation, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Mutations in three cohesin proteins, a key regulator of cohesin, NIPBL, and two structural components of the cohesin ring SMC1A and SMC3, etiologically account for about 65% of individuals with CdLS. Cohesin controls faithful chromosome segregation during the mitotic and meiotic cell cycles. Multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-strand DNA break repair and long-range regulation of transcription. Moreover, chromosome instability was recently associated with defective sister chromatid cohesion in several cancer studies, and an increasing number of human developmental disorders is being reported to result from disruption of this pathway. Here, we will discuss the human disorders caused by alterations of cohesin function (termed ,cohesinopathies'), with an emphasis on the clinical manifestations of CdLS and mechanistic studies of the CdLS-related proteins. [source] | ||||||||||||||||