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Sample records for pleiotropic activator prfa

A Naturally Occurring Mutation K220T in the Pleiotropic Activator PrfA of Listeria Monocytogenes Results in a Loss of Virulence Due to Decreasing DNA-Binding Affinity

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Velge,P.; Herler, M.; Johansson, J.; Roches, S.; Temoin, S.; Fedorov, A.; Gracieux, P.; Almo, S.; Goebel, W.; Cossart, P.

2007-01-01

The sequencing of prfA, encoding the transcriptional regulator of virulence genes, in 26 low-virulence field Listeria monocytogenes strains showed that eight strains exhibited the same single amino-acid substitution: PrfAK220T. These strains exhibited no expression of PrfA-regulated proteins and thus no virulence. This substitution inactivated PrfA, since expression of the PrfAK220T mutant gene in an EGD{Delta}prfA strain did not restore the haemolytic and phosphatidylcholine phospholipase C activities, in contrast to the wild-type prfA gene. The substitution of the lysine at position 220 occurred in the helix H. However, the data showed that the PrfAK220T protein is dimerized just as well as its wild-type counterpart, but does not bind to PrfA-boxes. PrfAK220T did not form a PrfA-DNA complex in electrophoretic mobility shift assays, but low concentrations of CI complexes (PrfAK220T-RNA polymerase-DNA complex) were formed by adding RNA polymerase, suggesting that PrfA interacted with RNA polymerase in solution in the absence of DNA. Formation of some transcriptionally active complexes was confirmed by in vitro runoff transcription assays and quantitative RT-PCR. Crystallographic analyses described the structure of native PrfA and highlighted the key role of allosteric changes in the activity of PrfA and especially the role of the Lys220 in the conformation of the helix-turn-helix (HTH) motif.
The virulence regulator PrfA promotes biofilm formation by Listeria monocytogenes.

Science.gov (United States)

Lemon, Katherine P; Freitag, Nancy E; Kolter, Roberto

2010-08-01

Listeria monocytogenes is a food-borne facultative intracellular pathogen. It is widespread in the environment and has several distinct life-styles. The key transcriptional activator PrfA positively regulates L. monocytogenes virulence genes to mediate the transition from extracellular, flagellum-propelled cell to intracellular pathogen. Here we report the first evidence that PrfA also has a significant positive impact on extracellular biofilm formation. Mutants lacking prfA were defective in surface-adhered biofilm formation. The DeltaprfA mutant exhibited wild-type flagellar motility, and its biofilm defect occurred after initial surface adhesion. We also observed that mutations that led to the constitutive expression of PrfA-dependent virulence genes had a minimal impact on biofilm formation. Furthermore, biofilm development was enhanced in a mutant encoding a PrfA protein variant unable to fully transition from the extracellular form to the virulent, intracellular activity conformation. These results indicate that PrfA positively regulates biofilm formation and suggest that PrfA has a global role in modulating the life-style of L. monocytogenes. The requirement of PrfA for optimal biofilm formation may provide selective pressure to maintain this critical virulence regulator when L. monocytogenes is outside host cells in the environment.
The metabolic regulator CodY links L. monocytogenes metabolism to virulence by directly activating the virulence regulatory gene, prfA

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Lobel, Lior; Sigal, Nadejda; Borovok, Ilya; Belitsky, Boris R.; Sonenshein, Abraham L.; Herskovits, Anat A.

2015-01-01

Summary Metabolic adaptations are critical to the ability of bacterial pathogens to grow within host cells and are normally preceded by sensing of host-specific metabolic signals, which in turn can influence the pathogen's virulence state. Previously, we reported that the intracellular bacterial pathogen Listeria monocytogenes responds to low availability of branched-chain amino acids (BCAA) within mammalian cells by up-regulating both BCAA biosynthesis and virulence genes. The induction of virulence genes required the BCAA-responsive transcription regulator, CodY, but the molecular mechanism governing this mode of regulation was unclear. In this report, we demonstrate that CodY directly binds the coding sequence of the L. monocytogenes master virulence activator gene, prfA, 15 nt downstream of its start codon, and that this binding results in up-regulation of prfA transcription specifically under low concentrations of BCAA. Mutating this site abolished CodY binding and reduced prfA transcription in macrophages, and attenuated bacterial virulence in mice. Notably, the mutated binding site did not alter prfA transcription or PrfA activity under other conditions that are known to activate PrfA, such as during growth in the presence of glucose-1-phosphate. This study highlights the tight crosstalk between L. monocytogenes metabolism and virulence' while revealing novel features of CodY-mediated regulation. PMID:25430920
Metabolic Genetic Screens Reveal Multidimensional Regulation of Virulence Gene Expression in Listeria monocytogenes and an Aminopeptidase That Is Critical for PrfA Protein Activation.

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Friedman, Sivan; Linsky, Marika; Lobel, Lior; Rabinovich, Lev; Sigal, Nadejda; Herskovits, Anat A

2017-06-01

Listeria monocytogenes is an environmental saprophyte and intracellular bacterial pathogen. Upon invading mammalian cells, the bacterium senses abrupt changes in its metabolic environment, which are rapidly transduced to regulation of virulence gene expression. To explore the relationship between L. monocytogenes metabolism and virulence, we monitored virulence gene expression dynamics across a library of genetic mutants grown under two metabolic conditions known to activate the virulent state: charcoal-treated rich medium containing glucose-1-phosphate and minimal defined medium containing limiting concentrations of branched-chain amino acids (BCAAs). We identified over 100 distinct mutants that exhibit aberrant virulence gene expression profiles, the majority of which mapped to nonessential metabolic genes. Mutants displayed enhanced, decreased, and early and late virulence gene expression profiles, as well as persistent levels, demonstrating a high plasticity in virulence gene regulation. Among the mutants, one was noteworthy for its particularly low virulence gene expression level and mapped to an X-prolyl aminopeptidase (PepP). We show that this peptidase plays a role in posttranslational activation of the major virulence regulator, PrfA. Specifically, PepP mediates recruitment of PrfA to the cytoplasmic membrane, a step identified as critical for PrfA protein activation. This study establishes a novel step in the complex mechanism of PrfA activation and further highlights the cross regulation of metabolism and virulence. Copyright © 2017 American Society for Microbiology.
Evaluation of the performance of quantitative detection of the Listeria monocytogenes prfA locus with droplet digital PCR.

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Witte, Anna Kristina; Fister, Susanne; Mester, Patrick; Schoder, Dagmar; Rossmanith, Peter

2016-11-01

Fast and reliable pathogen detection is an important issue for human health. Since conventional microbiological methods are rather slow, there is growing interest in detection and quantification using molecular methods. The droplet digital polymerase chain reaction (ddPCR) is a relatively new PCR method for absolute and accurate quantification without external standards. Using the Listeria monocytogenes specific prfA assay, we focused on the questions of whether the assay was directly transferable to ddPCR and whether ddPCR was suitable for samples derived from heterogeneous matrices, such as foodstuffs that often included inhibitors and a non-target bacterial background flora. Although the prfA assay showed suboptimal cluster formation, use of ddPCR for quantification of L. monocytogenes from pure bacterial cultures, artificially contaminated cheese, and naturally contaminated foodstuff was satisfactory over a relatively broad dynamic range. Moreover, results demonstrated the outstanding detection limit of one copy. However, while poorer DNA quality, such as resulting from longer storage, can impair ddPCR, internal amplification control (IAC) of prfA by ddPCR, that is integrated in the genome of L. monocytogenes ΔprfA, showed even slightly better quantification over a broader dynamic range. Graphical Abstract Evaluating the absolute quantification potential of ddPCR targeting Listeria monocytogenes prfA.
The chitinolytic activity of Listeria monocytogenes EGD is regulated by carbohydrates but also by the virulence regulator PrfA

DEFF Research Database (Denmark)

Larsen, Marianne Halberg; Leisner, Jørgen; Ingmer, Hanne

2010-01-01

Chitin, an insoluble polymer of N-acetyl-D-glucosamine (GlcNAc), is one of the most abundant carbohydrate polymers in marine and terrestrial environments. Chitin hydrolysis by Listeria monocytogenes depends on two chitinase-encoding genes, chiA and chiB, and the aim of this study was to investigate...... their regulation. Chitin induces the expression of both chitinases in late exponential growth phase, and chiA but not chiB is furthermore induced by the monomer GlcNAc. Furthermore, their expression is subjected to catabolite control. Chitinases expressed by bacterial pathogens have proven to be important not only...... in wild-type cells. In agreement with this, Northern blot analysis showed that the amounts of chiA and chiB transcripts upon induction by chitin were significantly lower in the prfA mutant than in the wild type. The chitinolytic activity and chiA and chiB expression were reduced in the absence of the sig...
Listeria-vectored vaccine expressing the Mycobacterium tuberculosis 30 kDa major secretory protein via the constitutively active prfA* regulon boosts BCG efficacy against tuberculosis.

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Jia, Qingmei; Dillon, Barbara Jane; Masleša-Galić, Saša; Horwitz, Marcus A

2017-06-19

A potent vaccine against tuberculosis, one of the world's deadliest diseases, is needed to enhance the immunity of people worldwide, most of whom have been vaccinated with the partially effective BCG vaccine. Here we investigate novel live attenuated recombinant Listeria monocytogenes (rLm) vaccines expressing the Mycobacterium tuberculosis (Mtb) 30 kDa major secretory protein (r30/Ag85B) (rLm30) as heterologous booster vaccines in animals primed with BCG. Using three attenuated Lm vectors, rLm Δ actA (LmI), rLm Δ actA Δ inlB (LmII), and rLm Δ actA Δ inlB prfA * (LmIII), we constructed five rLm30 vaccine candidates expressing the r30 linked in-frame to the Lm Listeriolycin O signal sequence and driven by the hly promoter (h30) or linked in-frame to the ActA N-terminus and driven by the actA promoter (a30). All five rLm30 vaccines secreted r30 in broth and macrophages; while rLm expressing r30 via a constitutively active prfA * regulon (rLmIII/a30) expressed the greatest amount of r30 in broth culture, all five rLm vaccines expressed equivalent amounts of r30 in infected macrophages. In comparative studies, boosting BCG-immunized mice with rLmIII/a30 induced the strongest antigen-specific T-cell responses, including splenic and lung polyfunctional CD4+ T-cells expressing the three cytokines of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) ( P vaccines were generally more potent booster vaccines than r30 in adjuvant and a recombinant adenovirus vaccine expressing r30. In a setting in which BCG alone was highly immunoprotective, boosting mice with rLmIII/a30, the most potent of the vaccines, significantly enhanced protection against aerosolized Mtb ( P <0.01). Copyright © 2017 American Society for Microbiology.
Antimicrobial medium- and long-chain free fatty acids prevent PrfA-dependent activation of virulence genes in Listeria monocytogenes

DEFF Research Database (Denmark)

Sternkopf Lillebæk, Eva Maria; Lambert Nielsen, Stine; Scheel Thomasen, Rikke

2017-01-01

of virulence factors required for bacterial entry, intracellular replication and cell-to-cell spread. PrfA-dependent activation of virulence genes occurs primarily in the blood and during intracellular infection. In contrast, PrfA does not play a significant role in regulation of virulence gene expression...... antimicrobial free fatty acids act to downregulate transcription of PrfA-activated virulence genes. Interestingly, the inhibitory effect is also evident in cells encoding a constitutively active variant of PrfA. Collectively, our data suggest that antimicrobial medium- and long-chain free fatty acids may act...... as signals to prevent PrfA-mediated activation of virulence genes in environments where PrfA activation is not required, such as in food and the gastrointestinal tract....
Pleiotropic Analysis of Lung Cancer and Blood Triglycerides

NARCIS (Netherlands)

Zuber, V.; Marconett, C.N.; Shi, J.; Hua, X.; Wheeler, W.; Yang, C.; Song, L; Dale, A.M.; Laplana, M.; Risch, A.; Witoelar, A.; Thompson, W.K.; Schork, A.J.; Bettella, F.; Wang, Y; Djurovic, S.; Zhou, B.; Borok, Z.; Heijden, H.F.M. van der; Graaf, J. de; Swinkels, D.W.; Aben, K.K.H.; McKay, J.; Hung, R.J.; Bikeboller, H.; Stevens, V.L.; Albanes, D.; Caporaso, N.E.; Han, Y.; Wei, Y.; Panadero, M.A.; Mayordomo, J.I.; Christiani, D.C.; Kiemeney, L.A.; Andreassen, O.A.; Houlston, R.; Amos, C.I.; Chatterjee, N.; Laird-Offringa, I.A.; Mills, I.G.; Landi, M.T.

2016-01-01

Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160
Apparent directional selection by biased pleiotropic mutation.

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Tanaka, Yoshinari

2010-07-01

Pleiotropic effects of deleterious mutations are considered to be among the factors responsible for genetic constraints on evolution by long-term directional selection acting on a quantitative trait. If pleiotropic phenotypic effects are biased in a particular direction, mutations generate apparent directional selection, which refers to the covariance between fitness and the trait owing to a linear association between the number of mutations possessed by individuals and the genotypic values of the trait. The present analysis has shown how the equilibrium mean value of the trait is determined by a balance between directional selection and biased pleiotropic mutations. Assuming that genes act additively both on the trait and on fitness, the total variance-standardized directional selection gradient was decomposed into apparent and true components. Experimental data on mutation bias from the bristle traits of Drosophila and life history traits of Daphnia suggest that apparent selection explains a small but significant fraction of directional selection pressure that is observed in nature; the data suggest that changes induced in a trait by biased pleiotropic mutation (i.e., by apparent directional selection) are easily compensated for by (true) directional selection.
Antimicrobial medium- and long-chain free fatty acids prevent PrfA-dependent activation of virulence genes in Listeria monocytogenes.

Science.gov (United States)

Sternkopf Lillebæk, Eva Maria; Lambert Nielsen, Stine; Scheel Thomasen, Rikke; Færgeman, Nils J; Kallipolitis, Birgitte H

The foodborne pathogen Listeria monocytogenes is the causative agent of the invasive disease listeriosis. Infection by L. monocytogenes involves bacterial crossing of the intestinal barrier and intracellular replication in a variety of host cells. The PrfA protein is the master regulator of virulence factors required for bacterial entry, intracellular replication and cell-to-cell spread. PrfA-dependent activation of virulence genes occurs primarily in the blood and during intracellular infection. In contrast, PrfA does not play a significant role in regulation of virulence gene expression in the intestinal environment. In the gastrointestinal phase of infection, the bacterium encounters a variety of antimicrobial agents, including medium- and long-chain free fatty acids that are commonly found in our diet and as active components of bile. Here we show that subinhibitory concentrations of specific antimicrobial free fatty acids act to downregulate transcription of PrfA-activated virulence genes. Interestingly, the inhibitory effect is also evident in cells encoding a constitutively active variant of PrfA. Collectively, our data suggest that antimicrobial medium- and long-chain free fatty acids may act as signals to prevent PrfA-mediated activation of virulence genes in environments where PrfA activation is not required, such as in food and the gastrointestinal tract. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
The Listeria monocytogenes Bile Stimulon under Acidic Conditions Is Characterized by Strain-Specific Patterns and the Upregulation of Motility, Cell Wall Modification Functions, and the PrfA Regulon

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Guariglia-Oropeza, Veronica; Orsi, Renato H.; Guldimann, Claudia; Wiedmann, Martin; Boor, Kathryn J.

2018-01-01

Listeria monocytogenes uses a variety of transcriptional regulation strategies to adapt to the extra-host environment, the gastrointestinal tract, and the intracellular host environment. While the alternative sigma factor SigB has been proposed to be a key transcriptional regulator that facilitates L. monocytogenes adaptation to the gastrointestinal environment, the L. monocytogenes' transcriptional response to bile exposure is not well-understood. RNA-seq characterization of the bile stimulon was performed in two L. monocytogenes strains representing lineages I and II. Exposure to bile at pH 5.5 elicited a large transcriptomic response with ~16 and 23% of genes showing differential transcription in 10403S and H7858, respectively. The bile stimulon includes genes involved in motility and cell wall modification mechanisms, as well as genes in the PrfA regulon, which likely facilitate survival during the gastrointestinal stages of infection that follow bile exposure. The fact that bile exposure induced the PrfA regulon, but did not induce further upregulation of the SigB regulon (beyond that expected by exposure to pH 5.5), suggests a model where at the earlier stages of gastrointestinal infection (e.g., acid exposure in the stomach), SigB-dependent gene expression plays an important role. Subsequent exposure to bile induces the PrfA regulon, potentially priming L. monocytogenes for subsequent intracellular infection stages. Some members of the bile stimulon showed lineage- or strain-specific distribution when 27 Listeria genomes were analyzed. Even though sigB null mutants showed increased sensitivity to bile, the SigB regulon was not found to be upregulated in response to bile beyond levels expected by exposure to pH 5.5. Comparison of wildtype and corresponding ΔsigB strains newly identified 26 SigB-dependent genes, all with upstream putative SigB-dependent promoters. PMID:29467736
ANGIOTENSIN RECEPTOR BLOCKERS WITH PLEIOTROPIC PROPERTIES: A NEW STANDARD IN CARDIOVASCULAR RISK MANAGEMENT AND TREATMENT OF HYPERTENSION

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V. I. Podzolkov

2017-01-01

Full Text Available An increase in the activity of the renin-angiotensin-aldosterone system is one of the most important mechanisms for the realization of the cardiovascular continuum. The role that angiotensin receptor blockers play in achieving target figures of blood pressure and reducing cardiovascular risk is discussed. The importance of pleiotropic properties of angiotensin receptor blockers (in particular, activation of peroxisome proliferator-activated receptors gamma – PPAR-γ in the management of patients with insulin resistance, obesity, dyslipidemia is also covered. The evidence base for the use of telmisartan as a drug with pleiotropic effect in patients with arterial hypertension and associated diseases (diabetes mellitus, obesity, renal dysfunction is discussed.
Are pleiotropic effects of statins real?

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Alberto Corsini

2007-11-01

Full Text Available Alberto Corsini, Nicola Ferri, Michele CortellaroDepartment of Pharmacological Sciences and Department of Clinical Sciences, “Luigi Sacco”, University of Milan, Milan, ItalyAbstract: The clinical benefits of statins are strongly related to their low density lipoproteincholesterol (LDL-C lowering properties. However, because mevalonic acid (MVA, the product of 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA reductase reaction, is the precursor not only of cholesterol but also of nonsteroidal isoprenoid compounds, the inhibition of HMG-CoA reductase may result in pleiotropic effects, independent of their hypocholesterolemic properties. The discrimination between the pleiotropic from LDL-C lowering effects may potentially be more evident during the early phase of treatment since plasma MVA levels drop up to 70% within 1–2 hours while a reduction of LDL-C, detectable after 24 hours, became significant after 6–7 days. Therefore, the deprivation of circulating MVA-derived isoprenoids in the early phase of treatment could be the main mechanism responsible for the atheroprotective effect of statins. This early window of protection in the absence of LDL-C lowering suggests that the anti-inflammatory and the pleiotropic properties of statins may have clinical importance. Therefore, acute coronary syndromes could represent a clinical condition for addressing the early benefits of statins therapy, ie, within 24 h of the event, independent of LDL-C lowering.Keywords: anti-inflammatory effects of statins, mevalonate pathway, LDL lowering, acute coronary syndrome, prenylated proteins
Pleiotropic effects of niacin: Current possibilities for its clinical use

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Zeman Miroslav

2016-12-01

Full Text Available Niacin was the first hypolipidemic drug to significantly reduce both major cardiovascular events and mortality in patients with cardiovascular disease. Niacin favorably influences all lipoprotein classes, including lipoprotein[a],and belongs to the most potent hypolipidemic drugs for increasing HDL-C. Moreover, niacin causes favorable changes to the qualitative composition of lipoprotein HDL. In addition to its pronounced hypolipidemic action, niacin exerts many other, non-hypolipidemic effects (e.g., antioxidative, anti-inflammatory, antithrombotic, which favorably influence the development and progression of atherosclerosis. These effects are dependent on activation of the specific receptor HCA2. Recent results published by the two large clinical studies, AIM-HIGH and HPS2-THRIVE, have led to the impugnation of niacin’s role in future clinical practice. However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.
Identification of a Peptide-Pheromone that Enhances Listeria monocytogenes Escape from Host Cell Vacuoles

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Xayarath, Bobbi; Alonzo, Francis; Freitag, Nancy E.

2015-01-01

Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following L. monocytogenes entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for L. monocytogenes secretion of a small peptide pheromone, pPplA, which enhances the escape of L. monocytogenes from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to L. monocytogenes its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol. PMID:25822753
Synthesis and Pharmacochemistry of New Pleiotropic Pyrrolyl Derivatives

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Markella Konstantinidou

2015-09-01

Full Text Available Within the framework of our attempts to synthesize pleiotropic anti-inflammatory agents, we have synthesized some chalcones and their corresponding 3,4-pyrrolyl derivatives. Chalcones constitute a class of compounds with high biological impact. They are known for a number of biological activities, including anti-inflammatory and free radical scavenging activities. They inhibit several enzymes implicated in the inflammatory process, such as lipoxygenase, cyclooxygenase (COX and lysozymes. The synthesized pyrroles have been studied for: (1 their in vitro inhibition of lipoxygenase; (2 their in vitro inhibition of COX; (3 their in vitro inhibition of lipid peroxidation; (4 their interaction with the stable, N-centered, free radical, 2,2-diphenyl-1-picrylhydrazyl (DPPH; (5 their inhibition on interleukin-6 (IL-6; (6 their anti-proteolytic activity; and (7 their in vivo anti-inflammatory activity using carrageenan-induced rat paw edema. Their physicochemical properties were determined to explain the biological results. Lipophilicity was experimentally determined. 2i and 2v were found to be promising multifunctional molecules with high antiproteolytic and anti-inflammatory activities in combination with anti-interleukin-6 activity.
Constrained vertebrate evolution by pleiotropic genes

DEFF Research Database (Denmark)

Hu, Haiyang; Uesaka, Masahiro; Guo, Song

2017-01-01

applied to vertebrates than chordates. Furthermore, we found that vertebrates' conserved mid-embryonic developmental programmes are intensively recruited to other developmental processes, and the degree of the recruitment positively correlates with their evolutionary conservation and essentiality...... for normal development. Thus, we propose that the intensively recruited genetic system during vertebrates' organogenesis period imposed constraints on its diversification through pleiotropic constraints, which ultimately led to the common anatomical pattern observed in vertebrates....
EDARV370A associated facial characteristics in Uyghur population revealing further pleiotropic effects.

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Peng, Qianqian; Li, Jinxi; Tan, Jingze; Yang, Yajun; Zhang, Manfei; Wu, Sijie; Liu, Yu; Zhang, Juan; Qin, Pengfei; Guan, Yaqun; Jiao, Yi; Zhang, Zhaoxia; Sabeti, Pardis C; Tang, Kun; Xu, Shuhua; Jin, Li; Wang, Sijia

2016-01-01

An adaptive variant of human Ectodysplasin receptor, EDARV370A, had undergone strong positive selection in East Asia. In mice and humans, EDARV370A was found to affect ectodermal-derived characteristics, including hair thickness, hair shape, active sweat gland density and teeth formation. Facial characteristics are also largely ectodermal derived. In this study, taking advantage of an admixed population of East Asian and European ancestry-the Uyghur, we aim to test whether EDARV370A is affecting facial characteristics and to investigate its pleiotropic nature and genetic model. In a sample of 1027 Uyghurs, we discover that EDARV370A is significantly associated with several facial characteristics, in particular shape of earlobe (P = 3.64 × 10 (-6) ) and type of chin (P = 9.23 × 10 (-5) ), with successful replication in other East Asian populations. Additionally, in this Uyghur population, we replicate previous association findings of incisors shoveling (P = 1.02 × 10 (-7) ), double incisors shoveling (P = 1.86 × 10 (-12) ) and hair straightness (P = 3.99 × 10 (-16) ), providing strong evidence supporting an additive model for the EDARV370A associations. Partial least square path model confirms EDARV370A systematically affect these weakly related ectodermal-derived characteristics, suggesting the pleiotropic effect of EDARV370A mainly plays roles in early embryo development. This study extends our knowledge about the pleiotropic nature of EDARV370A and provides potential clues to its adaptation fitness in human evolution.
Spontaneous Loss of Virulence in Natural Populations of Listeria monocytogenes.

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Maury, Mylène M; Chenal-Francisque, Viviane; Bracq-Dieye, Hélène; Han, Lei; Leclercq, Alexandre; Vales, Guillaume; Moura, Alexandra; Gouin, Edith; Scortti, Mariela; Disson, Olivier; Vázquez-Boland, José A; Lecuit, Marc

2017-11-01

The pathogenesis of Listeria monocytogenes depends on the ability of this bacterium to escape from the phagosome of the host cells via the action of the pore-forming toxin listeriolysin O (LLO). Expression of the LLO-encoding gene ( hly ) requires the transcriptional activator PrfA, and both hly and prfA genes are essential for L. monocytogenes virulence. Here, we used the hemolytic activity of LLO as a phenotypic marker to screen for spontaneous virulence-attenuating mutations in L. monocytogenes Sixty nonhemolytic isolates were identified among a collection of 57,820 confirmed L. monocytogenes strains isolated from a variety of sources (0.1%). In most cases (56/60; 93.3%), the nonhemolytic phenotype resulted from nonsense, missense, or frameshift mutations in prfA Five strains carried hly mutations leading to a single amino acid substitution (G299V) or a premature stop codon causing strong virulence attenuation in mice. In one strain, both hly and gshF (encoding a glutathione synthase required for full PrfA activity) were missing due to genomic rearrangements likely caused by a transposable element. The PrfA/LLO loss-of-function (PrfA - /LLO - ) mutants belonged to phylogenetically diverse clades of L. monocytogenes , and most were identified among nonclinical strains (57/60). Consistent with the rare occurrence of loss-of-virulence mutations, we show that prfA and hly are under purifying selection. Although occurring at a low frequency, PrfA - /LLO - mutational events in L. monocytogenes lead to niche restriction and open an evolutionary path for obligate saprophytism in this facultative intracellular pathogen. Copyright © 2017 Maury et al.

PAPA: a flexible tool for identifying pleiotropic pathways using genome-wide association study summaries.

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Wen, Yan; Wang, Wenyu; Guo, Xiong; Zhang, Feng

2016-03-15

: Pleiotropy is common in the genetic architectures of complex diseases. To the best of our knowledge, no analysis tool has been developed for identifying pleiotropic pathways using multiple genome-wide association study (GWAS) summaries by now. Here, we present PAPA, a flexible tool for pleiotropic pathway analysis utilizing GWAS summary results. The performance of PAPA was validated using publicly available GWAS summaries of body mass index and waist-hip ratio of the GIANT datasets. PAPA identified a set of pleiotropic pathways, which have been demonstrated to be involved in the development of obesity. PAPA program, document and illustrative example are available at http://sourceforge.net/projects/papav1/files/ : fzhxjtu@mail.xjtu.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Pleiotropic effects of herbicide-resistance genes on crop yield: a review.

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Darmency, Henri

2013-08-01

The rapid adoption of genetically engineered herbicide-resistant crop varieties (HRCVs)-encompassing 83% of all GM crops and nearly 8% of the worldwide arable area-is due to technical efficiency and higher returns. Other herbicide-resistant varieties obtained from genetic resources and mutagenesis have also been successfully released. Although the benefit for weed control is the main criteria for choosing HRCVs, the pleiotropic costs of genes endowing resistance have rarely been investigated in crops. Here the available data of comparisons between isogenic resistant and susceptible varieties are reviewed. Pleiotropic harmful effects on yield are reported in half of the cases, mostly with resistance mechanisms that originate from genetic resources and mutagenesis (atrazine in oilseed rape and millet, trifluralin in millet, imazamox in cotton) rather than genetic engineering (chlorsulfuron and glufosinate in some oilseed rape varieties, glyphosate in soybean). No effect was found for sethoxydim and bromoxynil resistance. Variable minor effects were found for imazamox, chlorsulfuron, glufosinate and glyphosate resistance. The importance of the breeding plan and the genetic background on the emergence of these effects is pointed out. Breeders' efforts to produce better varieties could compensate for the yield loss, which eliminates any possibility of formulating generic conclusions on pleiotropic effects that can be applied to all resistant crops. © 2013 Society of Chemical Industry.
Chinese hamster pleiotropic multidrug-resistant cells are not radioresistant

International Nuclear Information System (INIS)

Mitchell, J.B.; Gamson, J.; Russo, A.; Friedman, N.; DeGraff, W.; Carmichael, J.; Glatstein, E.

1988-01-01

The inherent cellular radiosensitivity of a Chinese hamster ovary pleiotropic cell line that is multidrug resistant (CHRC5) was compared to that of its parental cell line (AuxB1). Radiation survival curve parameters n and D0 were 4.5 and 1.1 Gy, respectively, for the CHRC5 line and 5.0 and 1.2 Gy, respectively, for the parental line. Thus, the inherent radiosensitivity of the two lines was similar even though key intracellular free radical scavenging and detoxifying systems employing glutathione, glutathione transferase, and catalase produced enzyme levels that were 2.0-, 1.9-, and 1.9-fold higher, respectively, in the drug-resistant cell line. Glutathione depletion by buthionine sulfoximine resulted in the same extent of aerobic radiosensitization in both lines (approximately 10%). Incorporation of iododeoxyuridine into cellular DNA sensitized both cell lines to radiation. These studies indicate that pleiotropic drug resistance does not necessarily confer radiation resistance
Assessment of pleiotropic transcriptome perturbations in Arabidopsis engineered for indirect insect defence.

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Houshyani, Benyamin; van der Krol, Alexander R; Bino, Raoul J; Bouwmeester, Harro J

2014-06-19

Molecular characterization is an essential step of risk/safety assessment of genetically modified (GM) crops. Holistic approaches for molecular characterization using omics platforms can be used to confirm the intended impact of the genetic engineering, but can also reveal the unintended changes at the omics level as a first assessment of potential risks. The potential of omics platforms for risk assessment of GM crops has rarely been used for this purpose because of the lack of a consensus reference and statistical methods to judge the significance or importance of the pleiotropic changes in GM plants. Here we propose a meta data analysis approach to the analysis of GM plants, by measuring the transcriptome distance to untransformed wild-types. In the statistical analysis of the transcriptome distance between GM and wild-type plants, values are compared with naturally occurring transcriptome distances in non-GM counterparts obtained from a database. Using this approach we show that the pleiotropic effect of genes involved in indirect insect defence traits is substantially equivalent to the variation in gene expression occurring naturally in Arabidopsis. Transcriptome distance is a useful screening method to obtain insight in the pleiotropic effects of genetic modification.
Why pleiotropic interventions are needed for Alzheimer's disease.

Science.gov (United States)

Frautschy, Sally A; Cole, Greg M

2010-06-01

drugs or cocktails that can independently limit the parallel steps of the AD cascade at all stages, but that do not completely inhibit the constitutive normal functions of these pathways. Based on this hypothesis, efforts in our laboratories have focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin in multiple models that cover many steps of the AD pathogenic cascade (Cole and Frautschy, Alzheimers Dement 2:284-286, 2006).
Pleiotropic effects of niacin: current possibilities for its clinical use

Czech Academy of Sciences Publication Activity Database

Zeman, M.; Vecka, M.; Perlík, F.; Staňková, B.; Hromádka, R.; Tvrzická, E.; Širc, Jakub; Hrib, Jakub; Žák, A.

2016-01-01

Roč. 66, č. 4 (2016), s. 449-469 ISSN 1330-0075 R&D Projects: GA MPO(CZ) FR-TI4/638 Institutional support: RVO:61389013 Keywords : niacin * pleiotropic effects * HCA2 receptor Subject RIV: CD - Macromolecular Chemistry Impact factor: 1.288, year: 2016
Pleiotropic Genes Affecting Carcass Traits in Bos indicus (Nellore Cattle Are Modulators of Growth.

Directory of Open Access Journals (Sweden)

Anirene G T Pereira

Full Text Available Two complementary methods, namely Multi-Trait Meta-Analysis and Versatile Gene-Based Test for Genome-wide Association Studies (VEGAS, were used to identify putative pleiotropic genes affecting carcass traits in Bos indicus (Nellore cattle. The genotypic data comprised over 777,000 single-nucleotide polymorphism markers scored in 995 bulls, and the phenotypic data included deregressed breeding values (dEBV for weight measurements at birth, weaning and yearling, as well visual scores taken at weaning and yearling for carcass finishing precocity, conformation and muscling. Both analyses pointed to the pleomorphic adenoma gene 1 (PLAG1 as a major pleiotropic gene. VEGAS analysis revealed 224 additional candidates. From these, 57 participated, together with PLAG1, in a network involved in the modulation of the function and expression of IGF1 (insulin like growth factor 1, IGF2 (insulin like growth factor 2, GH1 (growth hormone 1, IGF1R (insulin like growth factor 1 receptor and GHR (growth hormone receptor, suggesting that those pleiotropic genes operate as satellite regulators of the growth pathway.
The pleiotropic effects of paricalcitol: Beyond bone-mineral metabolism.

Science.gov (United States)

Egido, Jesús; Martínez-Castelao, Alberto; Bover, Jordi; Praga, Manuel; Torregrosa, José Vicente; Fernández-Giráldez, Elvira; Solozábal, Carlos

2016-01-01

Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease (CKD) that is characterised by elevated parathyroid hormone (PTH) levels and a series of bone-mineral metabolism anomalies. In patients with SHPT, treatment with paricalcitol, a selective vitamin D receptor activator, has been shown to reduce PTH levels with minimal serum calcium and phosphorus variations. The classic effect of paricalcitol is that of a mediator in mineral and bone homeostasis. However, recent studies have suggested that the benefits of treatment with paricalcitol go beyond PTH reduction and, for instance, it has a positive effect on cardiovascular disease and survival. The objective of this study is to review the most significant studies on the so-called pleiotropic effects of paricalcitol treatment in patients with CKD. Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.
Pleiotropic effects of coat colour-associated mutations in humans, mice and other mammals.

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Reissmann, Monika; Ludwig, Arne

2013-01-01

The characterisation of the pleiotropic effects of coat colour-associated mutations in mammals illustrates that sensory organs and nerves are particularly affected by disorders because of the shared origin of melanocytes and neurocytes in the neural crest; e.g. the eye-colour is a valuable indicator of disorders in pigment production and eye dysfunctions. Disorders related to coat colour-associated alleles also occur in the skin (melanoma), reproductive tract and immune system. Additionally, the coat colour phenotype of an individual influences its general behaviour and fitness. Mutations in the same genes often produce similar coat colours and pleiotropic effects in different species (e.g., KIT [reproductive disorders, lethality], EDNRB [megacolon] and LYST [CHS]). Whereas similar disorders and similar-looking coat colour phenotypes sometimes have a different genetic background (e.g., deafness [EDN3/EDNRB, MITF, PAX and SNAI2] and visual diseases [OCA2, RAB38, SLC24A5, SLC45A2, TRPM1 and TYR]). The human predilection for fancy phenotypes that ignore disorders and genetic defects is a major driving force for the increase of pleiotropic effects in domestic species and laboratory subjects since domestication has commenced approximately 18,000 years ago. Copyright © 2013 Elsevier Ltd. All rights reserved.
Pleiotropic Analysis of Lung Cancer and Blood Triglycerides.

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Zuber, Verena; Marconett, Crystal N; Shi, Jianxin; Hua, Xing; Wheeler, William; Yang, Chenchen; Song, Lei; Dale, Anders M; Laplana, Marina; Risch, Angela; Witoelar, Aree; Thompson, Wesley K; Schork, Andrew J; Bettella, Francesco; Wang, Yunpeng; Djurovic, Srdjan; Zhou, Beiyun; Borok, Zea; van der Heijden, Henricus F M; de Graaf, Jacqueline; Swinkels, Dorine; Aben, Katja K; McKay, James; Hung, Rayjean J; Bikeböller, Heike; Stevens, Victoria L; Albanes, Demetrius; Caporaso, Neil E; Han, Younghun; Wei, Yongyue; Panadero, Maria Angeles; Mayordomo, Jose I; Christiani, David C; Kiemeney, Lambertus; Andreassen, Ole A; Houlston, Richard; Amos, Christopher I; Chatterjee, Nilanjan; Laird-Offringa, Ite A; Mills, Ian G; Landi, Maria Teresa

2016-12-01

Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.
Pleiotropic effects of hemagglutinin amino acid substitutions of H5 influenza escape mutants

International Nuclear Information System (INIS)

Rudneva, Irina A.; Timofeeva, Tatiana A.; Ignatieva, Anna V.; Shilov, Aleksandr A.; Krylov, Petr S.; Ilyushina, Natalia A.; Kaverin, Nikolai V.

2013-01-01

In the present study we assessed pleiotropic characteristics of the antibody-selected mutations. We examined pH optimum of fusion, temperatures of HA heat inactivation, and in vitro and in vivo replication kinetics of the previously obtained influenza H5 escape mutants. Our results showed that HA1 N142K mutation significantly lowered the pH of fusion optimum. Mutations of the escape mutants located in the HA lateral loop significantly affected H5 HA thermostability (P<0.05). HA changes at positions 131, 144, 145, and 156 and substitutions at positions 131, 142, 145, and 156 affected the replicative ability of H5 escape mutants in vitro and in vivo, respectively. Overall, a co-variation between antigenic specificity and different HA phenotypic properties has been demonstrated. We believe that the monitoring of pleiotropic effects of the HA mutations found in H5 escape mutants is essential for accurate prediction of mutants with pandemic potential. - Highlights: • HA1 N142K mutation significantly lowered the pH of fusion optimum. • Mutations located in the HA lateral loop significantly affected H5 HA thermostability. • HA changes at positions 131, 142, 144, 145, and 156 affected the replicative ability of H5 mutants. • Acquisition of glycosylation site could lead to the emergence of multiple pleiotropic effects
Pleiotropic effects of hemagglutinin amino acid substitutions of H5 influenza escape mutants

Energy Technology Data Exchange (ETDEWEB)

Rudneva, Irina A.; Timofeeva, Tatiana A.; Ignatieva, Anna V.; Shilov, Aleksandr A.; Krylov, Petr S. [D.I. Ivanovsky Institute of Virology, 123098 Moscow (Russian Federation); Ilyushina, Natalia A., E-mail: Natalia.Ilyushina@fda.hhs.gov [FDA CDER, 29 Lincoln Drive, Bethesda, MD 20892 (United States); Kaverin, Nikolai V., E-mail: nik.kaverin@gmail.com [D.I. Ivanovsky Institute of Virology, 123098 Moscow (Russian Federation)

2013-12-15

In the present study we assessed pleiotropic characteristics of the antibody-selected mutations. We examined pH optimum of fusion, temperatures of HA heat inactivation, and in vitro and in vivo replication kinetics of the previously obtained influenza H5 escape mutants. Our results showed that HA1 N142K mutation significantly lowered the pH of fusion optimum. Mutations of the escape mutants located in the HA lateral loop significantly affected H5 HA thermostability (P<0.05). HA changes at positions 131, 144, 145, and 156 and substitutions at positions 131, 142, 145, and 156 affected the replicative ability of H5 escape mutants in vitro and in vivo, respectively. Overall, a co-variation between antigenic specificity and different HA phenotypic properties has been demonstrated. We believe that the monitoring of pleiotropic effects of the HA mutations found in H5 escape mutants is essential for accurate prediction of mutants with pandemic potential. - Highlights: • HA1 N142K mutation significantly lowered the pH of fusion optimum. • Mutations located in the HA lateral loop significantly affected H5 HA thermostability. • HA changes at positions 131, 142, 144, 145, and 156 affected the replicative ability of H5 mutants. • Acquisition of glycosylation site could lead to the emergence of multiple pleiotropic effects.
Genetic effects at pleiotropic loci are context-dependent with consequences for the maintenance of genetic variation in populations.

Directory of Open Access Journals (Sweden)

Heather A Lawson

2011-09-01

Full Text Available Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS components (obesity, dyslipidemia, and diabetes-related traits. MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL in an F(16 advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl:LG,SM-G16; n = 1002. Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over- or underdominance and ecological cross-over interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.
Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

Science.gov (United States)

Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fred; Schildkraut, Joellen; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Olama, Ali Amin Al; Berndt, Sonja I; Giovannucci, Edward; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter; Goode, Ellen L.; Permuth, Jennifer; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma’en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

2016-01-01

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. PMID:27197191
Pleiotropic effects of flowering time genes in the annual crucifer Arabidopsis thaliana (Brassicaceae)

NARCIS (Netherlands)

Van Tienderen, P.H.; Hammad, I.; Zwaal, F.C.

1996-01-01

Variation in flowering time of Arabidopsis thaliana was studied in an experiment with mutant lines. The pleiotropic effects of flowering time genes on morphology and reproductive yield were assessed under three levels of nutrient supply. At all nutrient levels flowering time and number of rosette
Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

Science.gov (United States)

Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D; Eeles, Rosalind A; Chatterjee, Nilanjan; Schumacher, Fredrick R; Schildkraut, Joellen M; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Amin Al Olama, Ali; Berndt, Sonja I; Giovannucci, Edward L; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J; Stevens, Victoria L; Wiklund, Fredrik; Willett, Walter C; Goode, Ellen L; Permuth, Jennifer B; Risch, Harvey A; Reid, Brett M; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hudson, Thomas J; Kocarnik, Jonathan K; Newcomb, Polly A; Schoen, Robert E; Slattery, Martha L; White, Emily; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-Silva, Isabel; Eliassen, A Heather; Figueroa, Jonine D; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A; Nevanlinna, Heli; Peeters, Petra H; Peto, Julian; Prentice, Ross L; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F; Schmutzler, Rita K; Southey, Melissa C; Tamimi, Rulla; Travis, Ruth C; Turnbull, Clare; Uitterlinden, Andre G; Wang, Zhaoming; Whittemore, Alice S; Yang, Xiaohong R; Zheng, Wei; Buchanan, Daniel D; Casey, Graham; Conti, David V; Edlund, Christopher K; Gallinger, Steven; Haile, Robert W; Jenkins, Mark; Le Marchand, Loïc; Li, Li; Lindor, Noralene M; Schmit, Stephanie L; Thibodeau, Stephen N; Woods, Michael O; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N; Stefansson, Kari; Sulem, Patrick; Chen, Y Ann; Tyrer, Jonathan P; Christiani, David C; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J; Gong, Jian; Peters, Ulrike; Gruber, Stephen B; Amos, Christopher I; Sellers, Thomas A; Easton, Douglas F; Hunter, David J; Haiman, Christopher A; Henderson, Brian E; Hung, Rayjean J

2016-09-01

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR. ©2016 American Association for Cancer Research.
Constrained vertebrate evolution by pleiotropic genes.

Science.gov (United States)

Hu, Haiyang; Uesaka, Masahiro; Guo, Song; Shimai, Kotaro; Lu, Tsai-Ming; Li, Fang; Fujimoto, Satoko; Ishikawa, Masato; Liu, Shiping; Sasagawa, Yohei; Zhang, Guojie; Kuratani, Shigeru; Yu, Jr-Kai; Kusakabe, Takehiro G; Khaitovich, Philipp; Irie, Naoki

2017-11-01

Despite morphological diversification of chordates over 550 million years of evolution, their shared basic anatomical pattern (or 'bodyplan') remains conserved by unknown mechanisms. The developmental hourglass model attributes this to phylum-wide conserved, constrained organogenesis stages that pattern the bodyplan (the phylotype hypothesis); however, there has been no quantitative testing of this idea with a phylum-wide comparison of species. Here, based on data from early-to-late embryonic transcriptomes collected from eight chordates, we suggest that the phylotype hypothesis would be better applied to vertebrates than chordates. Furthermore, we found that vertebrates' conserved mid-embryonic developmental programmes are intensively recruited to other developmental processes, and the degree of the recruitment positively correlates with their evolutionary conservation and essentiality for normal development. Thus, we propose that the intensively recruited genetic system during vertebrates' organogenesis period imposed constraints on its diversification through pleiotropic constraints, which ultimately led to the common anatomical pattern observed in vertebrates.
Logistic regression models for polymorphic and antagonistic pleiotropic gene action on human aging and longevity

DEFF Research Database (Denmark)

Tan, Qihua; Bathum, L; Christiansen, L

2003-01-01

In this paper, we apply logistic regression models to measure genetic association with human survival for highly polymorphic and pleiotropic genes. By modelling genotype frequency as a function of age, we introduce a logistic regression model with polytomous responses to handle the polymorphic...... situation. Genotype and allele-based parameterization can be used to investigate the modes of gene action and to reduce the number of parameters, so that the power is increased while the amount of multiple testing minimized. A binomial logistic regression model with fractional polynomials is used to capture...... the age-dependent or antagonistic pleiotropic effects. The models are applied to HFE genotype data to assess the effects on human longevity by different alleles and to detect if an age-dependent effect exists. Application has shown that these methods can serve as useful tools in searching for important...
Docosahexaenoic Acid Reduces Amyloid β Production via Multiple Pleiotropic Mechanisms*

Science.gov (United States)

Grimm, Marcus O. W.; Kuchenbecker, Johanna; Grösgen, Sven; Burg, Verena K.; Hundsdörfer, Benjamin; Rothhaar, Tatjana L.; Friess, Petra; de Wilde, Martijn C.; Broersen, Laus M.; Penke, Botond; Péter, Mária; Vígh, László; Grimm, Heike S.; Hartmann, Tobias

2011-01-01

Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing β- and γ-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in γ-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release. DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects. PMID:21324907
Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Directory of Open Access Journals (Sweden)

Alena Pecinova

2017-01-01

Full Text Available Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases, but only at very high concentrations (10−2–10−1 M that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.

Pleiotropic effects of type 2 diabetes management strategies on renal risk factors.

Science.gov (United States)

Muskiet, Marcel H A; Tonneijck, Lennart; Smits, Mark M; Kramer, Mark H H; Heerspink, Hiddo J Lambers; van Raalte, Daniël H

2015-05-01

In parallel with the type 2 diabetes pandemic, diabetic kidney disease has become the leading cause of end-stage renal disease worldwide, and is associated with high cardiovascular morbidity and mortality. As established in landmark randomised trials and recommended in clinical guidelines, prevention and treatment of diabetic kidney disease focuses on control of the two main renal risk factors, hyperglycaemia and systemic hypertension. Treatment of systemic hypertension with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers is advocated because these drugs seem to exert specific renoprotective effects beyond blood pressure lowering. Emerging evidence shows that obesity, glomerular hyperfiltration, albuminuria, and dyslipidaemia might also adversely affect the kidney in diabetes. Control of these risk factors could have additional benefits on renal outcome in patients with type 2 diabetes. However, despite multifactorial treatment approaches, residual risk for the development and progression of diabetic kidney disease in patients with type 2 diabetes remains, and novel strategies or therapies to treat the disease are urgently needed. Several drugs used in the treatment of type 2 diabetes are associated with pleiotropic effects that could favourably or unfavourably change patients' renal risk profile. We review the risk factors and treatment of diabetic kidney disease, and describe the pleiotropic effects of widely used drugs in type 2 diabetes management on renal outcomes, with special emphasis on antihyperglycaemic drugs. Copyright © 2015 Elsevier Ltd. All rights reserved.
Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin.

Science.gov (United States)

Makitrynskyy, Roman; Ostash, Bohdan; Tsypik, Olga; Rebets, Yuriy; Doud, Emma; Meredith, Timothy; Luzhetskyy, Andriy; Bechthold, Andreas; Walker, Suzanne; Fedorenko, Victor

2013-10-23

Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs). This raises questions about the regulatory signals that initiate and sustain moenomycin production. We now show that three pleiotropic regulatory genes for Streptomyces morphogenesis and antibiotic production-bldA, adpA and absB-exert multi-layered control over moenomycin biosynthesis in native and heterologous producers. The bldA gene for tRNA(Leu)UAA is required for the translation of rare UUA codons within two key moenomycin biosynthetic genes (moe), moeO5 and moeE5. It also indirectly influences moenomycin production by controlling the translation of the UUA-containing adpA and, probably, other as-yet-unknown repressor gene(s). AdpA binds key moe promoters and activates them. Furthermore, AdpA interacts with the bldA promoter, thus impacting translation of bldA-dependent mRNAs-that of adpA and several moe genes. Both adpA expression and moenomycin production are increased in an absB-deficient background, most probably because AbsB normally limits adpA mRNA abundance through ribonucleolytic cleavage. Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs. This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining.
Global Rebalancing of Cellular Resources by Pleiotropic Point Mutations Illustrates a Multi-scale Mechanism of Adaptive Evolution

DEFF Research Database (Denmark)

Utrilla, José; O'Brien, Edward J.; Chen, Ke

2016-01-01

Pleiotropic regulatory mutations affect diverse cellular processes, posing a challenge to our understanding of genotype-phenotype relationships across multiple biological scales. Adaptive laboratory evolution (ALE) allows for such mutations to be found and characterized in the context of clear se...
Cross-cancer genome-wide analysis of lung, ovary, breast, prostate, and colorectal cancer reveals novel pleiotropic associations

NARCIS (Netherlands)

Fehringer, G. (Gordon); P. Kraft (Peter); P.D.P. Pharoah (Paul); R. Eeles (Rosalind); Chatterjee, N. (Nilanjan); F.R. Schumacher (Fredrick R); J.M. Schildkraut (Joellen); S. Lindstrom (Stephen); P. Brennan (Paul); H. Bickeböller (Heike); R. Houlston (Richard); M.T. Landi (Maria Teresa); N.E. Caporaso (Neil); Risch, A. (Angela); A.A. Al Olama (Ali Amin); S.I. Berndt (Sonja); Giovannucci, E.L. (Edward L.); H. Grönberg (Henrik); Z. Kote-Jarai; Ma, J. (Jing); K.R. Muir (K.); M.J. Stampfer (Meir J.); Stevens, V.L. (Victoria L.); F. Wiklund (Fredrik); W.C. Willett (Walter C.); E.L. Goode (Ellen); Permuth, J.B. (Jennifer B.); H. Risch (Harvey); Reid, B.M. (Brett M.); Bezieau, S. (Stephane); H. Brenner (Hermann); Chan, A.T. (Andrew T.); J. Chang-Claude (Jenny); T.J. Hudson (Thomas); Kocarnik, J.K. (Jonathan K.); P. Newcomb (Polly); Schoen, R.E. (Robert E.); Slattery, M.L. (Martha L.); White, E. (Emily); M.A. Adank (Muriel); H. Ahsan (Habibul); K. Aittomäki (Kristiina); Baglietto, L. (Laura); Blomquist, C. (Carl); F. Canzian (Federico); K. Czene (Kamila); I. dos Santos Silva (Isabel); Eliassen, A.H. (A. Heather); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); O. Fletcher (Olivia); M. García-Closas (Montserrat); M.M. Gaudet (Mia); Johnson, N. (Nichola); P. Hall (Per); A. Hazra (Aditi); R. Hein (Rebecca); Hofman, A. (Albert); J.L. Hopper (John); A. Irwanto (Astrid); M. Johansson (Mattias); R. Kaaks (Rudolf); M.G. Kibriya (Muhammad); P. Lichtner (Peter); J. Liu (Jianjun); E. Lund (Eiliv); Makalic, E. (Enes); A. Meindl (Alfons); B. Müller-Myhsok (B.); Muranen, T.A. (Taru A.); H. Nevanlinna (Heli); P.H.M. Peeters; J. Peto (Julian); R. Prentice (Ross); N. Rahman (Nazneen); M.-J. Sanchez (Maria-Jose); D.F. Schmidt (Daniel); R.K. Schmutzler (Rita); M.C. Southey (Melissa); Tamimi, R. (Rulla); S.P.L. Travis (Simon); C. Turnbull (Clare); Uitterlinden, A.G. (Andre G.); Z. Wang (Zhaoming); A.S. Whittemore (Alice); X.R. Yang (Xiaohong); W. Zheng (Wei); D. Buchanan (Daniel); G. Casey (Graham); G. Conti (Giario); C.K. Edlund (Christopher); S. Gallinger (Steve); R. Haile (Robert); M. Jenkins (Mark); Marchand, L. (Loïcle); Li, L. (Li); N.M. Lindor (Noralane); Schmit, S.L. (Stephanie L.); S.N. Thibodeau (Stephen); M.O. Woods (Michael); T. Rafnar (Thorunn); J. Gudmundsson (Julius); S.N. Stacey (Simon); Stefansson, K. (Kari); P. Sulem (Patrick); Chen, Y.A. (Y. Ann); J.P. Tyrer (Jonathan); Christiani, D.C. (David C.); Wei, Y. (Yongyue); H. Shen (Hongbing); Z. Hu (Zhibin); X.-O. Shu (Xiao-Ou); Shiraishi, K. (Kouya); A. Takahashi (Atsushi); Y. Bossé (Yohan); M. Obeidat (Ma'en); D.C. Nickle (David); W. Timens (Wim); M. Freedman (Matthew); Li, Q. (Qiyuan); D. Seminara (Daniela); S.J. Chanock (Stephen); Gong, J. (Jian); U. Peters (Ulrike); S.B. Gruber (Stephen); Amos, C.I. (Christopher I.); T.A. Sellers (Thomas A.); D.F. Easton (Douglas F.); D. Hunter (David); C.A. Haiman (Christopher A.); B.E. Henderson (Brian); R.J. Hung (Rayjean)

2016-01-01

textabstractIdentifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851
Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

NARCIS (Netherlands)

Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindstrom, Sara; Brennan, Paul; Bickeboller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Gronberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomaki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Timens, Wim

2016-01-01

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820
Cross-cancer genome-wide analysis of lung, ovary, breast, prostate, and colorectal cancer reveals novel pleiotropic associations

NARCIS (Netherlands)

Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Buchanan, Daniel D.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Gallinger, Steven; Haile, Robert W.; Jenkins, Mark; Marchand, Loïcle; Li, Li; Lindor, Noralene M.; Schmit, Stephanie L.; Thibodeau, Stephen N.; Woods, Michael O.; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

2016-01-01

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820
Pleiotropic roles of Clostridium difficile sin locus

Science.gov (United States)

Ou, Junjun; Dupuy, Bruno

2018-01-01

Clostridium difficile is the primary cause of nosocomial diarrhea and pseudomembranous colitis. It produces dormant spores, which serve as an infectious vehicle responsible for transmission of the disease and persistence of the organism in the environment. In Bacillus subtilis, the sin locus coding SinR (113 aa) and SinI (57 aa) is responsible for sporulation inhibition. In B. subtilis, SinR mainly acts as a repressor of its target genes to control sporulation, biofilm formation, and autolysis. SinI is an inhibitor of SinR, so their interaction determines whether SinR can inhibit its target gene expression. The C. difficile genome carries two sinR homologs in the operon that we named sinR and sinR’, coding for SinR (112 aa) and SinR’ (105 aa), respectively. In this study, we constructed and characterized sin locus mutants in two different C. difficile strains R20291 and JIR8094, to decipher the locus’s role in C. difficile physiology. Transcriptome analysis of the sinRR’ mutants revealed their pleiotropic roles in controlling several pathways including sporulation, toxin production, and motility in C. difficile. Through various genetic and biochemical experiments, we have shown that SinR can regulate transcription of key regulators in these pathways, which includes sigD, spo0A, and codY. We have found that SinR’ acts as an antagonist to SinR by blocking its repressor activity. Using a hamster model, we have also demonstrated that the sin locus is needed for successful C. difficile infection. This study reveals the sin locus as a central link that connects the gene regulatory networks of sporulation, toxin production, and motility; three key pathways that are important for C. difficile pathogenesis. PMID:29529083
Evidence of a major locus for lipoprotein lipase (LPL) activity in addition to a pleiotropic locus for both LPL and fasting insulin: results from the HERITAGE Family Study.

Science.gov (United States)

Hong, Y; Rice, T; Després, J P; Gagnon, J; Nadeau, A; Bergeron, J; Pérusse, L; Bouchard, C; Leon, A S; Skinner, J S; Wilmore, J H; Rao, D C

1999-06-01

A major gene hypothesis for heparin releasable plasma lipoprotein lipase (PH-LPL) activity was assessed using segregation analyses of data on 495 members in 98 normolipidemic sedentary families of Caucasian descent who participated in the HERITAGE Family Study. Segregation analyses were performed on PH-LPL adjusted for age, and on PH-LPL activity adjusted for age and fasting insulin. Prior to adjustment for insulin, neither a major gene effect nor a multifactorial component could be rejected, and support for a major gene was equivocal i.e. neither the Mendelian transmission nor the no transmission (equal tau s) models were rejected. However, after adjusting for the effects of insulin, a major gene effect on PH-LPL activity was unambiguous. The putative locus accounted for 60% of the total phenotypic variance, and the homozygous recessive form affected 10% (q2) of the sample (i.e. gene frequency (q) = 0.31), and led to a low PH-LPL value. The lack of a significant multifactorial effect suggested that the familial etiology of PH-LPL activity adjusted for insulin was likely to be primarily a function of the major locus. In conclusion, the present study is the first to report segregation analyses on PH-LPL activity prior to and after adjusting for insulin, and suggests that there is an indication of a pleiotropic genetic effect on PH-LPL activity and insulin, in addition to a major gene effect on PH-LPL activity alone.
Pleiotropic opioid regulation of spinal endomorphin 2 release and its adaptations to opioid withdrawal are sexually dimorphic.

Science.gov (United States)

Chakrabarti, Sumita; Liu, Nai-Jiang; Zadina, James E; Sharma, Tarak; Gintzler, Alan R

2012-01-01

We studied adaptations to acute precipitated opioid withdrawal of spinal μ-opioid receptor (MOR)-coupled regulation of the release of endomorphin 2 (EM2). The release of this highly MOR-selective endogenous opioid from opioid-naive spinal tissue of male rats is subjected to MOR-coupled positive as well as negative modulation via cholera toxin-sensitive G(s) and pertussis toxin-sensitive G(i)/G(o), respectively. The net effect of this concomitant bidirectional modulation is inhibitory. MOR-coupled pleiotropic regulation of EM2 release is retained in opioid-withdrawn spinal tissue of male rats, but the balance of MOR-coupled inhibitory and facilitatory regulation shifted such that facilitatory regulation predominates. Augmented coupling of MOR to G(s) is causally associated with this change. Strikingly, pleiotropic characteristics of MOR-coupled regulation of spinal EM2 release and adaptations thereof to opioid withdrawal are male-specific. In females, MOR-coupled regulation of EM2 release from opioid-naive and -withdrawn spinal tissue does not have a significant G(s)-coupled facilitatory component, and MOR-coupled inhibition of EM2 release persists unabated in withdrawn preparations. The male-specific adaptations to chronic morphine that shift the relative predominance of opposing dual G protein-coupled MOR pathways provides a mechanism for mitigating inhibitory MOR signaling without losing MOR-coupled feedback regulation. These adaptations enable using endogenous EM2 as a substitute for morphine that had been precipitously removed. The sexually dimorphic functionality and regulation of spinal EM2/MOR-coupled signaling suggest the clinical utility of using sex-specific treatments for addiction that harness the activity of endogenous opioids.
Integration of genomic resources to uncover pleiotropic regions associated with age at puberty and reproductive longevity in sows

Science.gov (United States)

Commercial and experimental genetic resources were used to investigate genetic pleiotropic factors that influence age at puberty, litter-size and reproductive longevity. The phenotypes were complemented by high-density genotyping and whole genome and RNA sequencing. The SNPs from Porcine SNP60 BeadA...
Integrative genomic analysis identifies isoleucine and CodY as regulators of Listeria monocytogenes virulence.

Directory of Open Access Journals (Sweden)

Lior Lobel

2012-09-01

Full Text Available Intracellular bacterial pathogens are metabolically adapted to grow within mammalian cells. While these adaptations are fundamental to the ability to cause disease, we know little about the relationship between the pathogen's metabolism and virulence. Here we used an integrative Metabolic Analysis Tool that combines transcriptome data with genome-scale metabolic models to define the metabolic requirements of Listeria monocytogenes during infection. Twelve metabolic pathways were identified as differentially active during L. monocytogenes growth in macrophage cells. Intracellular replication requires de novo synthesis of histidine, arginine, purine, and branch chain amino acids (BCAAs, as well as catabolism of L-rhamnose and glycerol. The importance of each metabolic pathway during infection was confirmed by generation of gene knockout mutants in the respective pathways. Next, we investigated the association of these metabolic requirements in the regulation of L. monocytogenes virulence. Here we show that limiting BCAA concentrations, primarily isoleucine, results in robust induction of the master virulence activator gene, prfA, and the PrfA-regulated genes. This response was specific and required the nutrient responsive regulator CodY, which is known to bind isoleucine. Further analysis demonstrated that CodY is involved in prfA regulation, playing a role in prfA activation under limiting conditions of BCAAs. This study evidences an additional regulatory mechanism underlying L. monocytogenes virulence, placing CodY at the crossroads of metabolism and virulence.
Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways

DEFF Research Database (Denmark)

He, Hongbo; Yang, Dachun; Ma, Liqun

2010-01-01

Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR)-d...
Arabidopsis CPR5 is a senescence-regulatory gene with pleiotropic functions as predicted by the evolutionary theory of senescence

NARCIS (Netherlands)

Jing, Hai-Chun; Anderson, Lisa; Sturre, Marcel J. G.; Hille, Jacques; Dijkwel, Paul P.

2007-01-01

Arabidopsis CPR5 is a senescence-regulatory gene with pleiotropic functions as predicted by the evolutionary theory of senescence Hai-Chun Jing1,2, Lisa Anderson3, Marcel J.G. Sturre1, Jacques Hille1 and Paul P. Dijkwel1,* 1Molecular Biology of Plants, Groningen Biomolecular Sciences and
The pleiotropic effects of the seed germination inhibitor germostatin.

Science.gov (United States)

Ye, Yajin; Zhao, Yang

2016-01-01

Seed dormancy and germination are the most important adaptive traits of seed plants, which control the germination in a proper space and time. Internal genetic factors together with environmental cues govern seed dormancy and germination. Abscisic acid (ABA), a key phytohormone induces seed dormancy and inhibits seed germination through its molecular genetic signaling network responding the seed inherent physiological and environmental factors. Recently, auxin has been shown to be another phytohormone that induces seed dormancy. We have recently shown that germonstatin (GS), a small synthetic molecule identified by high through-put chemical genetic screenings, inhibits seed germination through up-regulating auxin signaling and inducing auxin biosynthesis. GERMOSTATIN RESISTANCE LOCUS 1 (GSR1) encodes a plant homeodomain (PHD) finger protein and is responsible for GS seed germination inhibition. Its knockdown mutant gsr1 displays decreased dormancy. In this report, we show that GS is not an ABA analog and provided 2 other GS-resistant mutants related to the chemical's function in seed germination inhibition other than gsr1, suggesting that GS may have pleiotropic effects through targeting different pathway governing seed germination.
Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases

Directory of Open Access Journals (Sweden)

Liang He

2016-10-01

Full Text Available Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1 endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2 time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM, cancer, cardiovascular diseases (CVDs and neurodegenerative diseases (NDs, and (3 both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08, out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2 and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory
Verbal memory improvement in first-episode psychosis APOE-ε4 carriers: a pleiotropic effect?

Directory of Open Access Journals (Sweden)

Vila-Rodriguez F

2017-12-01

Full Text Available Fidel Vila-Rodriguez,1 Donna J Lang,2 Heather Baitz,3 Kristina Gicas,3 Allen E Thorton,3 Thomas S Ehmann,1 Geoff N Smith,1 Alasdair M Barr,4 Ivan J Torres,1 Lili C Kopala,1 G William MacEwan,1 Daniel J Müller,5 James L Kennedy,5 William G Honer11Department of Psychiatry, 2Division of Neuroradiology, Department of Radiology, The University of British Columbia, Vancouver, 3Department of Psychology, Simon Fraser University, Burnaby, 4Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, BC, 5Department of Psychiatry, Centre for Mental Health and Addictions, University of Toronto, Toronto, ON, CanadaBackground: Verbal memory impairment is a core feature in schizophrenia even at early stages of the disease, but its etiopathogenesis is not fully understood. The APOE-ε4 is the main genetic risk factor for late-onset Alzheimer’s disease. Our primary goal was to ascertain whether APOE-ε4 status had a pleiotropic effect in early stages of the illness.Participants and methods: A total of 86 first-episode psychosis (FEP outpatients and 39 healthy volunteers were recruited. Demographic and clinical data, APOE genotyping, and a neuropsychological test battery including the California Verbal Learning Test – second edition (CVLT-II were administered and assessed at study entry and at 1-year follow-up. Data were analyzed using mixed-model repeated measures, where the dependent variable was verbal memory indexed by California Verbal Learning Test (CVLT Trials 1–5 total recall score.Results: FEP-APOE-ε4 carriers and FEP-APOE-ε4 noncarriers had similar symptom severity, clinical outcomes, premorbid and current intelligence quotient, and exposure to antipsychotics. There was a main effect of group on CVLT 1–5 (FEP =43.30 vs control =58.25; F[1, 119.7]=42.97; P<0.001 as well as an APOE-ε4 by group by time (F[4, 116.2]=2.73, P=0.033 interaction with only FEP-APOE-ε4 carriers showing improved verbal
Pleiotropic Effects of DDT Resistance on Male Size and Behaviour.

Science.gov (United States)

Rostant, Wayne G; Bowyer, Jemima; Coupland, Jack; Facey, James; Hosken, David J; Wedell, Nina

2017-07-01

Understanding the evolution and spread of insecticide resistance requires knowing the relative fitness of resistant organisms. In the absence of insecticides, resistance is predicted to be costly. The Drosophila melanogaster DDT resistance allele (DDT-R) is associated with a male mating cost. This could be because resistant males are generally smaller, but DDT-R may also alter courtship behaviours. Here we tested for body size and courtship effects of DDT-R on mating success in competitive and non-competitive mating trials respectively. We also assessed relative aggression in resistant and susceptible males because aggression can also influence mating success. While the effect of DDT-R on male size partly contributed to reduced mating success, resistant males also had lower rates of courtship and were less aggressive than susceptible males. These differences contribute to the observed DDT-R mating costs. Additionally, these pleiotropic effects of DDT-R are consistent with the history and spread of resistance alleles in nature.
4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

Energy Technology Data Exchange (ETDEWEB)

Mahal, Katharina, E-mail: katharina.mahal@uni-bayreuth.de [Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth (Germany); Kahlen, Philip, E-mail: philip.kahlen@uni-bayreuth.de [Department of Genetics, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth (Germany); Biersack, Bernhard, E-mail: bernhard.biersack@yahoo.com [Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth (Germany); Schobert, Rainer, E-mail: rainer.schobert@uni-bayreuth.de [Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth (Germany)

2015-08-15

Histone deacetylases (HDAC) which play a crucial role in cancer cell proliferation are promising drug targets. However, HDAC inhibitors (HDACi) modelled on natural hydroxamic acids such as trichostatin A frequently lead to resistance or even an increased agressiveness of tumours. As a workaround we developed 4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide (etacrox), a hydroxamic acid that combines HDAC inhibition with synergistic effects of the 4,5-diarylimidazole residue. Etacrox proved highly cytotoxic against a panel of metastatic and resistant cancer cell lines while showing greater specificity for cancer over non-malignant cells when compared to the approved HDACi vorinostat. Like the latter, etacrox and the closely related imidazoles bimacroxam and animacroxam acted as pan-HDACi yet showed some specificity for HDAC6. Akt signalling and interference with nuclear beta-catenin localisation were elicited by etacrox at lower concentrations when compared to vorinostat. Moreover, etacrox disrupted the microtubule and focal adhesion dynamics of cancer cells and inhibited the proteolytic activity of prometastatic and proangiogenic matrix metalloproteinases. As a consequence, etacrox acted strongly antimigratory and antiinvasive against various cancer cell lines in three-dimensional transwell invasion assays and also antiangiogenic in vivo with respect to blood vessel formation in the chorioallantoic membrane assay. These pleiotropic effects and its water-solubility and tolerance by mice render etacrox a promising new HDACi candidate. - Graphical abstract: A novel histone deacetylase inhibitor with pleiotropic anticancer effects. - Highlights: • Etacrox is a new HDACi with cytotoxic, antiangiogenic and antiinvasive activity. • Etacrox causes aberrant cancer cell signalling and cytoskeletal reorganisation. • Pro-metastatic and angiogenic matrix metalloproteinases are inhibited by etacrox. • Etacrox impairs blood vessel maturation in vivo and cancer cell
4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

International Nuclear Information System (INIS)

Mahal, Katharina; Kahlen, Philip; Biersack, Bernhard; Schobert, Rainer

2015-01-01

Histone deacetylases (HDAC) which play a crucial role in cancer cell proliferation are promising drug targets. However, HDAC inhibitors (HDACi) modelled on natural hydroxamic acids such as trichostatin A frequently lead to resistance or even an increased agressiveness of tumours. As a workaround we developed 4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide (etacrox), a hydroxamic acid that combines HDAC inhibition with synergistic effects of the 4,5-diarylimidazole residue. Etacrox proved highly cytotoxic against a panel of metastatic and resistant cancer cell lines while showing greater specificity for cancer over non-malignant cells when compared to the approved HDACi vorinostat. Like the latter, etacrox and the closely related imidazoles bimacroxam and animacroxam acted as pan-HDACi yet showed some specificity for HDAC6. Akt signalling and interference with nuclear beta-catenin localisation were elicited by etacrox at lower concentrations when compared to vorinostat. Moreover, etacrox disrupted the microtubule and focal adhesion dynamics of cancer cells and inhibited the proteolytic activity of prometastatic and proangiogenic matrix metalloproteinases. As a consequence, etacrox acted strongly antimigratory and antiinvasive against various cancer cell lines in three-dimensional transwell invasion assays and also antiangiogenic in vivo with respect to blood vessel formation in the chorioallantoic membrane assay. These pleiotropic effects and its water-solubility and tolerance by mice render etacrox a promising new HDACi candidate. - Graphical abstract: A novel histone deacetylase inhibitor with pleiotropic anticancer effects. - Highlights: • Etacrox is a new HDACi with cytotoxic, antiangiogenic and antiinvasive activity. • Etacrox causes aberrant cancer cell signalling and cytoskeletal reorganisation. • Pro-metastatic and angiogenic matrix metalloproteinases are inhibited by etacrox. • Etacrox impairs blood vessel maturation in vivo and cancer cell
α-Linolenic Acid, A Nutraceutical with Pleiotropic Properties That Targets Endogenous Neuroprotective Pathways to Protect against Organophosphate Nerve Agent-Induced Neuropathology

Directory of Open Access Journals (Sweden)

Tetsade Piermartiri

2015-11-01

Full Text Available α-Linolenic acid (ALA is a nutraceutical found in vegetable products such as flax and walnuts. The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in brain and involve the transcription factor nuclear factor kappa B (NF-κB, brain-derived neurotrophic factor (BDNF, a major neuroprotective protein in brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF. In this review, we discuss possible mechanisms of ALA efficacy against the highly toxic OP nerve agent soman. Organophosphate (OP nerve agents are highly toxic chemical warfare agents and a threat to military and civilian populations. Once considered only for battlefield use, these agents are now used by terrorists to inflict mass casualties. OP nerve agents inhibit the critical enzyme acetylcholinesterase (AChE that rapidly leads to a cholinergic crisis involving multiple organs. Status epilepticus results from the excessive accumulation of synaptic acetylcholine which in turn leads to the overactivation of muscarinic receptors; prolonged seizures cause the neuropathology and long-term consequences in survivors. Current countermeasures mitigate symptoms and signs as well as reduce brain damage, but must be given within minutes after exposure to OP nerve agents supporting interest in newer and more effective therapies. The pleiotropic properties of ALA result in a coordinated molecular and cellular program to restore neuronal networks and improve cognitive function in soman-exposed animals. Collectively, ALA should be brought to the clinic to treat the long-term consequences of nerve agents in survivors. ALA may be an effective therapy for other acute and chronic neurodegenerative disorders.

Biliary obstruction caused by intra-biliary tumor growth from recurred hepatocellular carcinoma after radiofrequency ablation: Case report

Energy Technology Data Exchange (ETDEWEB)

Yi, Ji Hyun; Kim, Jae Won [Dept. of Radiology, Yeungnam University College of Medicine, Daegu (Korea, Republic of)

2014-04-15

A 59-year-old man with a known central hepatocellular carcinoma (HCC) underwent a trans-arterial-chemo-embolization (TACE) and a post-TACE percutaneous radiofrequency ablation (PRFA). Two months after the PRFA, the patient presented jaundice and an abdominal computed tomography was obtained. An arterial enhancing mass adjacent to the ablated necrotic lesion with a continuously coexisting mass inside the right hepatic duct, suggestive of a HCC recurrence with a direct extension to the biliary tract was found. Finally a biliary tumor obstruction has been developed and a percutaneous transhepatic biliary drainage was performed. This case of biliary obstruction caused by directly invaded recurred HCC after PRFA will be reported because of its rare occurrence.
β-catenin functions pleiotropically in differentiation and tumorigenesis in mouse embryo-derived stem cells.

Directory of Open Access Journals (Sweden)

Noriko Okumura

Full Text Available The canonical Wnt/β-catenin signaling pathway plays a crucial role in the maintenance of the balance between proliferation and differentiation throughout embryogenesis and tissue homeostasis. β-Catenin, encoded by the Ctnnb1 gene, mediates an intracellular signaling cascade activated by Wnt. It also plays an important role in the maintenance of various types of stem cells including adult stem cells and cancer stem cells. However, it is unclear if β-catenin is required for the derivation of mouse embryo-derived stem cells. Here, we established β-catenin-deficient (β-cat(Δ/Δ mouse embryo-derived stem cells and showed that β-catenin is not essential for acquiring self-renewal potential in the derivation of mouse embryonic stem cells (ESCs. However, teratomas formed from embryo-derived β-cat(Δ/Δ ESCs were immature germ cell tumors without multilineage differentiated cell types. Re-expression of functional β-catenin eliminated their neoplastic, transformed phenotype and restored pluripotency, thereby rescuing the mutant ESCs. Our findings demonstrate that β-catenin has pleiotropic effects in ESCs; it is required for the differentiation of ESCs and prevents them from acquiring tumorigenic character. These results highlight β-catenin as the gatekeeper in differentiation and tumorigenesis in ESCs.
An Analytic Solution to the Computation of Power and Sample Size for Genetic Association Studies under a Pleiotropic Mode of Inheritance.

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Gordon, Derek; Londono, Douglas; Patel, Payal; Kim, Wonkuk; Finch, Stephen J; Heiman, Gary A

2016-01-01

Our motivation here is to calculate the power of 3 statistical tests used when there are genetic traits that operate under a pleiotropic mode of inheritance and when qualitative phenotypes are defined by use of thresholds for the multiple quantitative phenotypes. Specifically, we formulate a multivariate function that provides the probability that an individual has a vector of specific quantitative trait values conditional on having a risk locus genotype, and we apply thresholds to define qualitative phenotypes (affected, unaffected) and compute penetrances and conditional genotype frequencies based on the multivariate function. We extend the analytic power and minimum-sample-size-necessary (MSSN) formulas for 2 categorical data-based tests (genotype, linear trend test [LTT]) of genetic association to the pleiotropic model. We further compare the MSSN of the genotype test and the LTT with that of a multivariate ANOVA (Pillai). We approximate the MSSN for statistics by linear models using a factorial design and ANOVA. With ANOVA decomposition, we determine which factors most significantly change the power/MSSN for all statistics. Finally, we determine which test statistics have the smallest MSSN. In this work, MSSN calculations are for 2 traits (bivariate distributions) only (for illustrative purposes). We note that the calculations may be extended to address any number of traits. Our key findings are that the genotype test usually has lower MSSN requirements than the LTT. More inclusive thresholds (top/bottom 25% vs. top/bottom 10%) have higher sample size requirements. The Pillai test has a much larger MSSN than both the genotype test and the LTT, as a result of sample selection. With these formulas, researchers can specify how many subjects they must collect to localize genes for pleiotropic phenotypes. © 2017 S. Karger AG, Basel.
Coadjuvants in the Diabetic Complications: Nutraceuticals and Drugs with Pleiotropic Effects

Directory of Open Access Journals (Sweden)

Thiago Melo Costa Pereira

2016-08-01

Full Text Available Because diabetes mellitus (DM is a multifactorial metabolic disease, its prevention and treatment has been a constant challenge for basic and clinical investigators focused on translating their discoveries into clinical treatment of this complex disorder. In this review, we highlight recent experimental and clinical evidences of potential coadjuvants in the management of DM, such as polyphenols (quercetin, resveratrol and silymarin, cultured probiotic microorganisms and drugs acting through direct/indirect or pleiotropic effects on glycemic control in DM. Among several options, we highlight new promising therapeutic coadjuvants, including chemical scavengers, the probiotic kefir and the phosphodiesterase 5 inhibitors, which besides the reduction of hyperglycemia and ameliorate insulin resistance, they reduce oxidative stress and improve endothelial dysfunction in the systemic vascular circulation. In the near future, experimental studies are expected to clear the intracellular pathways involving coadjuvants. The design of clinical trials may also contribute to new strategies with coadjuvants against the harmful effects of diabetic complications.
Coadjuvants in the Diabetic Complications: Nutraceuticals and Drugs with Pleiotropic Effects

Science.gov (United States)

Pereira, Thiago Melo Costa; Pimenta, Fabio Silva; Porto, Marcella Lima; Baldo, Marcelo Perim; Campagnaro, Bianca Prandi; Gava, Agata Lages; Meyrelles, Silvana Santos; Vasquez, Elisardo Corral

2016-01-01

Because diabetes mellitus (DM) is a multifactorial metabolic disease, its prevention and treatment has been a constant challenge for basic and clinical investigators focused on translating their discoveries into clinical treatment of this complex disorder. In this review, we highlight recent experimental and clinical evidences of potential coadjuvants in the management of DM, such as polyphenols (quercetin, resveratrol and silymarin), cultured probiotic microorganisms and drugs acting through direct/indirect or pleiotropic effects on glycemic control in DM. Among several options, we highlight new promising therapeutic coadjuvants, including chemical scavengers, the probiotic kefir and the phosphodiesterase 5 inhibitors, which besides the reduction of hyperglycemia and ameliorate insulin resistance, they reduce oxidative stress and improve endothelial dysfunction in the systemic vascular circulation. In the near future, experimental studies are expected to clear the intracellular pathways involving coadjuvants. The design of clinical trials may also contribute to new strategies with coadjuvants against the harmful effects of diabetic complications. PMID:27527163
DasR is a pleiotropic regulator required for antibiotic production, pigment biosynthesis, and morphological development in Saccharopolyspora erythraea.

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Liao, Cheng-Heng; Xu, Ya; Rigali, Sébastien; Ye, Bang-Ce

2015-12-01

The GntR-family transcription regulator, DasR, was previously identified as pleiotropic, controlling the primary amino sugar N-acetylglucosamine (GlcNAc) and chitin metabolism in Saccharopolyspora erythraea and Streptomyces coelicolor. Due to the remarkable regulatory impact of DasR on antibiotic production and development in the model strain of S. coelicolor, we here identified and characterized the role of DasR to secondary metabolite production and morphological development in industrial erythromycin-producing S. erythraea. The physiological studies have shown that a constructed deletion of dasR in S. erythraea resulted in antibiotic, pigment, and aerial hyphae production deficit in a nutrient-rich condition. DNA microarray assay, combined with quantitative real-time reverse transcription PCR (qRT-PCR), confirmed these results by showing the downregulation of the genes relating to secondary metabolite production in the dasR null mutant. Notably, electrophoretic mobility shift assays (EMSA) showed DasR as being the first identified regulator that directly regulates the pigment biosynthesis rpp gene cluster. In addition, further studies indicated that GlcNAc, the major nutrient signal of DasR-responsed regulation, blocked secondary metabolite production and morphological development. The effects of GlcNAc were shown to be caused by DasR mediation. These findings demonstrated that DasR is an important pleiotropic regulator for both secondary metabolism and morphological development in S. erythraea, providing new insights for the genetic engineering of S. erythraea with increased erythromycin production.
Sub-therapeutic doses of fluvastatin and valsartan are more effective than therapeutic doses in providing beneficial cardiovascular pleiotropic effects in rats: A proof of concept study.

Science.gov (United States)

Janić, Miodrag; Lunder, Mojca; France Štiglic, Alenka; Jerin, Aleš; Skitek, Milan; Černe, Darko; Marc, Janja; Drevenšek, Gorazd; Šabovič, Mišo

2017-12-01

Statins and sartans can, in therapeutic doses, induce pleiotropic cardiovascular effects. Similar has recently been shown also for sub-therapeutic doses. We thus explored and compared the cardiovascular pleiotropic efficacy of sub-therapeutic vs. therapeutic doses. Wistar rats were randomly divided into 7 groups receiving fluvastatin, valsartan and their combination in sub-therapeutic and therapeutic doses, or saline. After 6weeks, the animals were euthanised, their hearts and thoracic aortas isolated, and blood samples taken. Endothelium-dependent relaxation of the thoracic aortae and ischaemic-reperfusion injury of the isolated hearts were assessed along with the related serum parameters and genes expression. Fluvastatin and valsartan alone or in combination were significantly more effective in sub-therapeutic than therapeutic doses. The sub-therapeutic combination greatly increased thoracic aorta endothelium-dependent relaxation and maximally protected the isolated hearts against ischaemia-reperfusion injury and was thus most effective. Beneficial effects were accompanied by increased levels of nitric oxide (NO) and decreased levels of asymmetric dimethylarginine (ADMA) in the serum (again prominently induced by the sub-therapeutic combination). Furthermore, nitric oxide synthase 3 (NOS3) and endothelin receptor type A (EDNRA) genes expression increased, but only in both combination groups and without significant differences between them. In the therapeutic dose groups, fluvastatin and valsartan decreased cholesterol values and systolic blood pressure. Sub-therapeutic doses of fluvastatin and valsartan are more effective in expressing cardiovascular pleiotropic effects than therapeutic doses of fluvastatin and/or valsartan. These results could be of significant clinical relevance. Copyright © 2017 Elsevier Inc. All rights reserved.
ORF Alignment: NC_000913 [GENIUS II[Archive

Lifescience Database Archive (English)

Full Text Available ... adenylate kinase activity; pleiotropic effects on ... glycerol-3-phosphate acyltransferase...ylate kinase activity; ... pleiotropic effects on glycerol-3-phosphate ... acyltransferase act...TP-AMP ... transphosphorylase) (AK) ref|NP_286215.1| adenylate ... kinase activity; pleiotropic effects
ORF Alignment: NC_002655 [GENIUS II[Archive

Lifescience Database Archive (English)

Full Text Available ... adenylate kinase activity; pleiotropic effects on ... glycerol-3-phosphate acyltransferase...ylate kinase activity; ... pleiotropic effects on glycerol-3-phosphate ... acyltransferase act...TP-AMP ... transphosphorylase) (AK) ref|NP_286215.1| adenylate ... kinase activity; pleiotropic effects
ORF Alignment: NC_002695 [GENIUS II[Archive

Lifescience Database Archive (English)

Full Text Available ... adenylate kinase activity; pleiotropic effects on ... glycerol-3-phosphate acyltransferase...ylate kinase activity; ... pleiotropic effects on glycerol-3-phosphate ... acyltransferase act...TP-AMP ... transphosphorylase) (AK) ref|NP_286215.1| adenylate ... kinase activity; pleiotropic effects
Why is intelligence correlated with semen quality?: Biochemical pathways common to sperm and neuron function and their vulnerability to pleiotropic mutations

OpenAIRE

Pierce, Arand; Miller, Geoffrey; Arden, Rosalind; Gottfredson, Linda S

2009-01-01

We recently found positive correlations between human general intelligence and three key indices of semen quality, and hypothesized that these correlations arise through a phenotype-wide ‘general fitness factor’ reflecting overall mutation load. In this addendum we consider some of the biochemical pathways that may act as targets for pleiotropic mutations that disrupt both neuron function and sperm function in parallel. We focus especially on the inter-related roles of polyunsaturated fatty a...
Why is intelligence correlated with semen quality?: Biochemical pathways common to sperm and neuron function and their vulnerability to pleiotropic mutations.

Science.gov (United States)

Pierce, Arand; Miller, Geoffrey; Arden, Rosalind; Gottfredson, Linda S

2009-09-01

We recently found positive correlations between human general intelligence and three key indices of semen quality, and hypothesized that these correlations arise through a phenotype-wide 'general fitness factor' reflecting overall mutation load. In this addendum we consider some of the biochemical pathways that may act as targets for pleiotropic mutations that disrupt both neuron function and sperm function in parallel. We focus especially on the inter-related roles of polyunsaturated fatty acids, exocytosis and receptor signaling.
Pleiotropic functions of embryonic sonic hedgehog expression link jaw and taste bud amplification with eye loss during cavefish evolution.

Science.gov (United States)

Yamamoto, Yoshiyuki; Byerly, Mardi S; Jackman, William R; Jeffery, William R

2009-06-01

This study addresses the role of sonic hedgehog (shh) in increasing oral-pharyngeal constructive traits (jaws and taste buds) at the expense of eyes in the blind cavefish Astyanax mexicanus. In cavefish embryos, eye primordia degenerate under the influence of hyperactive Shh signaling. In concert, cavefish show amplified jaw size and taste bud numbers as part of a change in feeding behavior. To determine whether pleiotropic effects of hyperactive Shh signaling link these regressive and constructive traits, shh expression was compared during late development of the surface-dwelling (surface fish) and cave-dwelling (cavefish) forms of Astyanax. After an initial expansion along the midline of early embryos, shh was elevated in the oral-pharyngeal region in cavefish and later was confined to taste buds. The results of shh inhibition and overexpression experiments indicate that Shh signaling has an important role in oral and taste bud development. Conditional overexpression of an injected shh transgene at specific times in development showed that taste bud amplification and eye degeneration are sensitive to shh overexpression during the same early developmental period, although taste buds are not formed until much later. Genetic crosses between cavefish and surface fish revealed an inverse relationship between eye size and jaw size/taste bud number, supporting a link between oral-pharyngeal constructive traits and eye degeneration. The results suggest that hyperactive Shh signaling increases oral and taste bud amplification in cavefish at the expense of eyes. Therefore, selection for constructive oral-pharyngeal traits may be responsible for eye loss during cavefish evolution via pleiotropic function of the Shh signaling pathway.
Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma.

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Luthra, Pratibha Mehta; Lal, Neetika

2016-02-15

GBM (Glioblastoma) is the most malignant human brain tumor with median survival of one year. The treatment involves surgery, radiotherapy and adjuvant chemotherapy mostly with the alkylation agents such as temozolomide (TMZ). Dietary polyphenol curcumin, isolated from the rhizome of the Curcuma longa (turmeric), has emerged as remarkable anti-cancer agent in the treatment of various peripheral cancers such as blood, lymphomas, multiple myeloma, melanoma as well as skin, lung, prostate, breast, ovarian, bladder, liver, gastrointestinal tract, pancreatic and colorectal epithelial cancers with a pleiotropic mode of action and also showed promise in alleviation of GBM. In this review, the mechanism of anticancer effect of curcumin in GBM has been discussed extensively. The clinical safety and pharmacokinetics of curcumin has been scrutinized to combat the challenges for the treatment of GBM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
A yigP mutant strain is a small colony variant of E. coli and shows pleiotropic antibiotic resistance.

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Xia, Hui; Tang, Qiongwei; Song, Jie; Ye, Jiang; Wu, Haizhen; Zhang, Huizhan

2017-12-01

Small colony variants (SCVs) are a commonly observed subpopulation of bacteria that have a small colony size and distinctive biochemical characteristics. SCVs are more resistant than the wild type to some antibiotics and usually cause persistent infections in the clinic. SCV studies have been very active during the past 2 decades, especially Staphylococcus aureus SCVs. However, fewer studies on Escherichia coli SCVs exist, so we studied an E. coli SCV during an experiment involving the deletion of the yigP locus. PCR and DNA sequencing revealed that the SCV was attributable to a defect in the yigP function. Furthermore, we investigated the antibiotic resistance profile of the E. coli SCV and it showed increased erythromycin, kanamycin, and d-cycloserine resistance, but collateral sensitivity to ampicillin, polymyxin, chloramphenicol, tetracycline, rifampin, and nalidixic acid. We tried to determine the association between yigP and the pleiotropic antibiotic resistance of the SCV by analyzing biofilm formation, cellular morphology, and coenzyme Q (Q 8 ) production. Our results indicated that impaired Q 8 biosynthesis was the primary factor that contributed to the increased resistance and collateral sensitivity of the SCV. This study offers a novel genetic basis for E. coli SCVs and an insight into the development of alternative antimicrobial strategies for clinical therapy.
The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.

Science.gov (United States)

Eagleson, Kathie L; Xie, Zhihui; Levitt, Pat

2017-03-01

People with autism spectrum disorder and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy-the influence of one gene on distinct phenotypes-raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multifunctional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with autism spectrum disorder, reduces transcription and disrupts socially relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways and has a complex protein interactome that is enriched in autism spectrum disorder and other NDD candidates. The interactome is coregulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, affecting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
NpPDR1, a pleiotropic drug resistance-type ATP-binding cassette transporter from Nicotiana plumbaginifolia, plays a major role in plant pathogen defense.

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Stukkens, Yvan; Bultreys, Alain; Grec, Sébastien; Trombik, Tomasz; Vanham, Delphine; Boutry, Marc

2005-09-01

Nicotiana plumbaginifolia NpPDR1, a plasma membrane pleiotropic drug resistance-type ATP-binding cassette transporter formerly named NpABC1, has been suggested to transport the diterpene sclareol, an antifungal compound. However, direct evidence for a role of pleiotropic drug resistance transporters in the plant defense is still lacking. In situ immunolocalization and histochemical analysis using the gusA reporter gene showed that NpPDR1 was constitutively expressed in the whole root, in the leaf glandular trichomes, and in the flower petals. However, NpPDR1 expression was induced in the whole leaf following infection with the fungus Botrytis cinerea, and the bacteria Pseudomonas syringae pv tabaci, Pseudomonas fluorescens, and Pseudomonas marginalis pv marginalis, which do not induce a hypersensitive response in N. plumbaginifolia, whereas a weaker response was observed using P. syringae pv syringae, which does induce a hypersensitive response. Induced NpPDR1 expression was more associated with the jasmonic acid than the salicylic acid signaling pathway. These data suggest that NpPDR1 is involved in both constitutive and jasmonic acid-dependent induced defense. Transgenic plants in which NpPDR1 expression was prevented by RNA interference showed increased sensitivity to sclareol and reduced resistance to B. cinerea. These data show that NpPDR1 is involved in pathogen resistance and thus demonstrate a new role for the ATP-binding cassette transporter family.
Activation of the Ca2+-sensing receptors increases currents through inward rectifier K+ channels via activation of phosphatidylinositol 4-kinase

OpenAIRE

Liu, Chung-Hung; Chang, Hsueh-Kai; Lee, Sue-Ping; Shieh, Ru-Chi

2016-01-01

Inward rectifier K+ channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP2). Stimulation of the Ca2+-sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both Gq/11, which decreases PIP2, and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP2. How membrane PIP2 levels are regulated by CaR activation and wheth...
Transition to an Aquatic Habitat Permitted the Repeated Loss of the Pleiotropic KLK8 Gene in Mammals.

Science.gov (United States)

Hecker, Nikolai; Sharma, Virag; Hiller, Michael

2017-11-01

Kallikrein related peptidase 8 (KLK8; also called neuropsin) is a serine protease that plays distinct roles in the skin and hippocampus. In the skin, KLK8 influences keratinocyte proliferation and desquamation, and activates antimicrobial peptides in sweat. In the hippocampus, KLK8 affects memory acquisition. Here, we examined the evolution of KLK8 in mammals and discovered that, out of 70 placental mammals, KLK8 is exclusively lost in three independent fully-aquatic lineages, comprising dolphin, killer whale, minke whale, and manatee. In addition, while the sperm whale has an intact KLK8 reading frame, the gene evolves neutrally in this species. We suggest that the distinct functions of KLK8 likely became obsolete in the aquatic environment, leading to the subsequent loss of KLK8 in several fully-aquatic mammalian lineages. First, the cetacean and manatee skin lacks sweat glands as an adaptation to the aquatic environment, which likely made the epidermal function of KLK8 obsolete. Second, cetaceans and manatees exhibit a proportionally small hippocampus, which may have rendered the hippocampal functions of KLK8 obsolete. Together, our results shed light on the genomic changes that correlate with skin and neuroanatomical differences of aquatic mammals, and show that even pleiotropic genes can be lost during evolution if an environmental change nullifies the need for the different functions of such genes. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
NpPDR1, a Pleiotropic Drug Resistance-Type ATP-Binding Cassette Transporter from Nicotiana plumbaginifolia, Plays a Major Role in Plant Pathogen Defense1

Science.gov (United States)

Stukkens, Yvan; Bultreys, Alain; Grec, Sébastien; Trombik, Tomasz; Vanham, Delphine; Boutry, Marc

2005-01-01

Nicotiana plumbaginifolia NpPDR1, a plasma membrane pleiotropic drug resistance-type ATP-binding cassette transporter formerly named NpABC1, has been suggested to transport the diterpene sclareol, an antifungal compound. However, direct evidence for a role of pleiotropic drug resistance transporters in the plant defense is still lacking. In situ immunolocalization and histochemical analysis using the gusA reporter gene showed that NpPDR1 was constitutively expressed in the whole root, in the leaf glandular trichomes, and in the flower petals. However, NpPDR1 expression was induced in the whole leaf following infection with the fungus Botrytis cinerea, and the bacteria Pseudomonas syringae pv tabaci, Pseudomonas fluorescens, and Pseudomonas marginalis pv marginalis, which do not induce a hypersensitive response in N. plumbaginifolia, whereas a weaker response was observed using P. syringae pv syringae, which does induce a hypersensitive response. Induced NpPDR1 expression was more associated with the jasmonic acid than the salicylic acid signaling pathway. These data suggest that NpPDR1 is involved in both constitutive and jasmonic acid-dependent induced defense. Transgenic plants in which NpPDR1 expression was prevented by RNA interference showed increased sensitivity to sclareol and reduced resistance to B. cinerea. These data show that NpPDR1 is involved in pathogen resistance and thus demonstrate a new role for the ATP-binding cassette transporter family. PMID:16126865

The beneficial pleiotropic effects of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) within the vasculature: A review of the evidence.

Science.gov (United States)

Forde, Hannah; Harper, Emma; Davenport, Colin; Rochfort, Keith D; Wallace, Robert; Murphy, Ronan P; Smith, Diarmuid; Cummins, Philip M

2016-04-01

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein that belongs to the tumour necrosis factor (TNF) cytokine superfamily. TRAIL is expressed by numerous cell types including vascular cells, immune cells and adipocytes. Although originally thought to induce apoptosis in malignant or transformed cells only, it is now known that TRAIL can bind up to 5 distinct receptors to activate complex signalling pathways, and is capable of exerting pleiotropic effects in non-transformed cells. In this respect, a number of clinical and animal studies point to the potential vasoprotective influence of TRAIL, with TRAIL deficiency being linked to accelerated atherosclerosis and vascular calcification. Moreover, exogenous TRAIL administration has been shown to exhibit anti-atherosclerotic activity in-vivo. In-vitro studies on TRAIL in this context have yielded conflicting results however, with evidence of both pro-atherogenic and vasoprotective effects ascribed to TRAIL. Notwithstanding these various studies, mechanistic information on the precise nature of TRAIL-mediated injury/protection within the vasculature, as well as the identity of the downstream molecular/cellular targets of TRAIL, is still quite limited. In this review, we will summarize our current knowledge of TRAIL regulation, signalling mechanisms, and its apparent involvement in CVD pathogenesis as a prelude to examining the existing evidence for TRAIL-mediated vasoprotection. To this end, extensive in vitro, in vivo, and clinical studies will be reviewed and critical findings highlighted. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
PLEIOTROPIC EFFECTS OF PARATHYROIDECTOMY AND AGONIST CALCIUM-SENSITIVE RECEPTOR, CINACALCET

Directory of Open Access Journals (Sweden)

L. V. Egshatyan

2013-01-01

Full Text Available Aim. To evaluate the effect of parathyroidectomy and cinacalcet on anemia, lipid profile and blood pressure (BP in uremic hyperparathyroidism.Material and methods. Uremic patients (n=39 treated with hemodialysis and having secondary hyperparathyroidism were included into the study. Radical parathyroidectomy was performed in 21 patients, 18 patients were treated with cinacalcet. BP measurement, determination of blood levels of albumin, total calcium, phosphorus, total cholesterol (TC, low (LDL and high density lipoproteins, triglycerides, intact parathyroid hormone, and hemoglobin were performed in all patients initially and during treatment. Doses of antihypertensive and erythropoiesis-stimulating agents were also assessed.Results. Calcium-phosphorus metabolism indices improved after 6 months of cinacalcet therapy and parathyroidectomy (p<0.05. BP reduction not requiring antihypertensive drugs dose adjustment was found in patients treated with cinacalcet. Significant BP reduction (p<0.05 was observed after parathyroidectomy and it required antihypertensive drugs cancellation or dose lowering. Cinacalcet therapy and parathyroidectomy led to increase in hemoglobin level by 2.02% (p=0.143 and 7.6% (p=0.029, respectively, as well as reduction in weekly dose of erythropoiesis-stimulating drugs by 2.7% (p=0.875 and 8.9% (p=0.751, respectively. Significant (p<0.05 decrease in LDL (5.6%, and triglycerides (23.7% levels was found in patients treated with cinacalcet. Reduction (p<0.05 in total cholesterol (1.4% and LDL (4.3% levels was observed after parathyroidectomy.Conclusion. The pleiotropic effects (reduction in BP and atherogenic lipids levels, as well as decrease in anemia resistant to the action of erythropoiesis-stimulating agents were found after parathyroidectomy and cinacalcet therapy additionally to calcium-phosphorus metabolism improvement.
Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation

OpenAIRE

Miralem, Tihomir; Lerner-Marmarosh, Nicole; Gibbs, Peter E. M.; Jenkins, Jermaine L.; Heimiller, Chelsea; Maines, Mahin D.

2016-01-01

Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1–3) are downstream of IRK and are activated by phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylating T308 before S473 autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present ...
Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

DEFF Research Database (Denmark)

Medina-Gomez, Carolina; Kemp, John P; Dimou, Niki L

2017-01-01

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone...... as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total...
Turning off flagellum rotation requires the pleiotropic gene pleD: pleA, pleC, and pleD define two morphogenic pathways in Caulobacter crescentus.

OpenAIRE

Sommer, J M; Newton, A

1989-01-01

We have identified mutations in three pleiotropic genes, pleA, pleC, and pleD, that are required for differentiation in Caulobacter crescentus. pleA and pleC mutants were isolated in an extensive screen for strains defective in both motility and adsorption of polar bacteriophage phi CbK; using temperature-sensitive alleles, we determined the time at which the two genes act. pleA was required for a short period at 0.7 of the swarmer cell cycle for flagellum biosynthesis, whereas pleC was requi...
Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Activity

Directory of Open Access Journals (Sweden)

Janna eBlechman

2013-05-01

Full Text Available Alternative splicing of the precursor mRNA encoding for the neuropeptide receptor PAC1/ADCYAP1R1 generates multiple protein products that exhibit pleiotropic activities. Recent studies in mammals and zebrafish have implicated some of these splice isoforms in control of both cellular and body homeostasis. Here, we review the regulation of PAC1 splice variants and their underlying signal transduction and physiological processes in the nervous system.
A novel pleiotropic effect of aspirin: Beneficial regulation of pro- and anti-inflammatory mechanisms in microglial cells.

Science.gov (United States)

Kata, Diana; Földesi, Imre; Feher, Liliana Z; Hackler, Laszlo; Puskas, Laszlo G; Gulya, Karoly

2017-06-01

Aspirin, one of the most widely used non-steroidal anti-inflammatory drugs, has extensively studied effects on the cardiovascular system. To reveal further pleiotropic, beneficial effects of aspirin on a number of pro- and anti-inflammatory microglial mechanisms, we performed morphometric and functional studies relating to phagocytosis, pro- and anti-inflammatory cytokine production (IL-1β, tumor necrosis factor-α (TNF-α) and IL-10, respectively) and analyzed the expression of a number of inflammation-related genes, including those related to the above functions, in pure microglial cells. We examined the effects of aspirin (0.1mM and 1mM) in unchallenged (control) and bacterial lipopolysaccharide (LPS)-challenged secondary microglial cultures. Aspirin affected microglial morphology and functions in a dose-dependent manner as it inhibited LPS-elicited microglial activation by promoting ramification and the inhibition of phagocytosis in both concentrations. Remarkably, aspirin strongly reduced the pro-inflammatory IL-1β and TNF-α production, while it increased the anti-inflammatory IL-10 level in LPS-challenged cells. Moreover, aspirin differentially regulated the expression of a number of inflammation-related genes as it downregulated such pro-inflammatory genes as Nos2, Kng1, IL1β, Ptgs2 or Ccr1, while it upregulated some anti-inflammatory genes such as IL10, Csf2, Cxcl1, Ccl5 or Tgfb1. Thus, the use of aspirin could be beneficial for the prophylaxis of certain neurodegenerative disorders as it effectively ameliorates inflammation in the brain. Copyright © 2017 Elsevier Inc. All rights reserved.
A natural variant of NAL1, selected in high-yield rice breeding programs, pleiotropically increases photosynthesis rate

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Takai, Toshiyuki; Adachi, Shunsuke; Taguchi-Shiobara, Fumio; Sanoh-Arai, Yumiko; Iwasawa, Norio; Yoshinaga, Satoshi; Hirose, Sakiko; Taniguchi, Yojiro; Yamanouchi, Utako; Wu, Jianzhong; Matsumoto, Takashi; Sugimoto, Kazuhiko; Kondo, Katsuhiko; Ikka, Takashi; Ando, Tsuyu; Kono, Izumi; Ito, Sachie; Shomura, Ayahiko; Ookawa, Taiichiro; Hirasawa, Tadashi; Yano, Masahiro; Kondo, Motohiko; Yamamoto, Toshio

2013-01-01

Improvement of leaf photosynthesis is an important strategy for greater crop productivity. Here we show that the quantitative trait locus GPS (GREEN FOR PHOTOSYNTHESIS) in rice (Oryza sativa L.) controls photosynthesis rate by regulating carboxylation efficiency. Map-based cloning revealed that GPS is identical to NAL1 (NARROW LEAF1), a gene previously reported to control lateral leaf growth. The high-photosynthesis allele of GPS was found to be a partial loss-of-function allele of NAL1. This allele increased mesophyll cell number between vascular bundles, which led to thickened leaves, and it pleiotropically enhanced photosynthesis rate without the detrimental side effects observed in previously identified nal1 mutants, such as dwarf plant stature. Furthermore, pedigree analysis suggested that rice breeders have repeatedly selected the high-photosynthesis allele in high-yield breeding programs. The identification and utilization of NAL1 (GPS) can enhance future high-yield breeding and provides a new strategy for increasing rice productivity. PMID:23985993
Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins.

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Banfi, Cristina; Baetta, Roberta; Gianazza, Erica; Tremoli, Elena

2017-06-01

Proteomic-based techniques provide a powerful tool for identifying the full spectrum of protein targets of a drug, elucidating its mechanism(s) of action, and identifying biomarkers of its efficacy and safety. Herein, we outline the technological advancements in the field, and illustrate the contribution of proteomics to the definition of the pharmacological profile of statins, which represent the cornerstone of the prevention and treatment of cardiovascular diseases (CVDs). Statins act by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, thus reducing cholesterol biosynthesis and consequently enhancing the clearance of low-density lipoproteins from the blood; however, HMG-CoA reductase inhibition can result in a multitude of additional effects beyond lipid lowering, known as 'pleiotropic effects'. The case of statins highlights the unique contribution of proteomics to the target profiling of a drug molecule. Copyright © 2017 Elsevier Ltd. All rights reserved.
Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift.

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Johnson, Norman A; Porter, Adam H

2007-01-01

Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.
Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac ▿

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van Leeuwen, Jolanda S.; Vermeulen, Nico P. E.; Vos, J. Chris

2011-01-01

Diclofenac is a widely used analgesic drug that can cause serious adverse drug reactions. We used Saccharomyces cerevisiae as a model eukaryote with which to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Although most yeast cells died during the initial diclofenac treatment, some survived and started growing again. Microarray analysis of the adapted cells identified three major processes involved in diclofenac detoxification and tolerance. In particular, pleiotropic drug resistance (PDR) genes and genes under the control of Rlm1p, a transcription factor in the protein kinase C (PKC) pathway, were upregulated in diclofenac-adapted cells. We tested if these processes or pathways were directly involved in diclofenac toxicity or resistance. Of the pleiotropic drug resistance gene products, the multidrug transporter Pdr5p was crucially important for diclofenac tolerance. Furthermore, deletion of components of the cell wall stress-responsive PKC pathway increased diclofenac toxicity, whereas incubation of cells with the cell wall stressor calcofluor white before the addition of diclofenac decreased its toxicity. Also, diclofenac induced flocculation, which might trigger the cell wall alterations. Genes involved in ribosome biogenesis and rRNA processing were downregulated, as were zinc-responsive genes. Paradoxically, deletion of the zinc-responsive transcription factor Zap1p or addition of the zinc chelator 1,10-phenanthroline significantly increased diclofenac toxicity, establishing a regulatory role for zinc in diclofenac resistance. In conclusion, we have identified three new pathways involved in diclofenac tolerance in yeast, namely, Pdr5p as the main contributor to the PDR response, cell wall signaling via the PKC pathway, and zinc homeostasis, regulated by Zap1p. PMID:21724882
Mutations in Barley Row Type Genes Have Pleiotropic Effects on Shoot Branching.

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Corinna Brit Liller

Full Text Available Cereal crop yield is determined by different yield components such as seed weight, seed number per spike and the tiller number and spikes. Negative correlations between these traits are often attributed to resource limitation. However, recent evidence suggests that the same genes or regulatory modules can regulate both inflorescence branching and tillering. It is therefore important to explore the role of genetic correlations between different yield components in small grain cereals. In this work, we studied pleiotropic effects of row type genes on seed size, seed number per spike, thousand grain weight, and tillering in barley to better understand the genetic correlations between individual yield components. Allelic mutants of nine different row type loci (36 mutants, in the original spring barley varieties Barke, Bonus and Foma and introgressed in the spring barley cultivar Bowman, were phenotyped under greenhouse and outdoor conditions. We identified two main mutant groups characterized by their relationships between seed and tillering parameters. The first group comprises all mutants with an increased number of seeds and significant change in tiller number at early development (group 1a or reduced tillering only at full maturity (group 1b. Mutants in the second group are characterized by a reduction in seeds per spike and tiller number, thus exhibiting positive correlations between seed and tiller number. Reduced tillering at full maturity (group 1b is likely due to resource limitations. In contrast, altered tillering at early development (groups 1a and 2 suggests that the same genes or regulatory modules affect inflorescence and shoot branching. Understanding the genetic bases of the trade-offs between these traits is important for the genetic manipulation of individual yield components.
Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study.

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Antje R Weseler

Full Text Available BACKGROUND: Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded. METHODS: In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets. RESULTS: In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05 by 5% (n = 11 and 7% (n = 9, respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P<0.05 in MOF supplemented subjects. We also observed that MOF supplementation exerts anti-inflammatory effects in blood towards ex vivo added bacterial endotoxin and significantly reduces expression of inflammatory genes in leukocytes. Conversely, alterations in macro- and microvascular function, platelet aggregation, plasma levels of nitric oxide surrogates, endothelin-1, C-reactive protein, fibrinogen, prostaglandin F2alpha, plasma antioxidant capacity and gene expression levels of antioxidant defense enzymes did not reach statistical significance after 8 weeks MOF supplementation. However, integrating all measured effects into a global, so-called vascular health index revealed a significant improvement of overall vascular health by MOF compared to placebo (P ≤ 0.05. CONCLUSION: Our
Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease

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Laura Ibanez

2018-04-01

the Alzheimer disease-causing genes (PSEN1 and PSEN2 are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.
Pleiotropic effects of statins

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Narasaraju Kavalipati

2015-01-01

Full Text Available Statins or 3-hydroxy-methylglutaryl coenzyme A (HMG CoA reductase inhibitors not only prevents the synthesis of cholesterol biosynthesis but also inhibits the synthesis of essential isoprenoid intermediates such as farnesyl pyrophosphate, geranylgeranyl pyrophosphate, isopentanyl adenosine, dolichols and polyisoprenoid side chains of ubiquinone, heme A, and nuclear lamins. These isoprenoid intermediates are required for activation of various intracellular/signaling proteins- small guanosine triphosphate bound protein Ras and Ras-like proteins like Rho, Rab, Rac, Ral, or Rap which plays an indispensible role in multiple cellular processes. Reduction of circulating isoprenoids intermediates as a result of HMG CoA reductase inhibition by statins prevents activation of these signalling proteins. Hence, the multiple effects of statins such as antiinflammatory effects, antioxidant effects, antiproliferative and immunomodulatory effects, plaque stability, normalization of sympathetic outflow, and prevention of platelet aggregation are due to reduction of circulating isoprenoids and hence inactivation of signalling proteins. These multiple lipid-independent effects of statins termed as statin pleiotropy would potentially open floodgates for research in multiple treatment domains catching attentions of researchers and clinician across the globe.
Ticagrelor, but not clopidogrel active metabolite, displays antithrombotic properties in the left atrial endocardium.

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Reiner, Martin F; Breitenstein, Alexander; Holy, Erik W; Glanzmann, Martina; Amstalden, Heidi; Stämpfli, Simon F; Bonetti, Nicole R; Falk, Volkmar; Keller, Stephan; Savarese, Gianluigi; Benussi, Stefano; Maisano, Francesco; Lüscher, Thomas F; Beer, Jürg H; Steffel, Jan; Camici, Giovanni G

2017-03-21

Oral anticoagulation is considered standard therapy for stroke prevention in atrial fibrillation (AF). Endocardial activation triggers expression of pro-thrombotic mediators including tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), and contributes to thrombus formation in the left atrial appendage (LAA) of AF patients. Recently, pleiotropic effects of specific P2Y12 receptor antagonists were demonstrated; however, whether these drugs possess antithrombotic effects on LAA endocardial cells currently remains unknown. LAA were obtained from 14 patients with known AF undergoing elective cardiac surgery including LAA removal at the University Hospital Zurich. LAA endocardial cells were isolated and pre-incubated with ticagrelor (10-7, 10-6, 10-5M) or clopidogrel active metabolite (CAM) (1.5 × 10-8, 1.5 × 10-7, 1.5 × 10-6 M) before stimulation with tumour necrosis factor-alpha (TNF-α) (10 ng/mL). Finally, TF and PAI-1 expression and activity were analysed. Ticagrelor, unlike CAM, concentration dependently decreased TNF-α-induced TF expression and TF activity in LAA endocardial cells. Further, ticagrelor, but not CAM reduced PAI-1 expression and enzyme activity in TNF-α-stimulated LAA endocardial cells. In contrast, TF pathway inhibitor (TFPI) remained unaffected by both dugs. Ticagrelor, but not CAM, reduces expression and activity of TF and PAI-1 in LAA endocardial cells isolated from patients with AF, indicating possible local antithrombotic effects. Such pleiotropic properties of ticagrelor may contribute to a reduction in thromboembolic complications in patients with AF. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.

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Vallon, Volker; Thomson, Scott C

2017-02-01

Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ∼80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ∼80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney's demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are
Genetics of human body size and shape: pleiotropic and independent genetic determinants of adiposity.

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Livshits, G; Yakovenko, K; Ginsburg, E; Kobyliansky, E

1998-01-01

The present study utilized pedigree data from three ethnically different populations of Kirghizstan, Turkmenia and Chuvasha. Principal component analysis was performed on a matrix of genetic correlations between 22 measures of adiposity, including skinfolds, circumferences and indices. Findings are summarized as follows: (1) All three genetic matrices were not positive definite and the first four factors retained even after exclusion RG > or = 1.0, explained from 88% to 97% of the total additive genetic variation in the 22 trials studied. This clearly emphasizes the massive involvement of pleiotropic gene effects in the variability of adiposity traits. (2) Despite the quite natural differences in pairwise correlations between the adiposity traits in the three ethnically different samples under study, factor analysis revealed a common basic pattern of covariability for the adiposity traits. In each of the three samples, four genetic factors were retained, namely, the amount of subcutaneous fat, the total body obesity, the pattern of distribution of subcutaneous fat and the central adiposity distribution. (3) Genetic correlations between the retained four factors were virtually non-existent, suggesting that several independent genetic sources may be governing the variation of adiposity traits. (4) Variance decomposition analysis on the obtained genetic factors leaves no doubt regarding the substantial familial and (most probably genetic) effects on variation of each factor in each studied population. The similarity of results in the three different samples indicates that the findings may be deemed valid and reliable descriptions of the genetic variation and covariation pattern of adiposity traits in the human species.
Identification of a cluster IV pleiotropic drug resistance transporter gene expressed in the style of Nicotiana plumbaginifolia.

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Trombik, Tomasz; Jasinski, Michal; Crouzet, Jérome; Boutry, Marc

2008-01-01

ATP-binding cassette transporters of the pleiotropic drug resistance (PDR) subfamily are composed of five clusters. We have cloned a gene, NpPDR2, belonging to the still uncharacterized cluster IV from Nicotiana plumbaginifolia. NpPDR2 transcripts were found in the roots and mature flowers. In the latter, NpPDR2 expression was restricted to the style and only after pollination. A 1.5-kb genomic sequence containing the putative NpPDR2 transcription promoter was fused to the beta-glucuronidase reporter gene. The GUS expression pattern confirmed the RT-PCR results that NpPDR2 was expressed in roots and the flower style and showed that it was localized around the conductive tissues. Unlike other PDR genes, NpPDR2 expression was not induced in leaf tissues by none of the hormones typically involved in biotic and abiotic stress response. Moreover, unlike NpPDR1 known to be involved in biotic stress response, NpPDR2 expression was not induced in the style upon Botrytis cinerea infection. In N. plumbaginifolia plants in which NpPDR2 expression was prevented by RNA interference, no unusual phenotype was observed, including at the flowering stage, which suggests that NpPDR2 is not essential in the reproductive process under the tested conditions.
Pleiotropic functions of the yeast Greatwall-family protein kinase Rim15p: a novel target for the control of alcoholic fermentation.

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Watanabe, Daisuke; Takagi, Hiroshi

2017-06-01

Rim15p, a Greatwall-family protein kinase in yeast Saccharomyces cerevisiae, is required for cellular nutrient responses, such as the entry into quiescence and the induction of meiosis and sporulation. In higher eukaryotes, the orthologous gene products are commonly involved in the cell cycle G 2 /M transition. How are these pleiotropic functions generated from a single family of protein kinases? Recent advances in both research fields have identified the conserved Greatwall-mediated signaling pathway and a variety of downstream target molecules. In addition, our studies of S. cerevisiae sake yeast strains revealed that Rim15p also plays a significant role in the control of alcoholic fermentation. Despite an extensive history of research on glycolysis and alcoholic fermentation, there has been no critical clue to artificial modification of fermentation performance of yeast cells. Our finding of an in vivo metabolic regulatory mechanism is expected to provide a major breakthrough in yeast breeding technologies for fermentation applications.

EGFR Activation and Ultraviolet Light‐Induced Skin Carcinogenesis

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Taghrid B. El-Abaseri

2007-01-01

Full Text Available The epidermal growth factor receptor (EGFR regulates the proliferation of keratinocytes through multiple mechanisms that differ depending on the localization of the cell within the skin. Ultraviolet (UV irradiation, the main etiologic factor in the development of skin cancer, also activates the receptor. In this review, we discuss how the UV-induced activation of EGFR regulates the response of the skin to UV. UV-induced EGFR activation increases keratinocyte proliferation, suppresses apoptosis, and augments and accelerates epidermal hyperplasia in response to UV. Pharmacological inhibition of the UV-induced activation of EGFR in a genetically initiated mouse skin tumorigenesis model suppresses tumorigenesis and the activation of mitogen-activated protein (MAP kinases and phosphatidyl inositol-3-kinase (PI3K/AKT signaling pathways. EGFR has pleiotropic, complex, and cell-type-specific functions in cutaneous keratinocytes; suggesting that the receptor is an appropriate target for the development of molecularly targeted therapies for skin cancer and other pathologies.
UV Irradiation and Pleiotropic Effects of Vitamin D in Chronic Kidney Disease - Benefits on Cardiovascular Comorbidities and Quality of Life.

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Krause, Rolfdieter; Stange, Rainer; Kaase, Heinrich; Holick, Michael F

2016-03-01

Vitamin D3 can be metabolized in the skin to 25(OH)D and 1,25(OH)2D because the skin expresses vitamin D-25-hydroxylase, 25(OH)D-1-alpha-hydroxylase, and the vitamin D receptor. The aim of this review was to discuss the pleiotropic effects after serial suberythemal UVB irradiation with a sun-simulating UV spectrum in end-stage kidney disease patients. Fourteen hemodialysis patients, with a mean age of 51 (range 41-57) years, were whole-body UV irradiated over 6 months. Patients demonstrated an increase in their hematocrit and required less erythropoietin. An increase in maximal oxygen uptake and workload capacity was associated with decreased lactic acid production. The patients demonstrated a decreased heart rate and systolic and diastolic blood pressure with an increase in the R-R-interval and the beat-to-beat-differences. Cardiovascular disease is the most important comorbidity. Exposure to simulated sunlight that contains both UVB and UVA reduce cardiovascular risk factors and improve quality of life. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan.

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Ashpole, Nicole M; Logan, Sreemathi; Yabluchanskiy, Andriy; Mitschelen, Matthew C; Yan, Han; Farley, Julie A; Hodges, Erik L; Ungvari, Zoltan; Csiszar, Anna; Chen, Sixia; Georgescu, Constantin; Hubbard, Gene B; Ikeno, Yuji; Sonntag, William E

2017-04-01

Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf f/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.
Transcriptome Comparative Profiling of Barley eibi1 Mutant Reveals Pleiotropic Effects of HvABCG31 Gene on Cuticle Biogenesis and Stress Responsive Pathways

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Eviatar Nevo

2013-10-01

Full Text Available Wild barley eibi1 mutant with HvABCG31 gene mutation has low capacity to retain leaf water, a phenotype associated with reduced cutin deposition and a thin cuticle. To better understand how such a mutant plant survives, we performed a genome-wide gene expression analysis. The leaf transcriptomes between the near-isogenic lines eibi1 and the wild type were compared using the 22-k Barley1 Affymetrix microarray. We found that the pleiotropic effect of the single gene HvABCG31 mutation was linked to the co-regulation of metabolic processes and stress-related system. The cuticle development involved cytochrome P450 family members and fatty acid metabolism pathways were significantly up-regulated by the HvABCG31 mutation, which might be anticipated to reduce the levels of cutin monomers or wax and display conspicuous cuticle defects. The candidate genes for responses to stress were induced by eibi1 mutant through activating the jasmonate pathway. The down-regulation of co-expressed enzyme genes responsible for DNA methylation and histone deacetylation also suggested that HvABCG31 mutation may affect the epigenetic regulation for barley development. Comparison of transcriptomic profiling of barley under biotic and abiotic stresses revealed that the functions of HvABCG31 gene to high-water loss rate might be different from other osmotic stresses of gene mutations in barley. The transcriptional profiling of the HvABCG31 mutation provided candidate genes for further investigation of the physiological and developmental changes caused by the mutant.
Hijacking of the pleiotropic cytokine interferon-γ by the type III secretion system of Yersinia pestis.

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Claire Gendrin

Full Text Available Yersinia pestis, the causative agent of bubonic plague, employs its type III secretion system to inject toxins into target cells, a crucial step in infection establishment. LcrV is an essential component of the T3SS of Yersinia spp, and is able to associate at the tip of the secretion needle and take part in the translocation of anti-host effector proteins into the eukaryotic cell cytoplasm. Upon cell contact, LcrV is also released into the surrounding medium where it has been shown to block the normal inflammatory response, although details of this mechanism have remained elusive. In this work, we reveal a key aspect of the immunomodulatory function of LcrV by showing that it interacts directly and with nanomolar affinity with the inflammatory cytokine IFNγ. In addition, we generate specific IFNγ mutants that show decreased interaction capabilities towards LcrV, enabling us to map the interaction region to two basic C-terminal clusters of IFNγ. Lastly, we show that the LcrV-IFNγ interaction can be disrupted by a number of inhibitors, some of which display nanomolar affinity. This study thus not only identifies novel potential inhibitors that could be developed for the control of Yersinia-induced infection, but also highlights the diversity of the strategies used by Y. pestis to evade the immune system, with the hijacking of pleiotropic cytokines being a long-range mechanism that potentially plays a key role in the severity of plague.
The LacI–Family Transcription Factor, RbsR, Is a Pleiotropic Regulator of Motility, Virulence, Siderophore and Antibiotic Production, Gas Vesicle Morphogenesis and Flotation in Serratia

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Chin M. Lee

2017-09-01

Full Text Available Gas vesicles (GVs are proteinaceous, gas-filled organelles used by some bacteria to enable upward movement into favorable air/liquid interfaces in aquatic environments. Serratia sp. ATCC39006 (S39006 was the first enterobacterium discovered to produce GVs naturally. The regulation of GV assembly in this host is complex and part of a wider regulatory network affecting various phenotypes, including antibiotic biosynthesis. To identify new regulators of GVs, a comprehensive mutant library containing 71,000 insertion mutants was generated by random transposon mutagenesis and 311 putative GV-defective mutants identified. Three of these mutants were found to have a transposon inserted in a LacI family transcription regulator gene (rbsR of the putative ribose operon. Each of these rbsR mutants was GV-defective; no GVs were visible by phase contrast microscopy (PCM or transmission electron microscopy (TEM. GV deficiency was caused by the reduction of gvpA1 and gvrA transcription (the first genes of the two contiguous operons in the GV gene locus. Our results also showed that a mutation in rbsR was highly pleiotropic; the production of two secondary metabolites (carbapenem and prodigiosin antibiotics was abolished. Interestingly, the intrinsic resistance to the carbapenem antibiotic was not affected by the rbsR mutation. In addition, the production of a siderophore, cellulase and plant virulence was reduced in the mutant, whereas it exhibited increased swimming and swarming motility. The RbsR protein was predicted to bind to regions upstream of at least 18 genes in S39006 including rbsD (the first gene of the ribose operon and gvrA. Electrophoretic mobility shift assays (EMSA confirmed that RbsR bound to DNA sequences upstream of rbsD, but not gvrA. The results of this study indicate that RbsR is a global regulator that affects the modulation of GV biogenesis, but also with complex pleiotropic physiological impacts in S39006.
Identification of an estrogen receptor α non covalent ubiquitin-binding surface: role in 17β-estradiol-induced transcriptional activity.

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Pesiri, Valeria; La Rosa, Piergiorgio; Stano, Pasquale; Acconcia, Filippo

2013-06-15

Ubiquitin (Ub)-binding domains (UBDs) located in Ub receptors decode the ubiquitination signal by non-covalently engaging the Ub modification on their binding partners and transduce the Ub signalling through Ub-based molecular interactions. In this way, inducible protein ubiquitination regulates diverse biological processes. The estrogen receptor alpha (ERα) is a ligand-activated transcription factor that mediates the pleiotropic effects of the sex hormone 17β-estradiol (E2). Fine regulation of E2 pleiotropic actions depends on E2-dependent ERα association with a plethora of binding partners and/or on the E2 modulation of receptor ubiquitination. Indeed, E2-induced ERα polyubiquitination triggers receptor degradation and transcriptional activity, and E2-dependent reduction in ERα monoubiquitination is crucial for E2 signalling. Monoubiquitinated proteins often contain UBDs, but whether non-covalent Ub-ERα binding could occur and play a role in E2-ERα signalling is unknown. Here, we report an Ub-binding surface within the ERα ligand binding domain that directs in vitro the receptor interaction with both ubiquitinated proteins and recombinant Ub chains. Mutational analysis reveals that ERα residues leucine 429 and alanine 430 are involved in Ub binding. Moreover, impairment of ERα association to ubiquitinated species strongly affects E2-induced ERα transcriptional activity. Considering the importance of UBDs in the Ub-based signalling network and the central role of different ERα binding partners in the modulation of E2-dependent effects, our discoveries provide novel insights into ERα activity that could also be relevant for ERα-dependent diseases.
Antiretroviral effect of lovastatin on HIV-1-infected individuals without highly active antiretroviral therapy (The LIVE study): a phase-II randomized clinical trial

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Montoya Carlos J; Jaimes Fabian; Higuita Edwin A; Convers-Páez Sandra; Estrada Santiago; Gutierrez Francisco; Amariles Pedro; Giraldo Newar; Peñaloza Cristina; Rugeles Maria T

2009-01-01

Abstract Background Highly active antiretroviral therapy produces a significant decrease in HIV-1 replication and allows an increase in the CD4 T-cell count, leading to a decrease in the incidence of opportunistic infections and mortality. However, the cost, side effects and complexity of antiretroviral regimens have underscored the immediate need for additional therapeutic approaches. Statins exert pleiotropic effects through a variety of mechanisms, among which there are several immunoregul...
Derangement of a factor upstream of RARalpha triggers the repression of a pleiotropic epigenetic network.

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Francesca Corlazzoli

Full Text Available Chromatin adapts and responds to extrinsic and intrinsic cues. We hypothesize that inheritable aberrant chromatin states in cancer and aging are caused by genetic/environmental factors. In previous studies we demonstrated that either genetic mutations, or loss, of retinoic acid receptor alpha (RARalpha, can impair the integration of the retinoic acid (RA signal at the chromatin of RA-responsive genes downstream of RARalpha, and can lead to aberrant repressive chromatin states marked by epigenetic modifications. In this study we tested whether the mere interference with the availability of RA signal at RARalpha, in cells with an otherwise functional RARalpha, can also induce epigenetic repression at RA-responsive genes downstream of RARalpha.To hamper the availability of RA at RARalpha in untransformed human mammary epithelial cells, we targeted the cellular RA-binding protein 2 (CRABP2, which transports RA from the cytoplasm onto the nuclear RARs. Stable ectopic expression of a CRABP2 mutant unable to enter the nucleus, as well as stable knock down of endogenous CRABP2, led to the coordinated transcriptional repression of a few RA-responsive genes downstream of RARalpha. The chromatin at these genes acquired an exacerbated repressed state, or state "of no return". This aberrant state is unresponsive to RA, and therefore differs from the physiologically repressed, yet "poised" state, which is responsive to RA. Consistent with development of homozygosis for epigenetically repressed loci, a significant proportion of cells with a defective CRABP2-mediated RA transport developed heritable phenotypes indicative of loss of function.Derangement/lack of a critical factor necessary for RARalpha function induces epigenetic repression of a RA-regulated gene network downstream of RARalpha, with major pleiotropic biological outcomes.
Association of the macrophage activating factor (MAF) precursor activity with polymorphism in vitamin D-binding protein.

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Nagasawa, Hideko; Sasaki, Hideyuki; Uto, Yoshihiro; Kubo, Shinichi; Hori, Hitoshi

2004-01-01

Serum vitamin D-binding protein (Gc protein or DBP) is a highly expressed polymorphic protein, which is a precursor of the inflammation-primed macrophage activating factor, GcMAF, by a cascade of carbohydrate processing reactions. In order to elucidate the relationship between Gc polymorphism and GcMAF precursor activity, we estimated the phagocytic ability of three homotypes of Gc protein, Gc1F-1F, Gc1S-1S and Gc2-2, through processing of their carbohydrate moiety. We performed Gc typing of human serum samples by isoelectric focusing (IEF). Gc protein from human serum was purified by affinity chromatography with 25-hydroxyvitamin D3-sepharose. A phagocytosis assay of Gc proteins, modified using beta-glycosidase and sialidase, was carried out. The Gc1F-1F phenotype was revealed to possess Galbeta1-4GalNAc linkage by the analysis of GcMAF precursor activity using beta1-4 linkage-specific galactosidase from jack bean. The GcMAF precursor activity of the Gc1F-1F phenotype was highest among three Gc homotypes. The Gc polymorphism and carbohydrate diversity of Gc protein are significant for its pleiotropic effects.
Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation.

Science.gov (United States)

Burdon, Kathryn P; McKay, James D; Sale, Michèle M; Russell-Eggitt, Isabelle M; Mackey, David A; Wirth, M Gabriela; Elder, James E; Nicoll, Alan; Clarke, Michael P; FitzGerald, Liesel M; Stankovich, James M; Shaw, Marie A; Sharma, Shiwani; Gajovic, Srecko; Gruss, Peter; Ross, Shelley; Thomas, Paul; Voss, Anne K; Thomas, Tim; Gécz, Jozef; Craig, Jamie E

2003-11-01

Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.
Clinical value of CT/MR-US fusion imaging for radiofrequency ablation of hepatic nodules

Energy Technology Data Exchange (ETDEWEB)

Lee, Jae Young, E-mail: leejy4u@snu.ac.kr [Department of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of); Institute of Radiation Medicine, Seoul National University Hospital, Seoul (Korea, Republic of); Choi, Byung Ihn [Department of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of); Institute of Radiation Medicine, Seoul National University Hospital, Seoul (Korea, Republic of); Chung, Yong Eun [Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Min Wook; Kim, Se Hyung; Han, Joon Koo [Department of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of); Institute of Radiation Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

2012-09-15

Objective: The aim of this study was to determine the registration error of an ultrasound (US) fusion imaging system during an ex vivo study and its clinical value for percutaneous radiofrequency ablation (pRFA) during an in vivo study. Materials and methods: An ex vivo study was performed using 4 bovine livers and 66 sonographically invisible lead pellets. Real-time CT-US fusion imaging was applied to assist the targeting of pellets with needles in each liver; the 4 sessions were performed by either an experienced radiologist (R1, 3 sessions) or an inexperienced resident (R2, 1 session). The distance between the pellet target and needle was measured. An in vivo study was retrospectively performed with 51 nodules (42 HCCs and 9 metastases; mean diameter, 16 mm) of 37 patients. Fusion imaging was used to create a sufficient safety margin (>5 mm) during pRFA in 24 nodules (group 1), accurately target 21 nodules obscured in the US images (group 2) and precisely identify 6 nodules surrounded by similar looking nodules (group 3). Image fusion was achieved using MR and CT images in 16 and 21 patients, respectively. The reablation rate, 1-year local recurrence rate and complications were assessed. Results: In the ex vivo study, the mean target–needle distances were 2.7 mm ± 1.9 mm (R1) and 3.1 ± 3.3 mm (R2) (p > 0.05). In the in vivo study, the reablation rates in groups 1–3 were 13%, 19% and 0%, respectively. At 1 year, the local recurrence rate was 11.8% (6/51). In our assessment of complications, one bile duct injury was observed. Conclusion: US fusion imaging system has an acceptable registration error and can be an efficacious tool for overcoming the major limitations of US-guided pRFA.
[In vitro study over statins effects on cellular growth curves and its reversibility with mevalonate].

Science.gov (United States)

Millan Núñez-Cortés, Jesús; Alvarez Rodriguez, Ysmael; Alvarez Novés, Granada; Recarte Garcia-Andrade, Carlos; Alvarez-Sala Walther, Luis

2014-01-01

HMG-CoA-Reductase inhibitors, also known as statins, are currently the most powerful cholesterol-lowering drugs available on the market. Clinical trials and experimental evidence suggest that statins have heavy anti-atherosclerotic effects. These are in part consequence of lipid lowering but also result from pleiotropic actions of the drugs. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL-c reduction or via a direct effect on cellular functions. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. So, although statins typically have similar effects on LDL-c levels, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects. In this paper we analize the in vitro effects of different statins over different cell lines from cells implicated in atherosclerotic process: endothelial cells, fibroblasts, and vascular muscular cells. In relation with our results we can proof that the effects of different dosis of different statins provides singular effects over growth curves of different cellular lines, a despite of a class-dependent effects. So, pleiotropic effects and its reversibility with mevalonate are different according with the molecule and the dosis. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.
Relative transcription of Listeria monocytogenes virulence genes in liver pâtés with varying NaCl content

DEFF Research Database (Denmark)

Olesen, Inger; Thorsen, Line; Jespersen, Lene

2010-01-01

three liver pâtés with reduced NaCl content of which one also has been supplied with organic acids (Ca-acetate and Ca-lactate). The three strains (EGD-e: reference strain; O57: more NaCl sensitive; 6896: more NaCl tolerant) were selected out of twelve strains based on their growth in BHI broth adjusted......B for both O57 and 6896 were significantly higher when the strains were grown in BHI compared to the standard liver pâté. Reducing the NaCl content of the standard liver pâté did not change relative transcription levels of prfA, inlA, sigB or clpC (except for prfA in O57 and sigB in 6896). However......, the presence of Ca-acetate and Ca-lactate induced relative transcription of the stress response gene, clpC, for all three strains. This study demonstrates that relative microbial gene transcription can be measured in complex food matrices and points to the need for designing experimental set-ups in real food...
Biological Activity of Lenalidomide and Its Underlying Therapeutic Effects in Multiple Myeloma

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Roberta Martiniani

2012-01-01

Full Text Available Lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide. It belongs to the second generation of immunomodulatory drugs (IMiDs and possesses pleiotropic properties. Even if lenalidomide has been shown to be active in the treatment of several hematologic malignancies, this review article is mostly focalized on its mode of action in multiple myeloma. The present paper is about the direct and indirect antitumor effects of lenalidomide on malignant plasmacells, bone marrow microenvironment, bone resorption and host’s immune response. The molecular mechanisms and targets of lenalidomide remain largely unknown, but recent evidence shows cereblon (CRBN as a possible mediator of its therapeutical effects.
Rifampicin-Resistance Mutations in the rpoB Gene in Bacillus velezensis CC09 have Pleiotropic Effects.

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Cai, Xun-Chao; Xi, Huan; Liang, Li; Liu, Jia-Dong; Liu, Chang-Hong; Xue, Ya-Rong; Yu, Xiang-Yang

2017-01-01

Rifampicin resistance (Rif r ) mutations in the RNA polymerase β subunit ( rpoB ) gene exhibit pleiotropic phenotypes as a result of their effects on the transcription machinery in prokaryotes. However, the differences in the effects of the mutations on the physiology and metabolism of the bacteria remain unknown. In this study, we isolated seven Rif r mutations in rpoB , including six single point mutations (H485Y, H485C, H485D, H485R, Q472R, and S490L) and one double point mutation (S490L/S617F) from vegetative cells of an endophytic strain, Bacillus velezensis CC09. Compared to the wild-type (WT) strain (CC09), the H485R and H485D mutants exhibited a higher degree of inhibition of Aspergillus niger spore germination, while the H485Y, S490L, Q472R, and S490L/S617F mutants exhibited a lower degree of inhibition due to their lower production of the antibiotic iturin A. These mutants all exhibited defective phenotypes in terms of pellicle formation, sporulation, and swarming motility. A hierarchical clustering analysis of the observed phenotypes indicated that the four mutations involving amino acid substitutions at H485 in RpoB belonged to the same cluster. In contrast, the S490L and Q472R mutations, as well as the WT strain, were in another cluster, indicating a functional connection between the mutations in B. velezensis and phenotypic changes. Our data suggest that Rif r mutations cannot only be used to study transcriptional regulation mechanisms, but can also serve as a tool to increase the production of bioactive metabolites in B. velezensis .
Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders.

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Tallulah Andrews

2015-03-01

Full Text Available Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51% groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects.
Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders.

Science.gov (United States)

Andrews, Tallulah; Meader, Stephen; Vulto-van Silfhout, Anneke; Taylor, Avigail; Steinberg, Julia; Hehir-Kwa, Jayne; Pfundt, Rolph; de Leeuw, Nicole; de Vries, Bert B A; Webber, Caleb

2015-03-01

Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51%) groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i) this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii) that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects.
Peptides derived from specific interaction sites of the fibroblast growth factor 2 - FGF receptor complexes induce receptor activation and signaling

DEFF Research Database (Denmark)

Manfè, Valentina; Kochoyan, Artur; Bock, Elisabeth

2010-01-01

J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06718.x Abstract Basic fibroblast growth factor (FGF2, bFGF) is the most extensively studied member of the FGF family and is involved in neurogenesis, differentiation, neuroprotection, and synaptic plasticity in the CNS. FGF2 executes its pleiotropic...... biologic actions by binding, dimerizing, and activating FGF receptors (FGFRs). The present study reports the physiologic impact of various FGF2-FGFR1 contact sites employing three different synthetic peptides, termed canofins, designed based on structural analysis of the interactions between FGF2 and FGFR1...
GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells

OpenAIRE

Tran, Dat Q.; Andersson, John; Wang, Rui; Ramsey, Heather; Unutmaz, Derya; Shevach, Ethan M.

2009-01-01

TGF-β family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-β is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGFβ-binding protein (LTBP) to produce a large latent form. Latent TGF-β is also found on the surface of activated FOXP3+ regulatory T cells (Tregs), but it is unclear how it is anchored to the cell membrane. We show that GARP or LRRC32, a leucine-rich repeat molecule ...

P-Ser-HPr-a link between carbon metabolism and the virulence of some pathogenic bacteria

DEFF Research Database (Denmark)

Mijakovic, Ivan

2005-01-01

HPr kinase/phosphorylase phosphorylates HPr, a phosphocarrier protein of the phosphoenolpyruvate:carbohydrate phosphotransferase system, at serine-46. P-Ser-HPr is the central regulator of carbon metabolism in Gram-positive bacteria, but also plays a role in virulence development of certain...... pathogens. In Listeria monocytogenes, several virulence genes, which depend on the transcription activator PrfA, are repressed by glucose, fructose, etc., in a catabolite repressor (CcpA)-independent mechanism. However, the catabolite co-repressor P-Ser-HPr was found to inhibit the activity of Prf...... is preceded by an operator site, which serves as target for the CcpA/P-Ser-HPr complex. Numerous Gram-negative pathogens also contain hprK, which is often organised in an operon with transcription regulators necessary for the development of virulence, indicating that in these organisms P-Ser-HPr also plays...
Purification and biochemical characterization of NpABCG5/NpPDR5, a plant pleiotropic drug resistance transporter expressed in Nicotiana tabacum BY-2 suspension cells.

Science.gov (United States)

Toussaint, Frédéric; Pierman, Baptiste; Bertin, Aurélie; Lévy, Daniel; Boutry, Marc

2017-05-04

Pleiotropic drug resistance (PDR) transporters belong to the ABCG subfamily of ATP-binding cassette (ABC) transporters and are involved in the transport of various molecules across plasma membranes. During evolution, PDR genes appeared independently in fungi and in plants from a duplication of a half-size ABC gene. The enzymatic properties of purified PDR transporters from yeast have been characterized. This is not the case for any plant PDR transporter, or, incidentally, for any purified plant ABC transporter. Yet, plant PDR transporters play important roles in plant physiology such as hormone signaling or resistance to pathogens or herbivores. Here, we describe the expression, purification, enzymatic characterization and 2D analysis by electron microscopy of NpABCG5/NpPDR5 from Nicotiana plumbaginifolia , which has been shown to be involved in the plant defense against herbivores. We constitutively expressed NpABCG5/NpPDR5, provided with a His-tag in a homologous system: suspension cells from Nicotiana tabacum (Bright Yellow 2 line). NpABCG5/NpPDR5 was targeted to the plasma membrane and was solubilized by dodecyl maltoside and purified by Ni-affinity chromatography. The ATP-hydrolyzing specific activity (27 nmol min -1 mg -1 ) was stimulated seven-fold in the presence of 0.1% asolectin. Electron microscopy analysis indicated that NpABCG5/NpPDR5 is monomeric and with dimensions shorter than those of known ABC transporters. Enzymatic data (optimal pH and sensitivity to inhibitors) confirmed that plant and fungal PDR transporters have different properties. These data also show that N. tabacum suspension cells are a convenient host for the purification and biochemical characterization of ABC transporters. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
Pleiotropic effects of statins in stroke prevention

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Yenny Yenny

2016-02-01

Full Text Available Cardiovascular disease is the leading cause of death and disability, and contributes substantially to healthcare budgets. The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA reductase inhibitor or statins, reducing mortality and cardiovascular morbidity in patients with established cardiovascular disease. Statins therefore have a place in the secondary prevention of cardiovascular disease. Recent experimental and clinical studies suggest that statins may exert vascular protective effect beyond cholesterol reduction. The cholesterol-independet or “pleiotropic” effects of statin include the upregulation and activation of endothelial nitric acid synthase (eNOS that can increase nitric oxide (NO production. Augmentation of NO production increases cerebral blood flow, which can lead to neuroprotection during brain ischaemia. By inhibiting mevalonate synthesis, statins prevent the formation of several isoprenoids (including farnesylpyrophosphate and geranylgeranylpyrophosphate. Inhibiting geranylgeranylation of RhoA small G proteins increases the stability of eNOS mRNA through the remodeling of endothelial actin microfilamens. Moreover, statins directly increase eNOS activity within minutes by activating the pathway involving phosphoinositide 3-kinase and protein kinase B. In the secondary prevention of stroke, the use of statins reduces the incidence of either recurrent stroke or other major vascular events and treatment should be initiated soon after the event. The use of statins does not increase hemorrhagic stroke or cancer and may also favor atherosclerotic plaque regression.
Pleiotropic effects of statins in stroke prevention

Directory of Open Access Journals (Sweden)

Yenny

2009-08-01

Full Text Available Cardiovascular disease is the leading cause of death and disability, and contributes substantially to healthcare budgets. The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA reductase inhibitor or statins, reducing mortality and cardiovascular morbidity in patients with established cardiovascular disease. Statins therefore have a place in the secondary prevention of cardiovascular disease. Recent experimental and clinical studies suggest that statins may exert vascular protective effect beyond cholesterol reduction. The cholesterol-independet or “pleiotropic” effects of statin include the upregulation and activation of endothelial nitric acid synthase (eNOS that can increase nitric oxide (NO production. Augmentation of NO production increases cerebral blood flow, which can lead to neuroprotection during brain ischaemia. By inhibiting mevalonate synthesis, statins prevent the formation of several isoprenoids (including farnesylpyrophosphate and geranylgeranylpyrophosphate. Inhibiting geranylgeranylation of RhoA small G proteins increases the stability of eNOS mRNA through the remodeling of endothelial actin microfilamens. Moreover, statins directly increase eNOS activity within minutes by activating the pathway involving phosphoinositide 3-kinase and protein kinase B. In the secondary prevention of stroke, the use of statins reduces the incidence of either recurrent stroke or other major vascular events and treatment should be initiated soon after the event. The use of statins does not increase hemorrhagic stroke or cancer and may also favor atherosclerotic plaque regression.
Pleiotropic consequences of misexpression of the developmentally ...

Indian Academy of Sciences (India)

these conditions would affect activities of the hnRNPs and other hsrω-RNA interacting proteins, which is likely to have cascading ... junk', make up the major part of the genome output in higher ..... nervous system (Lin and Goodman 1994).
The Combination of Physical Exercise with Muscle-Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10

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Michele Guescini

2017-01-01

Full Text Available Sarcopenia represents an increasing public health risk due to the rapid aging of the world’s population. It is characterized by both low muscle mass and function and is associated with mobility disorders, increased risk of falls and fractures, loss of independence, disabilities, and increased risk of death. Despite the urgency of the problem, the development of treatments for sarcopenia has lagged. Increased reactive oxygen species (ROS production and decreased antioxidant (AO defences seem to be important factors contributing to muscle impairment. Studies have been conducted to verify whether physical exercise and/or AOs could prevent and/or delay sarcopenia through a normalization of the etiologically relevant ROS imbalance. Despite the strong rationale, the results obtained were contradictory, particularly with regard to the effects of the tested AOs. A possible explanation might be that not all the agents included in the general heading of “AOs” could fulfill the requisites to counteract the complex series of events causing/accelerating sarcopenia: the combination of the muscle-directed antioxidants creatine and coenzyme Q10 with physical exercise as a biomedical rationale for pleiotropic prevention and/or treatment of sarcopenia is discussed.
Pleiotropic effects of bisphosphonates on osteosarcoma.

Science.gov (United States)

Ohba, Tetsuro; Cates, Justin M M; Cole, Heather A; Slosky, David A; Haro, Hirotaka; Ichikawa, Jiro; Ando, Takashi; Schwartz, Herbert S; Schoenecker, Jonathan G

2014-06-01

Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells. Published by Elsevier Inc.
Improved outcome of percutaneous radiofrequency ablation in renal cell carcinoma: a retrospective study of intraoperative contrast-enhanced ultrasonography in 73 patients.

Science.gov (United States)

Zhao, Xiaozhi; Wang, Wei; Zhang, Shiwei; Liu, Jun; Zhang, Fan; Ji, Changwei; Li, Xiaogong; Gan, Weidong; Zhang, Gutian; Guo, Hongqian

2012-10-01

To evaluate the impact of contrast-enhanced ultrasonography (CEUS) during percutaneous radiofrequency ablation (PRFA) procedure in renal cell carcinoma (RCC). From January 2008 to July 2010, 73 patients with sporadic unilateral RCC were enrolled to our study (57 men and 16 women, age range: 37-78 years, mean age 57.9 years). The diameter of the tumor was 1.7-5.8, 3.4 cm on average. The patients were divided into two groups depending on the intraoperative ultrasonography type: CEUS group and conventional ultrasound group. Patients in CEUS group received CEUS before insertion of the electrode, and the second CEUS was performed right after the initial ablation to dynamically evaluate the images. If there was highly suspicious residue, additional ablation and repeated CEUS were applied. Patients in the conventional ultrasound group received PRFA guided by gray-scale ultrasound. All of these patients received contrast-enhanced computed tomography (CT) examination 7 days after the procedure (patients in CEUS group received CEUS conducted with each CT scan), with subsequent CT and CEUS assessment at 3, 6, and every 6 months thereafter. The mean follow-up period was 22 months (range: 12-42 months). All tumors were biopsied before RFA. The local tumor control rate was 94.6% (35/37) in the CEUS group and 86.1% (31/36) in the conventional ultrasound group (P 73 m(2) (P > 0.05, compared with pre-GFR: 86.4 ± 26.2 mL/min/1.73 m(2)) in the CEUS group and 81.9 ± 22.8 mL/min/1.73 m(2) (P > 0.05, compared with pre-GFR: 83.5 ± 23.7 mL/min/1.73 m(2)) in the conventional ultrasound group. Intraoperative CEUS can "real-time" monitor the ablated area during PRFA procedure. This technique can help to achieve a higher success rate compared with conventional ultrasound. No impact of intraoperative CEUS has been found on GFR level.
Pleiotropic Associations of RARRES2 Gene Variants and Circulating Chemerin Levels: Potential Roles of Chemerin Involved in the Metabolic and Inflammation-Related Diseases

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Leay-Kiaw Er

2018-01-01

Full Text Available Chemerin, an adipokine and inflammatory mediator, is associated with metabolic, inflammation- and immune-mediated diseases. The genetic, clinical, and biomarker correlates of circulating chemerin levels have not been completely elucidated. We analyzed the determinants and correlates of retinoic acid receptor responder 2 (RARRES2; encoding chemerin gene variants and chemerin levels in the Taiwanese population. In total, 612 individuals were recruited. Clinical and metabolic phenotypes, 13 inflammatory markers, 5 adipokines, and 6 single-nucleotide polymorphisms (SNPs covering the RARRES2 region were analyzed. High chemerin levels and chemerin level tertiles were positively associated with multiple metabolic phenotypes and circulating inflammatory marker and adipokine levels and negatively associated with high-density lipoprotein cholesterol and adiponectin levels and estimated glomerular filtration rates (eGFRs. Genotype and haplotype analyses showed that RARRES2 SNPs were significantly associated with chemerin, fibrinogen, interleukin 6, and lipocalin 2 levels. Stepwise logistic regression analysis showed that C-reactive protein level, leptin level, triglyceride level, eGFR, rs3735167 genotypes, sex, and soluble P-selectin level were independently associated with chemerin levels. In conclusion, pleiotropic associations were noted between RARRES2 variants, circulating chemerin levels and multiple metabolic phenotypes and inflammatory marker levels. This study provides further evidence for the potential roles of chemerin in metabolic and inflammation-related diseases.
Pleiotropic Regulation of Virulence Genes in Streptococcus mutans by the Conserved Small Protein SprV.

Science.gov (United States)

Shankar, Manoharan; Hossain, Mohammad S; Biswas, Indranil

2017-04-15

Streptococcus mutans , an oral pathogen associated with dental caries, colonizes tooth surfaces as polymicrobial biofilms known as dental plaque. S. mutans expresses several virulence factors that allow the organism to tolerate environmental fluctuations and compete with other microorganisms. We recently identified a small hypothetical protein (90 amino acids) essential for the normal growth of the bacterium. Inactivation of the gene, SMU.2137, encoding this protein caused a significant growth defect and loss of various virulence-associated functions. An S. mutans strain lacking this gene was more sensitive to acid, temperature, osmotic, oxidative, and DNA damage-inducing stresses. In addition, we observed an altered protein profile and defects in biofilm formation, bacteriocin production, and natural competence development, possibly due to the fitness defect associated with SMU.2137 deletion. Transcriptome sequencing revealed that nearly 20% of the S. mutans genes were differentially expressed upon SMU.2137 deletion, thereby suggesting a pleiotropic effect. Therefore, we have renamed this hitherto uncharacterized gene as sprV ( s treptococcal p leiotropic r egulator of v irulence). The transcript levels of several relevant genes in the sprV mutant corroborated the phenotypes observed upon sprV deletion. Owing to its highly conserved nature, inactivation of the sprV ortholog in Streptococcus gordonii also resulted in poor growth and defective UV tolerance and competence development as in the case of S. mutans Our experiments suggest that SprV is functionally distinct from its homologs identified by structure and sequence homology. Nonetheless, our current work is aimed at understanding the importance of SprV in the S. mutans biology. IMPORTANCE Streptococcus mutans employs several virulence factors and stress resistance mechanisms to colonize tooth surfaces and cause dental caries. Bacterial pathogenesis is generally controlled by regulators of fitness that are
The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies.

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Reinhold J Medina

Full Text Available BACKGROUND: Current guidelines encourage the use of statins to reduce the risk of cardiovascular disease in diabetic patients; however the impact of these drugs on diabetic retinopathy is not well defined. Moreover, pleiotropic effects of statins on the highly specialised retinal microvascular endothelium remain largely unknown. The objective of this study was to investigate the effects of clinically relevant concentrations of simvastatin on retinal endothelium in vitro and in vivo. METHODS AND FINDINGS: Retinal microvascular endothelial cells (RMECs were treated with 0.01-10 microM simvastatin and a biphasic dose-related response was observed. Low concentrations enhanced microvascular repair with 0.1 microM simvastatin significantly increasing proliferation (p<0.05, and 0.01 microM simvastatin significantly promoting migration (p<0.05, sprouting (p<0.001, and tubulogenesis (p<0.001. High concentration of simvastatin (10 microM had the opposite effect, significantly inhibiting proliferation (p<0.01, migration (p<0.01, sprouting (p<0.001, and tubulogenesis (p<0.05. Furthermore, simvastatin concentrations higher than 1 microM induced cell death. The mouse model of oxygen-induced retinopathy was used to investigate the possible effects of simvastatin treatment on ischaemic retinopathy. Low dose simvastatin (0.2 mg/Kg promoted retinal microvascular repair in response to ischaemia by promoting intra-retinal re-vascularisation (p<0.01. By contrast, high dose simvastatin(20 mg/Kg significantly prevented re-vascularisation (p<0.01 and concomitantly increased pathological neovascularisation (p<0.01. We also demonstrated that the pro-vascular repair mechanism of simvastatin involves VEGF stimulation, Akt phosphorylation, and nitric oxide production; and the anti-vascular repair mechanism is driven by marked intracellular cholesterol depletion and related disorganisation of key intracellular structures. CONCLUSIONS: A beneficial effect of low
Role of AMP-activated protein kinase in mechanism of metformin action.

Science.gov (United States)

Zhou, G; Myers, R; Li, Y; Chen, Y; Shen, X; Fenyk-Melody, J; Wu, M; Ventre, J; Doebber, T; Fujii, N; Musi, N; Hirshman, M F; Goodyear, L J; Moller, D E

2001-10-01

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.
Telmisartan activates endothelial nitric oxide synthase via Ser1177 phosphorylation in vascular endothelial cells.

Directory of Open Access Journals (Sweden)

Masahiro Myojo

Full Text Available Because endothelial nitric oxide synthase (eNOS has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177 in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172 and eNOS and the concentration of intracellular guanosine 3',5'-cyclic monophosphate (cGMP. Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.
The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration

Science.gov (United States)

Hesse, Robert G; Kouklis, Gayle K; Ahituv, Nadav; Pomerantz, Jason H

2015-01-01

The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species’ regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF –p53 axis activation. DOI: http://dx.doi.org/10.7554/eLife.07702.001 PMID:26575287
Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.

Directory of Open Access Journals (Sweden)

Alexander M Kulminski

2016-11-01

Full Text Available Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC Study (N = 9,573 was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5% located in band 2q22.3 with risks of coronary heart disease (CHD, heart failure (HF, stroke, diabetes, cancer, neurodegenerative diseases (ND, and mortality in the ARIC study, the Framingham Heart Study (N = 4,434, and the Health and Retirement Study (N = 9,676. We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9, CHD by 35% (p = 8.9×10-6, HF by 55% (p = 9.7×10-5, stroke by 25% (p = 4.0×10-2, and ND by 100% (p = 1.3×10-3. This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.
Loss of Cln3 Function in the Social Amoeba Dictyostelium discoideum Causes Pleiotropic Effects That Are Rescued by Human CLN3

Science.gov (United States)

Huber, Robert J.

2014-01-01

The neuronal ceroid lipofuscinoses (NCL) are a group of inherited, severe neurodegenerative disorders also known as Batten disease. Juvenile NCL (JNCL) is caused by recessive loss-of-function mutations in CLN3, which encodes a transmembrane protein that regulates endocytic pathway trafficking, though its primary function is not yet known. The social amoeba Dictyostelium discoideum is increasingly utilized for neurological disease research and is particularly suited for investigation of protein function in trafficking. Therefore, here we establish new overexpression and knockout Dictyostelium cell lines for JNCL research. Dictyostelium Cln3 fused to GFP localized to the contractile vacuole system and to compartments of the endocytic pathway. cln3− cells displayed increased rates of proliferation and an associated reduction in the extracellular levels and cleavage of the autocrine proliferation repressor, AprA. Mid- and late development of cln3− cells was precocious and cln3− slugs displayed increased migration. Expression of either Dictyostelium Cln3 or human CLN3 in cln3− cells suppressed the precocious development and aberrant slug migration, which were also suppressed by calcium chelation. Taken together, our results show that Cln3 is a pleiotropic protein that negatively regulates proliferation and development in Dictyostelium. This new model system, which allows for the study of Cln3 function in both single cells and a multicellular organism, together with the observation that expression of human CLN3 restores abnormalities in Dictyostelium cln3− cells, strongly supports the use of this new model for JNCL research. PMID:25330233
Loss of Cln3 function in the social amoeba Dictyostelium discoideum causes pleiotropic effects that are rescued by human CLN3.

Directory of Open Access Journals (Sweden)

Robert J Huber

Full Text Available The neuronal ceroid lipofuscinoses (NCL are a group of inherited, severe neurodegenerative disorders also known as Batten disease. Juvenile NCL (JNCL is caused by recessive loss-of-function mutations in CLN3, which encodes a transmembrane protein that regulates endocytic pathway trafficking, though its primary function is not yet known. The social amoeba Dictyostelium discoideum is increasingly utilized for neurological disease research and is particularly suited for investigation of protein function in trafficking. Therefore, here we establish new overexpression and knockout Dictyostelium cell lines for JNCL research. Dictyostelium Cln3 fused to GFP localized to the contractile vacuole system and to compartments of the endocytic pathway. cln3- cells displayed increased rates of proliferation and an associated reduction in the extracellular levels and cleavage of the autocrine proliferation repressor, AprA. Mid- and late development of cln3- cells was precocious and cln3- slugs displayed increased migration. Expression of either Dictyostelium Cln3 or human CLN3 in cln3- cells suppressed the precocious development and aberrant slug migration, which were also suppressed by calcium chelation. Taken together, our results show that Cln3 is a pleiotropic protein that negatively regulates proliferation and development in Dictyostelium. This new model system, which allows for the study of Cln3 function in both single cells and a multicellular organism, together with the observation that expression of human CLN3 restores abnormalities in Dictyostelium cln3- cells, strongly supports the use of this new model for JNCL research.
The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells

NARCIS (Netherlands)

Koushyar, S.; Economides, G.; Zaat, S.; Jiang, W.; Bevan, C. L.; Dart, D. A.

2017-01-01

Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR.
Ultrasound-Guided Greater Occipital Nerve Blocks and Pulsed Radiofrequency Ablation for Diagnosis and Treatment of Occipital Neuralgia

OpenAIRE

VanderHoek, Matthew David; Hoang, Hieu T; Goff, Brandon

2013-01-01

Occipital neuralgia is a condition manifested by chronic occipital headaches and is thought to be caused by irritation or trauma to the greater occipital nerve (GON). Treatment for occipital neuralgia includes medications, nerve blocks, and pulsed radiofrequency ablation (PRFA). Landmark-guided GON blocks are the mainstay in both the diagnosis and treatment of occipital neuralgia. Ultrasound is being utilized more and more in the chronic pain clinic to guide needle advancement when performing...
Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases

DEFF Research Database (Denmark)

Xanthoulea, Sofia; Pasparakis, Manolis; Kousteni, Stavroula

2004-01-01

Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved...... to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation....... Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor-dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses...

Lysophosphatidic acid mediates pleiotropic responses in skeletal muscle cells

International Nuclear Information System (INIS)

Jean-Baptiste, Gael; Yang Zhao; Khoury, Chamel; Greenwood, Michael T.

2005-01-01

Lysophosphatidic acid (LPA) is a potent modulator of growth, cell survival, and apoptosis. Although all four LPA receptors are expressed in skeletal muscle, very little is known regarding the role they play in this tissue. We used RT-PCR to demonstrate that cultured skeletal muscle C2C12 cells endogenously express multiple LPA receptor subtypes. The demonstration that LPA mediates the activation of ERK1/2 MAP kinase and Akt/PKB in C2C12 cells is consistent with the widely observed mitogenic properties of LPA. In spite of these observations, LPA did not induce proliferation in C2C12 cells. Paradoxically, we found that prolonged treatment of C2C12 cells with LPA led to caspase 3 and PARP cleavage as well as the activation of stress-associated MAP kinases JNK and p38. In spite of these typically pro-apoptotic responses, LPA did not induce cell death. Blocking ERK1/2 and Akt/PKB activation with specific pharmacological inhibitors, nevertheless, stimulated LPA-mediated apoptosis. Taken together, these results suggest that both mitogenic and apoptotic responses serve to counterbalance the effects of LPA in cultured C2C12 cells
Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

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Kristian M. Hargadon

2016-08-01

Full Text Available TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1’s contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed.
Efectos pleiotrópicos de las estatinas: Características farmacológicas útiles en la prevención, tratamiento y regresión de la enfermedad cardiovascular Pleiotropic effect of statins: Useful pharmacological characteristics in prevention, treatment and regression of cardiovascular disease

Directory of Open Access Journals (Sweden)

Darío Echeverri

2005-09-01

Full Text Available Los resultados benéficos de las estatinas en el manejo de la hipercolesterolemia en los múltiples estudios clínicos, han demostrado, además, efectos no relacionados con la acción hipolipemiante. Estudios experimentales in-vitro y ex-vivo han documentado una gran evidencia de efectos tales como incremento en la expresión de óxido nítrico y efectos anti-inflamatorios, inmunomodulatorios, anti-trombóticos, anti-proliferativos y anti-oxidantes los cuales reciben el nombre de pleiotrópicos. Los potentes efectos hipolipemiantes y pleiotrópicos podrían explicar los beneficios en aterosclerosis, hipertensión arterial, diabetes mellitus, estenosis aórtica, psoriasis, esclerosis múltiple y rechazo post-transplante entre otras patologías. Sin embargo, la cantidad de información experimental a favor de estos efectos, debería estimular a la iniciación de mejores estudios para clarificar de una manera mayor el significado clínico.Among the beneficial results of statins in the treatment of hypercholesterolemia, other effects not related to the hypolipemic action have been demonstrated in multiple studies. Experimental in vitro and ex-vivo studies have documented a great evidence of different effects such as an increment in the nitric oxide (NO expression, as well as anti-inflammatory, immunomodulatory, anti-thrombotic, anti-proliferative, and anti-oxidant effects. These are the pleiotropic effects. The potent hypolipemic and pleiotropic effects could explain the benefit in atherosclerosis, arterial hypertension, diabetes mellitus, aortic stenosis, psoriasis, multiple sclerosis and post-transplant rejection, among other pathologies. Nevertheless, the amount of experimental information in favour of these effects should stimulate the initiation of better studies in order to clarify in an accurate way its clinical significance.
Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity

DEFF Research Database (Denmark)

Bonefeld-Jørgensen, E.C.; Andersen, H. R.; Rasmussen, T.H.

2001-01-01

pleiotropic effects on the estrogen- and androgen-receptor. In MCF-7 cells a slightly increased cell proliferation was observed at low concentrations (1-10 nM) in cells co-treated with 0.01 nM 17 beta -Estradiol. whereas the compounds inhibited cell growth significantly at 1 and 10 muM. In reporter gene (ERE-tk-CAT...
Gremlin promotes retinal pigmentation epithelial (RPE) cell proliferation, migration and VEGF production via activating VEGFR2-Akt-mTORC2 signaling.

Science.gov (United States)

Liu, Yuan; Chen, Zhijun; Cheng, Haixia; Chen, Juan; Qian, Jing

2017-01-03

Retinopathy of prematurity (ROP) is characterized by late-phase pathologic retinal vasoproliferation. Gremlin is a novel vascular endothelial growth factors (VEGF) receptor 2 (VEGFR2) agonist and promotes angiogenic response. We demonstrated that gremlin expression was significantly increased in retinas of ROP model mice, which was correlated with VEGF upregulation. In retinal pigmentation epithelial (RPE) cells, gremlin activated VEGFR2-Akt-mTORC2 (mammalian target of rapamycin complex 2) signaling, and promoted cell proliferation, migration and VEGF production. VEGFR inhibition (by SU5416) or shRNA knockdown almost abolished gremlin-mediated pleiotropic functions in RPE cells. Further, pharmacological inhibition of Akt-mTOR, or shRNA knockdown of key mTORC2 component (Rictor or Sin1) also attenuated gremlin-exerted activities in RPE cells. We conclude that gremlin promotes RPE cell proliferation, migration and VEGF production possibly via activating VEGFR2-Akt-mTORC2 signaling. Gremlin could be a novel therapeutic target of ROP or other retinal vasoproliferation diseases.
Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner

NARCIS (Netherlands)

Borissoff, Julian I.; Otten, Jeroen J. T.; Heeneman, Sylvia; Leenders, Peter; van Oerle, René; Soehnlein, Oliver; Loubele, Sarah T. B. G.; Hamulyák, Karly; Hackeng, Tilman M.; Daemen, Mat J. A. P.; Degen, Jay L.; Weiler, Hartmut; Esmon, Charles T.; van Ryn, Joanne; Biessen, Erik A. L.; Spronk, Henri M. H.; ten Cate, Hugo

2013-01-01

Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. Published experimental studies have yielded contradictory findings on the role of hypercoagulability in
Epigenetic potential of resveratrol and analogs in preclinical models of prostate cancer

Science.gov (United States)

Prostate cancer is affected by lifestyle, particularly diet. Dietary polyphenols such as resveratrol possess anticancer properties and, therefore, chemopreventive and therapeutic potentials. Resveratrol has pleiotropic effect exerting its biological activity through multiple pathways and targets ass...
Computer-aided discovery of biological activity spectra for anti-aging and anti-cancer olive oil oleuropeins.

Science.gov (United States)

Corominas-Faja, Bruna; Santangelo, Elvira; Cuyàs, Elisabet; Micol, Vicente; Joven, Jorge; Ariza, Xavier; Segura-Carretero, Antonio; García, Jordi; Menendez, Javier A

2014-09-01

Aging is associated with common conditions, including cancer, diabetes, cardiovascular disease, and Alzheimer's disease. The type of multi-targeted pharmacological approach necessary to address a complex multifaceted disease such as aging might take advantage of pleiotropic natural polyphenols affecting a wide variety of biological processes. We have recently postulated that the secoiridoids oleuropein aglycone (OA) and decarboxymethyl oleuropein aglycone (DOA), two complex polyphenols present in health-promoting extra virgin olive oil (EVOO), might constitute a new family of plant-produced gerosuppressant agents. This paper describes an analysis of the biological activity spectra (BAS) of OA and DOA using PASS (Prediction of Activity Spectra for Substances) software. PASS can predict thousands of biological activities, as the BAS of a compound is an intrinsic property that is largely dependent on the compound's structure and reflects pharmacological effects, physiological and biochemical mechanisms of action, and specific toxicities. Using Pharmaexpert, a tool that analyzes the PASS-predicted BAS of substances based on thousands of "mechanism-effect" and "effect-mechanism" relationships, we illuminate hypothesis-generating pharmacological effects, mechanisms of action, and targets that might underlie the anti-aging/anti-cancer activities of the gerosuppressant EVOO oleuropeins.
The flagellar master operon flhDC is a pleiotropic regulator involved in motility and virulence of the fish pathogen Yersinia ruckeri.

Science.gov (United States)

Jozwick, A K S; Graf, J; Welch, T J

2017-03-01

To investigate the function of the master flagellar operon flhDC in the fish pathogen Yersinia ruckeri and compare the effect of a constructed flhD mutation to a naturally occurring fliR mutation causing loss-of-motility in emergent biotype 2 (BT2) strains. Yersinia ruckeri flhD and fliR mutants were constructed in a motile strain. Both mutations caused loss-of-motility, ablation of flagellin synthesis and phospholipase secretion, similar to naturally occurring BT2 strains. Transcriptome analysis confirmed flhDC regulation of flagellar, chemotaxis and phospholipase loci as well as other genes of diverse function. The flhD mutation confers a competitive advantage within the fish host when compared with its parent strain, while this advantage was not seen with the naturally occurring fliR mutation. An intact flhD is necessary for expression of the flagellar secretion system as well as other diverse loci, consistent with a role for flhD as a pleiotropic regulator. The maintenance of the flhD locus in Y. ruckeri strains suggests its importance for aspects of Y. ruckeri biology other than virulence, since the flhD mutation conferred a competitive advantage during experimental challenge of rainbow trout. Yersinia ruckeri is the causative agent of enteric red mouth disease, an invasive septicaemia that affects farmed salmonid fish species. Disease outbreaks can cause severe economic losses in aquaculture. BT2 variants, which have independently emerged worldwide, are an increasing threat to farmed fish production. Knowledge of mechanisms involved in virulence, conserved functions and gene regulation among strains may be exploited for the development of novel disease control strategies to prevent pathogen growth or virulence phenotypes within aquaculture. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
Polymeric bile acid sequestrants: review of design, in vitro binding activities, and hypocholesterolemic effects

Czech Academy of Sciences Publication Activity Database

Heřmánková, Eva; Žák, A.; Poláková, Lenka; Hobzová, Radka; Hromádka, R.; Širc, Jakub

2018-01-01

Roč. 144, 20 January (2018), s. 300-317 ISSN 0223-5234 R&D Projects: GA MPO(CZ) FV10380; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : review * bile acid sequestrant * pleiotropic effect Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Medicinal chemistry Impact factor: 4.519, year: 2016
Activation of the Ca2+-sensing receptors increases currents through inward rectifier K+ channels via activation of phosphatidylinositol 4-kinase.

Science.gov (United States)

Liu, Chung-Hung; Chang, Hsueh-Kai; Lee, Sue-Ping; Shieh, Ru-Chi

2016-11-01

Inward rectifier K + channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP 2 ). Stimulation of the Ca 2+ -sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both G q/11 , which decreases PIP 2 , and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP 2 . How membrane PIP 2 levels are regulated by CaR activation and whether these changes modulate inward rectifier K + are unknown. In this study, we found that activation of CaR by the allosteric agonist, NPSR568, increased inward rectifier K + current (I K1 ) in guinea pig ventricular myocytes and currents mediated by Kir2.1 channels exogenously expressed in HEK293T cells with a similar sensitivity. Moreover, using the fluorescent PIP 2 reporter tubby-R332H-cYFP to monitor PIP 2 levels, we found that CaR activation in HEK293T cells increased membrane PIP 2 concentrations. Pharmacological studies showed that both phospholipase C (PLC) and PI-4-K are activated by CaR stimulation with the latter played a dominant role in regulating membrane PIP 2 and, thus, Kir currents. These results provide the first direct evidence that CaR activation upregulates currents through inward rectifier K + channels by accelerating PIP 2 synthesis. The regulation of I K1 plays a critical role in the stability of the electrical properties of many excitable cells, including cardiac myocytes and neurons. Further, synthetic allosteric modulators that increase CaR activity have been used to treat hyperparathyroidism, and negative CaR modulators are of potential importance in the treatment of osteoporosis. Thus, our results provide further insight into the roles played by CaR in the cardiovascular system and are potentially valuable for heart disease treatment and drug safety.
Eukaryotic translation initiation factor 5A of wheat: Identification ...

African Journals Online (AJOL)

STORAGESEVER

2009-05-18

. The available literature indi- cated that the expression of eIF5A was temporal and spatial difference and suppressing eIF5A activation causes pleiotropic effects. Transcript analysis reveals that two tobacco eIF5A genes ...
Characterization of Listeria monocytogenes isolated from Ganges water, human clinical and milk samples at Varanasi, India.

Science.gov (United States)

Soni, Dharmendra K; Singh, Rakesh K; Singh, Durg V; Dubey, Suresh K

2013-03-01

Listeria monocytogenes isolated from Ganges water, human clinical and milk samples were characterized by antibiotic susceptibility, serotype identification, detection of virulence genes and ERIC- and REP-PCR fingerprint analyses. All isolates were uniformly resistant to ampicillin, except two isolates, and showed variable resistance to gentamicin, cotrimoxazole, ofloxacin, rifampicin and tetracycline. Of the 20 isolates found positive for pathogens, seven (four human and three water isolates) belong to serogroups 4b, 4d and 4e; six (one human and five water isolates) belong to serogroups 1/2c and 3c; four milk isolates belong to serogroups 1/2b and 3b; and three milk isolates belong to serogroups 1/2a and 3a. Two water isolates, all human isolates, except one (Pb1) lacking inlJ gene, and three milk isolates possess inlA, inlC, plcA, prfA, actA, hlyA and iap genes. The remaining water and milk isolates showed variable presence of inlJ, plcA, prfA, and iap genes. ERIC- and REP-PCR based analyses collectively indicated that isolates of human clinical samples belong to identical or similar clone and isolates of water and milk samples belong to different clones. Overall study demonstrates the prevalence of pathogenic L. monocytogenes species in the environmental and clinical samples. Most of the isolates were resistant to commonly used antibiotics. Copyright © 2012 Elsevier B.V. All rights reserved.
Curcumin Conjugated with PLGA Potentiates Sustainability, Anti-Proliferative Activity and Apoptosis in Human Colon Carcinoma Cells

Science.gov (United States)

Waghela, Bhargav N.; Sharma, Anupama; Dhumale, Suhashini; Pandey, Shashibahl M.; Pathak, Chandramani

2015-01-01

Curcumin, an ingredient of turmeric, exhibits a variety of biological activities such as anti-inflammatory, anti-atherosclerotic, anti-proliferative, anti-oxidant, anti-cancer and anti-metastatic. It is a highly pleiotropic molecule that inhibits cell proliferation and induces apoptosis in cancer cells. Despite its imperative biological activities, chemical instability, photo-instability and poor bioavailability limits its utilization as an effective therapeutic agent. Therefore, enhancing the bioavailability of curcumin may improve its therapeutic index for clinical setting. In the present study, we have conjugated curcumin with a biodegradable polymer Poly (D, L-lactic-co-glycolic acid) and evaluated its apoptotic potential in human colon carcinoma cells (HCT 116). The results show that curcumin-PLGA conjugate efficiently inhibits cell proliferation and cell survival in human colon carcinoma cells as compared to native curcumin. Additionally, curcumin conjugated with PLGA shows improved cellular uptake and exhibits controlled release at physiological pH as compared to native curcumin. The curcumin-PLGA conjugate efficiently activates the cascade of caspases and promotes intrinsic apoptotic signaling. Thus, the results suggest that conjugation potentiates the sustainability, anti-proliferative and apoptotic activity of curcumin. This approach could be a promising strategy to improve the therapeutic index of cancer therapy. PMID:25692854
IMPACTS OF TISSUE-TYPE PLASMINOGEN ACTIVATOR (TPA ON NEURONAL SURVIVAL

Directory of Open Access Journals (Sweden)

Arnaud eChevilley

2015-10-01

Full Text Available Tissue-type plasminogen activator (tPA a serine protease is constituted of five functional domains through which it interacts with different substrates, binding proteins and receptors. In the last years, great interest has been given to the clinical relevance of targeting tPA in different diseases of the central nervous system, in particular stroke. Among its reported functions in the central nervous system, tPA displays both neurotrophic and neurotoxic effects. How can the protease mediate such opposite functions remain unclear but several hypotheses have been proposed. These include an influence of the degree of maturity and/or the type of neurons, of the level of tPA, of its origin (endogenous or exogenous or of its form (single chain tPA versus two chain tPA. In this review, we will provide a synthetic snapshot of our current knowledge regarding the natural history of tPA and discuss how it sustains its pleiotropic functions with focus on excitotoxic/ischemic neuronal death and neuronal survival.
Identification and characterization of pleiotropic and co-located resistance loci to leaf rust and stripe rust in bread wheat cultivar Sujata.

Science.gov (United States)

Lan, Caixia; Zhang, Yelun; Herrera-Foessel, Sybil A; Basnet, Bhoja R; Huerta-Espino, Julio; Lagudah, Evans S; Singh, Ravi P

2015-03-01

Two new co-located resistance loci, QLr.cim - 1AS/QYr.cim - 1AS and QLr.cim - 7BL/YrSuj , in combination with Lr46 / Yr29 and Lr67/Yr46 , and a new leaf rust resistance quantitative trait loci, conferred high resistance to rusts in adult plant stage. The tall Indian bread wheat cultivar Sujata displays high and low infection types to leaf rust and stripe rust, respectively, at the seedling stage in greenhouse tests. It was also highly resistant to both rusts at adult plant stage in field trials in Mexico. The genetic basis of this resistance was investigated in a population of 148 F5 recombinant inbred lines (RILs) derived from the cross Avocet × Sujata. The parents and RIL population were characterized in field trials for resistance to leaf rust during 2011 at El Batán, and 2012 and 2013 at Ciudad Obregón, Mexico, and for stripe rust during 2011 and 2012 at Toluca, Mexico; they were also characterized three times for stripe rust at seedling stage in the greenhouse. The RILs were genotyped with diversity arrays technology and simple sequence repeat markers. The final genetic map was constructed with 673 polymorphic markers. Inclusive composite interval mapping analysis detected two new significant co-located resistance loci, QLr.cim-1AS/QYr.cim-1AS and QLr.cim-7BL/YrSuj, on chromosomes 1AS and 7BL, respectively. The chromosomal position of QLr.cim-7BL overlapped with the seedling stripe rust resistance gene, temporarily designated as YrSuj. Two previously reported pleiotropic adult plant resistance genes, Lr46/Yr29 and Lr67/Yr46, and a new leaf rust resistance quantitative trait loci derived from Avocet were also mapped in the population. The two new co-located resistance loci are expected to contribute to breeding durable rust resistance in wheat. Closely linked molecular markers can be used to transfer all four resistance loci simultaneously to modern wheat varieties.
Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

OpenAIRE

Isomoto, Hajime; Moss, Joel; Hirayama, Toshiya

2010-01-01

Helicobacter pylori produces a vacuolating cytotoxin, VacA, and most virulent H. pylori strains secrete VacA. VacA binds to two types of receptor-like protein tyrosine phosphatase (RPTP), RPTPα and RPTPβ, on the surface of host cells. VacA bound to RPTPβ, relocates and concentrates in lipid rafts in the plasma membrane. VacA causes vacuolization, membrane anion-selective channel and pore formation, and disruption of endosomal and lysosomal activity in host cells. Secreted VacA is processed in...
TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.

Directory of Open Access Journals (Sweden)

Dorothée Diogo

Full Text Available Despite the success of genome-wide association studies (GWAS in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples, Exomechip genotyping (n = 18,409 case/control samples and targeted exon-sequencing (n = 2,236 case/controls samples to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2 independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3 x 10(-21, A928V (rs35018800, OR = 0.53, P = 1.2 x 10(-9, and I684S (rs12720356, OR = 0.86, P = 4.6 x 10(-7. Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6 x 10(-18, and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V may also protect against inflammatory bowel disease (IBD; P(omnibus = 0.005. Finally, in a phenome-wide association study (PheWAS assessing >500 phenotypes using electronic medical records (EMR in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells

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Tran, Dat Q.; Andersson, John; Wang, Rui; Ramsey, Heather; Unutmaz, Derya; Shevach, Ethan M.

2009-01-01

TGF-β family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-β is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGFβ-binding protein (LTBP) to produce a large latent form. Latent TGF-β is also found on the surface of activated FOXP3+ regulatory T cells (Tregs), but it is unclear how it is anchored to the cell membrane. We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-β to the cell surface. We demonstrate that platelets and activated Tregs co-express latent TGF-β and GARP on their membranes. The knockdown of GARP mRNA with siRNA prevented surface latent TGF-β expression on activated Tregs and recombinant latent TGF-β1 is able to bind directly with GARP. Confocal microscopy and immunoprecipitation strongly support their interactions. The role of TGF-β on Tregs appears to have dual functions, both for Treg-mediated suppression and infectious tolerance mechanism. PMID:19651619
GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells.

Science.gov (United States)

Tran, Dat Q; Andersson, John; Wang, Rui; Ramsey, Heather; Unutmaz, Derya; Shevach, Ethan M

2009-08-11

TGF-beta family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-beta is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGFbeta-binding protein (LTBP) to produce a large latent form. Latent TGF-beta is also found on the surface of activated FOXP3(+) regulatory T cells (Tregs), but it is unclear how it is anchored to the cell membrane. We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-beta to the cell surface. We demonstrate that platelets and activated Tregs co-express latent TGF-beta and GARP on their membranes. The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. Confocal microscopy and immunoprecipitation strongly support their interactions. The role of TGF-beta on Tregs appears to have dual functions, both for Treg-mediated suppression and infectious tolerance mechanism.

Pleiotropic action of proinsulin C-peptid

Directory of Open Access Journals (Sweden)

Michał Usarek

2012-03-01

Full Text Available Proinsulin C-peptide, released in equimolar amounts with insulin by pancreatic β cells, since its discovery in 1967 has been thought to be devoid of biological functions apart from correct insulin processing and formation of disulfide bonds between A and B chains. However, in the last two decades research has brought a substantial amount of data indicating a crucial role of C-peptide in regulating various processes in different types of cells and organs. C-peptide acts presumably via either G-protein-coupled receptor or directly inside the cell, after being internalized. However, a receptor binding this peptide has not been identified yet. This peptide ameliorates pathological changes induced by type 1 diabetes mellitus, including glomerular hyperfiltration, vessel endothelium inflammation and neuron demyelinization. In diabetic patients and diabetic animal models, C-peptide substitution in physiological doses improves the functional and structural properties of peripheral neurons and protects against hyperglycemia-induced apoptosis, promoting neuronal development, regeneration and cell survival. Moreover, it affects glycogen synthesis in skeletal muscles. In vitro C-peptide promotes disaggregation of insulin oligomers, thus enhancing its bioavailability and effects on metabolism. There are controversies concerning the biological action of C-peptide, particularly with respect to its effect on Na /K -ATPase activity. Surprisingly, the excess of circulating peptide associated with diabetes type 2 contributes to atherosclerosis development. In view of these observations, long-term, large-scale clinical investigations using C-peptide physiological doses need to be conducted in order to determine safety and health outcomes of long-term administration of C-peptide to diabetic patients.
Low Levels of Serum Paraoxonase Activities are Characteristic of Metabolic Syndrome and May Influence the Metabolic-Syndrome-Related Risk of Coronary Artery Disease

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Nicola Martinelli

2012-01-01

Full Text Available Low concentrations of plasma high-density lipoprotein (HDLs are characteristic in metabolic syndrome (MS. The antioxidant ability of HDLs is, at least in part, attributable to pleiotropic serum paraoxonase (PON1. Different PON1 activities have been assessed in 293 subjects with (=88 or without MS (=205 and with (=195 or without (=98 angiographically proven coronary artery disease (CAD. MS subjects had low PON1 activities, with a progressively decreasing trend by increasing the number of MS abnormalities. The activity versus 7-O-diethyl phosphoryl,3-cyano,4-methyl,7-hydroxycoumarin (DEPCyMC, which is considered a surrogate marker of PON1 concentration, showed the most significant association with MS, independently of both HDL and apolipoprotein A-I levels. Subjects with MS and low DEPCyMCase activity had the highest CAD risk (OR 4.34 with 95% CI 1.44–13.10, while no significant increase of risk was found among those with MS but high DEPCyMCase activity (OR 1.45 with 95% CI 0.47–4.46. Our results suggest that low PON1 concentrations are typical in MS and may modulate the MS-related risk of CAD.
Low levels of serum paraoxonase activities are characteristic of metabolic syndrome and may influence the metabolic-syndrome-related risk of coronary artery disease.

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Martinelli, Nicola; Micaglio, Roberta; Consoli, Letizia; Guarini, Patrizia; Grison, Elisa; Pizzolo, Francesca; Friso, Simonetta; Trabetti, Elisabetta; Pignatti, Pier Franco; Corrocher, Roberto; Olivieri, Oliviero; Girelli, Domenico

2012-01-01

Low concentrations of plasma high-density lipoprotein (HDLs) are characteristic in metabolic syndrome (MS). The antioxidant ability of HDLs is, at least in part, attributable to pleiotropic serum paraoxonase (PON1). Different PON1 activities have been assessed in 293 subjects with (n = 88) or without MS (n = 205) and with (n = 195) or without (n = 98) angiographically proven coronary artery disease (CAD). MS subjects had low PON1 activities, with a progressively decreasing trend by increasing the number of MS abnormalities. The activity versus 7-O-diethyl phosphoryl,3-cyano,4-methyl,7-hydroxycoumarin (DEPCyMC), which is considered a surrogate marker of PON1 concentration, showed the most significant association with MS, independently of both HDL and apolipoprotein A-I levels. Subjects with MS and low DEPCyMCase activity had the highest CAD risk (OR 4.34 with 95% CI 1.44-13.10), while no significant increase of risk was found among those with MS but high DEPCyMCase activity (OR 1.45 with 95% CI 0.47-4.46). Our results suggest that low PON1 concentrations are typical in MS and may modulate the MS-related risk of CAD.
Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease

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Sergio Davinelli

2012-01-01

Full Text Available Alzheimer’s disease (AD is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.
IL-20 gene expression is induced by IL-1beta through mitogen-activated protein kinase and NF-kappaB-dependent mechanisms

DEFF Research Database (Denmark)

Otkjaer, Kristian; Kragballe, Knud; Johansen, Claus

2007-01-01

IL-20 is a novel member of the IL-10 cytokine family with pleiotropic effects. Current knowledge of what triggers and regulates IL-20 gene expression is sparse. The aim of this study was to investigate the regulation of IL-20 expression in cultured normal human keratinocytes. The expression of IL...
The YvfTU Two-component System is involved in plcR expression in Bacillus cereus

NARCIS (Netherlands)

Brillard, Julien; Susanna, Kim; Michaud, Caroline; Dargaignaratz, Claire; Gohar, Michel; Nielsen-Leroux, Christina; Ramarao, Nalini; Kolsto, Anne-Brit; Nguyen-The, Christophe; Lereclus, Didier; Broussolle, Veronique

2008-01-01

Background: Most extracellular virulence factors produced by Bacillus cereus are regulated by the pleiotropic transcriptional activator PlcR. Among strains belonging to the B. cereus group, the plcR gene is always located in the vicinity of genes encoding the YvfTU two-component system. The putative
The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA

International Nuclear Information System (INIS)

Venema, J.; Mullenders, L.H.; Natarajan, A.T.; van Zeeland, A.A.; Mayne, L.V.

1990-01-01

Cells from patients with Cockayne syndrome (CS) are hypersensitive to UV-irradiation but have an apparently normal ability to remove pyrimidine dimers from the genome overall. We have measured the repair of pyrimidine dimers in defined DNA sequences in three normal and two CS cell strains. When compared to a nontranscribed locus, transcriptionally active genes were preferentially repaired in all three normal cell strains. There was no significant variation in levels of repair between various normal individuals or between two constitutively expressed genes, indicating that preferential repair may be a consistent feature of constitutively expressed genes in human cells. Neither CS strain, from independent complementation groups, was able to repair transcriptionally active DNA with a similar rate and to the same extent as normal cells, indicating that the genetic defect in CS lies in the pathway for repair of transcriptionally active DNA. These results have implications for understanding the pleiotropic clinical effects associated with disorders having defects in the repair of DNA damage. In particular, neurodegeneration appears to be associated with the loss of preferential repair of active genes and is not simply correlated with reduced levels of overall repair
Pleiotropic role of growth arrest-specific gene 6 in atherosclerosis

NARCIS (Netherlands)

Tjwa, Marc; Moons, Lieve; Lutgens, Esther

2009-01-01

Growth arrest-specific gene 6 (Gas6) belongs to the family of vitamin K-dependent coagulation proteins, but in contrast to its other members, has only a limited role in hemostasis. Instead, Gas6 plays a prominent role in conditions of injury, inflammation and repair. Gas6 amplifies the activation of
Computer-aided discovery of biological activity spectra for anti-aging and anti-cancer olive oil oleuropeins

OpenAIRE

Menendez, J.A.; García, J.; Segura-Carretero, A.; Ariza, X.; Joven, J.; Micol, V.; Cuyàs, E.; Santangelo, E.; Corominas-Faja, B.

2014-01-01

Aging is associated with common conditions, including cancer, diabetes, cardiovascular disease, and Alzheimer's disease. The type of multi-targeted pharmacological approach necessary to address a complex multifaceted disease such as aging might take advantage of pleiotropic natural polyphenols affecting a wide variety of biological processes. We have recently postulated that the secoiridoids oleuropein aglycone (OA) and decarboxymethyl oleuropein aglycone (DOA), two complex polyphenols presen...
Inhibition of TGFbeta1 Signaling Attenutates ATM Activity inResponse to Genotoxic Stress

Energy Technology Data Exchange (ETDEWEB)

Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose; Ravani, Shraddha A.; Glick, Adam B.; Lavin, Martin J.; Koslov, Sergei; Shiloh, Yosef; Barcellos-Hoff, Mary Helen

2006-09-15

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor {beta}1 (TGF{beta}), which is activated by radiation, is a potent and pleiotropic mediator of physiological and pathological processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}1 null murine epithelial cells or human epithelial cells treated with a small molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17 and p53, reduced {gamma}H2AX radiation-induced foci, and increased radiosensitivity compared to TGF{beta} competent cells. We determined that loss of TGF{beta} signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF{beta} restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM that directs epithelial cell stress responses, cell fate and tissue integrity. Thus, TGF{beta}1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF{beta} may be used to advantage in cancer therapy.
Potential use of recombinant human interleukin-6 in clinical oncology

NARCIS (Netherlands)

Veldhuis, GJ; Willemse, PHB; Mulder, NH; Limburg, PC; deVries, EGE

Recombinant human IL-6 (rhIL-6) is a pleiotropic cytokine with stimulatory actions on the hematopoietic system, the immune system and hepatocytes. Clinical interest in the use of this cytokine was raised because of its thrombopoietic properties and also because of its anti-tumor activity, which was
Pleiotropic effects of incretins

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Vishal Gupta

2012-01-01

Full Text Available Drugs that augment the incretin system [glucagon like peptide (GLP agonists and dipeptidyl peptidase-4 (DPP-4 inhibitors] represent a novel class of anti-hyperglycemic agents that have shown to improve the health and survival of beta-cells (improvement in postprandial hyperglycemia and suppress glucagon (improvement in fasting hyperglycemia. The incretins represent a large family of molecules referred to as the "glucagon superfamily of peptide hormones" of which more than 90% of the physiological effects of incretins are accomplished by GLP-1 7-37 and GLP1 7-36 amide and gastric insulinotropic peptide (GIP. GLP-1 mediates its effects via the GLP-1 receptor, which has a wide tissue distribution [pancreas, lung, heart, vascular smooth muscle cells, endothelial cells, macrophages and monocytes, kidney, gastrointestinal tract (stomach and intestine, central nervous system (neoortex, cerebellum, hypothalamus, hippocampus, brainstem nucleus tractus solitarius and peripheral nervous system]. This would imply that the incretin system has effects outside the pancreas. Over time data has accumulated to suggest that therapies that augment the incretin system has beneficial pleiotrophic effects. The incretins have shown to possess a cardiac-friendly profile, preserve neuronal cells and safeguard from neuronal degeneration, improve hepatic inflammation and hepatosteatosis, improve insulin resistance, promote weight loss and induce satiety. There is growing evidence that they may also be renoprotective promoting wound healing and bone health.
Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction.

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Nishikawa, Joy L; Boeszoermenyi, Andras; Vale-Silva, Luis A; Torelli, Riccardo; Posteraro, Brunella; Sohn, Yoo-Jin; Ji, Fei; Gelev, Vladimir; Sanglard, Dominique; Sanguinetti, Maurizio; Sadreyev, Ruslan I; Mukherjee, Goutam; Bhyravabhotla, Jayaram; Buhrlage, Sara J; Gray, Nathanael S; Wagner, Gerhard; Näär, Anders M; Arthanari, Haribabu

2016-02-25

Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi. The Gal11/Med15 KIX domain engages pleiotropic drug resistance transcription factor (Pdr1) orthologues, which are key regulators of the multidrug resistance pathway in Saccharomyces cerevisiae and in the clinically important human pathogen Candida glabrata. The prevalence of C. glabrata is rising, partly owing to its low intrinsic susceptibility to azoles, the most widely used antifungal agent. Drug-resistant clinical isolates of C. glabrata most commonly contain point mutations in Pdr1 that render it constitutively active, suggesting that this transcriptional activation pathway represents a linchpin in C. glabrata multidrug resistance. Here we perform sequential biochemical and in vivo high-throughput screens to identify small-molecule inhibitors of the interaction of the C. glabrata Pdr1 activation domain with the C. glabrata Gal11A KIX domain. The lead compound (iKIX1) inhibits Pdr1-dependent gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection. Determining the NMR structure of the C. glabrata Gal11A KIX domain provides a detailed understanding of the molecular mechanism of Pdr1 gene activation and multidrug resistance inhibition by iKIX1. We have demonstrated the feasibility of small-molecule targeting of a
Is the scavenger receptor MARCO a new immune checkpoint?

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Arredouani, Mohamed S

2014-11-01

Whereas macrophages use the scavenger receptor MARCO primarily in antimicrobial immunity by interacting with both exogenous and endogenous environments, in dendritic cells (DCs) MARCO is believed to pleiotropically link innate to adaptive immunity. MARCO exerts a significant modulatory effect on TLR-induced DC activation, thus offering novel avenues in cancer immunotherapy.
Discovery of curcumin, a component of golden spice, and its miraculous biological activities.

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Gupta, Subash C; Patchva, Sridevi; Koh, Wonil; Aggarwal, Bharat B

2012-03-01

1. Curcumin is the active ingredient of the dietary spice turmeric and has been consumed for medicinal purposes for thousands of years. Modern science has shown that curcumin modulates various signalling molecules, including inflammatory molecules, transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion molecules, growth factors, receptors, cell cycle regulatory proteins, chemokines, DNA, RNA and metal ions. 2. Because of this polyphenol's potential to modulate multiple signalling molecules, it has been reported to possess pleiotropic activities. First demonstrated to have antibacterial activity in 1949, curcumin has since been shown to have anti-inflammatory, anti-oxidant, pro-apoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic and antimalarial properties as well. Animal studies have suggested that curcumin may be active against a wide range of human diseases, including diabetes, obesity, neurological and psychiatric disorders and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys and gastrointestinal and cardiovascular systems. 3. Although many clinical trials evaluating the safety and efficacy of curcumin against human ailments have already been completed, others are still ongoing. Moreover, curcumin is used as a supplement in several countries, including India, Japan, the US, Thailand, China, Korea, Turkey, South Africa, Nepal and Pakistan. Although inexpensive, apparently well tolerated and potentially active, curcumin has not been approved for the treatment of any human disease. 4. In the present article, we discuss the discovery and key biological activities of curcumin, with a particular emphasis on its activities at the molecular and cellular levels, as well as in animals and humans. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell
Pleiotropic effect of his gene mutations on nitrogen fixation in Klebsiella pneumoniae

DEFF Research Database (Denmark)

Jensen, Jens Stougaard; Kennedy, C

1982-01-01

retained a Nif plate phenotype. A hisA mutation had a similar but more dramatic effect. At low concentrations of histidine the hisA mutant strain had only 5% of the nitrogenase activity found at high histidine concentration or in a his strain, and was also Nif on low histidine agar plates. Addition...... of adenine restored nitrogenase activity in the hisA but not the hisB, hisC, or hisD mutants. Low levels of intracellular ATP, a consequence of hisG enzyme activity, correlated with loss of nitrogen-fixing ability in the hisA mutant which failed to sustain nif gene expression under these conditions....... Synthesis of other major cell proteins was relatively unaffected indicating that nif gene expression is selectively regulated by the energy status of the organism....
Simvastatin promotes NPC1-mediated free cholesterol efflux from lysosomes through CYP7A1/LXRα signalling pathway in oxLDL-loaded macrophages.

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Xu, Xiaoyang; Zhang, Aolin; Halquist, Matthew S; Yuan, Xinxu; Henderson, Scott C; Dewey, William L; Li, Pin-Lan; Li, Ningjun; Zhang, Fan

2017-02-01

Statins, 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors, are the first-line medications prescribed for the prevention and treatment of coronary artery diseases. The efficacy of statins has been attributed not only to their systemic cholesterol-lowering actions but also to their pleiotropic effects that are unrelated to cholesterol reduction. These pleiotropic effects have been increasingly recognized as essential in statins therapy. This study was designed to investigate the pleiotropic actions of simvastatin, one of the most commonly prescribed statins, on macrophage cholesterol homeostasis with a focus on lysosomal free cholesterol egression. With simultaneous nile red and filipin staining, analysis of confocal/multi-photon imaging demonstrated that simvastatin markedly attenuated unesterified (free) cholesterol buildup in macrophages loaded with oxidized low-density lipoprotein but had little effect in reducing the sizes of cholesteryl ester-containing lipid droplets; the reduction in free cholesterol was mainly attributed to decreases in lysosome-compartmentalized cholesterol. Functionally, the egression of free cholesterol from lysosomes attenuated pro-inflammatory cytokine secretion. It was determined that the reduction of lysosomal free cholesterol buildup by simvastatin was due to the up-regulation of Niemann-Pick C1 (NPC1), a lysosomal residing cholesterol transporter. Moreover, the enhanced enzymatic production of 7-hydroxycholesterol by cytochrome P450 7A1 and the subsequent activation of liver X receptor α underscored the up-regulation of NPC1. These findings reveal a novel pleiotropic effect of simvastatin in affecting lysosomal cholesterol efflux in macrophages and the associated significance in the treatment of atherosclerosis. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Eco-Friendly Insecticide Discovery via Peptidomimetics: Design, Synthesis, and Aphicidal Activity of Novel Insect Kinin Analogues.

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Zhang, Chuanliang; Qu, Yanyan; Wu, Xiaoqing; Song, Dunlun; Ling, Yun; Yang, Xinling

2015-05-13

Insect kinin neuropeptides are pleiotropic peptides that are involved in the regulation of hindgut contraction, diuresis, and digestive enzyme release. They share a common C-terminal pentapeptide sequence of Phe(1)-Xaa(2)-Yaa(3)-Trp(4)-Gly(5)-NH2 (where Xaa(2) = His, Asn, Phe, Ser, or Tyr; Yaa(3) = Pro, Ser, or Ala). Recently, the aphicidal activity of insect kinin analogues has attracted the attention of researchers. Our previous work demonstrated that the sequence-simplified insect kinin pentapeptide analogue Phe-Phe-[Aib]-Trp-Gly-NH2 could retain good aphicidal activity and be the lead compound for the further discovery of eco-friendly insecticides which encompassed a broad array of biochemicals derived from micro-organisms and other natural sources. Using the peptidomimetics strategy, we chose Phe-Phe-[Aib]-Trp-Gly-NH2 as the lead compound, and we designed and synthesized three series, including 31 novel insect kinin analogues. The aphicidal activity of the new analogues against soybean aphid was determined. The results showed that all of the analogues exhibited aphicidal activity. Of particular interest was the analogue II-1, which exhibited improved aphicidal activity with an LC50 of 0.019 mmol/L compared with the lead compound (LC50 = 0.045 mmol/L) or the commercial insecticide pymetrozine (LC50 = 0.034 mmol/L). This suggests that the analogue II-1 could be used as a new lead for the discovery of potential eco-friendly insecticides.
Anti-biofilm activity: a function of Klebsiella pneumoniae capsular polysaccharide.

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Marina Dos Santos Goncalves

Full Text Available Competition and cooperation phenomena occur within highly interactive biofilm communities and several non-biocides molecules produced by microorganisms have been described as impairing biofilm formation. In this study, we investigated the anti-biofilm capacities of an ubiquitous and biofilm producing bacterium, Klebsiella pneumoniae. Cell-free supernatant from K. pneumoniae planktonic cultures showed anti-biofilm effects on most Gram positive bacteria tested but also encompassed some Gram negative bacilli. The anti-biofilm non-bactericidal activity was further investigated on Staphylococcus epidermidis, by determining the biofilm biomass, microscopic observations and agglutination measurement through a magnetic bead-mediated agglutination test. Cell-free extracts from K. pneumoniae biofilm (supernatant and acellular matrix also showed an influence, although to a lesser extend. Chemical analyses indicated that the active molecule was a high molecular weight polysaccharide composed of five monosaccharides: galactose, glucose, rhamnose, glucuronic acid and glucosamine and the main following sugar linkage residues [→ 2-α-L-Rhap-(1 →]; [→ 4-α-L-Rhap-(1 →]; [α-D-Galp-(1 →]; [→ 2,3-α-D-Galp-(1 →]; [→ 3-β-D-Galp-(1 →] and, [→ 4-β-D-GlcAp-(1 →]. Characterization of this molecule indicated that this component was more likely capsular polysaccharide (CPS and precoating of abiotic surfaces with CPS extracts from different serotypes impaired the bacteria-surface interactions. Thus the CPS of Klebsiella would exhibit a pleiotropic activity during biofilm formation, both stimulating the initial adhesion and maturation steps as previously described, but also repelling potential competitors.
Analysis and Quantitation of NF-[kappa]B Nuclear Translocation in Tumor Necrosis Factor Alpha (TNF-[alpha]) Activated Vascular Endothelial Cells

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Fuseler, John W.; Merrill, Dana M.; Rogers, Jennifer A.; Grisham, Matthew B.; Wolf, Robert E.

2006-07-01

Nuclear factor kappa B (NF-[kappa]B) is a heterodimeric transcription factor typically composed of p50 and p65 subunits and is a pleiotropic regulator of various inflammatory and immune responses. In quiescent cells, p50/p65 dimers are sequestered in the cytoplasm bound to its inhibitors, the I-[kappa]Bs, which prevent entry into the nucleus. Following cellular stimulation, the I-[kappa]Bs are rapidly degraded, activating NF-[kappa]B. The active form of NF-[kappa]B rapidly translocates into the nucleus, binding to consensus sequences in the promoter/enhancer region of various genes, promoting their transcription. In human vascular endothelial cells activated with tumor necrosis factor-alpha, the activation and translocation of NF-[kappa]B is rapid, reaching maximal nuclear localization by 30 min. In this study, the appearance of NF-[kappa]B (p65 subunit, p65-NF-[kappa]B) in the nucleus visualized by immunofluorescence and quantified by morphometric image analysis (integrated optical density, IOD) is compared to the appearance of activated p65-NF-[kappa]B protein in the nucleus determined biochemically. The appearance of p65-NF-[kappa]B in the nucleus measured by fluorescence image analysis and biochemically express a linear correlation (R2 = 0.9477). These data suggest that localization and relative protein concentrations of NF-[kappa]B can be reliably determined from IOD measurements of the immunofluorescent labeled protein.

Association of mutator activity with UV sensitivity in an aphidicolin-resistant mutant of Chinese hamster V79 cells

International Nuclear Information System (INIS)

Liu, P.K.; Chang, C.; Trosko, J.E.

1982-01-01

The spontaneous mutation rates of an ultraviolet light (UV)-sensitive aphidicolin-resistant mutant (aphsup(r)-4-2) and its revertants have been determined by 2 techniques. By using the fluctuation analysis, the mutant and its thymidine (TdR)-prototrophic 'revertant' were found to exhibit elevated spontaneous mutation rates at the 6-thioguanine- and diphtheria-toxin-resistant loci. In contrast, the TdR-auxotrophic 'revertant' did not show this property. Similar results were obtained by the multiple replating technique. From these comparative studies and other previous characterizations, it appears that a single gene mutation is responsible for the following pleiotropic phenotype: slow growth, UV sensitivity, high UV-induced mutability, high frequency of site-specific bromodeoxyuridine (BrdU)-dependent chromosome breaks and enhanced spontaneous mutation rate. Recent studies indicate that the mutation may be on the gene for DNA polymerase α. The results further indicate that thymidine auxotrophy or imbalance in nucleotide pools is not necessarily associated with the mutator activity in mammalian cells. (orig.)
[Virulent gene prevalence of foodborne Listeria monocytogenes in China in 2005].

Science.gov (United States)

Yang, Yang; Fu, Ping; Guo, Yun-Chang; Pei, Xiao-Yan; Liu, Xiu-Mei

2010-12-01

To study the virulent gene prevalence of foodborne Listeria monocytogenes (LM) isolated from China. 78 LM isolates derived from raw meat, cooked food, aquatic products and vegetables of 13 provinces and cities.LM isolates were investigated for prevalence of virulence genes (LIPI-1 (prfA, plcA, hly, mpl, actA, plcB); LIPI-2 (inlA, inlB), and iap) by PCR method. 87.2% (68/78) of the isolates were prfA positive, 98.7% (77/78) of the isolates were plcA, actA and plcB positive, 97.4% (76/78) of the isolates were hly positive, 87.2% (68/78) of the isolates were mpl positive, 92.3% (72/78) of the isolates were inlA positive, 100% (78/78) of the isolates were inlB positive, 98.7% (77/78) of the isolates were iap positive. Among 21 virulent gene negative isolates, there was 7 isolates lack of two or more virulence genes. The rate of virulence genes deletion isolates from cooked meat was 31.3% (10/32), the rate of virulence genes deletion isolates from raw meat was 16.1% (5/31), the rate of virulence genes deletion isolates from vegetables was 36.4% (4/11) and rate of virulence genes deletion isolates from seafood was 50% (2/4). No significant difference was found (χ(2) = 3.721, P > 0.05). The virulence gene array-1 strains were dominant among these isolates. Among 78 LM isolates, prevalent of virulent genes were different except inlB, virulence genes of LIP-1 were deleted prevalently among isolates, virulence gene deletion patterns were diverse.
Dual-species biofilm of Listeria monocytogenes and Escherichia coli on stainless steel surface.

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de Grandi, Aline Zago; Pinto, Uelinton Manoel; Destro, Maria Teresa

2018-04-12

Listeria monocytogenes is a Gram-positive bacterium commonly associated with foodborne diseases. Due its ability to survive under adverse environmental conditions and to form biofilm, this bacterium is a major concern for the food industry, since it can compromise sanitation procedures and increase the risk of post-processing contamination. Little is known about the interaction between L. monocytogenes and Gram-negative bacteria on biofilm formation. Thus, in order to evaluate this interaction, Escherichia coli and L. monocytogenes were tested for their ability to form biofilms together or in monoculture. We also aimed to evaluate the ability of L. monocytogenes 1/2a and its isogenic mutant strain (ΔprfA ΔsigB) to form biofilm in the presence of E. coli. We assessed the importance of the virulence regulators, PrfA and σ B , in this process since they are involved in many aspects of L. monocytogenes pathogenicity. Biofilm formation was assessed using stainless steel AISI 304 #4 slides immersed into brain heart infusion broth, reconstituted powder milk and E. coli preconditioned medium at 25 °C. Our results indicated that a higher amount of biofilm was formed by the wild type strain of L. monocytogenes than by its isogenic mutant, indicating that prfA and sigB are important for biofilm development, especially maturation under our experimental conditions. The presence of E. coli or its metabolites in preconditioned medium did not influence biofilm formation by L. monocytogenes. Our results confirm the possibility of concomitant biofilm formation by L. monocytogenes and E. coli, two bacteria of major significance in the food industry.
Novel time-dependent vascular actions of Δ9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

International Nuclear Information System (INIS)

O'Sullivan, Saoirse E.; Tarling, Elizabeth J.; Bennett, Andrew J.; Kendall, David A.; Randall, Michael D.

2005-01-01

Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, Δ 9 -tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPARγ). In vitro, THC (10 μM) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPARγ agonist rosiglitazone and was inhibited by the PPARγ antagonist GW9662 (1 μM), but not the cannabinoid CB 1 receptor antagonist AM251 (1 μM). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPARγ, transiently expressed in combination with retinoid X receptor α and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 μM). In vitro incubation with THC (1 or 10 μM, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPARγ ligands. The present results provide strong evidence that THC is a PPARγ ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors
Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator-Activated Receptor-γ: Therapeutic Implications for Cardiovascular Diseases

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Florence Gizard

2008-01-01

Full Text Available Proliferation of vascular smooth muscle cells (SMCs is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR γ is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD, used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPARγ is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPARγ in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPARγ in SMCs and outline the therapeutic implications of PPARγ activation for the treatment and prevention of atherosclerosis and its complications.
Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study

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Baslund, Bo; Tvede, Niels; Danneskiold-Samsøe, Bente

2005-01-01

Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous...... and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA....
Carvedilol, a third-generation β-blocker prevents oxidative stress-induced neuronal death and activates Nrf2/ARE pathway in HT22 cells

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Ouyang, Ying [Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Chen, Ziwei [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Tan, Min [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Department of Traditional Chinese Medicine Chemistry, College of Chinese Materia Madica, Guangzhou University of Chinese Medicine, Guangzhou 510006 (China); Liu, Anmin [Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Chen, Meihui [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Liu, Jun [Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Pi, Rongbiao, E-mail: pirb@mail.sysu.edu.cn [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Fang, Jianpei, E-mail: jpf2005@163.com [Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China)

2013-11-29

Highlights: •Carvedilol significantly prevented oxidative stress-induced cell death. •Carvedilol significantly decreased the production of ROS. •Carvedilol activated Nrf2/ARE pathway. •Carvedilol increased the protein levels of HO-1 and NQO-1. -- Abstract: Carvedilol, a nonselective β-adrenoreceptor blocker with pleiotropic activities has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. Nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cellular stress response pathway involved in neuroprotection. Here we investigated the effect of carvedilol on oxidative stress-induced cell death (glutamate 2 mM and H{sub 2}O{sub 2} 600 μM) and the activity of Nrf2/ARE pathway in HT22 hippocampal cells. Carvedilol significantly increased cell viability and decreased ROS in HT22 cells exposed to glutamate or H{sub 2}O{sub 2}. Furthermore, carvedilol activated the Nrf2/ARE pathway in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. Collectively, our results indicate that carvedilol protects neuronal cell against glutamate- and H{sub 2}O{sub 2}-induced neurotoxicity possibly through activating the Nrf2/ARE signaling pathway.
Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension.

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Donazzan, Luca; Mahfoud, Felix; Ewen, Sebastian; Ukena, Christian; Cremers, Bodo; Kirsch, Carl-Martin; Hellwig, Dirk; Eweiwi, Tareq; Ezziddin, Samer; Esler, Murray; Böhm, Michael

2016-04-01

To investigate, whether renal denervation (RDN) has a direct effect on cardiac sympathetic activity and innervation density. RDN demonstrated its efficacy not only in reducing blood pressure (BP) in certain patients, but also in decreasing cardiac hypertrophy and arrhythmias. These pleiotropic effects occur partly independent from the observed BP reduction. Eleven patients with resistant hypertension (mean office systolic BP 180 ± 18 mmHg, mean antihypertensive medications 6.0 ± 1.5) underwent I-123-mIBG scintigraphy to exclude pheochromocytoma. We measured cardiac sympathetic innervation and activity before and 9 months after RDN. Cardiac sympathetic innervation was assessed by heart to mediastinum ratio (H/M) and sympathetic activity by wash out ratio (WOR). Effects on office BP, 24 h ambulatory BP monitoring, were documented. Office systolic BP and mean ambulatory systolic BP were significantly reduced from 180 to 141 mmHg (p = 0.006) and from 149 to 129 mmHg (p = 0.014), respectively. Cardiac innervation remained unchanged before and after RDN (H/M 2.5 ± 0.5 versus 2.6 ± 0.4, p = 0.285). Cardiac sympathetic activity was significantly reduced by 67 % (WOR decreased from 24.1 ± 12.7 to 7.9 ± 25.3 %, p = 0.047). Both, responders and non-responders experienced a reduction of cardiac sympathetic activity. RDN significantly reduced cardiac sympathetic activity thereby demonstrating a direct effect on the heart. These changes occurred independently from BP effects and provide a pathophysiological basis for studies, investigating the potential effect of RDN on arrhythmias and heart failure.
Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives

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Antonio Simone Laganà

2016-06-01

Full Text Available Background: Peroxisome proliferator-activated receptors (PPARs have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; Methods: Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; Results: PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; Conclusion: PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer.
The role of Vif oligomerization and RNA chaperone activity in HIV-1 replication.

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Batisse, Julien; Guerrero, Santiago; Bernacchi, Serena; Sleiman, Dona; Gabus, Caroline; Darlix, Jean-Luc; Marquet, Roland; Tisné, Carine; Paillart, Jean-Christophe

2012-11-01

The viral infectivity factor (Vif) is essential for the productive infection and dissemination of HIV-1 in non-permissive cells that involve most natural HIV-1 target cells. Vif counteracts the packaging of two cellular cytidine deaminases named APOBEC3G (A3G) and A3F by diverse mechanisms including the recruitment of an E3 ubiquitin ligase complex and the proteasomal degradation of A3G/A3F, the inhibition of A3G mRNA translation or by a direct competition mechanism. In addition, Vif appears to be an active partner of the late steps of viral replication by participating in virus assembly and Gag processing, thus regulating the final stage of virion formation notably genomic RNA dimerization and by inhibiting the initiation of reverse transcription. Vif is a small pleiotropic protein with multiple domains, and recent studies highlighted the importance of Vif conformation and flexibility in counteracting A3G and in binding RNA. In this review, we will focus on the oligomerization and RNA chaperone properties of Vif and show that the intrinsic disordered nature of some Vif domains could play an important role in virus assembly and replication. Experimental evidence demonstrating the RNA chaperone activity of Vif will be presented. Copyright © 2012 Elsevier B.V. All rights reserved.
Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

Energy Technology Data Exchange (ETDEWEB)

O' Sullivan, Saoirse E [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Tarling, Elizabeth J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Bennett, Andrew J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Kendall, David A [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Randall, Michael D [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom)

2005-11-25

Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.
The PPARα/p16INK4a Pathway inhibits Vascular Smooth Muscle Cell Proliferation by repressing Cell Cycle-dependent Telomerase Activation

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Gizard, Florence; Nomiyama, Takashi; Zhao, Yue; Findeisen, Hannes M.; Heywood, Elizabeth B.; Jones, Karrie L.; Staels, Bart; Bruemmer, Dennis

2009-01-01

Peroxisome Proliferator-Activated Receptor (PPAR) α, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARα activation suppresses G1→S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16INK4a (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARα is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARα activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect which was dependent on p16. The inhibition of cell proliferation by PPARα activation was lost in VSMC following TERT overexpression or knock-down, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARα. Finally, we demonstrate that PPARα agonists suppress telomerase activation during the proliferative response following vascular injury indicating that these findings are applicable in vivo. In concert, these results demonstrate that the anti-proliferative effects of PPARα in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade. PMID:18818403
miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1

DEFF Research Database (Denmark)

Brønnum, Hasse; Andersen, Ditte C; Schneider, Mikael

2013-01-01

and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic......, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist...... that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs...
Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples

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Marcella Zollino

2017-10-01

Full Text Available Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15–30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR family and the interconnected molecular pathways in most cases. However it can occur in association with other gene variants and with a variety of chromosome abnormalities as well, usually in association with intellectual disability (ID and additional physical anomalies. Evaluating the molecular properties of the genes undergoing intragenic mutations or copy number variations (CNVs along with prevalence of craniosynostosis in different conditions and animal models if available, we made an attempt to define two distinct groups of unusual syndromic craniosynostosis, which can reflect direct effects of emerging new candidate genes with roles in suture homeostasis or a non-specific phenotypic manifestation of pleiotropic genes, respectively. RASopathies and 9p23p22.3 deletions are reviewed as examples of conditions in the first group. In particular, we found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC syndrome. Chromatinopathies and neurocristopathies are presented as examples of conditions in the second group. We observed that craniosynostosis is uncommon on average in these conditions. It was randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat–Wilson syndromes and in KAT6B-related disorders. As an exception, trigonocephaly in Bohring-Opitz syndrome reflects specific molecular properties of the chromatin modifier ASXL1 gene. Surveillance for craniosynostosis in syndromic forms of
Anti-Inflammatory and Immunomodulatory Mechanism of Tanshinone IIA for Atherosclerosis

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Zhuo Chen

2014-01-01

Full Text Available Tanshinone IIA (Tan II A is widely used in the treatment of cardiovascular diseases as an active component of Salvia miltiorrhiza Bunge. It has been demonstrated to have pleiotropic effects for atherosclerosis. From the anti-inflammatory and immunomodulatory mechanism perspective, this paper reviewed major progresses of Tan IIA in antiatherosclerosis research, including immune cells, antigens, cytokines, and cell signaling pathways.
Fragile X mental retardation protein controls ion channel expression and activity.

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Ferron, Laurent

2016-10-15

Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders is fragile X syndrome, the most common cause of inherited intellectual disability and autism. FMRP is an RNA-binding protein involved in the control of local translation, which has pleiotropic effects, in particular on synaptic function. Analysis of the brain FMRP transcriptome has revealed hundreds of potential mRNA targets encoding postsynaptic and presynaptic proteins, including a number of ion channels. FMRP has been confirmed to bind voltage-gated potassium channels (K v 3.1 and K v 4.2) mRNAs and regulates their expression in somatodendritic compartments of neurons. Recent studies have uncovered a number of additional roles for FMRP besides RNA regulation. FMRP was shown to directly interact with, and modulate, a number of ion channel complexes. The sodium-activated potassium (Slack) channel was the first ion channel shown to directly interact with FMRP; this interaction alters the single-channel properties of the Slack channel. FMRP was also shown to interact with the auxiliary β4 subunit of the calcium-activated potassium (BK) channel; this interaction increases calcium-dependent activation of the BK channel. More recently, FMRP was shown to directly interact with the voltage-gated calcium channel, Ca v 2.2, and reduce its trafficking to the plasma membrane. Studies performed on animal models of fragile X syndrome have revealed links between modifications of ion channel activity and changes in neuronal excitability, suggesting that these modifications could contribute to the phenotypes observed in patients with fragile X-associated disorders. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.
Statins and oxidative stress in the cardiovascular system.

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Margaritis, Marios; Sanna, Fabio; Antoniades, Charalambos

2017-09-26

Statins are widely established as an important class of medications for primary and secondary prevention of cardiovascular disease. In addition to their lipid-lowering effects, mounting evidence suggests that statins exhibit non-lipid-lowering mediated effects in the cardiovascular system. These so called "pleiotropic" effects are partly due to antioxidant properties of statins. These are mediated by inhibition of the mevalonate pathway, which interferes with small GTP-ase protein prenylation. This, in turn, leads to anti-oxidant effects of statins via a plethora of mechanisms. Statins prevent the activation of the pro-oxidant enzyme NADPH-oxidase by interfering with Rac1 activation and translocation to the membrane, as well as reducing expression of crucial subunits of NADPH-oxidase. Statins also enhance the expression, enzymatic activity and coupling of endothelial nitric oxide synthase (eNOS), through mevalonate-dependent effects. The net result is a restoration of the redox balance in the cardiovascular system, with subsequent anti-atherosclerotic and cardioprotective effects. While the evidence from basic science studies and animal models is strong, more clinical trials are required to establish the relevance of these pleiotropic effects to human cardiovascular disease and potentially lead to expanded indications for statin treatment or alternative therapeutic strategies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Sensitivity to acetic acid, ability to colonize abiotic surfaces and virulence potential of Listeria monocytogenes EGD-e after incubation on parsley leaves.

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Rieu, A; Guzzo, J; Piveteau, P

2010-02-01

To investigate how the survival of Listeria monocytogenes on parsley leaves may affect its ability to sustain process-related harsh conditions and its virulence. Parsley seedlings were spot inoculated with stationary phase cells of L. monocytogenes EGD-e and incubated for 15 days. Each day, bacterial cells were harvested and enumerated, and their ability to survive acetic acid challenge (90 min, pH 4.0), to colonize abiotic surfaces and to grow as biofilms was assessed. After a 3-log decrease over the first 48 h, the population stabilized to about 10(6) CFU g(-1) until the sixth day. After the sixth day, L. monocytogenes was no longer detected, even after specific enrichment. Incubation on parsley leaves affected the ability of L. monocytogenes to survive acetic acid challenge (90 min, pH 4.0) and to adhere to stainless steel although the ability to grow as biofilm was preserved. To further investigate these physiological alterations, the mRNA levels of six target genes (bsh, clpC, groEL, inlA, opuC, prfA) was quantified using reverse transcription qPCR after 5 h of incubation on parsley leaves. A decrease was observed in all but one (bsh) target, including groEL and clpC which are involved in resistance to salt and acid. Moreover, the decrease in the levels of inlA, prfA and opuC transcripts after incubation on parsley suggested a repression of some genes involved in pathogenicity. In vitro assessment of mammalian cell adherence and invasion using Caco-2 cells confirmed the repression of the virulence factor InlA; however, the virulence potential in vivo in the chick embryo model was not affected. Listeria monocytogenes did undergo rapid changes to adapt its physiology to the phyllosphere. This study highlights the physiological changes undergone by L. monocytogenes during/after survival on parsley leaves.
Y-box Binding Protein-1 Enhances Oncogenic Transforming Growth Factor β Signaling in Breast Cancer Cells via Triggering Phospho-Activation of Smad2.

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Stope, Matthias B; Weiss, Martin; Koensgen, Dominique; Popp, Simone L; Joffroy, Christian; Mustea, Alexander; Buck, Miriam B; Knabbe, Cornelius

2017-12-01

Transforming growth factor β (TGFβ) plays a role in diverse oncogenic pathways including cell proliferation and cell motility and is regulated by the pleiotropic factor Y-box binding protein-1 (YB-1). In breast cancer, Sma/Mad related protein 2 (Smad2) represents the most common downstream transducer in TGFβ signaling. Here, YB-1's impact on Smad2 phospho-activation was characterized by incubation of the breast cancer cell line MCF-7 with or without TGFβ1 in the absence or presence of overexpressed YB-1 protein. The phospho-status of Smad2 was assessed via western blotting. Analysis of MCF-7 cells revealed no induction of total Smad2 neither in the presence of TGFβ1, nor during YB-1 overexpression. In contrast, incubation with TGFβ1 led to an increase of phosphorylated Smad2 forms which was significantly amplified by simultaneously overexpressed YB-1 (2.8±0.2-fold). Oncogenic YB-1 indirectly enhances TGFβ signaling cascades via Smad2 phospho-activation and may represent a promising factor for future diagnosis and therapy of breast cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
Pleiotropy among common genetic loci identified for cardiometabolic disorders and C-reactive protein.

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Symen Ligthart

Full Text Available Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS. We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463 as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10 appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18 had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.

Role of Osteal Macrophages in Bone Metabolism

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Sun Wook Cho

2015-03-01

Full Text Available Macrophages have been shown to have pleiotropic functions in various pathophysiologies, especially in terms of anti-inflammatory and regenerative activity. Recently, the novel functions of bone marrow resident macrophages (called osteal macrophages were intensively studied in bone development, remodeling and tissue repair processes. This review discusses the current evidence for a role of osteal macrophages in bone modeling, remodeling, and fracture healing processes.
Cycles of light and dark co-ordinate reversible colony differentiation in Listeria monocytogenes.

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Tiensuu, Teresa; Andersson, Christopher; Rydén, Patrik; Johansson, Jörgen

2013-02-01

Recently, several light receptors have been identified in non-phototrophic bacteria, but their physiological roles still remain rather elusive. Here we show that colonies of the saprophytic bacterium Listeria monocytogenes undergo synchronized multicellular behaviour on agar plates, in response to oscillating light/dark conditions, giving rise to alternating ring formation (opaque and translucent rings). On agar plates, bacteria from opaque rings survive increased levels of reactive oxygen species (ROS), as well as repeated cycles of light and dark, better than bacteria from translucent rings. The ring formation is strictly dependent on a blue-light receptor, Lmo0799, acting through the stress-sigma factor, σ(B) . A transposon screening identified 48 mutants unable to form rings at alternating light conditions, with several of them showing a decreased σ(B) activity/level. However, some of the tested mutants displayed a varied σ(B) activity depending on which of the two stress conditions tested (light or H(2) O(2) exposure). Intriguingly, the transcriptional regulator PrfA and the virulence factor ActA were shown to be required for ring formation by a mechanism involving activation of σ(B) . All in all, this suggests a distinct pathway for Lmo0799 that converge into a common signalling pathway for σ(B) activation. Our results show that night and day cycles co-ordinate a reversible differentiation of a L. monocytogenes colony at room temperature, by a process synchronized by a blue-light receptor and σ(B) . © 2013 Blackwell Publishing Ltd.
High molecular weight FGF2 isoforms demonstrate canonical receptor-mediated activity and support human embryonic stem cell self-renewal

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Denis Kole

2017-05-01

Full Text Available Basic fibroblast growth factor (FGF2 is a highly pleiotropic member of a large family of growth factors with a broad range of activities, including mitogenesis and angiogenesis (Ornitz et al., 1996; Zhang et al., 2006, and it is known to be essential for maintenance of balance between survival, proliferation, and self-renewal in human pluripotent stem cells (Eiselleova et al., 2009; Zoumaro-Djayoon et al., 2011. A single FGF2 transcript can be translated into five FGF2 protein isoforms, an 18 kDa low molecular weight (LMW isoform and four larger high molecular weight (HMW isoforms (Arese et al., 1999; Arnaud et al., 1999. As they are not generally secreted, high molecular weight (HMW FGF2 isoforms have predominantly been investigated intracellularly; only a very limited number of studies have investigated their activity as extracellular factors. Here we report over-expression, isolation, and biological activity of all recombinant human FGF2 isoforms. We show that HMW FGF2 isoforms can support self-renewal of human embryonic stem cells (hESCs in vitro. Exogenous supplementation with HMW FGF2 isoforms also activates the canonical FGFR/MAPK pathway and induces mitogenic activity in a manner similar to that of the 18 kDa FGF2 isoform. Though all HMW isoforms, when supplemented exogenously, are able to recapitulate LMW FGF2 activity to some degree, it appears that certain isoforms tend to do so more poorly, demonstrating a lesser functional response by several measures. A better understanding of isoform-specific FGF2 effects will lead to a better understanding of developmental and pathological FGF2 signaling.
Phenotypic and Genotypic Characterization of Atypical Listeria monocytogenes and Listeria innocua Isolated from Swine Slaughterhouses and Meat Markets

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Luisa Zanolli Moreno

2014-01-01

Full Text Available In the last decade, atypical Listeria monocytogenes and L. innocua strains have been detected in food and the environment. Because of mutations in the major virulence genes, these strains have different virulence intensities in eukaryotic cells. In this study, we performed phenotypic and genotypic characterization of atypical L. monocytogenes and L. innocua isolates obtained from swine slaughterhouses and meat markets. Forty strains were studied, including isolates of L. monocytogenes and L. innocua with low-hemolytic activity. The isolates were characterized using conventional phenotypic Listeria identification tests and by the detection and analysis of L. monocytogenes-specific genes. Analysis of 16S rRNA was used for the molecular identification of the Listeria species. The L. monocytogenes isolates were positive for all of the virulence genes studied. The atypical L. innocua strains were positive for hly, plcA, and inlC. Mutations in the InlC, InlB, InlA, PI-PLC, PC-PLC, and PrfA proteins were detected in the atypical isolates. Further in vitro and transcriptomic studies are being developed to confirm the role of these mutations in Listeria virulence.
OrfX, a Nucleomodulin Required for Listeria monocytogenes Virulence

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Andrzej Prokop

2017-10-01

Full Text Available Listeria monocytogenes is a bacterial pathogen causing severe foodborne infections in humans and animals. Listeria can enter into host cells and survive and multiply therein, due to an arsenal of virulence determinants encoded in different loci on the chromosome. Several key Listeria virulence genes are clustered in Listeria pathogenicity island 1. This important locus also contains orfX (lmo0206, a gene of unknown function. Here, we found that OrfX is a small, secreted protein whose expression is positively regulated by PrfA, the major transcriptional activator of Listeria virulence genes. We provide evidence that OrfX is a virulence factor that dampens the oxidative response of infected macrophages, which contributes to intracellular survival of bacteria. OrfX is targeted to the nucleus and interacts with the regulatory protein RybP. We show that in macrophages, the expression of OrfX decreases the level of RybP, which controls cellular infection. Collectively, these data reveal that Listeria targets RybP and evades macrophage oxidative stress for efficient infection. Altogether, OrfX is after LntA, the second virulence factor acting directly in the nucleus.
Identification of cytosolic peroxisome proliferator binding protein as a member of the heat shock protein HSP70 family.

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Alvares, K; Carrillo, A; Yuan, P M; Kawano, H; Morimoto, R I; Reddy, J K

1990-01-01

Clofibrate and many of its structural analogues induce proliferation of peroxisomes in the hepatic parenchymal cells of rodents and certain nonrodent species including primates. This induction is tissue specific, occurring mainly in the liver parenchymal cells and to a lesser extent in the kidney cortical epithelium. The induction of peroxisomes is associated with a predictable pleiotropic response, characterized by hepatomegaly, and increased activities and mRNA levels of certain peroxisomal...
Preparation of curcumin loaded nanoparticles: physicochemical characterization and in vitro evaluation

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Drakalska, Elena; Momekova, Denitsa; Rangelov, Stanislav; Lambov, Nikolay

2016-01-01

Curcumin is the active principle of the spice turmeric, produced by the rhizome of Curcuma longa (Zingiberaceae), which is widely used in traditional eastern medicine as a hepatoprotective, anti-infectious and anti-inflammatory remedy. A compelling body of recent evidence has shown that curcumin is endowed by pleiotropic antineoplastic effects, due to modulation of NFkB and other cell signaling pathways, implicated in cell survival, apoptosis and angiogenesis.
Leptin: A biomarker for sleep disorders?

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Pan, Weihong; Kastin, Abba J.

2013-01-01

Leptin, a pleiotropic protein hormone produced mainly by fat cells, regulates metabolic activity and many other physiological functions. The intrinsic circadian rhythm of blood leptin is modulated by gender, development, feeding, fasting, sleep, obesity, and endocrine disorders. Hyperleptinemia is implicated in leptin resistance. To determine the specificity and sensitivity of leptin concentrations in sleep disorders, we summarize here the alterations of leptin in four conditions in animal an...
Interaction of human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol-dependent kinase 1 regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation.

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Miralem, Tihomir; Lerner-Marmarosh, Nicole; Gibbs, Peter E M; Jenkins, Jermaine L; Heimiller, Chelsea; Maines, Mahin D

2016-08-01

Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1-3) are downstream of IRK and are activated by phosphatidylinositol-dependent kinase 1 (PDK1) phosphorylating T(308) before S(473) autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present in hBVR. Phosphorylation of glycogen synthase kinase 3 (GSK3) isoforms α/β by Akts inhibits their activity; nonphosphorylated GSK3β inhibits activation of various genes. We examined the role of hBVR in PDK1/Akt1/GSK3 signaling and Akt1 in hBVR phosphorylation. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. hBVR and Akt1 coimmunoprecipitated, and in-cell Förster resonance energy transfer (FRET) and glutathione S-transferase pulldown analyses identified Akt1 pleckstrin homology domain as the interactive domain. hBVR activates phosphorylation of Akt1 at S(473) independent of hBVR's kinase competency. Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target. Underlined amino acids are the essential residues of the signaling motifs. In cells, hBVR-activated Akt1 increased both GSK3α/β and forkhead box of the O class transcription class 3 (FoxO3) phosphorylation and inhibited total GSK3 activity; depletion of hBVR released inhibition and stimulated glucose uptake. Immunoprecipitation analysis showed that PDK1 and hBVR interact through hBVR's PDK1 binding (161)RFGFPAFS motif and formation of the PDK1/hBVR/Akt1 complex. sihBVR blocked complex formation. Findings identify hBVR as a previously unknown coactivator of Akt1 and as a key mediator of Akt1/GSK3 pathway, as well as define a key role for hBVR in Akt1 activation by PDK1.-Miralem, T., Lerner
IL-6 Impairs Myogenic Differentiation by Downmodulation of p90RSK/eEF2 and mTOR/p70S6K Axes, without Affecting AKT Activity

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Michele Pelosi

2014-01-01

Full Text Available IL-6 is a multifaceted pleiotropic cytokine, which is produced by a variety of cell types and targets different cells and tissues. In physiological conditions, IL-6 can be locally and transiently produced by skeletal muscle and plays an important role in muscle homeostasis. Circulating IL-6 levels are normally very low or undetectable but are dramatically increased in several pathologic conditions. In this study, we aimed to define the potential molecular mechanisms underlying the effects of IL-6 on myogenic program. We explored the molecular mechanisms through which exogenous IL-6, or the conditioned medium from the murine C-26 adenocarcinoma cells (a cellular model that secretes high levels of IL-6 and induces cancer cachexia in mice, interferes with the myogenic program. Our study revealed that IL-6 induces the activation of the Stat3 signaling and promotes the downmodulation of the p90RSK/eEF2 and mTOR/p70S6K axes, while it does not affect the activation of AKT. We thus identified potential molecular mediators of the inhibitory effects of IL-6 on myogenic program.
MzrA: a novel modulator of the EnvZ/OmpR two-component regulon

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Gerken, Henri; Charlson, Emily S; Cicirelli, Elisha M; Kenney, Linda J; Misra, Rajeev

2009-01-01

Analysis of suppressors that alleviate the acute envelope stress phenotype of a ΔbamBΔdegP strain of Escherichia coli identified a novel protein MzrA and pleiotropic envZ mutations. Genetic evidence shows that overexpression of MzrA – formerly known as YqjB and EcfM – modulates the activity of EnvZ/OmpR similarly to pleiotropic EnvZ mutants and alter porin expression. However, porin expression in strains devoid of MzrA or overexpressing it is still sensitive to medium osmolarity, pH and procaine, all of which modulate EnvZ/OmpR activities. Thus, MzrA appears to alter the output of the EnvZ/OmpR system but not its ability to receive and respond to various environmental signals. Localization and topology experiments indicate that MzrA is a type II membrane protein, with its N-terminus exposed in the cytoplasm and C-terminus in the periplasm. Bacterial two-hybrid experiments determined that MzrA specifically interacts with EnvZ but not with OmpR or the related membrane sensor kinase, CpxA. This and additional genetic and biochemical evidence suggest that the interaction of MzrA with EnvZ would either enhance EnvZ's kinase activity or reduce its phosphatase activity, thus elevating the steady state levels of OmpR∼P. Furthermore, our data show that MzrA links the two-component envelope stress response regulators, CpxA/CpxR and EnvZ/OmpR. PMID:19432797
Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer.

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Kassiotis, George; Stoye, Jonathan P

2017-10-19

Like all other mammals, humans harbour an astonishing number of endogenous retroviruses (ERVs), as well as other retroelements, embedded in their genome. These remnants of ancestral germline infection with distinct exogenous retroviruses display various degrees of open reading frame integrity and replication capability. Modern day exogenous retroviruses, as well as the infectious predecessors of ERVs, are demonstrably oncogenic. Further, replication-competent ERVs continue to cause cancers in many other species of mammal. Moreover, human cancers are characterized by transcriptional activation of human endogenous retroviruses (HERVs). These observations conspire to incriminate HERVs as causative agents of human cancer. However, exhaustive investigation of cancer genomes suggests that HERVs have entirely lost the ability for re-infection and thus the potential for insertional mutagenic activity. Although there may be non-insertional mechanisms by which HERVs contribute to cancer development, recent evidence also uncovers potent anti-tumour activities exerted by HERV replication intermediates or protein products. On balance, it appears that HERVs, despite their oncogenic past, now represent potential targets for immune-mediated anti-tumour mechanisms.This article is part of the themed issue 'Human oncogenic viruses'. © 2017 The Authors.
Characterization of the Pseudomonas aeruginosa recA gene: the Les- phenotype

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Kokjohn, T.A.; Miller, R.V.

1988-01-01

The Les- phenotype (lysogeny establishment deficient) is a pleiotropic effect of the lesB908 mutation of Pseudomonas aeruginosa PAO. lesB908-containing strains are also (i) deficient in general recombination, (ii) sensitive to UV irradiation, and (iii) deficient in UV-stimulated induction of prophages. The P. aeruginosa recA-containing plasmid pKML3001 complemented each of these pleiotropic characteristics of the lesB908 mutation, supporting the hypothesis that lesB908 is an allele of the P. aeruginosa recA gene. The phenotypic effects of the lesB908 mutation may be best explained by the hypothesis that the lesB908 gene product is altered in such a way that it has lost synaptase activity but possesses intrinsic protease activity in the absence of DNA damage. The Les- phenotype is a result of the rapid destruction of newly synthesized phage repressor, resulting in lytic growth of the infecting virus. This hypothesis is consistent with the observations that increasing the number of copies of the phage repressor gene by increasing the multiplicity of infection (i.e., average number of phage genomes per cell) or by introducing the cloned phage repressor gene into a lesB908 mutant will also suppress the Les- phenotype in a phage-specific fashion
In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

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D.O. Gonçalves

2011-02-01

Full Text Available Statins are among the most prescribed drugs in recent clinical practice. They are also known for their pleiotropic actions, which are independent of their lipid-lowering properties. The effect of lovastatin was investigated against carrageenan-induced paw edema in male Wistar rats (200-250 g and on leukocyte migration, as measured by carrageenan-induced peritonitis in male Swiss mice (20-25 g, which are models of acute inflammation. Lovastatin (administered 1 h prior to carrageenan, at oral doses of 2, 5, and 10 mg/kg, markedly attenuated paw edema formation in rats at the 4th hour after carrageenan injection (25, 43, and 37% inhibition, respectively. Inhibitions of 20, 45 and 80% were observed in the leukocyte migration, as evaluated by carrageenan-induced peritonitis in mice with lovastatin doses of 0.5, 1 and 5 mg/kg, as compared to controls. Furthermore, lovastatin (administered 1 h before initiation reduced the nociceptive effect of the formalin test in mice, at both phases, at doses of 2, 5, and 10 mg/kg: first phase (51, 65, and 70%, respectively and second phase (73, 57, and 66% inhibition of licking time, respectively. The anti-nociceptive activity of lovastatin was inhibited by naloxone (3 mg/kg, sc. Lovastatin (0.01, 0.1, and 1 µg/mL inhibited by 23, 79, and 86%, respectively, the release of myeloperoxidase from human neutrophils. Leukocyte (predominantly neutrophils infiltration was almost completely reduced by lovastatin treatment, as observed in the model of acute paw edema with hematoxylin and eosin staining. In addition, lovastatin decreased the number of cells expressing tumor necrosis factor-α (TNF-α and the inducible form of nitric oxide synthase (iNOS activity. Therefore, the alterations in leukocyte activity and cytokine release could contribute to the anti-inflammatory activity of lovastatin.
Factors determining Staphylococcus aureus susceptibility to photoantimicrobial chemotherapy: RsbU activity, staphyloxanthin level and membrane fluidity.

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Monika Kossakowska-Zwierucho

2016-07-01

Full Text Available Photoantimicrobial chemotherapy (PACT constitutes a particular type of stress condition, in which bacterial cells induce a pleiotropic and as yet unexplored effect. In light of this, the key master regulators are of putative significance to the overall phototoxic outcome. In Staphylococcus aureus, the alternative sigma factor σB controls the expression of genes involved in the response to environmental stress. We show that aberration of any sigB operon genes in S. aureus USA300 isogenic mutants causes a pronounced sensitization (>5 log10 reduction in CFU drop to PACT with selected photosensitizers, namely protoporphyrin diarginate, zinc phthalocyanine and rose bengal. This effect is partly due to aberration-coupled staphyloxanthin synthesis inhibition. We identified frequent mutations in RsbU, a σB activator, in PACT-vulnerable clinical isolates of S. aureus, resulting in σB activity impairment. Locations of significant changes in protein structure (IS256 insertion, early STOP codon occurrence, substitutions A230T and A276D were shown in a theoretical model of S. aureus RsbU. As a phenotypic hallmark of PACT-vulnerable S. aureus strains, we observed an increased fluidity of bacterial cell membrane, which is a result of staphyloxanthin content and other yet unidentified factors. Our research indicates σB as a promising target of adjunctive antimicrobial therapy and suggests that enhanced cell membrane fluidity may be an adjuvant strategy in photoantimicrobial chemotherapy.
Defining the action spectrum of potential PGC-1α activators on a mitochondrial and cellular level in vivo.

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Hofer, Annette; Noe, Natalie; Tischner, Christin; Kladt, Nikolay; Lellek, Veronika; Schauß, Astrid; Wenz, Tina

2014-05-01

Previous studies have demonstrated a therapeutic benefit of pharmaceutical PGC-1α activation in cellular and murine model of disorders linked to mitochondrial dysfunction. While in some cases, this effect seems to be clearly associated with boosting of mitochondrial function, additional alterations as well as tissue- and cell-type-specific effects might play an important role. We initiated a comprehensive analysis of the effects of potential PGC-1α-activating drugs and pharmaceutically targeted the PPAR (bezafibrate, rosiglitazone), AMPK (AICAR, metformin) and Sirt1 (resveratrol) pathways in HeLa cells, neuronal cells and PGC-1α-deficient MEFs to get insight into cell type specificity and PGC-1α dependence of their working action. We used bezafibrate as a model drug to assess the effect on a tissue-specific level in a murine model. Not all analyzed drugs activate the PGC pathway or alter mitochondrial protein levels. However, they all affect supramolecular assembly of OXPHOS complexes and OXPHOS protein stability. In addition, a clear drug- and cell-type-specific influence on several cellular stress pathways as well as on post-translational modifications could be demonstrated, which might be relevant to fully understand the action of the analyzed drugs in the disease state. Importantly, the effect on the activation of mitochondrial biogenesis and stress response program upon drug treatment is PGC-1α dependent in MEFs demonstrating not only the pleiotropic effects of this molecule but points also to the working mechanism of the analyzed drugs. The definition of the action spectrum of the different drugs forms the basis for a defect-specific compensation strategy and a future personalized therapeutic approach.
The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors.

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De Gregorio, Danilo; Posa, Luca; Ochoa-Sanchez, Rafael; McLaughlin, Ryan; Maione, Sabatino; Comai, Stefano; Gobbi, Gabriella

2016-11-01

d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT 1 and 5-HT 2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5-20μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT 2A and D 2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30-120μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D 2 receptor antagonist haloperidol (50μg/kg, i.v.) and by the 5-HT 1A receptor antagonist WAY-100,635 (500μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR 1 ) antagonist EPPTB (5mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT 1A, D 2 and TAAR 1 receptors. Copyright © 2016 Elsevier Ltd. All rights reserved.
What affects the predictability of evolutionary constraints using a G-matrix? The relative effects of modular pleiotropy and mutational correlation.

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Chebib, Jobran; Guillaume, Frédéric

2017-10-01

Phenotypic traits do not always respond to selection independently from each other and often show correlated responses to selection. The structure of a genotype-phenotype map (GP map) determines trait covariation, which involves variation in the degree and strength of the pleiotropic effects of the underlying genes. It is still unclear, and debated, how much of that structure can be deduced from variational properties of quantitative traits that are inferred from their genetic (co) variance matrix (G-matrix). Here we aim to clarify how the extent of pleiotropy and the correlation among the pleiotropic effects of mutations differentially affect the structure of a G-matrix and our ability to detect genetic constraints from its eigen decomposition. We show that the eigenvectors of a G-matrix can be predictive of evolutionary constraints when they map to underlying pleiotropic modules with correlated mutational effects. Without mutational correlation, evolutionary constraints caused by the fitness costs associated with increased pleiotropy are harder to infer from evolutionary metrics based on a G-matrix's geometric properties because uncorrelated pleiotropic effects do not affect traits' genetic correlations. Correlational selection induces much weaker modular partitioning of traits' genetic correlations in absence then in presence of underlying modular pleiotropy. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.
Prolactin-induced neuroprotection against glutamate excitotoxicity is mediated by the reduction of [Ca2+]i overload and NF-κB activation

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Rivero-Segura, Nadia A.; Flores-Soto, Edgar; García de la Cadena, Selene; Coronado-Mares, Isabel; Gomez-Verjan, Juan C.; Ferreira, Diana G.; Cabrera-Reyes, Erika Alejandra; Lopes, Luísa V.; Massieu, Lourdes

2017-01-01

Prolactin (PRL) is a peptidic hormone that displays pleiotropic functions in the organism including different actions in the brain. PRL exerts a neuroprotective effect against excitotoxicity produced by glutamate (Glu) or kainic acid in both in vitro and in vivo models. It is well known that Glu excitotoxicity causes cell death through apoptotic or necrotic pathways due to intracellular calcium ([Ca2+] i) overload. Therefore, the aim of the present study was to assess the molecular mechanisms by which PRL maintains cellular viability of primary cultures of rat hippocampal neurons exposed to Glu excitotoxicity. We determined cell viability by monitoring mitochondrial activity and using fluorescent markers for viable and dead cells. The intracellular calcium level was determined by a fluorometric assay and proteins involved in the apoptotic pathway were determined by immunoblot. Our results demonstrated that PRL afforded neuroprotection against Glu excitotoxicity, as evidenced by a decrease in propidium iodide staining and by the decrease of the LDH activity. In addition, the MTT assay shows that PRL maintains normal mitochondrial activity even in neurons exposed to Glu. Furthermore, the Glu-induced intracellular [Ca2+]i overload was attenuated by PRL. These data correlate with the reduction found in the level of active caspase-3 and the pro-apoptotic ratio (Bax/Bcl-2). Concomitantly, PRL elicited the nuclear translocation of the transcriptional factor NF-κB, which was detected by immunofluorescence and confocal microscopy. To our knowledge, this is the first report demonstrating that PRL prevents Glu excitotoxicity by a mechanism involving the restoration of the intracellular calcium homeostasis and mitochondrial activity, as well as an anti-apoptotic action possibly mediated by the activity of NF-κB. Overall, the current results suggest that PRL could be of potential therapeutic advantage in the treatment of neurodegenerative diseases. PMID:28475602
Listeria Monocytogenes Persistence in Ready-to-Eat Sausages and in Processing Plants.

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Mureddu, Anna; Mazza, Roberta; Fois, Federica; Meloni, Domenico; Bacciu, Roberto; Piras, Francesca; Mazzette, Rina

2014-01-21

Listeria monocytogenes is of major concern in the fermented meat products and is able to persist in their processing environments. The aim of the present work was to evaluate the virulence profile and the persistence capacity of L. monocytogenes strains isolated in Sardinian fermented sausages processing plants. Food (ground meat, sausages at the end of acidification and ripening stage) and environmental samples (a total of n. 385), collected from 4 meat processing plants located in Sardinia (Italy), were examined to detect L. monocytogenes presence. All the L. monocytogenes isolates were identified by polymerase chain reaction (PCR) method. A subset of strains was also characterised by multiplex PCR-based serogrouping, using the lmo0737 , lmo1118 , ORF2819 and ORF2110 genes. Three different multiplex PCRs were used to obtain the virulence profiles by the rrn , hlyA , actA , prfA , inlA , inlB , iap , plcA , plcB and mpl marker genes. Furthermore, in vitro biofilm forming ability and resistance to disinfectants were carried out on microtiter plate. The overall prevalence was 31.5% in food, and 68.5% in environmental samples. The prevalent serotype resulted 1/2c (43%), followed by 1/2a (40%), 4b (8.6%), and 1/2b (8.6%). The amplification products of the virulence genes were found in all the isolates with the following prevalence: 77.1% hlyA ; 100% rrn ; 100% prfA ; 97.1% iap ; 65.7% inlB ; 88.6% inlA ; 100% plcA ; 100% plcB and 74.3% mpl . As for biofilm forming ability, 37.1% of the strains were positive and resulted weak producer, but all the isolates were sensible to disinfectants showing a reduction of L. monocytogenes growth after each incubation time. More appropriate technologies and application of measures of hygienic control should be implemented to prevent the L. monocytogenes growth and cross-contamination in salsiccia sarda processing plants.

Listeria monocytogenes persistence in ready-to-eat sausages and in processing plants

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Anna Mureddu

2014-02-01

Full Text Available Listeria monocytogenes is of major concern in the fermented meat products and is able to persist in their processing environments. The aim of the present work was to evaluate the virulence profile and the persistence capacity of L. monocytogenes strains isolated in Sardinian fermented sausages processing plants. Food (ground meat, sausages at the end of acidification and ripening stage and environmental samples (a total of n. 385, collected from 4 meat processing plants located in Sardinia (Italy, were examined to detect L. monocytogenes presence. All the L. monocytogenes isolates were identified by polymerase chain reaction (PCR method. A subset of strains was also characterised by multiplex PCR-based serogrouping, using the lmo0737, lmo1118, ORF2819 and ORF2110 genes. Three different multiplex PCRs were used to obtain the virulence profiles by the rrn, hlyA, actA, prfA, inlA, inlB, iap, plcA, plcB and mpl marker genes. Furthermore, in vitro biofilm forming ability and resistance to disinfectants were carried out on microtiter plate. The overall prevalence was 31.5% in food, and 68.5% in environmental samples. The prevalent serotype resulted 1/2c (43%, followed by 1/2a (40%, 4b (8.6%, and 1/2b (8.6%. The amplification products of the virulence genes were found in all the isolates with the following prevalence: 77.1% hlyA; 100% rrn; 100% prfA; 97.1% iap; 65.7% inlB; 88.6% inlA; 100% plcA; 100% plcB and 74.3% mpl. As for biofilm forming ability, 37.1% of the strains were positive and resulted weak producer, but all the isolates were sensible to disinfectants showing a reduction of L. monocytogenes growth after each incubation time. More appropriate technologies and application of measures of hygienic control should be implemented to prevent the L. monocytogenes growth and crosscontamination in salsiccia sarda processing plants.
A small diffusible signal molecule is responsible for the global control of virulence and exoenzyme production in the plant pathogen Erwinia carotovora.

OpenAIRE

Pirhonen, M; Flego, D; Heikinheimo, R; Palva, E T

1993-01-01

Virulence of the plant pathogen Erwinia carotovora subsp. carotovora is dependent on the production and secretion of a complex arsenal of plant cell wall-degrading enzymes. Production of these exoenzymes is controlled by a global regulatory mechanism. A virulent mutants in one of the regulatory loci, expI, show a pleiotropic defect in the growth phase-dependent transcriptional activation of exoenzyme gene expression. The expI gene encodes a 26 kDa polypeptide that is structurally and function...
Functional characterization of the mammalian iAAA protease subunit, YME1L

OpenAIRE

Majczak, Joanna

2008-01-01

The iAAA protease is an ATP-dependent proteolytic complex in the mitochondrial inner membrane and belongs to the highly conserved family of AAA proteins. In the yeast Saccharomyces cerevisiae, the iAAA protease is a homo-oligomeric complex composed of Yme1p subunits which are active in the intermembrane space and mediate protein quality control. Yeast cells lacking Yme1p are characterized by pleiotropic phenotypes including a respiratory deficiency at elevated temperature and an aberrant mito...
Enhanced Edar signalling has pleiotropic effects on craniofacial and cutaneous glands.

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Shie Hong Chang

2009-10-01

Full Text Available The skin carries a number of appendages, including hair follicles and a range of glands, which develop under the influence of EDAR signalling. A gain of function allele of EDAR is found at high frequency in human populations of East Asia, with genetic evidence suggesting recent positive selection at this locus. The derived EDAR allele, estimated to have reached fixation more than 10,000 years ago, causes thickening of hair fibres, but the full spectrum of phenotypic changes induced by this allele is unknown. We have examined the changes in glandular structure caused by elevation of Edar signalling in a transgenic mouse model. We find that sebaceous and Meibomian glands are enlarged and that salivary and mammary glands are more elaborately branched with increased Edar activity, while the morphology of eccrine sweat and tracheal submucosal glands appears to be unaffected. Similar changes to gland sizes and structures may occur in human populations carrying the derived East Asian EDAR allele. As this allele attained high frequency in an environment that was notably cold and dry, increased glandular secretions could represent a trait that was positively selected to achieve increased lubrication and reduced evaporation from exposed facial structures and upper airways.
Vitamin D Effects on Pregnancy and the Placenta

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Shin, Joong Sik; Choi, Mee Yun; Longtine, Mark S.; Nelson, D. Michael

2010-01-01

Vitamin D is a pleiotropic secosteroid hormone important for health and disease prevention. The actions of vitamin D are mediated by the vitamin D receptor that binds the active form of vitamin D [1,25(OH)2D] to induce both transcriptional and non-genomic responses. Vitamin D has well known classical functions in calcium uptake and bone metabolism, but more recent work highlights the importance of the nonclassical actions of vitamin D in a variety of cell types. These actions include modulati...
Insertional inactivation of a chromosomal locus that modulates expression of potential virulence determinants in Staphylococcus aureus.

OpenAIRE

Cheung, A L; Wolz, C; Yeaman, M R; Bayer, A S

1995-01-01

A single insertion of transposon Tn551 into a unique chromosomal locus of Staphylococcus aureus ISP479C has resulted in a pleiotropic effect on the expression of both extracellular and cell wall proteins. In particular, the expression of cell wall protein A and clumping activity with fibrinogen were rendered undetectable in the mutant 1E3 compared with the parent. The secretion of alpha-hemolysin in mutant 1E3 was modestly increased. Southern blot and phenotypic analyses indicated that this l...
In vivo transcriptional profiling of Listeria monocytogenes and mutagenesis identify new virulence factors involved in infection.

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Ana Camejo

2009-05-01

Full Text Available Listeria monocytogenes is a human intracellular pathogen able to colonize host tissues after ingestion of contaminated food, causing severe invasive infections. In order to gain a better understanding of the nature of host-pathogen interactions, we studied the L. monocytogenes genome expression during mouse infection. In the spleen of infected mice, approximately 20% of the Listeria genome is differentially expressed, essentially through gene activation, as compared to exponential growth in rich broth medium. Data presented here show that, during infection, Listeria is in an active multiplication phase, as revealed by the high expression of genes involved in replication, cell division and multiplication. In vivo bacterial growth requires increased expression of genes involved in adaptation of the bacterial metabolism and stress responses, in particular to oxidative stress. Listeria interaction with its host induces cell wall metabolism and surface expression of virulence factors. During infection, L. monocytogenes also activates subversion mechanisms of host defenses, including resistance to cationic peptides, peptidoglycan modifications and release of muramyl peptides. We show that the in vivo differential expression of the Listeria genome is coordinated by a complex regulatory network, with a central role for the PrfA-SigB interplay. In particular, L. monocytogenes up regulates in vivo the two major virulence regulators, PrfA and VirR, and their downstream effectors. Mutagenesis of in vivo induced genes allowed the identification of novel L. monocytogenes virulence factors, including an LPXTG surface protein, suggesting a role for S-layer glycoproteins and for cadmium efflux system in Listeria virulence.
TNFSF14 (LIGHT Exhibits Inflammatory Activities in Lung Fibroblasts Complementary to IL-13 and TGF-β

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Ricardo da Silva Antunes

2018-03-01

Full Text Available The cytokine TNFSF14 [homologous to Lymphotoxin, exhibits Inducible expression and competes with HSV Glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes (LIGHT] has been shown in mouse models to be important for development of lung tissue remodeling that is characteristic of asthma, idiopathic pulmonary fibrosis (IPF, and systemic sclerosis (SSc. However, its cellular targets are not fully delineated. In the present report, we show that LTβR and HVEM, the receptors for LIGHT, are constitutively expressed in primary human lung fibroblasts (HLFs. We asked whether LIGHT could promote inflammatory and remodeling-relevant activity in HLFs and how this was similar to, or distinct from, IL-13 or TGF-β, two cytokines strongly implicated in the pathogenesis of asthma, IPF, and SSc. Accumulation of myofibroblasts expressing alpha smooth muscle actin is a feature of lung inflammatory diseases. LIGHT promoted cell cycle progression and proliferation of HLFs, but not alpha smooth muscle actin expression. In contrast, TGF-β upregulated alpha smooth muscle actin but did not drive their proliferation. LIGHT also increased the gene or protein expression of a number of proinflammatory mediators, including ICAM-1 and VCAM-1, IL-6 and GM-CSF, the chemokines CCL5 and 20, and CXCL5, 11, and 12, and lung remodeling-associated proteinases MMP-9 and ADAM8. These were dependent on LTβR but not HVEM. LIGHT displayed overlapping and synergistic activities with IL-13 for a number of the activities, but LIGHT additionally enhanced the gene expression of several molecules, including the innate cytokines IL-33 and TSLP, which were not upregulated by IL-13. Our results highlight the varied and pleiotropic effects of LIGHT in HLFs. LIGHT might then be a therapeutic target for modulation of inflammation and remodeling associated with asthma and other similar diseases of the lung that involve fibroblasts.
Selectivity Profiling and Biological Activity of Novel β-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors.

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Katharina Rüben

Full Text Available DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer's disease. The β-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A with even higher potency. Here we characterized a series of novel harmine analogs with minimal or absent MAO-A inhibitory activity. We identified several inhibitors with submicromolar potencies for DYRK1A and selectivity for DYRK1A and DYRK1B over the related kinases DYRK2 and HIPK2. An optimized inhibitor, AnnH75, inhibited CLK1, CLK4, and haspin/GSG2 as the only off-targets in a panel of 300 protein kinases. In cellular assays, AnnH75 dose-dependently reduced the phosphorylation of three known DYRK1A substrates (SF3B1, SEPT4, and tau without negative effects on cell viability. AnnH75 inhibited the cotranslational tyrosine autophosphorylation of DYRK1A and threonine phosphorylation of an exogenous substrate protein with similar potency. In conclusion, we have characterized an optimized β-carboline inhibitor as a highly selective chemical probe that complies with desirable properties of drug-like molecules and is suitable to interrogate the function of DYRK1A in biological studies.
Lack of formylated methionyl-tRNA has pleiotropic effects on Bacillus subtilis.

Science.gov (United States)

Cai, Yanfei; Chandrangsu, Pete; Gaballa, Ahmed; Helmann, John D

2017-02-01

Bacteria initiate translation using a modified amino acid, N-formylmethionine (fMet), adapted specifically for this function. Most proteins are processed co-translationally by peptide deformylase (PDF) to remove this modification. Although PDF activity is essential in WT cells and is the target of the antibiotic actinonin, bypass mutations in the fmt gene that eliminate the formylation of Met-tRNAMet render PDF dispensable. The extent to which the emergence of fmt bypass mutations might compromise the therapeutic utility of actinonin is determined, in part, by the effects of these bypass mutations on fitness. Here, we characterize the phenotypic consequences of an fmt null mutation in the model organism Bacillus subtilis. An fmt null mutant is defective for several post-exponential phase adaptive programmes including antibiotic resistance, biofilm formation, swarming and swimming motility and sporulation. In addition, a survey of well-characterized stress responses reveals an increased sensitivity to metal ion excess and oxidative stress. These diverse phenotypes presumably reflect altered synthesis or stability of key proteins involved in these processes.
An efficient Bayesian meta-analysis approach for studying cross-phenotype genetic associations.

Directory of Open Access Journals (Sweden)

Arunabha Majumdar

2018-02-01

Full Text Available Simultaneous analysis of genetic associations with multiple phenotypes may reveal shared genetic susceptibility across traits (pleiotropy. For a locus exhibiting overall pleiotropy, it is important to identify which specific traits underlie this association. We propose a Bayesian meta-analysis approach (termed CPBayes that uses summary-level data across multiple phenotypes to simultaneously measure the evidence of aggregate-level pleiotropic association and estimate an optimal subset of traits associated with the risk locus. This method uses a unified Bayesian statistical framework based on a spike and slab prior. CPBayes performs a fully Bayesian analysis by employing the Markov Chain Monte Carlo (MCMC technique Gibbs sampling. It takes into account heterogeneity in the size and direction of the genetic effects across traits. It can be applied to both cohort data and separate studies of multiple traits having overlapping or non-overlapping subjects. Simulations show that CPBayes can produce higher accuracy in the selection of associated traits underlying a pleiotropic signal than the subset-based meta-analysis ASSET. We used CPBayes to undertake a genome-wide pleiotropic association study of 22 traits in the large Kaiser GERA cohort and detected six independent pleiotropic loci associated with at least two phenotypes. This includes a locus at chromosomal region 1q24.2 which exhibits an association simultaneously with the risk of five different diseases: Dermatophytosis, Hemorrhoids, Iron Deficiency, Osteoporosis and Peripheral Vascular Disease. We provide an R-package 'CPBayes' implementing the proposed method.
Assessment of the potential activity of major dietary compounds as selective estrogen receptor modulators in two distinct cell models for proliferation and differentiation

Energy Technology Data Exchange (ETDEWEB)

Lecomte, Sylvain; Lelong, Marie; Bourgine, Gaëlle [Institut de Recherche en Santé-Environnement-Travail (IRSET), Inserm UMR 1085, Team Transcription, Environment and Cancer, University of Rennes 1, 9 Avenue du Pr Léon Bernard, 35000 Rennes (France); Efstathiou, Theo [Laboratoire Nutrinov, Technopole Atalante Champeaux, 8 rue Jules Maillard de la Gournerie, 35012 Rennes Cedex (France); Saligaut, Christian [Institut de Recherche en Santé-Environnement-Travail (IRSET), Inserm UMR 1085, Team Transcription, Environment and Cancer, University of Rennes 1, 9 Avenue du Pr Léon Bernard, 35000 Rennes (France); Pakdel, Farzad, E-mail: farzad.pakdel@univ-rennes1.fr [Institut de Recherche en Santé-Environnement-Travail (IRSET), Inserm UMR 1085, Team Transcription, Environment and Cancer, University of Rennes 1, 9 Avenue du Pr Léon Bernard, 35000 Rennes (France)

2017-06-15

Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as a model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases. - Highlights: • SERM activity of dietary compounds on proliferation and differentiation is studied. • All the dietary compounds tested transactivate estrogen receptors. • Apigenin and
Induction of λ prophage in lysogenic E.Coli exposed to ionizing radiation of different let

International Nuclear Information System (INIS)

Bonev, M.; Kozubek, S.; Krasavin, E.A.; Cherevatenko, A.P.

1988-01-01

Induction of λ prophage in lysogenic E. coli cells exposed to ionizing radiation of different LET was studied as a function of dose I(D). Activities of pleiotropic RecA protein were shown to contribute to the shape of the I(D) curve. The experimental data were fitted by the function I(D)=αD(1-exp(-D 0 -1 xD))exp(-βD). Inducibility α increased with increasing LET which was related to the increased incidence of DNA lesions being a SOS - system call
Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.

Science.gov (United States)

Eichner, Ruth; Heider, Michael; Fernández-Sáiz, Vanesa; van Bebber, Frauke; Garz, Anne-Kathrin; Lemeer, Simone; Rudelius, Martina; Targosz, Bianca-Sabrina; Jacobs, Laura; Knorn, Anna-Maria; Slawska, Jolanta; Platzbecker, Uwe; Germing, Ulrich; Langer, Christian; Knop, Stefan; Einsele, Herrmann; Peschel, Christian; Haass, Christian; Keller, Ulrich; Schmid, Bettina; Götze, Katharina S; Kuster, Bernhard; Bassermann, Florian

2016-07-01

Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.
Activated human neutrophils release hepatocyte growth factor/scatter factor.

LENUS (Irish Health Repository)

McCourt, M

2012-02-03

BACKGROUND: Hepatocyte growth factor or scatter factor (HGF\\/SF) is a pleiotropic cytokine that has potent angiogenic properties. We have previously demonstrated that neutrophils (PMN) are directly angiogenic by releasing vascular endothelial growth factor (VEGF). We hypothesized that the acute inflammatory response can stimulate PMN to release HGF. AIMS: To examine the effects of inflammatory mediators on PMN HGF release and the effect of recombinant human HGF (rhHGF) on PMN adhesion receptor expression and PMN VEGF release. METHODS: In the first experiment, PMN were isolated from healthy volunteers and stimulated with tumour necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), interleukin-8 (IL-8), and formyl methionyl-leucyl-phenylalanine (fMLP). Culture supernatants were assayed for HGF using ELISA. In the second experiment, PMN were lysed to measure total HGF release and HGF expression in the PMN was detected by Western immunoblotting. Finally, PMN were stimulated with rhHGF. PMN CD 11a, CD 11b, and CD 18 receptor expression and VEGF release was measured using flow cytometry and ELISA respectively. RESULTS: TNF-alpha, LPS and fMLP stimulation resulted in significantly increased release of PMN HGF (755+\\/-216, 484+\\/-221 and 565+\\/-278 pg\\/ml, respectively) compared to controls (118+\\/-42 pg\\/ml). IL-8 had no effect. Total HGF release following cell lysis and Western blot suggests that HGF is released from intracellular stores. Recombinant human HGF did not alter PMN adhesion receptor expression and had no effect on PMN VEGF release. CONCLUSIONS: This study demonstrates that pro-inflammatory mediators can stimulate HGF release from a PMN intracellular store and that activated PMN in addition to secreting VEGF have further angiogenic potential by releasing HGF.
Pathoadaptation of a Human Pathogen Through Non-Coding Intergenic Mutations

DEFF Research Database (Denmark)

Khademi, Seyed Mohammad Hossein

in CF adaptation of P. aeruginosa and their expressions are altered by the mutation. It was established that mutations upstream ampR increased tolerance of P. aeruginosa to some β-lactam antibiotics. Mutations in promoter of phuR, encoding receptor of pseudomonas heme uptake system, conferred growth...... advantage in the presence of hemoglobin demonstrating that P. aeruginosa has adapted towards utilization of iron from hemoglobin. Further investigation of phuR promoter mutation revealed pleiotropic effects on expression of many other genes. The pleiotropic effect by this mutation was contingent...
Resveratrol strongly enhances the retinoic acid-induced superoxide generating activity via up-regulation of gp91-phox gene expression in U937 cells.

Science.gov (United States)

Kikuchi, Hidehiko; Mimuro, Hitomi; Kuribayashi, Futoshi

2018-01-01

The membrane bound cytochrome b 558 composed of gp91-phox and p22-phox proteins, and cytosolic proteins p40-, p47-and p67-phox are important components of superoxide (O 2 - )-generating system in phagocytes. Here, we describe that resveratrol, a pleiotropic phytochemical belonging to the stilbenoids, dramatically activates the O 2 - -generating system during retinoic acid (RA)-induced differentiation of human monoblastic leukemia U937 cells to macrophage-like cells. When U937 cells were cultured in the presence of RA and resveratrol, the O 2 - -generating activity increased more than 5-fold compared with that in the absence of the latter. Semiquantitative RT-PCR showed that co-treatment with RA and resveratrol strongly enhanced transcription of the gp91-phox compared with those of the RA-treatment only. On the other hand, immunoblot analysis revealed that co-treatment with RA and resveratrol caused remarkable accumulation of protein levels of gp91-phox (to 4-fold), p22-phox (to 5-fold) and p47-phox (to 4-fold) compared with those of the RA-treatment alone. In addition, ChIP assay suggested that resveratrol participates in enhancing the gene expression of gp91-phox via promoting acetylation of Lys-9 residues and Lys-14 residues of histone H3 within chromatin around the promoter regions of the gene. These results suggested that resveratrol strongly enhances the RA-induced O 2 - -generating activity via up-regulation of gp91-phox gene expression in U937 cells. Copyright © 2017 Elsevier Inc. All rights reserved.
Pleiotropic consequences of misexpression of the developmentally ...

Indian Academy of Sciences (India)

Author Affiliations. Moushami Mallik1 2 Subhash C Lakhotia1. Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi 221 005, India; Molecular Neurogenetics Laboratory, Max-Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149 Muenster, Germany ...
Pleiotropic genes for metabolic syndrome and inflammation

DEFF Research Database (Denmark)

Kraja, Aldi T; Chasman, Daniel I; North, Kari E

2014-01-01

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factor...
The Pleiotropic Effect of Physical Exercise on Mitochondrial Dynamics in Aging Skeletal Muscle

Directory of Open Access Journals (Sweden)

Elena Barbieri

2015-01-01

Full Text Available Decline in human muscle mass and strength (sarcopenia is one of the principal hallmarks of the aging process. Regular physical exercise and training programs are certain powerful stimuli to attenuate the physiological skeletal muscle alterations occurring during aging and contribute to promote health and well-being. Although the series of events that led to these muscle adaptations are poorly understood, the mechanisms that regulate these processes involve the “quality” of skeletal muscle mitochondria. Aerobic/endurance exercise helps to maintain and improve cardiovascular fitness and respiratory function, whereas strength/resistance-exercise programs increase muscle strength, power development, and function. Due to the different effect of both exercises in improving mitochondrial content and quality, in terms of biogenesis, dynamics, turnover, and genotype, combined physical activity programs should be individually prescribed to maximize the antiaging effects of exercise.

Putative role of glycogen as a peripheral biomarker of GSK3β activity.

Science.gov (United States)

Frizzo, Marcos Emilio

2013-09-01

Glycogen synthase kinase 3-β (GSK3β) has a pivotal role in several intracellular signaling cascades that are involved in gene transcription, cytoskeletal reorganization, energy metabolism, cell cycle regulation, and apoptosis. This kinase has pleiotropic functions, and the importance of its activity has recently been shown in neurons and platelets. In addition to its regulatory function in several physiological events, changes in GSK3β activity have been associated with many psychiatric and neurodegenerative illnesses, such as Alzheimer's disease, schizophrenia and autism-spectrum disorders. Beside the reports of its involvement in several pathologies, it has become increasingly apparent that GSK3β might be a common therapeutic target for different classes of psychiatric drugs, and also that the GSK3β ratio may be a useful parameter to determine the biochemical changes that might occur during antidepressant treatment. Although GSK3β is commonly described as a key enzyme in a plethora of signaling cascades, originally it was identified as playing an important role in the regulation of glycogen synthesis, given its ability to inactivate glycogen synthase (GS) by phosphorylation. Acting as a constitutively active kinase, GSK3β phosphorylates GS, which results in a decrease of glycogen production. GSK3β phosphorylation increases glycogen synthesis and storage, while its dephosphorylation decreases glycogen synthesis. Inactivation of GSK3β leads to dephosphorylation of GS and increase in glycogen synthesis in the adipose tissue, muscle and liver. Glycogen levels are reduced by antidepressant treatment, and this effect seems to be related to an effect of drugs on GSK3β activity. Peripherally, glycogen is also abundantly found in platelets, where it is considered a major energy source, required for a variety of its functions, including the release reaction. Recently, analysis of platelets from patients with late-life major depression showed that active forms of
The λ prophage induction in lysogens E.coli by exposure to ionizing radiation of different LET

International Nuclear Information System (INIS)

Bonev, M.N.; Kozubek, S.; Krasavin, E.A.; Cherevatenko, A.P.

1988-01-01

The dependence of λ prophage induction on the dose I(D) in lysogens of E.coli irradiated by ionizing radiation with different LET(L) has been investigated. The role of the balance of pleiotropic activities of RecA protein has been analysed. The expermental data were fitted by the function I(D)αD(1-exp(-D 0 -1 D))exp(-βD). The increase of induction potency α with increasing L was connected with increasing production of DNA lesions which are a signal for the SOS-system induction
NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions

International Nuclear Information System (INIS)

Madhyastha, Radha; Madhyastha, HarishKumar; Pengjam, Yutthana; Nakajima, Yuichi; Omura, Sayuri; Maruyama, Masugi

2014-01-01

Highlights: • Transforming growth factor beta 1 (TGFβ1) induces miR-21 in high glucose conditions. • NFkappaB activation and subsequent ROS generation are necessary for TGFβ1’s effect. • TGFβ1 facilitates binding of NFkB p65 to miR-21 promoter. • SMAD proteins bind to R-SBE sites on primary miR-21, in NFkB dependent manner. - Abstract: Transforming growth factor beta1 (TGFβ1) is a pleiotropic growth factor with a very broad spectrum of effects on wound healing. Chronic non-healing wounds such as diabetic foot ulcers express reduced levels of TGFβ1. On the other hand, our previous studies have shown that the microRNA miR-21 is differentially regulated in diabetic wounds and that it promotes migration of fibroblast cells. Although interplay between TGFβ1 and miR-21 are studied in relation to cancer, their interaction in the context of chronic wounds has not yet been investigated. In this study, we examined if TGFβ1 could stimulate miR-21 in fibroblasts that are subjected to high glucose environment. MiR-21 was, in fact, induced by TGFβ1 in high glucose conditions. The induction by TGFβ1 was dependent on NFκB activation and subsequent ROS generation. TGFβ1 was instrumental in degrading the NFκB inhibitor IκBα and facilitating the nuclear translocation of NFκB p65 subunit. EMSA studies showed enhanced DNA binding activity of NFκB in the presence of TGFβ1. ChIP assay revealed binding of p65 to miR-21 promoter. NFκB activation was also required for the nuclear translocation of Smad 4 protein and subsequent direct interaction of Smad proteins with primary miR-21 as revealed by RNA-IP studies. Our results show that manipulation of TGFβ1–NFκB–miR-21 pathway could serve as an innovative approach towards therapeutics to heal diabetic ulcers
NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions

Energy Technology Data Exchange (ETDEWEB)

Madhyastha, Radha, E-mail: radharao@med.miyazaki-u.ac.jp; Madhyastha, HarishKumar; Pengjam, Yutthana; Nakajima, Yuichi; Omura, Sayuri; Maruyama, Masugi

2014-09-05

Highlights: • Transforming growth factor beta 1 (TGFβ1) induces miR-21 in high glucose conditions. • NFkappaB activation and subsequent ROS generation are necessary for TGFβ1’s effect. • TGFβ1 facilitates binding of NFkB p65 to miR-21 promoter. • SMAD proteins bind to R-SBE sites on primary miR-21, in NFkB dependent manner. - Abstract: Transforming growth factor beta1 (TGFβ1) is a pleiotropic growth factor with a very broad spectrum of effects on wound healing. Chronic non-healing wounds such as diabetic foot ulcers express reduced levels of TGFβ1. On the other hand, our previous studies have shown that the microRNA miR-21 is differentially regulated in diabetic wounds and that it promotes migration of fibroblast cells. Although interplay between TGFβ1 and miR-21 are studied in relation to cancer, their interaction in the context of chronic wounds has not yet been investigated. In this study, we examined if TGFβ1 could stimulate miR-21 in fibroblasts that are subjected to high glucose environment. MiR-21 was, in fact, induced by TGFβ1 in high glucose conditions. The induction by TGFβ1 was dependent on NFκB activation and subsequent ROS generation. TGFβ1 was instrumental in degrading the NFκB inhibitor IκBα and facilitating the nuclear translocation of NFκB p65 subunit. EMSA studies showed enhanced DNA binding activity of NFκB in the presence of TGFβ1. ChIP assay revealed binding of p65 to miR-21 promoter. NFκB activation was also required for the nuclear translocation of Smad 4 protein and subsequent direct interaction of Smad proteins with primary miR-21 as revealed by RNA-IP studies. Our results show that manipulation of TGFβ1–NFκB–miR-21 pathway could serve as an innovative approach towards therapeutics to heal diabetic ulcers.
Listeria monocytogenes en alimentos: ¿son todos los aislamientos igual de virulentos? Foodborne Listeria monocytogenes: are all the isolates equally virulent?

Directory of Open Access Journals (Sweden)

V. López

2006-12-01

Full Text Available Listeria monocytogenes es un patógeno humano que se transmite a través de los alimentos y que causa infecciones graves, con una alta tasa de mortalidad. A pesar de la ubicuidad del microorganismo, la tasa real de la enfermedad es bastante baja y se asocia casi siempre a condiciones predisponentes. Tradicionalmente se consideraba que los aislamientos presentes en los alimentos y en el ambiente tenían la misma capacidad patogénica que los aislamientos de origen clínico. Pero el análisis de mutaciones en los genes de determinados factores de virulencia (internalina, hemolisina, fosfolipasas, proteína de superficie ActA y proteína reguladora PrfA, los estudios cuantitativos realizados con cultivos celulares y la genética de poblaciones, están replanteando la discusión sobre la variabilidad de la virulencia de L. monocytogenes. A pesar de todos estos avances, no existe un único marcador que permita comprobar la virulencia de los aislamientos naturales de esta especie. Probablemente en el futuro, la combinación de diferentes marcadores moleculares permitirá detectar los alimentos contaminados sólo por los clones virulentos de L. monocytogenes, con lo que se mejorará la prevención de la listeriosis humana transmitida por alimentos.Listeria monocytogenes is a foodborne human pathogen responsible for invasive infections presenting overall a high mortality. Despite the ubiquity of the microorganism, the actual disease rate is quite low and the disease is most often associated with an underlying predisposition. Foodborne and environmental isolates were traditionally considered of similar pathogenicity compared to clinical isolates. But the analysis of mutations in the genes encoding specific virulence factors (internalin, hemolysin, phospholipases, surface protein ActA and regulator protein PrfA, quantitative studies with cell cultures and population genetics have raised considerable concerns about virulence differences among L
An Expanded Role for the RFX Transcription Factor DAF-19, with Dual Functions in Ciliated and Nonciliated Neurons.

Science.gov (United States)

De Stasio, Elizabeth A; Mueller, Katherine P; Bauer, Rosemary J; Hurlburt, Alexander J; Bice, Sophie A; Scholtz, Sophie L; Phirke, Prasad; Sugiaman-Trapman, Debora; Stinson, Loraina A; Olson, Haili B; Vogel, Savannah L; Ek-Vazquez, Zabdiel; Esemen, Yagmur; Korzynski, Jessica; Wolfe, Kelsey; Arbuckle, Bonnie N; Zhang, He; Lombard-Knapp, Gaelen; Piasecki, Brian P; Swoboda, Peter

2018-03-01

Regulatory Factor X (RFX) transcription factors (TFs) are best known for activating genes required for ciliogenesis in both vertebrates and invertebrates. In humans, eight RFX TFs have a variety of tissue-specific functions, while in the worm Caenorhabditis elegans , the sole RFX gene, daf-19 , encodes a set of nested isoforms. Null alleles of daf-19 confer pleiotropic effects including altered development with a dauer constitutive phenotype, complete absence of cilia and ciliary proteins, and defects in synaptic protein maintenance. We sought to identify RFX/ daf-19 target genes associated with neuronal functions other than ciliogenesis using comparative transcriptome analyses at different life stages of the worm. Subsequent characterization of gene expression patterns revealed one set of genes activated in the presence of DAF-19 in ciliated sensory neurons, whose activation requires the daf-19c isoform, also required for ciliogenesis. A second set of genes is downregulated in the presence of DAF-19, primarily in nonsensory neurons. The human orthologs of some of these neuronal genes are associated with human diseases. We report the novel finding that daf-19a is directly or indirectly responsible for downregulation of these neuronal genes in C. elegans by characterizing a new mutation affecting the daf-19a isoform ( tm5562 ) and not associated with ciliogenesis, but which confers synaptic and behavioral defects. Thus, we have identified a new regulatory role for RFX TFs in the nervous system. The new daf-19 candidate target genes we have identified by transcriptomics will serve to uncover the molecular underpinnings of the pleiotropic effects that daf-19 exerts on nervous system function. Copyright © 2018 by the Genetics Society of America.
Peroxisome proliferator-binding protein: identification and partial characterization of nafenopin-, clofibric acid-, and ciprofibrate-binding proteins from rat liver.

Science.gov (United States)

Lalwani, N D; Alvares, K; Reddy, M K; Reddy, M N; Parikh, I; Reddy, J K

1987-01-01

Peroxisome proliferators (PP) induce a highly predictable pleiotropic response in rat and mouse liver that is characterized by hepatomegaly, increase in peroxisome number in hepatocytes, and induction of certain peroxisomal enzymes. The PP-binding protein (PPbP) was purified from rat liver cytosol by a two-step procedure involving affinity chromatography and ion-exchange chromatography. Three PP, nafenopin and its structural analogs clofibric acid and ciprofibrate, were used as affinity ligands and eluting agents. This procedure yields a major protein with an apparent Mr of 70,000 on NaDodSO4/PAGE in the presence of reducing agent and Mr 140,000 (Mr 140,000-160,000) on gel filtration and polyacrylamide gradient gel electrophoresis under nondenaturing conditions, indicating that the active protein is a dimer. This protein has an acidic pI of 4.2 under nondenaturing conditions, which rises to 5.6 under denaturing conditions. The isolation of the same Mr 70,000 protein with three different, but structurally related, agents as affinity ligands and the immunological identity of the isolated proteins constitute strong evidence that this protein is the PPbP capable of recognizing PP that are structurally related to clofibrate. The PPbP probably plays an important role in the regulation of PP-induced pleiotropic response. Images PMID:3474650
Comparison of ALS functionality and plant growth in ALS-inhibitor susceptible and resistant Myosoton aquaticum L.

Science.gov (United States)

Liu, Weitang; Bai, Shuang; Jia, Sisi; Guo, Wenlei; Zhang, Lele; Li, Wei; Wang, Jinxin

2017-10-01

Herbicide target-site resistance mutations may cause pleiotropic effects on plant ecology and physiology. The effect of several known (Pro197Ser, Pro197Leu Pro197Ala, and Pro197Glu) target-site resistance mutations of the ALS gene on both ALS functionality and plant vegetative growth of weed Myosoton aquaticum L. (water chickweed) have been investigated here. The enzyme kinetics of ALS from four purified water chickweed populations that each homozygous for the specific target-site resistance-endowing mutations were characterized and the effect of these mutations on plant growth was assessed via relative growth rate (RGR) analysis. Plants homozygous for Pro197Ser and Pro197Leu exhibited higher extractable ALS activity than susceptible (S) plants, while all ALS mutations with no negative change in ALS kinetics. The Pro197Leu mutation increased ALS sensitivity to isoleucine and valine, and Pro197Glu mutation slightly increased ALS sensitivity to isoleucine. RGR results indicated that none of these ALS resistance mutations impose negative pleiotropic effects on relative growth rate. However, resistant (R) seeds had a lowed germination rate than S seeds. This study provides baseline information on ALS functionality and plant growth characteristics associated with ALS inhibitor resistance-endowing mutations in water chickweed. Copyright © 2017. Published by Elsevier Inc.
BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis.

Science.gov (United States)

Pediaditakis, Iosif; Kourgiantaki, Alexandra; Prousis, Kyriakos C; Potamitis, Constantinos; Xanthopoulos, Kleanthis P; Zervou, Maria; Calogeropoulou, Theodora; Charalampopoulos, Ioannis; Gravanis, Achille

2016-01-01

Neurotrophin receptors mediate a plethora of signals affecting neuronal survival. The p75 pan-neurotrophin receptor controls neuronal cell fate after its selective activation by immature and mature isoforms of all neurotrophins. It also exerts pleiotropic effects interacting with a variety of ligands in different neuronal or non-neuronal cells. In the present study, we explored the biophysical and functional interactions of a blood-brain-barrier (BBB) permeable, C17-spiroepoxy steroid derivative, BNN27, with p75 NTR receptor. BNN27 was recently shown to bind to NGF high-affinity receptor, TrkA. We now tested the p75 NTR -mediated effects of BNN27 in mouse Cerebellar Granule Neurons (CGNs), expressing p75 NTR , but not TrkA receptors. Our findings show that BNN27 physically interacts with p75 NTR receptors in specific amino-residues of its extracellular domain, inducing the recruitment of p75 NTR receptor to its effector protein RIP2 and the simultaneous release of RhoGDI in primary neuronal cells. Activation of the p75 NTR receptor by BNN27 reverses serum deprivation-induced apoptosis of CGNs resulting in the decrease of the phosphorylation of pro-apoptotic JNK kinase and of the cleavage of Caspase-3, effects completely abolished in CGNs, isolated from p75 NTR null mice. In conclusion, BNN27 represents a lead molecule for the development of novel p75 NTR ligands, controlling specific p75 NTR -mediated signaling of neuronal cell fate, with potential applications in therapeutics of neurodegenerative diseases and brain trauma.
Neuro, cardio, and reno protective activities of rosuvastatin in streptozotocin-induced type 2 diabetic rats undergoing treatment with metformin and glimepiride

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Shailaja Rondi

2014-01-01

Full Text Available Diabetes is associated with complications like neuropathy, nephropathy, cardiomyopathy, and retinopathy due to increased oxidative stress and serum lipids. In the present study, rosuvastatin, a HMG-CoA inhibitor, was investigated for its protective effect in neuropathy, nephropathy, and cardiomyopathy based on the lipid-lowering property along with its pleiotropic effects such as improved blood flow to the organ and antioxidant defense. Type 2 diabetes was induced in Wistar rats by single i.p. administration of streptozotocin (50 mg/kg. These diabetic rats were treated with daily doses of rosuvastatin (10 mg/kg alone, metformin (120 mg/kg and glimepiride (1 mg/kg and rosuvastatin in combination with metformin (120 mg/kg and glimepiride (1 mg/kg for a period of 6 weeks. The biochemical parameters involved in neuropathy, renopathy, and cardiopathy were estimated. Treatment resulted in significant (P < 0.05 decrease in thiobarbituric acid reactive substances (TBARS and increase in levels of glutathione peroxidise and catalase in brain and kidney homogenates. Significant (P < 0.05 increase in high-density lipoproteins and decrease in creatinine kinase, triglycerides, total serum cholesterol represents the cardioprotective action, whereas significant (P < 0.05 increase in the latency in the hotplate model shows the neuroprotective activity, and significant (P < 0.05 decrease in blood urea nitrogen, creatinine levels and increase in serum total protein levels suggested the renoprotective actions. The unique properties of rosuvastatin such as antioxidant defense and lipid-lowering nature might have resulted in cardio, neuro, and renoprotective activity in type 2 diabetic rats treated with metformin and glimepiride.
Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.

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Yuki Enoki

Full Text Available Reactive oxygen species (ROS and nitric oxide (NO are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX, one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1 influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress and nitrotyrosine (a nitrative marker in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites and IFN-γ in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.
The intrinsic cephalosporin resistome of Listeria monocytogenes in the context of stress response, gene regulation, pathogenesis and therapeutics.

Science.gov (United States)

Krawczyk-Balska, A; Markiewicz, Z

2016-02-01

Intrinsic resistance to antibiotics is a serious therapeutic problem in the case of many bacterial species. The Gram-positive human pathogen Listeria monocytogenes is intrinsically resistant to broad spectrum cephalosporin antibiotics, which are commonly used in therapy of bacterial infections. Besides three penicillin-binding proteins the intrinsic cephalosporin resistome of L. monocytogenes includes multidrug resistance transporter transporters, proteins involved in peptidoglycan biosynthesis and modification, cell envelope proteins with structural or general detoxification function, cytoplasmic proteins with unknown function and regulatory proteins. Analysis of the regulation of the expression of genes involved in the intrinsic resistance of L. monocytogenes to cephalosporins highlights the high complexity of control of the intrinsic resistance phenotype. The regulation of the transcription of the intrinsic resistome determinants involves the activity of eight regulators, namely LisR, CesR, LiaR, VirR, σ(B) , σ(H) , σ(L) and PrfA, of which the most prominent role play LisR, CesR and σ(B) . Furthermore, the vast majority of the intrinsic resistome determinants contribute to the tolerance of different stress conditions and virulence. A study indicates that O-acetyltransferase OatA is the most promising candidate for co-drug development since an agent targeting OatA should sensitize L. monocytogenes to certain antibiotics, therefore improving the efficacy of listeriosis treatment as well as food preservation measures. © 2015 The Society for Applied Microbiology.
IL-1RI (Interleukin-1 Receptor Type I Signalling is Essential for Host Defence and Hemichannel Activity During Acute Central Nervous System Bacterial Infection

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Juan Xiong

2012-03-01

Full Text Available Staphylococcus aureus is a common aetiological agent of bacterial brain abscesses. We have previously established that a considerable IL-1 (interleukin-1 response is elicited immediately following S. aureus infection, where the cytokine can exert pleiotropic effects on glial activation and blood–brain barrier permeability. To assess the combined actions of IL-1α and IL-1β during CNS (central nervous system infection, host defence responses were evaluated in IL-1RI (IL-1 receptor type I KO (knockout animals. IL-1RI KO mice were exquisitely sensitive to intracerebral S. aureus infection, as demonstrated by enhanced mortality rates and bacterial burdens within the first 24 h following pathogen exposure compared with WT (wild-type animals. Loss of IL-1RI signalling also dampened the expression of select cytokines and chemokines, concomitant with significant reductions in neutrophil and macrophage infiltrates into the brain. In addition, the opening of astrocyte hemichannels during acute infection was shown to be dependent on IL-1RI activity. Collectively, these results demonstrate that IL-1RI signalling plays a pivotal role in the genesis of immune responses during the acute stage of brain abscess development through S. aureus containment, inflammatory mediator production, peripheral immune cell recruitment, and regulation of astrocyte hemichannel activity. Taken in the context of previous studies with MyD88 (myeloid differentiation primary response gene 88 and TLR2 (Toll-like receptor 2 KO animals, the current report advances our understanding of MyD88-dependent cascades and implicates IL-1RI signalling as a major antimicrobial effector pathway during acute brain-abscess formation.
Bisphosphonates as potential adjuvants for patients with cancers of the digestive system.

Science.gov (United States)

Ang, Celina; Doyle, Erin; Branch, Andrea

2016-01-21

Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.
Novel leads from Heliotropium ovalifolium, 4,7,8-trimethoxy-naphthalene-2-carboxylic acid and 6-hydroxy-5,7-dimethoxy-naphthalene-2-carbaldehyde show specific IL-6 inhibitory activity in THP-1 cells and primary human monocytes.

Science.gov (United States)

Kulkarni-Almeida, Asha; Suthar, Ashish; Goswami, Hitesh; Vishwakarma, Ram; Chauhan, Vijay Singh; Balakrishnan, Arun; Sharma, Somesh

2008-12-01

From our screening program, we identified the anti-inflammatory effects of the extracts of Heliotropium ovalifolium in its ability to inhibit specific cytokines. The H. ovalifolium extract was found to be moderately active with an IC(50) equaling 10 microg/ml for inhibition of interleukin-6 (IL-6) in a human monocytic cell line. Interleukin-6 is a pleiotropic cytokine with implications in the regulation of the immune response, inflammation and hematopoiesis. This prompted us to examine and identify the active molecules that are responsible for the bioactivity in THP-1 cells. Bioassay guided fractionation identified two compounds 4,7,8-trimethoxy-naphthalene-2-carboxylic acid and 6-hydroxy-5,7-dimethoxy-naphthalene-2-carbaldehyde with an IC(50) of 2.4 and 2.0 microM for IL-6 inhibition and an IC(50) of 15.6 and 7.0 microM for tumor necrosis factor-alpha (TNF-alpha) inhibition in THP-1 cells. The protein expression data were supported by the inhibitory effect on mRNA gene expression. The compounds isolated from H. ovalifolium were also non-toxic in human peripheral blood monocytes from normal donors and the activity profile was similar to that obtained on THP-1 cells. Thus, we believe that these scaffolds may be of interest to develop leads for treating rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease and other inflammatory disorders. However, more detailed investigations need to be carried out to explain the efficacy of these compounds as drugs.
Activated type I TGFbeta receptor (Alk5) kinase confers enhancedsurvival to mammary epithelial cells and accelerates mammary tumorprogression

Energy Technology Data Exchange (ETDEWEB)

Muraoka-Cook, Rebecca S.; Shin, Incheol; Yi, Jae Youn; Easterly,Evangeline; Barcellos-Hoff, Mary Helen; Yingling, Jonathan M.; Zent, Roy; Arteaga, Carlos L.

2005-01-02

The transforming growth factor-betas (TGF{beta}s) are members of a large superfamily of pleiotropic cytokines that also includes the activins and the bone morphogenetic proteins (BMPs). Members of the TGF{beta} family regulate complex physiological processes such cell proliferation, differentiation, adhesion, cell-cell and cell-matrix interactions, motility, and cell death, among others (Massague, 1998). Dysregulation of TGF{beta} signaling contributes to several pathological processes including cancer, fibrosis, and auto-immune disorders (Massague et al., 2000). The TGF{beta}s elicit their biological effects by binding to type II and type I transmembrane receptor serine-threonine kinases (T{beta}RII and T{beta}RI) which, in turn, phosphorylated Smad 2 and Smad 3. Phosphorylated Smad 2/3 associate with Smad 4 and, as a heteromeric complex, translocate to the nucleus where they regulate gene transcription. The inhibitory Smad7 down regulates TGF{beta} signaling by binding to activated T{beta}RI and interfering with its ability to phosphorylate Smad 2/3 (Derynck and Zhang, 2003; Shi and Massague, 2003). Signaling is also regulated by Smad proteolysis. TGF{beta} receptor-mediated activation results in multi-ubiquitination of Smad 2 in the nucleus and subsequent degradation of Smad 2 by the proteasome (Lo and Massague, 1999). Activation of TGF{beta} receptors also induces mobilization of a Smad 7-Smurf complex from the nucleus to the cytoplasm; this complex recognizes the activated receptors and mediates their ubiquitination and internalization via caveolin-rich vesicles, leading to termination of TGF{beta} signaling (Di Guglielmo et al., 2003). Other signal transducers/pathways have been implicated in TGF{beta} actions. These include the extracellular signal-regulated kinase (Erk), c-Jun N-terminal kinase (Jnk), p38 mitogen-activated protein kinase (MAPK), protein phosphatase PP2A, phosphatidylinositol-3 kinase (PI3K), and the family of Rho GTPases [reviewed in
The role of tumor necrosis factor-α and TNF-α receptors in cerebral arteries following cerebral ischemia in rat

DEFF Research Database (Denmark)

Maddahi, Aida; Kruse, Lars S; Chen, Qing-Wen

2011-01-01

Tumour necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine, which is rapidly upregulated in the brain after injury. TNF-α acts by binding to its receptors, TNF-R1 (p55) and TNF-R2 (p75), on the cell surface. The aim of this study was first to investigate if there is altered expre...... expression of TNF-α and TNF-α receptors in cerebral artery walls following global or focal ischemia, and after organ culture. Secondly, we asked if the expression was regulated via activation of the MEK-ERK1/2 pathway....
The role of tumor necrosis factor-α and TNF-α receptors in cerebral arteries following cerebral ischemia in rat

DEFF Research Database (Denmark)

Maddahi, Aida; Kruse, Lars S; Chen, Qing-Wen

2011-01-01

Tumour necrosis factor-a (TNF-a) is a pleiotropic pro-inflammatory cytokine, which is rapidly upregulated in the brain after injury. TNF-a acts by binding to its receptors, TNF-R1 (p55) and TNF-R2 (p75), on the cell surface. The aim of this study was first to investigate if there is altered expre...... expression of TNF-a and TNF-a receptors in cerebral artery walls following global or focal ischemia, and after organ culture. Secondly, we asked if the expression was regulated via activation of the MEK-ERK1/2 pathway....
Mutational analysis and genetic cloning of the agnostic locus, which regulates learning ability in Drosophila.

Science.gov (United States)

Peresleni, A I; Savvateeva, E V; Peresleni, I V; Sharagina, L M

1997-01-01

P-insertion mutations were obtained and localized by in situ methods at the agnostic gene (agn: 1-38.9; 11AB) in Drosophila. All agn mutants showed a wide spectrum of pleiotropic effects: an EMS-induced mutation of the agn-ts398 improved the ability to develop a conditioned defensive response and increased the activity of cAMP metabolic enzymes; spontaneous mutation of agnX1 showed morphological defects of the brain. P-insertion mutations were used to clone the gene; a restriction map of 80 kb in length was determined, and the insertion was localized to a fragment of 9 kb.
Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.

Science.gov (United States)

Lau, Colleen M; Nish, Simone A; Yogev, Nir; Waisman, Ari; Reiner, Steven L; Reizis, Boris

2016-03-07

A common genetic alteration in acute myeloid leukemia is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L). Constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of classical DCs (cDCs) and plasmacytoid DCs. The expansion originated in DC progenitors, was cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice. The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Both canonical Batf3-dependent CD8(+) cDCs and noncanonical CD8(+) cDCs were expanded and showed specific alterations in their expression profiles. Flt3(ITD) mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T (T reg) cells. Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity without T reg cells. Thus, the FLT3-ITD mutation directly affects DC development, indirectly modulating T cell homeostasis and supporting T reg cell expansion. We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. © 2016 Lau et al.

Effect of co-culture with enterocinogenic E. faecium on L. monocytogenes key virulence gene expression

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Eleftherios H. Drosinos

2016-08-01

Full Text Available The aim of the present study was to assess the expression of key virulence genes during co-culture of L. monocytogenes with a bacteriocinogenic E. faecium strain in liquid growth medium. For that purpose, BHI broth was inoculated with 7 log CFU·mL–1 L. monocytogenes and 4, 5 or 6 log CFU·mL–1 E. faecium. Sampling took place after 8 and 24 h of incubation, corresponding to the maximum and minimum of enterocin production, respectively. The RNA was extracted, stabilized and expression of prfA, sigB, hly, plcA, plcB, inlA, inlB, inlC and inlJ, was assessed by RT-qPCR. Most of the genes were downregulated during co-culture at 5 °C. Moreover, a statistically significant effect of the inoculum level was evident in most of the cases. On the contrary, no effect on the transcription level of most of the genes was observed during co-culture at 37 °C.
Pleiotropic Effects of Thyroid Hormones: Learning from Hypothyroidism

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Martha Franco

2011-01-01

Full Text Available Hypothyroidism induces several metabolic changes that allow understanding some physiopathological mechanisms. Under experimental hypothyroid conditions in rats, heart and kidney are protected against oxidative damage induced by ischemia reperfusion. An increased resistance to opening of the permeability transition pore seems to be at the basis of such protection. Moreover, glomerular filtration rate of hypothyroid kidney is low as a result of adenosine receptors-induced renal vasoconstriction. The vascular tone of aorta is also regulated by adenosine in hypothyroid conditions. In other context, thyroid hormones regulate lipoprotein metabolism. High plasma level of LDL cholesterol is a common feature in hypothyroidism, due to a low expression of the hepatic LDL receptor. In contrast, HDL-cholesterol plasma levels are variable in hypothyroidism; several proteins involved in HDL metabolism and structure are expressed at lower levels in experimental hypothyroidism. Based on the positive influence of thyroid hormones on lipoprotein metabolism, thyromimetic drugs are promising for the treatment of dyslipidemias. In summary, hypothyroid status has been useful to understand molecular mechanisms involved in ischemia reperfusion, regulation of vascular function and intravascular metabolism of lipoproteins.
Pleiotropic phenotypes of the salt-tolerant and cytosine ...

Indian Academy of Sciences (India)

2SKA Institution for Research, Education and Development (SKAIRED), 4/11 Sarv Priya Vihar, ... wild-type parent cv Nirmal were characterized for overall cytosine methylation at .... (ii) altered in the expression of genes involved in the perfor-.
Pleiotropic function of ezrin in human metastatic melanomas.

Science.gov (United States)

Federici, Cristina; Brambilla, Daria; Lozupone, Francesco; Matarrese, Paola; de Milito, Angelo; Lugini, Luana; Iessi, Elisabetta; Cecchetti, Serena; Marino, Marialucia; Perdicchio, Maurizio; Logozzi, Mariantonia; Spada, Massimo; Malorni, Walter; Fais, Stefano

2009-06-15

The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors. Copyright 2008 UICC.
Pleiotropic phenotypes of the salt-tolerant and cytosine ...

Indian Academy of Sciences (India)

of Catharanthus roseus possessing Mendelian inheritance. Renu Kumari, Vishakha ...... Bowman J. L. 2004 Class III HD-Zip gene regulation, the golden fleece of .... Arabidopsis has multiple effects on plant development, includ- ing early flowering and .... germination is revealed by the misexpression of a homologous gene ...
Pleiotropic Mechanisms Indicated for Sex Differences in Autism.

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Ileena Mitra

2016-11-01

Full Text Available Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs. Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.
Attenuated, oncolytic, but not wild-type measles virus infection has pleiotropic effects on human neutrophil function.

Science.gov (United States)

Zhang, Yu; Patel, Bella; Dey, Aditi; Ghorani, Ehsan; Rai, Lena; Elham, Mohammed; Castleton, Anna Z; Fielding, Adele K

2012-02-01

We previously showed that neutrophils play a role in regression of human tumor xenografts in immunodeficient mice following oncolytic vaccine measles virus (MV-Vac) treatment. In this study, we sought, using normal human neutrophils, to identify potential neutrophil-mediated mechanisms for the attenuated MV-Vac induced effects seen in vivo, by comparison with those consequent on wild-type (WT-MV) infection. Both MV-Vac and WT-MV infected and replicated within neutrophils, despite lack of SLAM expression. In both cases, neutrophils survived longer ex vivo postinfection. Furthermore, MV-Vac (but not WT-MV) infection activated neutrophils and stimulated secretion of several specific antitumor cytokines (IL-8, TNF-α, MCP-1, and IFN-α) via induction of de novo RNA and protein synthesis. In addition, MV-Vac (but not WT-MV) infection caused TRAIL secretion in the absence of de novo synthesis by triggering release of prefabricated TRAIL, via a direct effect upon degranulation. The differences between the outcome of infection by MV-Vac and WT-MV were not entirely explained by differential infection and replication of the viruses within neutrophils. To our knowledge, this is the first demonstration of potential mechanisms of oncolytic activity of an attenuated MV as compared with its WT parent. Furthermore, our study suggests that neutrophils have an important role to play in the antitumor effects of oncolytic MV.
Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2

DEFF Research Database (Denmark)

Ueda, Takeshi; Nagamachi, Akiko; Takubo, Keiyo

2015-01-01

We previously reported deficiency for Samd9L, which was cloned as a candidate gene for -7/7q- syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further...... with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron specific gene family member 2 (Nsg2) and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved....... These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation....
Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects.

Directory of Open Access Journals (Sweden)

Christin Buro

2014-06-01

Full Text Available Schistosome parasites cause schistosomiasis, one of the most important infectious diseases worldwide. For decades Praziquantel (PZQ is the only drug widely used for controlling schistosomiasis. The absence of a vaccine and fear of PZQ resistance have motivated the search for alternatives. Studies on protein kinases (PKs demonstrated their importance for diverse physiological processes in schistosomes. Among others two Abl tyrosine kinases, SmAbl1 and SmAbl2, were identified in Schistosoma mansoni and shown to be transcribed in the gonads and the gastrodermis. SmAbl1 activity was blocked by Imatinib, a known Abl-TK inhibitor used in human cancer therapy (Gleevec/Glivec. Imatinib exhibited dramatic effects on the morphology and physiology of adult schistosomes in vitro causing the death of the parasites.Here we show modeling data supporting the targeting of SmAbl1/2 by Imatinib. A biochemical assay confirmed that SmAbl2 activity is also inhibited by Imatinib. Microarray analyses and qRT-PCR experiments were done to unravel transcriptional processes influenced by Imatinib in adult schistosomes in vitro demonstrating a wide influence on worm physiology. Surface-, muscle-, gut and gonad-associated processes were affected as evidenced by the differential transcription of e.g. the gynecophoral canal protein gene GCP, paramyosin, titin, hemoglobinase, and cathepsins. Furthermore, transcript levels of VAL-7 and egg formation-associated genes such as tyrosinase 1, p14, and fs800-like were affected as well as those of signaling genes including a ribosomal protein S6 kinase and a glutamate receptor. Finally, a comparative in silico analysis of the obtained microarray data sets and previous data analyzing the effect of a TGFβR1 inhibitor on transcription provided first evidence for an association of TGFβ and Abl kinase signaling. Among others GCP and egg formation-associated genes were identified as common targets.The data affirm broad negative effects of
Nitric oxide synthesis-promoting effects of valsartan in human umbilical vein endothelial cells via the Akt/adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway

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Yingshuai Zhao

2017-05-01

Full Text Available Valsartan (VAL, an antagonist of angiotensin II receptor type 1, has antihypertensive and multiple cardiovascular protective effects. The pleiotropic functions of VAL are related to the increased synthesis and biological activity of intravascular nitric oxide (NO. In this study, the role and mechanisms of VAL in the synthesis of NO were examined in human umbilical vein endothelial cells (HUVECs. Ten µmol/L of VAL was used to treat EA.hy926 cells for 30 minutes, 1, 3, 6, 12, and 24 hours, and three concentrations of VAL (i.e., 10, 1, and 0.1 µmol/L were used to treat EA.hy926 cells for 24 hours. The cells were divided into five groups: control, VAL, VAL + Compound C (adenosine monophosphate-activated protein kinase [AMPK] inhibitor, 1 µmol/L, VAL + LY294002 (Akt [protein kinase B] inhibitor, 10 µmol/L, and VAL + L-nitro-arginine methyl ester (L-NAME, endothelial NO synthase [eNOS] inhibitor, 500 µmol/L groups. The NO content in the VAL-treated HUVEC line (EA.hy926 was detected using the nitrate reductase method, and western blot was used to detect the phosphorylation of Akt, AMPK, and eNOS, as well as the changes in total protein levels. VAL increased NO synthesis in EA.hy926 cells in time- and dose-dependent manners (p < 0.05 and the intracellular phosphorylation levels of Akt, AMPK, and eNOS at the corresponding time points. LY294002, Compound C, and L-NAME could inhibit the VAL-promoted NO synthesis. VAL activated Akt, AMPK, and eNOS, thus promoting NO synthesis and playing a protective role in endothelial cells. These results partially explained the mechanisms underlying the cardiovascular protective effects of VAL.
The Role and Regulation of TNF-Alpha in Normal Rat Mammary Gland During Development and in Breast Cancer

National Research Council Canada - National Science Library

Varela, Linda

1998-01-01

The pleiotropic cytokine tumor necrosis factor-alpha (TNF) has previously been shown to regulate both the proliferation and differentiation of normal rat mammary epithelial cells (MEC) in primary culture...
Whole genome expression profiling associates activation of unfolded protein response with impaired production and release of epinephrine after recurrent hypoglycemia.

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Juhye Lena Kim

Full Text Available Recurrent hypoglycemia can occur as a major complication of insulin replacement therapy, limiting the long-term health benefits of intense glycemic control in type 1 and advanced type 2 diabetic patients. It impairs the normal counter-regulatory hormonal and behavioral responses to glucose deprivation, a phenomenon known as hypoglycemia associated autonomic failure (HAAF. The molecular mechanisms leading to defective counter-regulation are not completely understood. We hypothesized that both neuronal (excessive cholinergic signaling between the splanchnic nerve fibers and the adrenal medulla and humoral factors contribute to the impaired epinephrine production and release in HAAF. To gain further insight into the molecular mechanism(s mediating the blunted epinephrine responses following recurrent hypoglycemia, we utilized a global gene expression profiling approach. We characterized the transcriptomes during recurrent (defective counter-regulation model and acute hypoglycemia (normal counter-regulation group in the adrenal medulla of normal Sprague-Dawley rats. Based on comparison analysis of differentially expressed genes, a set of unique genes that are activated only at specific time points after recurrent hypoglycemia were revealed. A complementary bioinformatics analysis of the functional category, pathway, and integrated network indicated activation of the unfolded protein response. Furthermore, at least three additional pathways/interaction networks altered in the adrenal medulla following recurrent hypoglycemia were identified, which may contribute to the impaired epinephrine secretion in HAAF: greatly increased neuropeptide signaling (proenkephalin, neuropeptide Y, galanin; altered ion homeostasis (Na+, K+, Ca2+ and downregulation of genes involved in Ca2+-dependent exocytosis of secretory vesicles. Given the pleiotropic effects of the unfolded protein response in different organs, involved in maintaining glucose homeostasis, these
Statins and transcriptional regulation: The FXR connection

International Nuclear Information System (INIS)

Habeos, Ioannis; Ziros, Panos G.; Psyrogiannis, Agathoklis; Vagenakis, Apostolos G.; Papavassiliou, Athanasios G.

2005-01-01

Farnesoid X receptor (FXR) is a nuclear receptor involved in lipoprotein as well as glucose metabolism. Statins are widely used hypolipidemic agents with many pleiotropic actions. It is known that statins affect other nuclear hormone receptors, but no reports are available on the effect of these drugs on FXR. Employing an animal model (Syrian hamsters), we hereby present evidence to demonstrate that Simvastatin, a broadly prescribed statin, decreases the expression of FXR at both the RNA and protein levels and down-regulates its DNA-binding activity. This novel property may have important implications on the mode statins influence on lipoprotein and carbohydrate homeostasis in the organism
VEGF-independent angiogenic pathways induced by PDGF-C

Science.gov (United States)

Kumar, Anil; Zhang, Fan; Lee, Chunsik; Li, Yang; Tang, Zhongshu; Arjunan, Pachiappan

2010-01-01

VEGF is believed to be a master regulator in both developmental and pathological angiogenesis. The role of PDGF-C in angiogenesis, however, is only at the beginning of being revealed. We and others have shown that PDGF-C is a critical player in pathological angiogenesis because of its pleiotropic effects on multiple cellular targets. The angiogenic pathways induced by PDGF-C are, to a large extent, VEGF-independent. These pathways may include, but not limited to, the direct effect of PDGF-C on vascular cells, the effect of PDGF-C on tissue stroma fibroblasts, and its effect on macrophages. Taken together, the pleiotropic, versatile and VEGF-independent angiogenic nature of PDGF-C has placed it among the most important target genes for antiangiogenic therapy. PMID:20871734
Atrial natriuretic peptide down-regulates LPS/ATP-mediated IL-1β release by inhibiting NF-kB, NLRP3 inflammasome and caspase-1 activation in THP-1 cells.

Science.gov (United States)

Mezzasoma, Letizia; Antognelli, Cinzia; Talesa, Vincenzo Nicola

2016-02-01

Atrial natriuretic peptide (ANP) is an hormone/paracrine/autocrine factor regulating cardiovascular homeostasis by guanylyl cyclase natriuretic peptide receptor (NPR-1). ANP plays an important role also in regulating inflammatory and immune systems by altering macrophages functions and cytokines secretion. Interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine involved in a wide range of biological responses, including the immunological one. Unlike other cytokines, IL-1β production is rigorously controlled. Primarily, NF-kB activation is required to produce pro-IL-1β; subsequently, NALP3 inflammasome/caspase-1 activation is required to cleave pro-IL-1β into the active secreted protein. NALP3 is a molecular platform capable of sensing a large variety of signals and a major player in innate immune defense. Due to their pleiotropism, IL-1β and NALP3 dysregulation is a common feature of a wide range of diseases. Therefore, identifying molecules regulating IL-1β/NALP3/caspase-1 expression is an important step in the development of new potential therapeutic agents. The aim of our study was to evaluate the effect of ANP on IL-1β/NALP3/caspase-1 expression in LPS/ATP-stimulated human THP1 monocytes. We provided new evidence of the direct involvement of ANP/NPR-1/cGMP axis on NF-kB/NALP3/caspase-1-mediated IL-1β release and NF-kB-mediated pro-IL-1β production. In particular, ANP inhibited both NF-kB and NALP3/caspase-1 activation leading to pro- and mature IL-1β down-regulation. Our data, pointing out a modulatory role of this endogenous peptide on IL-1β release and on NF-kB/NALP3/caspase-1 activation, indicate an important anti-inflammatory and immunomodulatory effect of ANP via these mechanisms. We suggest a possible employment of ANP for the treatment of inflammatory/immune-related diseases and IL-1β/NALP3-associated disorders, affecting millions of people worldwide.
Plasmid-cured Chlamydia caviae activates TLR2-dependent signaling and retains virulence in the guinea pig model of genital tract infection.

Science.gov (United States)

Frazer, Lauren C; Darville, Toni; Chandra-Kuntal, Kumar; Andrews, Charles W; Zurenski, Matthew; Mintus, Margaret; AbdelRahman, Yasser M; Belland, Robert J; Ingalls, Robin R; O'Connell, Catherine M

2012-01-01

Loss of the conserved "cryptic" plasmid from C. trachomatis and C. muridarum is pleiotropic, resulting in reduced innate inflammatory activation via TLR2, glycogen accumulation and infectivity. The more genetically distant C. caviae GPIC is a natural pathogen of guinea pigs and induces upper genital tract pathology when inoculated intravaginally, modeling human disease. To examine the contribution of pCpGP1 to C. caviae pathogenesis, a cured derivative of GPIC, strain CC13, was derived and evaluated in vitro and in vivo. Transcriptional profiling of CC13 revealed only partial conservation of previously identified plasmid-responsive chromosomal loci (PRCL) in C. caviae. However, 2-deoxyglucose (2DG) treatment of GPIC and CC13 resulted in reduced transcription of all identified PRCL, including glgA, indicating the presence of a plasmid-independent glucose response in this species. In contrast to plasmid-cured C. muridarum and C. trachomatis, plasmid-cured C. caviae strain CC13 signaled via TLR2 in vitro and elicited cytokine production in vivo similar to wild-type C. caviae. Furthermore, inflammatory pathology induced by infection of guinea pigs with CC13 was similar to that induced by GPIC, although we observed more rapid resolution of CC13 infection in estrogen-treated guinea pigs. These data indicate that either the plasmid is not involved in expression or regulation of virulence in C. caviae or that redundant effectors prevent these phenotypic changes from being observed in C. caviae plasmid-cured strains.
Plasmid-cured Chlamydia caviae activates TLR2-dependent signaling and retains virulence in the guinea pig model of genital tract infection.

Directory of Open Access Journals (Sweden)

Lauren C Frazer

Full Text Available Loss of the conserved "cryptic" plasmid from C. trachomatis and C. muridarum is pleiotropic, resulting in reduced innate inflammatory activation via TLR2, glycogen accumulation and infectivity. The more genetically distant C. caviae GPIC is a natural pathogen of guinea pigs and induces upper genital tract pathology when inoculated intravaginally, modeling human disease. To examine the contribution of pCpGP1 to C. caviae pathogenesis, a cured derivative of GPIC, strain CC13, was derived and evaluated in vitro and in vivo. Transcriptional profiling of CC13 revealed only partial conservation of previously identified plasmid-responsive chromosomal loci (PRCL in C. caviae. However, 2-deoxyglucose (2DG treatment of GPIC and CC13 resulted in reduced transcription of all identified PRCL, including glgA, indicating the presence of a plasmid-independent glucose response in this species. In contrast to plasmid-cured C. muridarum and C. trachomatis, plasmid-cured C. caviae strain CC13 signaled via TLR2 in vitro and elicited cytokine production in vivo similar to wild-type C. caviae. Furthermore, inflammatory pathology induced by infection of guinea pigs with CC13 was similar to that induced by GPIC, although we observed more rapid resolution of CC13 infection in estrogen-treated guinea pigs. These data indicate that either the plasmid is not involved in expression or regulation of virulence in C. caviae or that redundant effectors prevent these phenotypic changes from being observed in C. caviae plasmid-cured strains.
G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.

Science.gov (United States)

Conrad, Kirk P

2016-09-01

Important roles for G-protein-coupled receptors (GPCRs) have been identified in the maternal physiological adaptations to pregnancy and in the pathogenesis of preeclampsia. On this basis, GPCRs are potential therapeutic targets for preeclampsia. In this review, vasopressin and apelin are initially considered in this context before the focus on the hormone relaxin and its cognate receptor, the relaxin/insulin-like family peptide receptor 1 (RXFP1). Based on both compelling scientific rationale and a promising safety profile, the relaxin ligand-receptor system is comprehensively evaluated as a potential therapeutic endpoint in preeclampsia. The published literature relating to the topic was searched through January 2016 using PubMed. Relaxin is a peptide hormone secreted by the corpus luteum; it circulates in the luteal phase and during pregnancy. Activation of RXFP1 is vasodilatory; thus, relaxin supplementation is expected to at least partly restore the fundamental vasodilatory changes of normal pregnancy, thereby alleviating maternal organ hypoperfusion, which is a major pathogenic manifestation of severe preeclampsia. Specifically, by exploiting its pleiotropic hemodynamic attributes in preeclampsia, relaxin administration is predicted to (i) reverse robust arterial myogenic constriction; (ii) blunt systemic and renal vasoconstriction in response to activation of the angiotensin II receptor, type 1; (iii) mollify the action of endogenous vasoconstrictors on uterine spiral arteries with failed remodeling and retained smooth muscle; (iv) increase arterial compliance; (v) enhance insulin-mediated glucose disposal by promoting skeletal muscle vasodilation and (vi) mobilize and activate bone marrow-derived angiogenic progenitor cells, thereby repairing injured endothelium and improving maternal vascularity in organs such as breast, uterus, pancreas, skin and fat. By exploiting its pleiotropic molecular attributes in preeclampsia, relaxin supplementation is
Notch signalling mediates reproductive constraint in the adult worker honeybee

Science.gov (United States)

Duncan, Elizabeth J.; Hyink, Otto; Dearden, Peter K.

2016-01-01

The hallmark of eusociality is the reproductive division of labour, in which one female caste reproduces, while reproduction is constrained in the subordinate caste. In adult worker honeybees (Apis mellifera) reproductive constraint is conditional: in the absence of the queen and brood, adult worker honeybees activate their ovaries and lay haploid male eggs. Here, we demonstrate that chemical inhibition of Notch signalling can overcome the repressive effect of queen pheromone and promote ovary activity in adult worker honeybees. We show that Notch signalling acts on the earliest stages of oogenesis and that the removal of the queen corresponds with a loss of Notch protein in the germarium. We conclude that the ancient and pleiotropic Notch signalling pathway has been co-opted into constraining reproduction in worker honeybees and we provide the first molecular mechanism directly linking ovary activity in adult worker bees with the presence of the queen. PMID:27485026
Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis.

Directory of Open Access Journals (Sweden)

Mei-Xue Dong

Full Text Available Recombinant tissue plasminogen activator (rtPA is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA on cerebral infarction besides its thrombolysis property in mechanical animal stroke.Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger's test were obtained to detect publication bias.We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate.This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.

Ghrelin – a pleiotropic hormone secreted from endocrine X/A-like cells of the stomach

Directory of Open Access Journals (Sweden)

Andreas eStengel

2012-02-01

Full Text Available The gastric X/A-like endocrine cell receives growing attention due it its peptide products with ghrelin being the best characterized. This peptide hormone was identified a decade ago as a stimulator of food intake and to date remains the only known peripherally produced and centrally acting orexigenic hormone. In addition, subsequent studies identified numerous other functions of this peptide including the modulation of gastrointestinal motility, the maintenance of energy homeostasis and an impact on reproduction. Moreover, ghrelin is also involved in the response to stress and assumed to play a role in coping functions and exert a modulatory action on immune pathways. Our knowledge on the regulation of ghrelin has markedly advanced during the past years by the identification of the ghrelin acylating enzyme, ghrelin-O-acyltransferase, and by the description of changes in expression, activation and release under different metabolic as well as physically and psychically challenging conditions. However, our insight on regulatory processes of ghrelin at the cellular and subcellular levels is still very limited and warrants further investigation.
Simvastatin improves final visual outcome in acute optic neuritis

DEFF Research Database (Denmark)

Tsakiri, Anna; Kallenbach, Klaus; Fuglø, Dan

2012-01-01

In recent years, small-scale clinical trials have indicated that statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors exert pleiotropic immunomodulatory effects, with potential therapeutic implications in multiple sclerosis (MS)....
Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders

Directory of Open Access Journals (Sweden)

A. Janus

2016-01-01

Full Text Available Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes.
Pleiotropic Effects of Neurotransmission during Development: Modulators of Modularity

Science.gov (United States)

Thompson, Barbara L.; Stanwood, Gregg D.

2009-01-01

The formation and function of the mammalian cerebral cortex relies on the complex interplay of a variety of genetic and environmental factors through protracted periods of gestational and postnatal development. Biogenic amine systems are important neuromodulators, both in the adult nervous system, and during critical epochs of brain development.…
NPHP4 Variants Are Associated With Pleiotropic Heart Malformations

NARCIS (Netherlands)

French, Vanessa M.; van de Laar, Ingrid M. B. H.; Wessels, Marja W.; Rohe, Christan; Roos-Hesselink, Jolien W.; Wang, Guangliang; Frohn-Mulder, Ingrid M. E.; Severijnen, Lies-Anne; de Graaf, Bianca M.; Schot, Rachel; Breedveld, Guido; Mientjes, Edwin; van Tienhoven, Marianne; Jadot, Elodie; Jiang, Zhengxin; Verkerk, Annemieke; Swagemakers, Sigrid; Venselaar, Hanka; Rahimi, Zohreh; Najmabadi, Hossein; Meijers-Heijboer, Hanne; de Graaff, Esther; Helbing, Wim A.; Willemsen, Rob; Devriendt, Koen; Belmont, John W.; Oostra, Ben A.; Amack, Jeffrey D.; Bertoli-Avella, Aida M.

2012-01-01

Rationale: Congenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs. Objective: To identify genetic
NPHP4 variants are associated with pleiotropic heart malformations.

NARCIS (Netherlands)

French, V.M.; Laar, I.M. van de; Wessels, M.W.; Rohe, C.; Roos-Hesselink, J.W.; Wang, G.; Frohn-Mulder, I.M.; Severijnen, L.A.; Graaf, B.M. de; Schot, R.; Breedveld, G.; Mientjes, E.; Tienhoven, M. van; Jadot, E.; Jiang, Z.; Verkerk, A.; Swagemakers, S.; Venselaar, H.; Rahimi, Z.; Najmabadi, H.; Meijers-Heijboer, H.; Graaff, E. de; Helbing, W.A.; Willemsen, R.; Devriendt, K.; Belmont, J.W.; Oostra, B.A.; Amack, J.D.; Bertoli-Avella, A.M.

2012-01-01

RATIONALE: Congenital heart malformations are a major cause of morbidity and mortality, especially in young children. Failure to establish normal left-right (L-R) asymmetry often results in cardiovascular malformations and other laterality defects of visceral organs. OBJECTIVE: To identify genetic
Pleiotropic effects of simvastatin in physically trained ovariectomized rats

International Nuclear Information System (INIS)

Bernardes, N.; Brito, J.O.; Fernandes, T.G.; Llesuy, S.F.; Irigoyen, M.C.; Belló-Klein, A.; De Angelis, K.

2013-01-01

This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin-treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 ± 2 and sedentary+simvastatin = 107 ± 2 mmHg) compared to the sedentary group (122 ± 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (≈21%) and trained+simvastatin groups (≈57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

Science.gov (United States)

Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C; Tudawe, Thavisha; Seviour, Elena G; San Lucas, F Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T; Maitra, Anirban; Nagrath, Deepak

2016-01-01

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions. DOI: http://dx.doi.org/10.7554/eLife.10250.001 PMID:26920219
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism.

Science.gov (United States)

Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C; Tudawe, Thavisha; Seviour, Elena G; San Lucas, F Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T; Maitra, Anirban; Nagrath, Deepak

2016-02-27

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.
Pleiotropic effects of simvastatin in physically trained ovariectomized rats

Energy Technology Data Exchange (ETDEWEB)

Bernardes, N. [Universidade Nove de Julho (UNINOVE), São Paulo, SP (Brazil); Unidade de Hipertensão, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Brito, J.O. [Universidade Nove de Julho (UNINOVE), São Paulo, SP (Brazil); Fernandes, T.G. [Laboratório de Fisiologia Cardiovascular, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universdade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Llesuy, S.F. [University of Buenos Aires, Buenos Aires (Argentina); Irigoyen, M.C. [Unidade de Hipertensão, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Belló-Klein, A. [Laboratório de Fisiologia Cardiovascular, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universdade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); De Angelis, K. [Universidade Nove de Julho (UNINOVE), São Paulo, SP (Brazil)

2013-05-24

This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin-treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 ± 2 and sedentary+simvastatin = 107 ± 2 mmHg) compared to the sedentary group (122 ± 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (≈21%) and trained+simvastatin groups (≈57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats.
Calprotectin - a Pleiotropic Molecule in Acute and Chronic Inflammation

Czech Academy of Sciences Publication Activity Database

Stříž, I.; Trebichavský, Ilja

2004-01-01

Roč. 53, - (2004), s. 245-253 ISSN 0862-8408 R&D Projects: GA MŠk ME 580; GA MZd NI6843 Keywords : calprotectin * mrp8/14 * s100a9 Subject RIV: EE - Microbiology, Virology Impact factor: 1.140, year: 2004
Chitinase Expression in Listeria monocytogenes Is Influenced by lmo0327, Which Encodes an InternalinLike Protein

DEFF Research Database (Denmark)

Paspaliari, Dafni Katerina; Kastbjerg, Vicky Gaedt; Ingmer, Hanne

2017-01-01

The chitinolytic system of Listeria monocytogenes thus far comprises two chitinases, ChiA and ChiB, and a lytic polysaccharide monooxygenase, Lmo2467. The role of the system in the bacterium appears to be pleiotropic, as besides mediating hydrolysis of chitin, the second most ubiquitous...... chitinase activities enabling them to utilize chitin as the sole source of carbon and nitrogen. Interestingly, several bacterial chitinases may also be involved in host pathogenesis. For example, in the important food borne pathogen Listeria monocytogenes, the chitinases ChiA and ChiB, and the lytic...... ChiA and ChiB in the culture supernatants of the mutant strain. Our results provide new information regarding the function of the lmo0325-lmo0327 locus in L. monocytogenes and link it to the expression of chitinolytic activity.Importance: Many bacteria from terrestrial and marine environments express...
Review Article Therapeutic Potential of Statins in Age-related ...

African Journals Online (AJOL)

2011-08-09

Aug 9, 2011 ... Keywords: Age-related macular, Non-invasive treatment, Pleiotropic effects, Prevention, Statins. Received 14 June ... two types: non-exudative or “dry', characterised by .... Dam Eye Study in Wisconsin, statin use at the 10-.
nitrosoguanidine-induced cadmium resistant mutants of Aspergillus

Indian Academy of Sciences (India)

Unknown

nitrosoguanidine-induced cadmium resistant mutants of. Aspergillus niger. SAMAR ... gens and UV irradiation to study transportation of cad- mium ion through cell ..... Rowley W S 1993 Yeast bZib proteins mediate pleiotropic drug and metal ...
Reference: 278 [Arabidopsis Phenome Database[Archive

Lifescience Database Archive (English)

Full Text Available functional ERA1 gene, which encodes the beta-subunit of protein farnesyltransferase (PFT), exhibit pleiotropic effects...gnaling and meristem development. Here, we report the effects of T-DNA insertion mutations in the Arabidopsi
Protein phosphorylation in bcterial signaling and regulation

KAUST Repository

Mijakovic, Ivan

2016-01-01

. Evolutionary studies based on genome comparison indicate that BY-kinases exist only in bacteria. They are non-essential (present in about 40% bacterial genomes), and their knockouts lead to pleiotropic phenotypes, since they phosphorylate many substrates
Inhibition of herpes simplex-1 virus replication by 25-hydroxycholesterol and 27-hydroxycholesterol.

Science.gov (United States)

Cagno, Valeria; Civra, Andrea; Rossin, Daniela; Calfapietra, Simone; Caccia, Claudio; Leoni, Valerio; Dorma, Nicholas; Biasi, Fiorella; Poli, Giuseppe; Lembo, David

2017-08-01

Oxysterols are known pleiotropic molecules whose antiviral action has been recently discovered. Here reported is the activity of a panel of oxysterols against HSV-1 with the identification of a new mechanism of action. A marked antiviral activity not only of 25HC but also of 27HC against HSV-1 was observed either if the oxysterols were added before or after infection, suggesting an activity unrelated to the viral entry inhibition as proposed by previous literature. Therefore, the relation between the pro-inflammatory activity of oxysterols and the activation of NF-kB and IL-6 induced by HSV-1 in the host cell was investigated. Indeed, cell pre-incubation with oxysterols further potentiated IL-6 production as induced by HSV-1 infection with a consequent boost of the interleukin's total cell secretion. Further, a direct antiviral effect of IL-6 administration to HSV-1 infected cells was demonstrated, disclosing an additional mechanism of antiviral action by both 25HC and 27HC. Copyright © 2017. Published by Elsevier B.V.
Inhibition of herpes simplex-1 virus replication by 25-hydroxycholesterol and 27-hydroxycholesterol

Directory of Open Access Journals (Sweden)

Valeria Cagno

2017-08-01

Full Text Available Oxysterols are known pleiotropic molecules whose antiviral action has been recently discovered. Here reported is the activity of a panel of oxysterols against HSV-1 with the identification of a new mechanism of action. A marked antiviral activity not only of 25HC but also of 27HC against HSV-1 was observed either if the oxysterols were added before or after infection, suggesting an activity unrelated to the viral entry inhibition as proposed by previous literature. Therefore, the relation between the pro-inflammatory activity of oxysterols and the activation of NF-kB and IL-6 induced by HSV-1 in the host cell was investigated. Indeed, cell pre-incubation with oxysterols further potentiated IL-6 production as induced by HSV-1 infection with a consequent boost of the interleukin's total cell secretion. Further, a direct antiviral effect of IL-6 administration to HSV-1 infected cells was demonstrated, disclosing an additional mechanism of antiviral action by both 25HC and 27HC. Keywords: Oxysterols, 27-hydroxycholesterol, 25-hydroxycholesterol, Herpes simplex-1, Viral inhibition, Interleukin-6
Occurrence and phenotypic and molecular characterization of Listeriamonocytogenes and Salmonella spp. in slaughterhouses in southern Brazil.

Science.gov (United States)

Iglesias, Mariana Almeida; Kroning, Isabela Schneid; Decol, Luana Tombini; de Melo Franco, Bernadette Dora Gombossy; Silva, Wladimir Padilha da

2017-10-01

This study addressed the occurrence of Listeriamonocytogenes and Salmonella spp. in bovine carcasses at two slaughterhouses in southern Brazil. Then, the antimicrobial susceptibility profile and the virulence potential of the isolates were evaluated. Two hundred carcasses were sampled at four steps of the slaughter process, with L. monocytogenes being isolated in 12 and Salmonella spp. in 17 carcasses. All L. monocytogenes isolates carried the hlyA, prfA, plcA, plcB, actA, iap, mpl, inlA, inlB, inlC, and inlJ genes, while Salmonella spp. carried invA and hilA. Among the L. monocytogenes isolates, all of them presented virulence determinants and one showed multi-drug resistance. In relationship to Salmonella spp. isolates, many serogroups frequently related to outbreaks of foodborne diseases were identified and four isolates showed resistance to more than one antimicrobial agent. This data highlights the importance of a rigid hygienic-sanitary control during the slaughter process to reduce the risk of cross-contamination and lower the consumer exposure to L. monocytogenes and Salmonella spp. infections. Copyright © 2017 Elsevier Ltd. All rights reserved.
Listeria monocytogenes differential transcriptome analysis reveals temperature-dependent Agr regulation and suggests overlaps with other regulons.

Science.gov (United States)

Garmyn, Dominique; Augagneur, Yoann; Gal, Laurent; Vivant, Anne-Laure; Piveteau, Pascal

2012-01-01

Listeria monocytogenes is a ubiquitous, opportunistic pathogenic organism. Environmental adaptation requires constant regulation of gene expression. Among transcriptional regulators, AgrA is part of an auto-induction system. Temperature is an environmental cue critical for in vivo adaptation. In order to investigate how temperature may affect AgrA-dependent transcription, we compared the transcriptomes of the parental strain L. monocytogenes EGD-e and its ΔagrA mutant at the saprophytic temperature of 25°C and in vivo temperature of 37°C. Variations of transcriptome were higher at 37°C than at 25°C. Results suggested that AgrA may be involved in the regulation of nitrogen transport, amino acids, purine and pyrimidine biosynthetic pathways and phage-related functions. Deregulations resulted in a growth advantage at 37°C, but affected salt tolerance. Finally, our results suggest overlaps with PrfA, σB, σH and CodY regulons. These overlaps may suggest that through AgrA, Listeria monocytogenes integrates information on its biotic environment.

Antinociception induced by atorvastatin in different pain models.

Science.gov (United States)

Garcia, G G; Miranda, H F; Noriega, V; Sierralta, F; Olavarría, L; Zepeda, R J; Prieto, J C

2011-11-01

Atorvastatin is a statin that inhibits the 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Several landmark clinical trials have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. It is assumed that the beneficial effects of statin therapy are entirely due to cholesterol reduction. Statins have an additional activity (pleiotropic effect) that has been associated to their anti-inflammatory effects. The aim of the present study was to assess the antinociceptive activity of atorvastatin in five animal pain models. The daily administration of 3-100mg/kg of atorvastatin by oral gavage induced a significant dose-dependent antinociception in the writhing, tail-flick, orofacial formalin and formalin hind paw tests. However, this antinociceptive activity of atorvastatin was detectable only at high concentrations in the hot plate assay. The data obtained in the present study demonstrates the effect of atorvastatin to reduce nociception and inflammation in different animal pain models. Copyright © 2011 Elsevier Inc. All rights reserved.
Molecular discrimination and genetic relationships between some ...

African Journals Online (AJOL)

SAM

2014-03-12

Mar 12, 2014 ... presented as a savory dish or accompaniment. However, botanically, the ... highly polymorphic, easy and fast to detect and not possessing pleiotropic ..... France with the mean similarity index of 0.371 and 0. 352, respectively.
Perioperative Statin Therapy Is Not Associated With Reduced Risk of Anastomotic Leakage After Colorectal Resection

DEFF Research Database (Denmark)

Bisgård, Anne Sofie; Noack, Morten Westergaard; Klein, Mads

2013-01-01

Anastomotic leakage is a serious complication of colorectal surgery. Several studies have demonstrated the beneficial pleiotropic effects of statins, and preliminary studies have suggested that perioperative statin treatment may be associated with reduced risk of anastomotic leakage....
A quadratically regularized functional canonical correlation analysis for identifying the global structure of pleiotropy with NGS data.

Science.gov (United States)

Lin, Nan; Zhu, Yun; Fan, Ruzong; Xiong, Momiao

2017-10-01

Investigating the pleiotropic effects of genetic variants can increase statistical power, provide important information to achieve deep understanding of the complex genetic structures of disease, and offer powerful tools for designing effective treatments with fewer side effects. However, the current multiple phenotype association analysis paradigm lacks breadth (number of phenotypes and genetic variants jointly analyzed at the same time) and depth (hierarchical structure of phenotype and genotypes). A key issue for high dimensional pleiotropic analysis is to effectively extract informative internal representation and features from high dimensional genotype and phenotype data. To explore correlation information of genetic variants, effectively reduce data dimensions, and overcome critical barriers in advancing the development of novel statistical methods and computational algorithms for genetic pleiotropic analysis, we proposed a new statistic method referred to as a quadratically regularized functional CCA (QRFCCA) for association analysis which combines three approaches: (1) quadratically regularized matrix factorization, (2) functional data analysis and (3) canonical correlation analysis (CCA). Large-scale simulations show that the QRFCCA has a much higher power than that of the ten competing statistics while retaining the appropriate type 1 errors. To further evaluate performance, the QRFCCA and ten other statistics are applied to the whole genome sequencing dataset from the TwinsUK study. We identify a total of 79 genes with rare variants and 67 genes with common variants significantly associated with the 46 traits using QRFCCA. The results show that the QRFCCA substantially outperforms the ten other statistics.
Inactivation of the Ecs ABC Transporter of Staphylococcus aureus Attenuates Virulence by Altering Composition and Function of Bacterial Wall

NARCIS (Netherlands)

Jonsson, Ing-Marie; Juuti, Jarmo T.; Francois, Patrice; AlMajidi, Rana; Pietiainen, Milla; Girard, Myriam; Lindholm, Catharina; Saller, Manfred J.; Driessen, Arnold J. M.; Kuusela, Pentti; Bokarewa, Maria; Schrenzel, Jacques; Kontinen, Vesa P.

2010-01-01

Background: Ecs is an ATP-binding cassette (ABC) transporter present in aerobic and facultative anaerobic Gram-positive Firmicutes. Inactivation of Bacillus subtilis Ecs causes pleiotropic changes in the bacterial phenotype including inhibition of intramembrane proteolysis. The molecule(s)
Levosimendan beyond inotropy and acute heart failure

DEFF Research Database (Denmark)

Farmakis, Dimitrios; Alvarez, Julian; Gal, Tuvia Ben

2016-01-01

pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps....
Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

NARCIS (Netherlands)

H.W.M. van de Ven (Marieke); J.-O. Andressoo (Jaan-Olle); V.B. Holcomb (Valerie); M.M. von Lindern (Marieke); W.M.C. Jong (Willeke); C.I. de Zeeuw (Chris); Y. Suh (Yousin); P. Hasty (Paul); J.H.J. Hoeijmakers (Jan); G.T.J. van der Horst (Gijsbertus); J.R. Mitchell (James)

2006-01-01

textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular
Antiretroviral effect of lovastatin on HIV-1-infected individuals without highly active antiretroviral therapy (The LIVE study: a phase-II randomized clinical trial

Directory of Open Access Journals (Sweden)

Montoya Carlos J

2009-06-01

Full Text Available Abstract Background Highly active antiretroviral therapy produces a significant decrease in HIV-1 replication and allows an increase in the CD4 T-cell count, leading to a decrease in the incidence of opportunistic infections and mortality. However, the cost, side effects and complexity of antiretroviral regimens have underscored the immediate need for additional therapeutic approaches. Statins exert pleiotropic effects through a variety of mechanisms, among which there are several immunoregulatory effects, related and unrelated to their cholesterol-lowering activity that can be useful to control HIV-1 infection. Methods/design Randomized, double-blinded, placebo controlled, single-center, phase-II clinical trial. One hundred and ten chronically HIV-1-infected patients, older than 18 years and naïve for antirretroviral therapy (i.e., without prior or current management with antiretroviral drugs will be enrolled at the outpatient services from the most important centres for health insurance care in Medellin-Colombia. The interventions will be lovastatin (40 mg/day, orally, for 12 months; 55 patients or placebo (55 patients. Our primary aim will be to determine the effect of lovastatin on viral replication. The secondary aim will be to determine the effect of lovastatin on CD4+ T-cell count in peripheral blood. As tertiary aims we will explore differences in CD8+ T-cell count, expression of activation markers (CD38 and HLA-DR on CD4 and CD8 T cells, cholesterol metabolism, LFA-1/ICAM-1 function, Rho GTPases function and clinical evolution between treated and not treated HIV-1-infected individuals. Discussion Preliminary descriptive studies have suggested that statins (lovastatin may have anti HIV-1 activity and that their administration is safe, with the potential effect of controlling HIV-1 replication in chronically infected individuals who had not received antiretroviral medications. Considering that there is limited clinical data available on
Quantitative Trait Loci for Fertility Traits in Finnish Ayrshire Cattle

DEFF Research Database (Denmark)

Schulman, Nina F; Sahana, Goutam; Lund, Mogens S

2008-01-01

A whole genome scan was carried out to detect quantitative trait loci (QTL) for fertility traits in Finnish Ayrshire cattle. The mapping population consisted of 12 bulls and 493 sons. Estimated breeding values for days open, fertility treatments, maternal calf mortality and paternal non-return rate...... combinations, which were observed significant in the regression method. Twenty-two chromosome-wise significant QTL were detected. Several of the detected QTL areas were overlapping with milk production QTL previously identified in the same population. Multi-trait QTL analyses were carried out to test...... if these effects were due to a pleiotropic QTL affecting fertility and milk yield traits or to linked QTL causing the effects. This distinction could only be made with confidence on BTA1 where a QTL affecting milk yield is linked to a pleiotropic QTL affecting days open and fertility treatments...
Fernblock (Polypodium leucotomos Extract: Molecular Mechanisms and Pleiotropic Effects in Light-Related Skin Conditions, Photoaging and Skin Cancers, a Review

Directory of Open Access Journals (Sweden)

Concepcion Parrado

2016-06-01

Full Text Available Healthier life styles include increased outdoors time practicing sports and walking. This means increased exposure to the sun, leading to higher risk of sunburn, photoaging and skin cancer. In addition to topical barrier products, oral supplementations of various botanicals endowed with antioxidant activity are emerging as novel method of photoprotection. Polypodium leucotomos extract (PL, commercial name Fernblock®, IFC Group, Spain is a powerful antioxidant due to its high content of phenolic compounds. PL is administered orally, with proven safety, and it can also be used topically. Its mechanisms include inhibition of the generation and release of reactive oxygen species (ROS by ultraviolet (UV light. It also prevents UV- and ROS-induced DNA damage with inhibition of AP1 and NF-κB and protection of natural antioxidant enzyme systems. At the cellular level, PL decreases cellular apoptosis and necrosis mediated UV and inhibits abnormal extracellular matrix remodeling. PL reduces inflammation, prevents immunosuppression, activates tumor suppressor p53 and inhibits UV-induced cyclooxygenase-2 (COX-2 enzyme expression. In agreement with increased p53 activity, PL decreased UV radiation-induced cell proliferation. PL also prevents common deletions mitochondrial DNA damage induced by UVA, and MMP-1 expression induced Visible Light and Infrared Radiation. These cellular and molecular effects are reflected in inhibitions of carcinogenesis and photoaging.
Disparate modes of evolution shaped modern prion (PRNP) and prion-related doppel (PRND) variation in domestic cattle

Science.gov (United States)

Previous investigations aimed at determining whether the mammalian prion protein actually facilitates tangible molecular aspects of either a discrete or pleiotropic functional niche have been debated, especially given the apparent absence of overt behavioral or physiological phenotypes associated wi...
Yield and Amino Acid Composition of Pulp and Protein Extracted and Recovered from Legumes and Grass

DEFF Research Database (Denmark)

Kragbæk Damborg, Vinni; Stødkilde-Jørgensen, Lene; Jensen, Søren Krogh

2015-01-01

Understanding the underlying pleiotropic relationships among quantitative traits is integral to predict correlated responses to artificial selection. The availability of large-scale next-generation sequence data in cattle has provided an opportunity to examine whether pleiotropy is responsible fo...
Associations between a polymorphism in the pleiotropic GCKR and Age-related phenotypes: the HALCyon programme.

Directory of Open Access Journals (Sweden)

Tamuno Alfred

Full Text Available The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP rs1260326 (P446L in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported.As part of the Healthy Ageing across the Life Course (HALCyon collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI, blood lipid levels, lung function, and cognitive and physical capability.We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on z-score= -0.04, p-value=0.0001, n=16,251. Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability.Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability.
Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

NARCIS (Netherlands)

van de Ven, Marieke; Andressoo, Jaan-Olle; Holcomb, Valerie B.; von Lindern, Marieke; Jong, Willeke M. C.; de Zeeuw, Chris I.; Suh, Yousin; Hasty, Paul; Hoeijmakers, Jan H. J.; van der Horst, Gijsbertus T. J.; Mitchell, James R.

2006-01-01

How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a
Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense?

NARCIS (Netherlands)

van der Poll, T.; Lowry, S. F.

1995-01-01

Tumor necrosis factor-alpha (TNF) exerts numerous influences which, in association with severe infection, subserve both detrimental as well as beneficial host responses. The current review addresses recent insights into the structure and function of this pleiotropic cytokine, with a particular
Lipid and bile acid analysis

NARCIS (Netherlands)

Argmann, Carmen A.; Houten, Sander M.; Champy, Marie-France; Auwerx, Johan

2006-01-01

Lipids are important body constituents that are vital for cellular, tissue, and whole-body homeostasis. Lipids serve as crucial membrane components, constitute the body's main energy reservoir, and are important signaling molecules. As a consequence of these pleiotropic functions, many common
Granzyme A Produces Bioactive IL-1β through a Nonapoptotic Inflammasome-Independent Pathway

Directory of Open Access Journals (Sweden)

Dagmar Hildebrand

2014-11-01

Full Text Available Bacterial components are recognized by the immune system through activation of the inflammasome, eventually causing processing of the proinflammatory cytokine interleukin-1β (IL-1β, a pleiotropic cytokine and one of the most important mediators of inflammation, through the protease caspase-1. Synthesis of the precursor protein and processing into its bioactive form are tightly regulated, given that disturbed control of IL-1β release can cause severe autoinflammatory diseases or contribute to cancer development. We show that the bacterial Pasteurella multocida toxin (PMT triggers Il1b gene transcription in macrophages independently of Toll-like receptor signaling through RhoA/Rho-kinase-mediated NF-κΒ activation. Furthermore, PMT mediates signal transducer and activator of transcription (STAT protein-controlled granzyme A (a serine protease expression in macrophages. The exocytosed granzyme A enters target cells and mediates IL-1β maturation independently of caspase-1 and without inducing cytotoxicity. These findings show that macrophages can induce an IL-1β-initiated immune response independently of inflammasome activity.
Physiological characterisation of acuB deletion in Aspergillus niger

DEFF Research Database (Denmark)

Meijer, Susan Lisette; De Jongh, Willem Adriaan; Olsson, Lisbeth

2009-01-01

The acuB gene of Aspergillus niger is an ortholog of facB in Aspergillus nidulans. Under carbon-repression conditions, facB is repressed, thereby preventing acetate metabolism when the repressing carbon source is present. Even though facB is reported to be repressed directly by CreA, it is believed...... that a basal level of FacB activity exists under glucose-repressive conditions. In the present study, the effect of deletion of acuB on the physiology of A. niger was assessed. Differences in organic acid and acetate production, enzyme activities and extracellular amino and non-amino organic acid production...... were determined under glucose-repressing and -derepressing conditions. Furthermore, consumption of alternative carbon sources (e.g. xylose, citrate, lactate and succinate) was investigated. It was shown that AcuB has pleiotropic effects on the physiology of A. niger. The results indicate that metabolic...
FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

Directory of Open Access Journals (Sweden)

Ai-Luen Wu

Full Text Available Fibroblast growth factor 19 (FGF19 is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4, although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB. In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.
GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules

Science.gov (United States)

Hur, Eun-Mi; Saijilafu; Lee, Byoung Dae; Kim, Seong-Jin; Xu, Wen-Lin; Zhou, Feng-Quan

2011-01-01

Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding activity mediates axon growth inhibition induced by suppression of GSK3 activity via preventing MT protrusion into the growth cone periphery, whereas the plus end-binding property supports axon extension via stabilizing the growing ends of axonal MTs. We propose a model in which CLASP transduces GSK3 activity levels to differentially control axon growth by coordinating the stability and configuration of growth cone MTs. PMID:21937714

Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study.

Science.gov (United States)

Weseler, Antje R; Ruijters, Erik J B; Drittij-Reijnders, Marie-José; Reesink, Koen D; Haenen, Guido R M M; Bast, Aalt

2011-01-01

Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded. In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets. In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, Pbenefit of an 8 weeks supplementation with 200 mg/d MOF in humans. ClinicalTrials.gov NCT00742287.
Thioredoxin A Is Essential for Motility and Contributes to Host Infection of Listeria monocytogenes via Redox Interactions

Directory of Open Access Journals (Sweden)

Changyong Cheng

2017-06-01

Full Text Available Microbes employ the thioredoxin system to defend against oxidative stress and ensure correct disulfide bonding to maintain protein function. Listeria monocytogenes has been shown to encode a putative thioredoxin, TrxA, but its biological roles and underlying mechanisms remain unknown. Here, we showed that expression of L. monocytogenes TrxA is significantly induced in bacteria treated with the thiol-specific oxidizing agent, diamide. Deletion of trxA markedly compromised tolerance of the pathogen to diamide, and mainly impaired early stages of infection in human intestinal epithelial Caco-2 cells. In addition, most trxA mutant bacteria were not associated with polymerized actin, and the rare bacteria that were associated with polymerized actin displayed very short tails or clouds during infection. Deletion or constitutive overexpression of TrxA, which was regulated by SigH, severely attenuated the virulence of the pathogen. Transcriptome analysis of L. monocytogenes revealed over 270 genes that were differentially transcribed in the ΔtrxA mutant compared to the wild-type, especially for the virulence-associated genes plcA, mpl, hly, actA, and plcB. Particularly, deletion of TrxA completely reduced LLO expression, and thereby led to a thoroughly impaired hemolytic activity. Expression of these virulence factors are positively regulated by the master regulator PrfA that was found here to use TrxA to maintain its reduced forms for activation. Interestingly, the trxA deletion mutant completely lacked flagella and was non-motile. We further confirmed that this deficiency is attributable to TrxA in maintaining the reduced intracellular monomer status of MogR, the key regulator for flagellar formation, to ensure correct dimerization. In summary, we demonstrated for the first time that L. monocytogenes thioredoxin A as a vital cellular reductase is essential for maintaining a highly reducing environment in the bacterial cytosol, which provides a
Thioredoxin A Is Essential for Motility and Contributes to Host Infection of Listeria monocytogenes via Redox Interactions.

Science.gov (United States)

Cheng, Changyong; Dong, Zhimei; Han, Xiao; Wang, Hang; Jiang, Li; Sun, Jing; Yang, Yongchun; Ma, Tiantian; Shao, Chunyan; Wang, Xiaodu; Chen, Zhongwei; Fang, Weihuan; Freitag, Nancy E; Huang, Huarong; Song, Houhui

2017-01-01

Microbes employ the thioredoxin system to defend against oxidative stress and ensure correct disulfide bonding to maintain protein function. Listeria monocytogenes has been shown to encode a putative thioredoxin, TrxA, but its biological roles and underlying mechanisms remain unknown. Here, we showed that expression of L. monocytogenes TrxA is significantly induced in bacteria treated with the thiol-specific oxidizing agent, diamide. Deletion of trxA markedly compromised tolerance of the pathogen to diamide, and mainly impaired early stages of infection in human intestinal epithelial Caco-2 cells. In addition, most trxA mutant bacteria were not associated with polymerized actin, and the rare bacteria that were associated with polymerized actin displayed very short tails or clouds during infection. Deletion or constitutive overexpression of TrxA, which was regulated by SigH, severely attenuated the virulence of the pathogen. Transcriptome analysis of L. monocytogenes revealed over 270 genes that were differentially transcribed in the Δ trxA mutant compared to the wild-type, especially for the virulence-associated genes plcA, mpl, hly, actA , and plcB . Particularly, deletion of TrxA completely reduced LLO expression, and thereby led to a thoroughly impaired hemolytic activity. Expression of these virulence factors are positively regulated by the master regulator PrfA that was found here to use TrxA to maintain its reduced forms for activation. Interestingly, the trxA deletion mutant completely lacked flagella and was non-motile. We further confirmed that this deficiency is attributable to TrxA in maintaining the reduced intracellular monomer status of MogR, the key regulator for flagellar formation, to ensure correct dimerization. In summary, we demonstrated for the first time that L. monocytogenes thioredoxin A as a vital cellular reductase is essential for maintaining a highly reducing environment in the bacterial cytosol, which provides a favorable condition for
Role of pleiotropy during adaptation of TEM-1 β-lactamase to two novel antibiotics

NARCIS (Netherlands)

Schenk, M.F.; Witte, Sariette; Salverda, M.L.M.; Koopmanschap, Bertha; Krug, Joachim; Visser, de J.A.G.M.

2015-01-01

Pleiotropy is a key feature of the genotype-phenotype map, and its form and extent have many evolutionary implications, including for the dynamics of adaptation and the evolution of specialization. Similarly, pleiotropic effects of antibiotic resistance mutations may affect the evolution of
Metformin Improves Endothelial Function and Reduces Blood Pressure in Diabetic Spontaneously Hypertensive Rats Independent from Glycemia Control : Comparison to Vildagliptin

NARCIS (Netherlands)

Hamidi Shishavan, Mahdi; Henning, Robert H; van Buiten, Azuwerus; Goris, Maaike; Deelman, Leo E; Buikema, Hendrik

2017-01-01

Metformin confers vascular benefits beyond glycemia control, possibly via pleiotropic effects on endothelial function. In type-1-diabetes-mellitus (T1DM-)patients metformin improved flow-mediated dilation but also increased prostaglandin(PG)-F-2 alpha, a known endothelial-contracting factor. To
Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα

NARCIS (Netherlands)

Tortarolo, Massimo; Lo Coco, Daniele; Veglianese, Pietro; Vallarola, Antonio; Giordana, Maria Teresa; Marcon, Gabriella; Beghi, Ettore; Poloni, Marco; Strong, Michael J.; Iyer, Anand M.; Aronica, Eleonora; Bendotti, Caterina

2017-01-01

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system
Slide 1

Indian Academy of Sciences (India)

Wnt signaling is involved in multiple developmental events during embryogenesis and is implicated in adult tissue maintenance. Wnt signaling is pleiotropic with effects that include mitogenic stimulation, cell fate specification and differentiation Perturbation in Wnt signaling promote both human neurogenerative disorders ...
The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

NARCIS (Netherlands)

Witkamp, R.F.

2014-01-01

The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management
The association between autism and errors in early embryogenesis: what is the causal mechanism?

NARCIS (Netherlands)

Ploeger, A.; Raijmakers, M.E.J.; van der Maas, H.L.J.; Galis, F.

2010-01-01

The association between embryonic errors and the development of autism has been recognized in the literature, but the mechanism underlying this association remains unknown. We propose that pleiotropic effects during a very early and specific stage of embryonic development—early organogenesis—can
Plasma insulin-like growth factor I levels are higher in depressive and anxiety disorders, but lower in antidepressant medication users

NARCIS (Netherlands)

Bot, Mariska; Milaneschi, Yuri; Penninx, Brenda W J H; Drent, Madeleine L

It has been postulated that many peripheral and (neuro)biological systems are involved in psychiatric disorders such as depression. Some studies found associations of depression and antidepressant treatment with insulin-like growth factor 1 (IGF-I) - a pleiotropic hormone affecting neuronal growth,
Cracking anxiety in the mouse : a quantitative (epi)genetic approach

NARCIS (Netherlands)

Labots, M.

2017-01-01

The aim of this thesis was to improve existing methodologies and apply genetic strategies in order to identify (main-effect, epistatic, multiple and pleiotropic) quantitative trait loci and to decipher functional candidate genes for anxiety-related behavior and baseline blood plasma total
Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders

Directory of Open Access Journals (Sweden)

Zhimin Chen

2017-08-01

Conclusions: Nrg4 exerts pleiotropic beneficial effects on energy balance and glucose and lipid metabolism to ameliorate obesity-associated metabolic disorders. Biologic therapeutics based on Nrg4 may improve both type 2 diabetes and non-alcoholic fatty liver disease (NAFLD in patients.
Sustained activation of toll-like receptor 9 induces an invasive phenotype in lung fibroblasts: possible implications in idiopathic pulmonary fibrosis.

Science.gov (United States)

Kirillov, Varvara; Siler, Jonathan T; Ramadass, Mahalakshmi; Ge, Lingyin; Davis, James; Grant, Geraldine; Nathan, Steven D; Jarai, Gabor; Trujillo, Glenda

2015-04-01

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive scarring of the lung parenchyma, resulting in a steady decline of lung function and ultimately respiratory failure. The disease course of IPF is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in IPF and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 (TLR9). Activation of TLR9 in vivo exacerbated IPF in mice and induced differentiation of myofibroblasts in vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor (TGF)-β, a pleiotropic cytokine central to IPF pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-β in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated α-smooth muscle actin(+)/platelet-derived growth factor receptor α(+)/CD44(+)/matrix metalloproteinase-14(+)/matrix metalloproteinase-2(+) myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-β and TLR9 responses in myofibroblasts collaborate to drive rapid progression of IPF. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
The Gas6/TAM System and Multiple Sclerosis.

Science.gov (United States)

Bellan, Mattia; Pirisi, Mario; Sainaghi, Pier Paolo

2016-10-28

Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done in the understanding of the biological activities of this highly pleiotropic system, which plays a role in the regulation of immune response, inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Recent findings have further related Gas6 and TAM receptors to neuroinflammation in general and, specifically, to multiple sclerosis (MS). In this paper, we review the biology of the Gas6/TAM system and the current evidence supporting its potential role in the pathogenesis of MS.
Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism

DEFF Research Database (Denmark)

Rao, Fangwen; Wessel, Jennifer; Wen, Gen

2007-01-01

biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine...... hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable......, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention...
RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

Directory of Open Access Journals (Sweden)

Azamat Aslanukov

2006-10-01

Full Text Available The Ran-binding protein 2 (RanBP2 is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/- are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/- mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.
RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

Science.gov (United States)

Aslanukov, Azamat; Bhowmick, Reshma; Guruju, Mallikarjuna; Oswald, John; Raz, Dorit; Bush, Ronald A; Sieving, Paul A; Lu, Xinrong; Bock, Cheryl B; Ferreira, Paulo A

2006-10-01

The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/-) are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/-) mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.
Identification of novel genetic loci for osteoporosis and/or rheumatoid arthritis using cFDR approach.

Directory of Open Access Journals (Sweden)

Rou Zhou

Full Text Available There are co-morbidity between osteoporosis (OP and rheumatoid arthritis (RA. Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck BMD (a major risk factor for osteoporosis (n = 53,236 and RA (n = 80,799. The conditional quantile-quantile (Q-Q plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR. We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.
The ubiquitin ligase Cullin5^SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation

DEFF Research Database (Denmark)

Paul, Indranil; Batth, Tanveer S; Iglesias-Gato, Diego

2017-01-01

SOCS2 is a pleiotropic E3 ligase. Its deficiency is associated with gigantism and organismal lethality upon inflammatory challenge. However, mechanistic understanding of SOCS2 function is dismal due to our unawareness of its protein substrates. We performed a mass spectrometry based proteomic pro...
On the evolution of pesticide resistance in Phytophthora infestans : an experimental evolution approach

NARCIS (Netherlands)

Bosmans, S.

2009-01-01

Resistance to antimicrobial agents is a serious problem for both medicine and agriculture. The initial success of such toxins is due to absence of resistant genotypes in pathogen populations before treatment. The initial low frequency of resistance may be explained by negative pleiotropic effects of

Ankaferd Blood Stopper induces apoptosis and regulates PAR1 and ...

African Journals Online (AJOL)

Background: Ankaferd Blood Stopper (ABS) is a preparation of plant extracts originally used as a hemostatic agent. It has pleiotropic effects in many cellular processes such as cell cycle regulation, apoptosis, angiogenesis, signal transduction, inflammation, immunologic processes and metabolic pathways as well as ...
The promise of genomics in the study of plant-pollinator interactions

Science.gov (United States)

2013-01-01

Flowers exist in exceedingly complex fitness landscapes, in which subtle variation in each trait can affect the pollinators, herbivores and pleiotropically linked traits in other plant tissues. A whole-genome approach to flower evolution will help our understanding of plant-pollinator interactions. PMID:23796166
Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

DEFF Research Database (Denmark)

Dias, Vinali L; Rajpert-De Meyts, Ewa; McLachlan, Robert

2009-01-01

Activin is a pleiotropic growth factor belonging to the transforming growth factor-beta (TGFB) superfamily of signaling molecules. Regulated activin signaling is known to influence several steps in rodent male gamete differentiation. TGFB ligand isoforms, TGFB1-B3, also influence germ cell surviv...
Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features

NARCIS (Netherlands)

Niturad, Cristina Elena; Lev, Dorit; Kalscheuer, Vera M; Charzewska, Agnieszka; Schubert, Julian; Lerman-Sagie, Tally; Kroes, Hester Y.; Oegema, Renske; Traverso, Monica; Specchio, Nicola; Lassota, Maria; Chelly, Jamel; Bennett-Back, Odeya; Carmi, Nirit; Koffler-Brill, Tal; Iacomino, Michele; Trivisano, Marina; Capovilla, Giuseppe; Striano, Pasquale; Nawara, Magdalena; Rzoca, Sylwia; Fischer, Ute; Bienek, Melanie; Jensen, Corinna; Hu, Hao; Thiele, Holger; Altmüller, Janine; Krause, Roland; May, Patrick; Becker, Felicitas; Balling, Rudi; Biskup, Saskia; Haas, Stefan A.; Nürnberg, Peter; Van Gassen, Koen L.I.; Lerche, Holger; Zara, Federico; Maljevic, Snezana; Leshinsky-Silver, Esther

2017-01-01

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical
A Novel Pleiotropic Anti-Inflammatory Drug to Reduce ARDS Incidence

Science.gov (United States)

2017-07-01

the gut , which significantly reduced TRB-N0224 adsorption. To solve this problem we have requested a one-year no-cost extension to use an intravenous...use or care of human subjects, vertebrate animals, biohazards, and/or select agents: Nothing to report. Products: Nothing to report Participants
PprA, a pleiotropic protein for radioresistance, works through DNA ...

Indian Academy of Sciences (India)

GFP-PprA fusion was subcultured in fresh TYG medium containing spectinomycin (75 .... action on the damaged site in the genome. These results sug- gested that ... toroidal structure, which once upon a time was thought to be the basis for its ...
Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production

Czech Academy of Sciences Publication Activity Database

Pecinová, Alena; Drahota, Zdeněk; Kovalčíková, Jana; Kovářová, Nikola; Pecina, Petr; Alán, Lukáš; Zima, Michal; Houštěk, Josef; Mráček, Tomáš

2017-01-01

Roč. 2017, č. 2017 (2017), č. článku 7038603. ISSN 1942-0900 R&D Projects: GA ČR(CZ) GA16-12726S; GA MŠk(CZ) LL1204 Institutional support: RVO:67985823 Keywords : brown adipose tissue * mitochondria * respiratory chain oxidoreductases * mitochondrial glycerophosphate dehydrogenase * superoxide production * biguanides * metformin Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 4.593, year: 2016
Cytosine hypomethylation at CHG and CHH sites in the pleiotropic ...

Indian Academy of Sciences (India)

Ribonuclease/transcriptional repressor (R/TR). 59. MULTICOPY SUPRESSOR OF IRA1 (MSI). 60. AP2-domain DNA-binding protein (ORCA3). 61. LEAFY PETIOLE (LEP). 62. GLYCINE-RICH PROTEIN 2B (ATGRP2B). 63. LEAFY COTYLEDON 2 (LEC2). 64. YELLOW-LEAF-SPECIFIC GENE 9 (YLS9). 65. TRANSCRIPTION ...
Cytosine hypomethylation at CHG and CHH sites in the pleiotropic ...

Indian Academy of Sciences (India)

2013-12-16

Dec 16, 2013 ... The abasic gap left behind by the demethylase action is filled by any of the DNA ...... Inactivation of a DNA methylation pathway in maize reproduc- tive organs ... of diversity for morphological and yield related traits among.
Cytosine hypomethylation at CHG and CHH sites in the pleiotropic ...

Indian Academy of Sciences (India)

Keywords. bisulphite sequencing; CMT3; DNA demethylases; DNA methyl transferases; demethylation; excision repair; mutagenic hot spots; phylogenetic relationships; 5S rDNA; 18S rDNA; RdDM; spontaneous mutagenesis.
Pleiotropic functions of magnetic nanoparticles for ex vivo gene transfer.

Science.gov (United States)

Kami, Daisuke; Kitani, Tomoya; Kishida, Tsunao; Mazda, Osam; Toyoda, Masashi; Tomitaka, Asahi; Ota, Satoshi; Ishii, Ryuga; Takemura, Yasushi; Watanabe, Masatoshi; Umezawa, Akihiro; Gojo, Satoshi

2014-08-01

Gene transfer technique has various applications, ranging from cellular biology to medical treatments for diseases. Although nonviral vectors, such as episomal vectors, have been developed, it is necessary to improve their gene transfer efficacy. Therefore, we attempted to develop a highly efficient gene delivery system combining an episomal vector with magnetic nanoparticles (MNPs). In comparison with the conventional method using transfection reagents, polyethylenimine-coated MNPs introduced episomal vectors more efficiently under a magnetic field and could express the gene in mammalian cells with higher efficiency and for longer periods. This novel in vitro separation method of gene-introduced cells utilizing the magnetic property of MNPs significantly facilitated the separation of cells of interest. Transplanted cells in vivo were detected using magnetic resonance. These results suggest that MNPs play multifunctional roles in ex vivo gene transfer, such as improvement of gene transfer efficacy, separation of cells, and detection of transplanted cells. This study convincingly demonstrates enhanced efficiency of gene transfer via magnetic nanoparticles. The method also enables magnetic sorting of cells positive for the transferred gene, and in vivo monitoring of the process with MRI. Copyright © 2014 Elsevier Inc. All rights reserved.
The Pleiotropic Role of L1CAM in Tumor Vasculature

Directory of Open Access Journals (Sweden)

Francesca Angiolini

2017-01-01

Full Text Available Angiogenesis, the formation of new vessels, is a key step in the development, invasion, and dissemination of solid tumors and, therefore, represents a viable target in the context of antitumor therapy. Indeed, antiangiogenic approaches have given promising results in preclinical models and entered the clinical practice. However, in patients, the results obtained so far with antiangiogenic drugs have not completely fulfilled expectations, especially because their effect has been transient with tumors developing resistance and evasion mechanisms. A better understanding of the mechanisms that underlie tumor vascularization and the functional regulation of cancer vessels is a prerequisite for the development of novel and alternative antiangiogenic treatments. The L1 cell adhesion molecule (L1CAM, a cell surface glycoprotein previously implicated in the development and plasticity of the nervous system, is aberrantly expressed in the vasculature of various cancer types. L1CAM plays multiple pro-angiogenic roles in the endothelial cells of tumor-associated vessels, thus emerging as a potential therapeutic target. In addition, L1CAM prevents the maturation of cancer vasculature and its inhibition promotes vessel normalization, a process that is thought to improve the therapeutic response of tumors to cytotoxic drugs. We here provide an overview on tumor angiogenesis and antiangiogenic therapies and summarize the current knowledge on the biological role of L1CAM in cancer vasculature. Finally, we highlight the clinical implications of targeting L1CAM as a novel antiangiogenic and vessel-normalizing approach.
Quaternary ammonium salt N-(dodecyloxycarboxymethyl)- N,N,N ...

Indian Academy of Sciences (India)

2016-10-22

Oct 22, 2016 ... growth. The phenotype of this mutant was pleiotropic. The IMR mutant exhibited resistance to ethanol, osmotic shock ... environmental conditions, e.g., temperature or salinity. (Anthoni ... are used in anesthesiology as muscle relaxants (Lee 2001). ... against yeast depends on a medium pH; lower inhibitory.
Integration of gene expression profiling of hypothalamic arcuate nucleus with genome-wide associations to discover functional variants associated with age at puberty in gilts

Science.gov (United States)

Age at puberty (AP) in gilts is a moderately heritable trait (h2 = 0.37) and the earliest indicator of sow reproductive longevity. Therefore, quantifying the pleiotropic sources that influence both AP and reproductive longevity is important in understanding the differences in sow fertility. In this ...
Quantitative Trait Loci Affecting Calving Traits in Danish Holstein Cattle

DEFF Research Database (Denmark)

Thomasen, J R; Guldbrandtsen, B; Sørensen, P

2008-01-01

The objectives of this study were 1) to detect quantitative trait loci (QTL) affecting direct and maternal calving traits at first calving in the Danish Holstein population, 2) to distinguish between pleiotropic and linked QTL for chromosome regions affecting more than one trait, and 3) to detect...
Transcriptome analysis of temporal regulation of carbon metabolism by CcpA in Bacillus subtilis reveals additional target genes

NARCIS (Netherlands)

Lulko, Andrzej T.; Buist, Girbe; Kok, Jan; Kuipers, Oscar P.

2007-01-01

The pleiotropic regulator of carbon metabolism in Grampositive bacteria, CcpA, regulates gene expression by binding to so-called cre elements, which are located either upstream or in promoter regions, or in open-reading frames. In this study we compared the transcriptomes of Bacillus subtilis 168
Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

PprA, a pleiotropic protein for radioresistance, works through DNA gyrase and shows cellular dynamics during postirradiation recovery in Deinococcus radiodurans .... Gene interactions and genetics of blast resistance and yield attributes in rice (Oryza ... Molecular mapping of a stripe rust resistance gene in wheat line C51.
Fasting, circadian rhythms, and time restricted feeding in healthy lifespan

Science.gov (United States)

Longo, Valter D.; Panda, Satchidananda

2016-01-01

Summary Feeding in most animals is confined to a defined period, leaving short periods of fasting that coincide with sleep. Fasting enables organisms to enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which feeding time is restricted to certain hours of the day, allows the daily fasting period to last >12 h, thus imparting pleiotropic benefits in multiple organisms. Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMD, both basic science and translational research are warranted to develop fasting-associated interventions into effective and inexpensive treatments with the potential to improve healthspan. PMID:27304506
Recent insights into Protein Phosphatase 2A structure and regulation: the reasons why PP2A is no longer considered as a lazy passive housekeeping enzyme

Directory of Open Access Journals (Sweden)

Martin, M.

2010-01-01

Full Text Available Although intracellular signal transduction is often portrayed as a protein kinase "domino effect", the counterbalancing function of phosphatases, and thus the control of phosphatase activity, is equally relevant to proper regulation of cellular function. Protein Phosphatase 2A (PP2A is a widely expressed family of protein phosphatases made of a core dimer, composed of a catalytic (C subunit and a structural (A subunit, in association with a third variable regulatory (B subunit. Although viewed as a constitutive housekeeping enzyme in the past, PP2A is a highly regulated phosphatase and is emerging as an important regulator of multiple cellular processes involving protein phosphorylation. The regulation of PP2A is mainly accomplished by the identity of the regulatory B-type subunit, which determines substrate specificity, subcellular localization and catalytic activity of the PP2A holoenzyme. In agreement with this, recent findings on the structure and post-translational modifications of PP2A emphasize the importance of PP2A holoenzyme composition in its regulation and pleiotropic activities.
Antioxidant Functions of the Aryl Hydrocarbon Receptor

Directory of Open Access Journals (Sweden)

Cornelia Dietrich

2016-01-01

Full Text Available The aryl hydrocarbon receptor (AhR is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

Science.gov (United States)

Bivalacqua, Trinity J; Musicki, Biljana; Hsu, Lewis L; Berkowitz, Dan E; Champion, Hunter C; Burnett, Arthur L

2013-01-01

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.
Differential cellular responses by oncogenic levels of c-Myc expression in long-term confluent retinal pigment epithelial cells.

Science.gov (United States)

Wang, Yiping; Cheng, Xiangdong; Samma, Muhammad Kaleem; Kung, Sam K P; Lee, Clement M; Chiu, Sung Kay

2018-06-01

c-Myc is a highly pleiotropic transcription factor known to control cell cycle progression, apoptosis, and cellular transformation. Normally, ectopic expression of c-Myc is associated with promoting cell proliferation or triggering cell death via activating p53. However, it is not clear how the levels of c-Myc lead to different cellular responses. Here, we generated a series of stable RPE cell clones expressing c-Myc at different levels, and found that consistent low level of c-Myc induced cellular senescence by activating AP4 in post-confluent RPE cells, while the cells underwent cell death at high level of c-Myc. In addition, high level of c-Myc could override the effect of AP4 on cellular senescence. Further knockdown of AP4 abrogated senescence-like phenotype in cells expressing low level of c-Myc, and accelerated cell death in cells with medium level of c-Myc, indicating that AP4 was required for cellular senescence induced by low level of c-Myc.
Tryptophan metabolism in tsetse flies and the consequences of its derangement

Directory of Open Access Journals (Sweden)

R. H. Gooding

1987-01-01

Full Text Available Literature comparing salmon and wild type Glossina morsitans morsitans and that comparing tan and wild type Glossina palpalis palpalis is reviewed. New information is presented on behaviour and biochemistry of salmon and wild type G. m. morsitans. The eye color mutants result from two lesions in the tryptophan to xanthommatin pathway: lack of tryptophan oxygenase in G. m morsitans and failure to produce or retain xanthommatin in eyes (but not in testes of G. p. palpalis. The salmon allele in G. m. morsitans is pleiotropic and profoundly affects many aspects of fly biology including longevity, reproductive capacity, vision, vectorial capacity and duration of flight, but not circadian rhythms. The tan allele in G. p. palpalis has little effect upon the biology of flies under laboratory conditions, except that tan flies appear less active than normal. Adult tsetse flies metabolize tryptophan to kynurenine which is excreted; fluctuations in activities of the enzymes producing kynurenine suggest this pathway is under metabolic control.
Interleukin-6 myokine signaling in skeletal muscle

DEFF Research Database (Denmark)

Muñoz-Cánoves, Pura; Scheele, Camilla; Pedersen, Bente K

2013-01-01

Interleukin (IL)-6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL-6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL-6 signaling has b...
Fish oil and omega-3 fatty acids in cardiovascular disease: do they really work?

NARCIS (Netherlands)

Kromhout, D.; Yasuda, S.; Geleijnse, J.M.; Shimokawa, H.

2012-01-01

Omega-3 fatty acids, which are found abundantly in fish oil, exert pleiotropic cardiometabolic effects with a diverse range of actions. The results of previous studies raised a lot of interest in the role of fish oil and omega-3 fatty acids in primary and secondary prevention of cardiovascular
Differential Effects of Long Term FTY720 Treatment on Endothelial versus Smooth Muscle Cell Signaling to S1P in Rat Mesenteric Arteries

NARCIS (Netherlands)

Shishavan, Mahdi Hamidi; Bidadkosh, Arash; Yazdani, Saleh; Lambooy, Sebastiaan; van den Born, Jacob; Buikema, Hendrik; Henning, Robert H.; Deelman, Leo E.

2016-01-01

The sphingosine-1-phosphate (S1P) analog FTY720 exerts pleiotropic effects on the cardiovascular system and causes down-regulation of S1P receptors. Myogenic constriction is an important mechanism regulating resistance vessel function and is known to be modulated by S1P. Here we investigated
Celiac Disease Genetics : Past, Present and Future Challenges

NARCIS (Netherlands)

Wijmenga, Cisca; Gutierrez Achury, Javier

In the past few years there has been enormous progress in unraveling the genetic basis of celiac disease (CD). Apart from the well-known association to HLA, there are currently 40 genomic loci associated to CD. Most of these loci show pleiotropic effects across many autoimmune diseases and highlight
Genome-wide identification, functional analysis and expression ...

African Journals Online (AJOL)

The plant pleiotropic drug resistance (PDR) family of ATP-binding cassette (ABC) transporters has comprehensively been researched in relation to transport of antifungal agents and resistant pathogens. In our study, analyses of the whole family of PDR genes present in the potato genome were provided. This analysis ...
MicroRNA Gene Regulatory Networks in Peripheral Nerve Sheath Tumors

Science.gov (United States)

2012-09-01

1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202- 4302. Respondents should be aware that notwithstanding any other provision of law , no...Reinhardt F, Benaich N, Calogrias D, Szasz AM, Wang ZC, Brock JE, Richardson AL, Weinberg RA (2009) A pleiotropically acting microRNA, miR-31, inhibits breast
Genome-wide identification, functional analysis and expression ...

African Journals Online (AJOL)

Fuyou Fu

2013-07-24

Jul 24, 2013 ... Key words: ABC transporter, potato, pleiotropic drug resistance (PDR), RNA-seq. INTRODUCTION ..... of relative transcript accumulation of each of 55 PDR genes as determined by RNA-seq analysis are presented as a heatmap, with ... specificities provide clues to the endogenous function of the individual ...
Primary cilia and coordination of receptor tyrosine kinase (RTK) and transforming growth factor β (TGF-β) signaling

DEFF Research Database (Denmark)

Christensen, Søren Tvorup; Morthorst, Stine Kjær; Mogensen, Johanne Bay

2017-01-01

are at the root of a pleiotropic group of diseases and syndromic disorders called ciliopathies. In this review, we present an overview of primary cilia-mediated regulation of receptor tyrosine kinase (RTK) and transforming growth factor β (TGF-β) signaling. Further, we discuss how defects in the coordination...
Nutritional habits, lifestyle, and genetic predisposition in cardiovascular and metabolic traits in Turkish population.

Science.gov (United States)

Karaca, Sefayet; Erge, Sema; Cesuroglu, Tomris; Polimanti, Renato

2016-06-01

Cardiovascular and metabolic traits (CMT) are influenced by complex interactive processes including diet, lifestyle, and genetic predisposition. The present study investigated the interactions of these risk factors in relation to CMTs in the Turkish population. We applied bootstrap agglomerative hierarchical clustering and Bayesian network learning algorithms to identify the causative relationships among genes involved in different biological mechanisms (i.e., lipid metabolism, hormone metabolism, cellular detoxification, aging, and energy metabolism), lifestyle (i.e., physical activity, smoking behavior, and metropolitan residency), anthropometric traits (i.e., body mass index, body fat ratio, and waist-to-hip ratio), and dietary habits (i.e., daily intakes of macro- and micronutrients) in relation to CMTs (i.e., health conditions and blood parameters). We identified significant correlations between dietary habits (soybean and vitamin B12 intakes) and different cardiometabolic diseases that were confirmed by the Bayesian network-learning algorithm. Genetic factors contributed to these disease risks also through the pleiotropy of some genetic variants (i.e., F5 rs6025 and MTR rs180508). However, we also observed that certain genetic associations are indirect since they are due to the causative relationships among the CMTs (e.g., APOC3 rs5128 is associated with low-density lipoproteins cholesterol and, by extension, total cholesterol). Our study applied a novel approach to integrate various sources of information and dissect the complex interactive processes related to CMTs. Our data indicated that complex causative networks are present: causative relationships exist among CMTs and are affected by genetic factors (with pleiotropic and non-pleiotropic effects) and dietary habits. Copyright © 2016 Elsevier Inc. All rights reserved.
Autosomal mutations affecting Y chromosome loops in Drosophila melanogaster

Directory of Open Access Journals (Sweden)

Petrucci Romano

2008-04-01

Full Text Available Abstract Background The Y chromosome of Drosophila melanogaster harbors several genes required for male fertility. The genes for these fertility factors are very large in size and contain conspicuous amounts of repetitive DNA and transposons. Three of these loci (ks-1, kl-3 and kl-5 have the ability to develop giant lampbrush-like loops in primary spermatocytes, a cytological manifestation of their active state in these cells. Y-loops bind a number of non-Y encoded proteins, but the mechanisms regulating their development and their specific functions are still to be elucidated. Results Here we report the results of a screen of 726 male sterile lines to identify novel autosomal genes controlling Y-loop function. We analyzed mutant testis preparations both in vivo and by immunofluorescence using antibodies directed against Y-loop-associated proteins. This screen enabled us to isolate 17 mutations at 15 loci whose wild-type function is required for proper Y-loop morphogenesis. Six of these loci are likely to specifically control loop development, while the others display pleiotropic effects on both loops and meiotic processes such as spermiogenesis, sperm development and maturation. We also determined the map position of the mutations affecting exclusively Y-loop morphology. Conclusion Our cytological screening permitted us to identify novel genetic functions required for male spermatogenesis, some of which show pleiotropic effects. Analysis of these mutations also shows that loop development can be uncoupled from meiosis progression. These data represent a useful framework for the characterization of Y-loop development at a molecular level and for the study of the genetic control of heterochromatin.
Fell-Muir lecture: connective tissue growth factor (CCN2) – a pernicious and pleiotropic player in the development of kidney fibrosis

Science.gov (United States)

Mason, Roger M

2013-01-01

Connective tissue growth factor (CTGF, CCN2) is a member of the CCN family of matricellular proteins. It interacts with many other proteins, including plasma membrane proteins, modulating cell function. It is expressed at low levels in normal adult kidney cells but is increased in kidney diseases, playing important roles in inflammation and in the development of glomerular and interstitial fibrosis in chronic disease. This review reports the evidence for its expression in human and animal models of chronic kidney disease and summarizes data showing that anti-CTGF therapy can successfully attenuate fibrotic changes in several such models, suggesting that therapies targeting CTGF and events downstream of it in renal cells may be useful for the treatment of human kidney fibrosis. Connective tissue growth factor stimulates the development of fibrosis in the kidney in many ways including activating cells to increase extracellular matrix synthesis, inducing cell cycle arrest and hypertrophy, and prolonging survival of activated cells. The relationship between CTGF and the pro-fibrotic factor TGFβ is examined and mechanisms by which CTGF promotes signalling by the latter are discussed. No specific cellular receptors for CTGF have been discovered but it interacts with and activates several plasma membrane proteins including low-density lipoprotein receptor-related protein (LRP)-1, LRP-6, tropomyosin-related kinase A, integrins and heparan sulphate proteoglycans. Intracellular signalling and downstream events triggered by such interactions are reviewed. Finally, the relationships between CTGF and several anti-fibrotic factors, such as bone morphogenetic factor-4 (BMP4), BMP7, hepatocyte growth factor, CCN3 and Oncostatin M, are discussed. These may determine whether injured tissue heals or progresses to fibrosis. PMID:23110747
Cyclic versus Hemi-Bastadins. Pleiotropic Anti-Cancer Effects: from Apoptosis to Anti-Angiogenic and Anti-Migratory Effects

Directory of Open Access Journals (Sweden)

Peter Proksch

2013-03-01

Full Text Available Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. We are currently developing a specific inhalation formulation for DBHB enabling this compound to avoid plasmatic albumin binding through its direct delivery to the lungs to combat primary as well as secondary (metastases tumors.
Semaphorin7A and its receptors: pleiotropic regulators of immune cell function, bone homeostasis, and neural development.

Science.gov (United States)

Jongbloets, Bart C; Ramakers, Geert M J; Pasterkamp, R Jeroen

2013-03-01

Semaphorins form a large, evolutionary conserved family of cellular guidance signals. The semaphorin family contains several secreted and transmembrane proteins, but only one GPI-anchored member, Semaphorin7A (Sema7A). Although originally identified in immune cells, as CDw108, Sema7A displays widespread expression outside the immune system. It is therefore not surprising that accumulating evidence supports roles for this protein in a wide variety of biological processes in different organ systems and in disease. Well-characterized biological effects of Sema7A include those during bone and immune cell regulation, neuron migration and neurite growth. These effects are mediated by two receptors, plexinC1 and integrins. However, most of what is known today about Sema7A signaling concerns Sema7A-integrin interactions. Here, we review our current knowledge of Sema7A function and signaling in different organ systems, highlighting commonalities between the cellular effects and signaling pathways activated by Sema7A in different cell types. Furthermore, we discuss a potential role for Sema7A in disease and provide directions for further research. Copyright © 2013 Elsevier Ltd. All rights reserved.
Functional genetics of intraspecific ecological interactions in Arabidopsis thaliana.

Science.gov (United States)

Wolf, Jason B; Mutic, Joshua J; Kover, Paula X

2011-05-12

Studying the genetic basis of traits involved in ecological interactions is a fundamental part of elucidating the connections between evolutionary and ecological processes. Such knowledge allows one to link genetic models of trait evolution with ecological models describing interactions within and between species. Previous work has shown that connections between genetic and ecological processes in Arabidopsis thaliana may be mediated by the fact that quantitative trait loci (QTL) with 'direct' effects on traits of individuals also have pleiotropic 'indirect' effects on traits expressed in neighbouring plants. Here, we further explore these connections by examining functional relationships between traits affected directly and indirectly by the same QTL. We develop a novel approach using structural equation models (SEMs) to determine whether observed pleiotropic effects result from traits directly affected by the QTL in focal individuals causing the changes in the neighbours' phenotypes. This hypothesis was assessed using SEMs to test whether focal plant phenotypes appear to mediate the connection between the focal plants' genotypes and the phenotypes of their neighbours, or alternatively, whether the connection between the focal plants' genotypes and the neighbours' phenotypes is mediated by unmeasured traits. We implement this analysis using a QTL of major effect that maps to the well-characterized flowering locus, FRIGIDA. The SEMs support the hypothesis that the pleiotropic indirect effects of this locus arise from size and developmental timing-related traits in focal plants affecting the expression of developmental traits in their neighbours. Our findings provide empirical insights into the genetics and nature of intraspecific ecological interactions. Our technique holds promise in directing future work into the genetic basis and functional relationship of traits mediating and responding to ecological interactions.
Mitochondrial functionality in female reproduction

Directory of Open Access Journals (Sweden)

Łukasz Gąsior

2017-01-01

Full Text Available In most animal species female germ cells are the source of mitochondrial genome for the whole body of individuals. As a source of mitochondrial DNA for future generations the mitochondria in the female germ line undergo dynamic quantitative and qualitative changes. In addition to maintaining the intact template of mitochondrial genome from one generation to another, mitochondrial role in oocytes is much more complex and pleiotropic. The quality of mitochondria determines the ability of meiotic divisions, fertilization ability, and activation after fertilization or sustaining development of a new embryo. The presence of normal number of functional mitochondria is also crucial for proper implantation and pregnancy maintaining. This article addresses issues of mitochondrial role and function in mammalian oocyte and presents new approaches in studies of mitochondrial function in female germ cells.
3-Bromopyruvate: a novel antifungal agent against the human pathogen Cryptococcus neoformans.

Science.gov (United States)

Dyląg, Mariusz; Lis, Paweł; Niedźwiecka, Katarzyna; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

2013-05-03

We have investigated the antifungal activity of the pyruvic acid analogue: 3-bromopyruvate (3-BP). Growth inhibition by 3-BP of 110 strains of yeast-like and filamentous fungi was tested by standard spot tests or microdilution method. The human pathogen Cryptococcus neoformans exhibited a low Minimal Inhibitory Concentration (MIC) of 0.12-0.15 mM 3-BP. The high toxicity of 3-BP toward C. neoformans correlated with high intracellular accumulation of 3-BP and also with low levels of intracellular ATP and glutathione. Weak cytotoxicity towards mammalian cells and lack of resistance conferred by the PDR (Pleiotropic Drug Resistance) network in the yeast Saccharomyces cerevisiae, are other properties of 3-BP that makes it a novel promising anticryptococcal drug. Copyright © 2013 Elsevier Inc. All rights reserved.
Low molecular weight protein tyrosine phosphatases control antibiotic production in Streptomyces coelicolor A3(2)

DEFF Research Database (Denmark)

Sohoni, Sujata Vijay; Lieder, Sarah; Bapat, Prashant Madhusudhan

2014-01-01

3700 was established usingpara-nitrophenyl phosphate and the tyrosine-phosphorylated protein PtkA from Bacillus subtilis as substrates. Theoptimum pH for the Sco3700 phosphatase activity was 6.8, and KM for pNPP was 14.3 mM compared to pH 6.0and KM0.75 mM for PtpA. The potential of Sco3700...... of ACT in the ptpA over expression strain. Furthermore, a significantly earlier onset of ACT productionwas observed when ptpA was over expressed. Sco3700 overexpression had a pleiotropic effect on the cell, and thestrain exhibited lower productivities and final concentrations of antibiotics. We conclude...... that Sco3700 is indeed atyrosine phosphatase, and it contributes to regulation of antibiotic production in S. coelicolor affecting the timing ofonset of the antibiotic production...

Novel insights in preventing Gram-negative bacterial infection in cirrhotic patients: review on the effects of GM-CSF in maintaining homeostasis of the immune system.

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Xu, Dong; Zhao, Manzhi; Song, Yuhu; Song, Jianxin; Huang, Yuancheng; Wang, Junshuai

2015-01-01

Cirrhotic patients with dysfunctional and/or low numbers of leukocytes are often infected with bacteria, especially Gram-negative bacteria, which is characterized by producing lipopolysaccharide (LPS). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that influences the production, maturation, function, and survival of various immune cells. In this paper, we reviewed not only Toll-like receptors 4 (TLR4) signaling pathway and its immunological effect, but also the specific stimulating function and autocrine performance of GM-CSF on hematopoietic cells, as well as the recent discovery of innate response activator-B cells in protection against microbial sepsis and the direct LPS-TLR4 signaling on hematopoiesis. Thus we concluded that GM-CSF might play important roles in preventing Gram-negative bacterial infections in cirrhotic patients through maintaining immune system functions and homeostasis.
Role of transforming growth factor-beta (TGF) beta in the physiopathology of rheumatoid arthritis.

Science.gov (United States)

Gonzalo-Gil, Elena; Galindo-Izquierdo, María

2014-01-01

Transforming growth factor-beta (TGF-β) is a cytokine with pleiotropic functions in hematopoiesis, angiogenesis, cell proliferation, differentiation, migration and apoptosis. Although its role in rheumatoid arthritis is not well defined, TGF-β activation leads to functional immunomodulatory effects according to environmental conditions. The function of TGF-β in the development of arthritis in murine models has been extensively studied with controversial results. Recent findings point to a non-relevant role for TGF-β in a mice model of collagen-induced arthritis. The study of TGF-β on T-cell responses has shown controversial results as an inhibitor or promoter of the inflammatory response. This paper presents a review of the role of TGF-β in animal models of arthritis. Copyright © 2013 Elsevier España, S.L. All rights reserved.
New therapeutic options for the metabolic syndrome: what's next?

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Flordellis, Christodoulos S; Ilias, Ioannis; Papavassiliou, Athanasios G

2005-08-01

The metabolic syndrome (MSX), characterized by obesity, insulin resistance, dyslipidemia and hypertension, increases the risk of cardiovascular morbidity and mortality. It has recently been hypothesized that MSX and type 2 diabetes are caused by triglyceride and long-chain fatty acid accumulation in liver, muscle, pancreatic islets and selected brain areas. This lipocentric approach is integrated with analysis of inflammation associated with end-organ damage, including the vascular wall. Genes and proteins contributing to insulin resistance, beta cell dysfunction and vascular wall damage have been identified. Transcription factors and coactivators, including peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 are crucial in mediating insulin resistance and accelerating vascular wall inflammation, and represent promising therapeutic targets. New pharmacological strategies include dual PPARalpha/gamma agonists, drugs with pleiotropic effects or combination therapies.
[All diuretics used in the treatment of hypertension are not the same].

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Asil, Serkan; Atalar, Enver

2017-01-01

Diuretics have been used for years to treat hypertension as both a monotherapy and in combination. Hydrochlorothiazide, indapamide, and chlorthalidone have frequently been considered in the same category as thiazide diuretics, but there is no evidence that their activities are similar. Studies have shown that chlorthalidone and indapamide reduce cardiovascular morbidity and mortality; however, there is no study indicating that hydrochlorothiazide has beneficial effects on cardiovascular outcomes such as myocardial infarction, renal failure, stroke, or death. Hydrochlorothiazide has less effect on blood pressure, a high risk of metabolic side effects, and may not have pleiotropic effects. As a result, it is not accurate to evaluate chlorthalidone and indapamide as similar to thiazide diuretics. Indapamide or chlorthalidone is a better choice of diuretic for use in the treatment of hypertension.
Convergent Synthesis of Two Fluorescent Ebselen-Coumarin Heterodimers.

Science.gov (United States)

Küppers, Jim; Schulz-Fincke, Anna Christina; Palus, Jerzy; Giurg, Mirosław; Skarżewski, Jacek; Gütschow, Michael

2016-07-08

The organo-seleniumdrug ebselen exhibits a wide range of pharmacological effects that are predominantly due to its interference with redox systems catalyzed by seleno enzymes, e.g., glutathione peroxidase and thioredoxin reductase. Moreover, ebselen can covalently interact with thiol groups of several enzymes. According to its pleiotropic mode of action, ebselen has been investigated in clinical trials for the prevention and treatment of different ailments. Fluorescence-labeled probes containing ebselen are expected to be suitable for further biological and medicinal studies. We therefore designed and synthesized two coumarin-tagged activity-based probes bearing the ebselen warhead. The heterodimers differ by the nature of the spacer structure, for which-in the second compound-a PEG/two-amide spacer was introduced. The interaction of this probe and of ebselen with two cysteine proteases was investigated.
Computational identification of fertility functions of bovine Reprimo ...

African Journals Online (AJOL)

Improvement in fertility is possible through gene assisted selection. Cattle fertility and genes underlying it should be thoroughly studied and exploited to find solution to declining cattle fertility. Reprimo (RPRM) gene is a pleiotropic gene involved in suppression of cancer, regulation of mitotic cell cycle, cell cycle arrest and ...
Sugar - hormone crosstalk in seed development: Two redundant pathways of IAA biosynthesis are regulated differentially in the invertase-deficient miniature1 (mn1) seed mutant in maize

Science.gov (United States)

The miniature1 (mn1) seed phenotype is a loss-of-function mutation at the Mn1 locus that encodes a cell wall invertase; its deficiency leads to pleiotropic changes including altered sugar levels and decreased levels of IAA throughout seed development. To understand the molecular details of such suga...
Induced mutations of rust resistance genes in wheat

International Nuclear Information System (INIS)

McIntosh, R.A.

1983-01-01

Induced mutations are being used as a tool to study genes for resistance in wheat. It was found that Pm1 can be separated from Lr20 and Sr15, but these two react like a single pleiotropic gene. Mutants were further examined in crosses and backmutations have been attempted. (author)
Clinical utility of a 377 gene custom next-generation sequencing ...

Indian Academy of Sciences (India)

Epilepsy is one of the most common neurological disorders with about 500 genes thought to be involved across the phenotypic spectrum (Busch et al. 2014; Ran et al. 2014), which includes monogenic, multigenic, epistatic and pleiotropic phenotype manifestations (Busch et al. 2014; Thomas et al. 2014), driving the need ...
Dicty_cDB: Contig-U12372-1 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available 2e-11 AP005795_18( AP005795 |pid:none) Oryza sativa Japonica Group genom... 74 2e-11 AY155346_1( AY155346 |pid:none) Bactrocera cucu...rbitae white eye pr... 73 2e-11 (Q9M9E1) RecName: Full=Pleiotropic drug resistance
Identification and functional characterization of the Lactococcus lactis CodY-regulated branched-chain amino acid permease BcaP (CtrA)

NARCIS (Netherlands)

den Hengst, CD; Groeneveld, M; Kuipers, OP; Kok, J; Hengst, Chris D. den

Transcriptome analyses have previously revealed that a gene encoding the putative amino acid transporter CtrA (YhdG) is one of the major targets of the pleiotropic regulator CodY in Lactococcus lactis and Bacillus subtilis. The role of ctrA in L. lactis was further investigated with respect to both
Human Lipoxygenase Pathway Gene Variation and Association with Markers of Subclinical Atherosclerosis in the Diabetes Heart Study

Directory of Open Access Journals (Sweden)

Kathryn P. Burdon

2010-01-01

Conclusions. Polymorphisms within ALOX12, ALOX5, and ALOX5AP are genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease.
Altered Middle Lamella Homogalacturonan and Disrupted Deposition of (1¿5)-a -_L-Arabinan in the Pericarp of Cnr, a Ripening Mutant of Tomato¹

DEFF Research Database (Denmark)

Orfila, C.; Seymour, G.B; Willats, William George Tycho

2001-01-01

Cnr (colorless non-ripening) is a pleiotropic tomato (Lycopersicon esculentum) fruit ripening mutant with altered tissue properties including weaker cell-to-cell contacts in the pericarp (A.J. Thompson, M. Tor, C.S. Barry, J. Vrebalov, C. Orfila, M.C. Jarvis, J.J. Giovannoni, D. Grierson, G...
ATM directs DNA damage responses and proteostasis via genetically separable pathways.

Science.gov (United States)

Lee, Ji-Hoon; Mand, Michael R; Kao, Chung-Hsuan; Zhou, Yi; Ryu, Seung W; Richards, Alicia L; Coon, Joshua J; Paull, Tanya T

2018-01-09

The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage-related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of a variant ATM incapable of activation by oxidative stress resulted in widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicate ATM in the control of protein homeostasis. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) is essential for IL-21-induced signal transduction through ERK1/2 pathway

International Nuclear Information System (INIS)

Juliana, Farha M.; Nara, Hidetoshi; Onoda, Tadashi; Rahman, Mizanur; Araki, Akemi; Jin, Lianjin; Fujii, Hodaka; Tanaka, Nobuyuki; Hoshino, Tomoaki; Asao, Hironobu

2012-01-01

Highlights: ► IL-21 induces nuclear accumulation of Ape1/Ref-1 protein. ► Ape1/Ref-1 is indispensable in IL-21-induced cell proliferation and survival signal. ► Ape1/Ref-1 is required for IL-21-induced ERK1/2 activation. -- Abstract: IL-21 is a pleiotropic cytokine that regulates T-cell and B-cell differentiation, NK-cell activation, and dendritic cell functions. IL-21 activates the JAK-STAT, ERK, and PI3K pathways. We report here that Ape1/Ref-1 has an essential role in IL-21-induced cell growth signal transduction. Overexpression of Ape1/Ref-1 enhances IL-21-induced cell proliferation, but it is suppressed by overexpressing an N-terminal deletion mutant of Ape1/Ref-1 that lacks the redox domain. Furthermore, knockdown of the Ape1/Ref-1 mRNA dramatically compromises IL-21-induced ERK1/2 activation and cell proliferation with increasing cell death. These impaired activities are recovered by the re-expression of Ape1/Ref-1 in the knockdown cells. Our findings are the first demonstration that Ape1/Ref-1 is an indispensable molecule for the IL-21-mediated signal transduction through ERK1/2 activation.
Deletion of lipoprotein PG0717 in Porphyromonas gingivalis W83 reduces gingipain activity and alters trafficking in and response by host cells.

Directory of Open Access Journals (Sweden)

Leticia Reyes

Full Text Available P. gingivalis (Pg, a causative agent of chronic generalized periodontitis, has been implicated in promoting cardiovascular disease. Expression of lipoprotein gene PG0717 of Pg strain W83 was found to be transiently upregulated during invasion of human coronary artery endothelial cells (HCAEC, suggesting this protein may be involved in virulence. We characterized the virulence phenotype of a PG0717 deletion mutant of pg W83. There were no differences in the ability of W83Δ717 to adhere and invade HCAEC. However, the increased proportion of internalized W83 at 24 hours post-inoculation was not observed with W83∆717. Deletion of PG0717 also impaired the ability of W83 to usurp the autophagic pathway in HCAEC and to induce autophagy in Saos-2 sarcoma cells. HCAEC infected with W83Δ717 also secreted significantly greater amounts of MCP-1, IL-8, IL-6, GM-CSF, and soluble ICAM-1, VCAM-1, and E-selectin when compared to W83. Further characterization of W83Δ717 revealed that neither capsule nor lipid A structure was affected by deletion of PG0717. Interestingly, the activity of both arginine (Rgp and lysine (Kgp gingipains was reduced in whole-cell extracts and culture supernatant of W83Δ717. RT-PCR revealed a corresponding decrease in transcription of rgpB but not rgpA or kgp. Quantitative proteome studies of the two strains revealed that both RgpA and RgpB, along with putative virulence factors peptidylarginine deiminase and Clp protease were significantly decreased in the W83Δ717. Our results suggest that PG0717 has pleiotropic effects on W83 that affect microbial induced manipulation of host responses important for microbial clearance and infection control.
An antimicrobial peptidomimetic induces Mucorales cell death through mitochondria-mediated apoptosis.

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E Magda Barbu

Full Text Available The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK2 with pleiotropic action ranging from targeted (i.e., ligand-directed activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS, and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections.
An antimicrobial peptidomimetic induces Mucorales cell death through mitochondria-mediated apoptosis.

Science.gov (United States)

Barbu, E Magda; Shirazi, Fazal; McGrath, Danielle M; Albert, Nathaniel; Sidman, Richard L; Pasqualini, Renata; Arap, Wadih; Kontoyiannis, Dimitrios P

2013-01-01

The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK)2 with pleiotropic action ranging from targeted (i.e., ligand-directed) activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK)2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK)2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS), and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK)2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections.
17β-Estradiol-induced cell proliferation requires estrogen receptor (ER) α monoubiquitination.

Science.gov (United States)

La Rosa, Piergiorgio; Pesiri, Valeria; Marino, Maria; Acconcia, Filippo

2011-07-01

Protein monoubiquitination (monoUbq) (i.e., the attachment of one single ubiquitin to the substrate) is a non-proteolytic reversible modification that controls protein functions. Among other proteins, the estrogen receptor α (ERα), which mediates the pleiotropic effects of the cognate hormone 17β-estradiol (E2), is a monoubiquitinated protein. Although it has been demonstrated that E2 rapidly reduces ERα monoUbq in breast cancer cells, the impact of monoUbq in the regulation of the ERα activities is poorly appreciated. Here, we show that mutation of the ERα monoUbq sites prevents the E2-induced ERα phosphorylation in the serine residue 118 (S118), reduces ERα transcriptional activity, and precludes the ERα-mediated extranuclear activation of signaling pathways (i.e., AKT activation) thus impeding the E2-induced cyclin D1 promoter activation and consequently cell proliferation. In addition, the interference with ERα monoUbq deregulates E2-induced association of ERα to the insulin like growth factor receptor (IGF-1-R). Altogether these data demonstrate an inherent role for monoUbq in ERα signaling and point to the physiological function of ERα monoUbq in the regulation of E2-induced cell proliferation. Copyright © 2011 Elsevier Inc. All rights reserved.
Arabidopsis thaliana cdd1 mutant uncouples the constitutive activation of salicylic acid signalling from growth defects.

Science.gov (United States)

Swain, Swadhin; Roy, Shweta; Shah, Jyoti; Van Wees, Saskia; Pieterse, Corné M; Nandi, Ashis K

2011-12-01

Arabidopsis genotypes with a hyperactive salicylic acid-mediated signalling pathway exhibit enhanced disease resistance, which is often coupled with growth and developmental defects, such as dwarfing and spontaneous necrotic lesions on the leaves, resulting in reduced biomass yield. In this article, we report a novel recessive mutant of Arabidopsis, cdd1 (constitutive defence without defect in growth and development1), that exhibits enhanced disease resistance associated with constitutive salicylic acid signalling, but without any observable pleiotropic phenotype. Both NPR1 (NON-EXPRESSOR OF PATHOGENESIS-RELATED GENES1)-dependent and NPR1-independent salicylic acid-regulated defence pathways are hyperactivated in cdd1 mutant plants, conferring enhanced resistance against bacterial pathogens. However, a functional NPR1 allele is required for the cdd1-conferred heightened resistance against the oomycete pathogen Hyaloperonospora arabidopsidis. Salicylic acid accumulates at elevated levels in cdd1 and cdd1 npr1 mutant plants and is necessary for cdd1-mediated PR1 expression and disease resistance phenotypes. In addition, we provide data which indicate that the cdd1 mutation negatively regulates the npr1 mutation-induced hyperactivation of ethylene/jasmonic acid signalling. © 2011 The Authors. Molecular Plant Pathology © 2011 BSPP and Blackwell Publishing Ltd.

A Systematic Genetic Screen to Dissect the MicroRNA Pathway in Drosophila.

Science.gov (United States)

Pressman, Sigal; Reinke, Catherine A; Wang, Xiaohong; Carthew, Richard W

2012-04-01

A central goal of microRNA biology is to elucidate the genetic program of miRNA function and regulation. However, relatively few of the effectors that execute miRNA repression have been identified. Because such genes may function in many developmental processes, mutations in them are expected to be pleiotropic and thus are discarded in most standard genetic screens. Here, we describe a systematic screen designed to identify all Drosophila genes in ∼40% of the genome that function in the miRNA pathway. To identify potentially pleiotropic genes, the screen analyzed clones of homozygous mutant cells in heterozygous animals. We identified 45 mutations representing 24 genes, and we molecularly characterized 9 genes. These include 4 previously known genes that encode core components of the miRNA pathway, including Drosha, Pasha, Dicer-1, and Ago1. The rest are new genes that function through chromatin remodeling, signaling, and mRNA decapping. The results suggest genetic screens that use clonal analysis can elucidate the miRNA program and that ∼100 genes are required to execute the miRNA program.
The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations.

Science.gov (United States)

Fuchs, Helmut; Sabrautzki, Sibylle; Przemeck, Gerhard K H; Leuchtenberger, Stefanie; Lorenz-Depiereux, Bettina; Becker, Lore; Rathkolb, Birgit; Horsch, Marion; Garrett, Lillian; Östereicher, Manuela A; Hans, Wolfgang; Abe, Koichiro; Sagawa, Nobuho; Rozman, Jan; Vargas-Panesso, Ingrid L; Sandholzer, Michael; Lisse, Thomas S; Adler, Thure; Aguilar-Pimentel, Juan Antonio; Calzada-Wack, Julia; Ehrhard, Nicole; Elvert, Ralf; Gau, Christine; Hölter, Sabine M; Micklich, Katja; Moreth, Kristin; Prehn, Cornelia; Puk, Oliver; Racz, Ildiko; Stoeger, Claudia; Vernaleken, Alexandra; Michel, Dian; Diener, Susanne; Wieland, Thomas; Adamski, Jerzy; Bekeredjian, Raffi; Busch, Dirk H; Favor, John; Graw, Jochen; Klingenspor, Martin; Lengger, Christoph; Maier, Holger; Neff, Frauke; Ollert, Markus; Stoeger, Tobias; Yildirim, Ali Önder; Strom, Tim M; Zimmer, Andreas; Wolf, Eckhard; Wurst, Wolfgang; Klopstock, Thomas; Beckers, Johannes; Gailus-Durner, Valerie; Hrabé de Angelis, Martin

2016-12-07

The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3 N294K/N294K ), which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC). Scube3 N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3 In addition, alterations in energy metabolism, behavior, and neurological functions were detected in Scube3 N294K/N294K mice. The Scube3 N294K/N294K mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function. Copyright © 2016 Fuchs et al.
Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

DEFF Research Database (Denmark)

Chami, Nathalie; Chen, Ming-Huei; Slater, Andrew J

2016-01-01

array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p
The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations

Directory of Open Access Journals (Sweden)

Helmut Fuchs

2016-12-01

Full Text Available The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein family consists of three independent members, Scube1–3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and their roles during adulthood. Here, we present the first Scube3 mutant mouse line (Scube3N294K/N294K, which clearly shows phenotypic alterations by carrying a missense mutation in exon 8, and thus contributes to our understanding of SCUBE3 functions. We performed a detailed phenotypic characterization in the German Mouse Clinic (GMC. Scube3N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function, and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB, associated with the chromosomal region of human SCUBE3. In addition, alterations in energy metabolism, behavior, and neurological functions were detected in Scube3N294K/N294K mice. The Scube3N294K/N294K mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function.
The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations

DEFF Research Database (Denmark)

Fuchs, Helmut; Sabrautzki, Sibylle; Przemeck, Gerhard K H

2016-01-01

The vertebrate Scube (Signal peptide, CUB, and EGF-like domain-containing protein) family consists of three independent members, Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Limited information about the general function of this gene family is available, and the...
Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

NARCIS (Netherlands)

Chami, N. (Nathalie); M.-H. Chen (Ming-Huei); Slater, A.J. (Andrew J.); Eicher, J.D. (John D.); E. Evangelou (Evangelos); Tajuddin, S.M. (Salman M.); Love-Gregory, L. (Latisha); T. Kacprowski (Tim); U.M. Schick (Ursula); Nomura, A. (Akihiro); Giri, A. (Ayush); Lessard, S. (Samuel); J. Brody (Jennifer); C. Schurmann (Claudia); V.S. Pankratz (Shane); L.R. Yanek (Lisa); A. Manichaikul (Ani); R. Pazoki (Raha); E. Mihailov (Evelin); W.D. Hill (W. David); Raffield, L.M. (Laura M.); A.D. Burt (Alastair); T.M. Bartz (Traci M.); D.M. Becker (Diane); L.C. Becker (Lewis); E.A. Boerwinkle (Eric); J. Bork-Jensen (Jette); E.P. Bottinger (Erwin); M.L. O'Donoghue (Michelle L.); D.R. Crosslin (David); de Denus, S. (Simon); Dubé, M.-P. (Marie-Pierre); P. Elliott (Paul); G. Engström; M. Evans (Michele); J. Floyd (James); M. Fornage (Myriam); Gao, H. (He); A. Greinacher (Andreas); V. Gudnason (Vilmundur); T. Hansen (T.); T.B. Harris (Tamara); C. Hayward (Caroline); Hernesniemi, J. (Jussi); H. Highland (Heather); J.N. Hirschhorn (Joel); Hofman, A. (Albert); Irvin, M.R. (Marguerite R.); M. Kähönen (Mika); E.M. Lange (Ethan); Launer, L.J. (Lenore J.); T. Lehtimäki (Terho); Li, J. (Jin); D.C. Liewald (David C.); A. Linneberg (Allan); Y. Liu (YongMei); Y. Lu (Yingchang); L.-P. Lyytikäinen (Leo-Pekka); R. Mägi (Reedik); J. Mathias (Jasmine); O. Melander (Olle); A. Metspalu (Andres); K. Mononen (Kari); M.A. Nalls (Michael); D.A. Nickerson (Deborah); K. Nikus (Kjell); C.J. O'Donnell (Christopher); M. Orho-Melander (Marju); O. Pedersen (Oluf); A. Petersmann (Astrid); Polfus, L. (Linda); B.M. Psaty (Bruce); O.T. Raitakari (Olli T.); Raitoharju, E. (Emma); Richard, M. (Melissa); K.M. Rice (Kenneth); F. Rivadeneira Ramirez (Fernando); Rotter, J.I. (Jerome I.); Schmidt, F. (Frank); A.V. Smith (Albert Vernon); J.M. Starr (John); K.D. Taylor (Kent); A. Teumer (Alexander); Thuesen, B.H. (Betina H.); Torstenson, E.S. (Eric S.); R.P. Tracy (Russell); I. Tzoulaki; N.A. Zakai (Neil); Vacchi-Suzzi, C. (Caterina); C.M. van Duijn (Cornelia); F.J.A. van Rooij (Frank); M. Cushman (Mary Ann); I.J. Deary (Ian J.); Velez Edwards, D.R. (Digna R.); Vergnaud, A.-C. (Anne-Claire); L.C. Wallentin (Lars); D. Waterworth (Dawn); White, H.D. (Harvey D.); J.F. Wilson (James); A.B. Zonderman; S. Kathiresan (Sekar); N. Grarup (Niels); T. Esko (Tõnu); R.J.F. Loos (Ruth); L.A. Lange (Leslie); Faraday, N. (Nauder); Abumrad, N.A. (Nada A.); T.L. Edwards (Todd L.); S.K. Ganesh (Santhi); P. Auer (Paul); A.D. Johnson (Andrew); A. Reiner (Alexander); G. Lettre (Guillaume)

2016-01-01

textabstractRed blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an
HIV-1 pre-mRNA commitment to Rev mediated export through PSF and Matrin 3

International Nuclear Information System (INIS)

Kula, Anna; Gharu, Lavina; Marcello, Alessandro

2013-01-01

Human immunodeficiency virus gene expression and replication are regulated at several levels. Incompletely spliced viral RNAs and full-length genomic RNA contain the RRE element and are bound by the viral trans-acting protein Rev to be transported out of the nucleus. Previously we found that the nuclear matrix protein MATR3 was a cofactor of Rev-mediated RNA export. Here we show that the pleiotropic protein PSF binds viral RNA and is associated with MATR3. PSF is involved in the maintenance of a pool of RNA available for Rev activity. However, while Rev and PSF bind the viral pre-mRNA at the site of viral transcription, MATR3 interacts at a subsequent step. We propose that PSF and MATR3 define a novel pathway for RRE-containing HIV-1 RNAs that is hijacked by the viral Rev protein.
Inositol polyphosphate multikinase is a coactivator for serum response factor-dependent induction of immediate early genes

Science.gov (United States)

Kim, Eunha; Tyagi, Richa; Lee, Joo-Young; Park, Jina; Kim, Young-ran; Beon, Jiyoon; Chen, Po Yu; Cha, Jiyoung Y.; Snyder, Solomon H.; Kim, Seyun

2013-01-01

Inositol polyphosphate multikinase (IPMK) is a notably pleiotropic protein. It displays both inositol phosphate kinase and phosphatidylinositol kinase catalytic activities. Noncatalytically, IPMK stabilizes the mammalian target of rapamycin complex 1 and acts as a transcriptional coactivator for CREB-binding protein/E1A binding protein p300 and tumor suppressor protein p53. Serum response factor (SRF) is a major transcription factor for a wide range of immediate early genes. We report that IPMK, in a noncatalytic role, is a transcriptional coactivator for SRF mediating the transcription of immediate early genes. Stimulation by serum of many immediate early genes is greatly reduced by IPMK deletion. IPMK stimulates expression of these genes, an influence also displayed by catalytically inactive IPMK. IPMK acts by binding directly to SRF and thereby enhancing interactions of SRF with the serum response element of diverse genes. PMID:24248338
Convergent Synthesis of Two Fluorescent Ebselen-Coumarin Heterodimers

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Jim Küppers

2016-07-01

Full Text Available The organo-seleniumdrug ebselen exhibits a wide range of pharmacological effects that are predominantly due to its interference with redox systems catalyzed by seleno enzymes, e.g., glutathione peroxidase and thioredoxin reductase. Moreover, ebselen can covalently interact with thiol groups of several enzymes. According to its pleiotropic mode of action, ebselen has been investigated in clinical trials for the prevention and treatment of different ailments. Fluorescence-labeled probes containing ebselen are expected to be suitable for further biological and medicinal studies. We therefore designed and synthesized two coumarin-tagged activity-based probes bearing the ebselen warhead. The heterodimers differ by the nature of the spacer structure, for which—in the second compound—a PEG/two-amide spacer was introduced. The interaction of this probe and of ebselen with two cysteine proteases was investigated.
Transcription Factor NF-κB: An Update on Intervention Strategies.

Science.gov (United States)

Panday, Arvind; Inda, Maria Eugenia; Bagam, Prathyusha; Sahoo, Malaya K; Osorio, Diana; Batra, Sanjay

2016-12-01

The nuclear factor (NF)-κB family of transcription factors are ubiquitous and pleiotropic molecules that regulate the expression of more than 150 genes involved in a broad range of processes including inflammation, immunity, cell proliferation, differentiation, and survival. The chronic activation or dysregulation of NF-κB signaling is the central cause of pathogenesis in many disease conditions and, therefore, NF-κB is a major focus of therapeutic intervention. Because of this, understanding the relationship between NF-κB and the induction of various downstream signaling molecules is imperative. In this review, we provide an updated synopsis of the role of NF-κB in DNA repair and in various ailments including cardiovascular diseases, HIV infection, asthma, herpes simplex virus infection, chronic obstructive pulmonary disease, and cancer. Furthermore, we also discuss the specific targets for selective inhibitors and future therapeutic strategies.
New insights into the autotaxin/LPA axis in cancer development and metastasis

Energy Technology Data Exchange (ETDEWEB)

Leblanc, Raphaël; Peyruchaud, Olivier, E-mail: olivier.peyruchaud@inserm.fr

2015-05-01

Lysophosphatidic acid (LPA) is a simple lipid with a single fatty acyl chain linked to a glycerophosphate backbone. Despite the simplicity of its structure but owing to its interactions with a series of at least six G protein-coupled receptors (LPA{sub 1–6}), LPA exerts pleiotropic bioactivities including stimulation of proliferation, migration and survival of many cell types. Autotaxin (ATX) is a unique enzyme with a lysophospholipase D (lysoPLD) activity that is responsible for the levels of LPA in the blood circulation. Both LPA receptor family members and ATX/LysoPLD are aberrantly expressed in many human cancers. This review will present the more striking as well as novel experimental evidences using cell lines, cancer mouse models and transgenic animals identifying the roles for ATX and LPA receptors in cancer progression, tumor cell invasion and metastasis.
Cytokine signalling in embryonic stem cells

DEFF Research Database (Denmark)

Kristensen, David Møbjerg; Kalisz, Mark; Nielsen, Jens Høiriis

2006-01-01

Cytokines play a central role in maintaining self-renewal in mouse embryonic stem (ES) cells through a member of the interleukin-6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK-STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric...... pathways seem to converge on c-myc as a common target to promote self-renewal. Whereas LIF does not seem to stimulate self-renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling...... via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem...
A genome-wide association study for milk production traits in Danish Jersey cattle using a 50K single nucleotide polymorphism chip

DEFF Research Database (Denmark)

Mai, Duy Minh; Sahana, Goutam; Christiansen, Freddy

2010-01-01

on BTA4, BTA5, BTA13, BTA20, and BTA29 were new QTL for fat index. We found 7 pleiotropic or very closely linked QTL. Most of the QTL were associated with polymorphisms within narrow regions and several may represent the effects of polymorphisms of genes: DGAT1, casein, ARFGAP3, CYP11B1, and CDC...
ATP as a Multi-target Danger Signal in the Brain

Directory of Open Access Journals (Sweden)

Ricardo J Rodrigues

2015-04-01

Full Text Available ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR, which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
The Small Protein HemP Is a Transcriptional Activator for the Hemin Uptake Operon in Burkholderia multivorans ATCC 17616.

Science.gov (United States)

Sato, Takuya; Nonoyama, Shouta; Kimura, Akane; Nagata, Yuji; Ohtsubo, Yoshiyuki; Tsuda, Masataka

2017-08-15

Iron and heme play very important roles in various metabolic functions in bacteria, and their intracellular homeostasis is maintained because high concentrations of free forms of these molecules greatly facilitate the Fenton reaction-mediated production of large amounts of reactive oxygen species that severely damage various biomolecules. The ferric uptake regulator (Fur) from Burkholderia multivorans ATCC 17616 is an iron-responsive global transcriptional regulator, and its fur deletant exhibits pleiotropic phenotypes. In this study, we found that the phenotypes of the fur deletant were suppressed by an additional mutation in hemP The transcription of hemP was negatively regulated by Fur under iron-replete conditions and was constitutive in the fur deletant. Growth of a hemP deletant was severely impaired in a medium containing hemin as the sole iron source, demonstrating the important role of HemP in hemin utilization. HemP was required as a transcriptional activator that specifically binds the promoter-containing region upstream of a Fur-repressive hmuRSTUV operon, which encodes the proteins for hemin uptake. A hmuR deletant was still able to grow using hemin as the sole iron source, albeit at a rate clearly lower than that of the wild-type strain. These results strongly suggested (i) the involvement of HmuR in hemin uptake and (ii) the presence in ATCC 17616 of at least part of other unknown hemin uptake systems whose expression depends on the HemP function. Our in vitro analysis also indicated high-affinity binding of HemP to hemin, and such a property might modulate transcriptional activation of the hmu operon. IMPORTANCE Although the hmuRSTUV genes for the utilization of hemin as a sole iron source have been identified in a few Burkholderia strains, the regulatory expression of these genes has remained unknown. Our analysis in this study using B. multivorans ATCC 17616 showed that its HemP protein is required for expression of the hmuRSTUV operon, and the
Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

Directory of Open Access Journals (Sweden)

Trinity J Bivalacqua

Full Text Available Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.
Systematic Analysis of the Multiple Bioactivities of Green Tea through a Network Pharmacology Approach

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Shoude Zhang

2014-01-01

Full Text Available During the past decades, a number of studies have demonstrated multiple beneficial health effects of green tea. Polyphenolics are the most biologically active components of green tea. Many targets can be targeted or affected by polyphenolics. In this study, we excavated all of the targets of green tea polyphenolics (GTPs though literature mining and target calculation and analyzed the multiple pharmacology actions of green tea comprehensively through a network pharmacology approach. In the end, a total of 200 Homo sapiens targets were identified for fifteen GTPs. These targets were classified into six groups according to their related disease, which included cancer, diabetes, neurodegenerative disease, cardiovascular disease, muscular disease, and inflammation. Moreover, these targets mapped into 143 KEGG pathways, 26 of which were more enriched, as determined though pathway enrichment analysis and target-pathway network analysis. Among the identified pathways, 20 pathways were selected for analyzing the mechanisms of green tea in these diseases. Overall, this study systematically illustrated the mechanisms of the pleiotropic activity of green tea by analyzing the corresponding “drug-target-pathway-disease” interaction network.
Normalization of TAM post-receptor signaling reveals a cell invasive signature for Axl tyrosine kinase.

Science.gov (United States)

Kimani, Stanley G; Kumar, Sushil; Davra, Viralkumar; Chang, Yun-Juan; Kasikara, Canan; Geng, Ke; Tsou, Wen-I; Wang, Shenyan; Hoque, Mainul; Boháč, Andrej; Lewis-Antes, Anita; De Lorenzo, Mariana S; Kotenko, Sergei V; Birge, Raymond B

2016-09-06

Tyro3, Axl, and Mertk (TAMs) are a family of three conserved receptor tyrosine kinases that have pleiotropic roles in innate immunity and homeostasis and when overexpressed in cancer cells can drive tumorigenesis. In the present study, we engineered EGFR/TAM chimeric receptors (EGFR/Tyro3, EGFR/Axl, and EGF/Mertk) with the goals to interrogate post-receptor functions of TAMs, and query whether TAMs have unique or overlapping post-receptor activation profiles. Stable expression of EGFR/TAMs in EGFR-deficient CHO cells afforded robust EGF inducible TAM receptor phosphorylation and activation of downstream signaling. Using a series of unbiased screening approaches, that include kinome-view analysis, phosphor-arrays, RNAseq/GSEA analysis, as well as cell biological and in vivo readouts, we provide evidence that each TAM has unique post-receptor signaling platforms and identify an intrinsic role for Axl that impinges on cell motility and invasion compared to Tyro3 and Mertk. These studies demonstrate that TAM show unique post-receptor signatures that impinge on distinct gene expression profiles and tumorigenic outcomes.
Adenosine diphosphate sugar pyrophosphatase prevents glycogen biosynthesis in Escherichia coli

Science.gov (United States)

Moreno-Bruna, Beatriz; Baroja-Fernández, Edurne; Muñoz, Francisco José; Bastarrica-Berasategui, Ainara; Zandueta-Criado, Aitor; Rodríguez-López, Milagros; Lasa, Iñigo; Akazawa, Takashi; Pozueta-Romero, Javier

2001-01-01

An adenosine diphosphate sugar pyrophosphatase (ASPPase, EC 3.6.1.21) has been characterized by using Escherichia coli. This enzyme, whose activities in the cell are inversely correlated with the intracellular glycogen content and the glucose concentration in the culture medium, hydrolyzes ADP-glucose, the precursor molecule of glycogen biosynthesis. ASPPase was purified to apparent homogeneity (over 3,000-fold), and sequence analyses revealed that it is a member of the ubiquitously distributed group of nucleotide pyrophosphatases designated as “nudix” hydrolases. Insertional mutagenesis experiments leading to the inactivation of the ASPPase encoding gene, aspP, produced cells with marginally low enzymatic activities and higher glycogen content than wild-type bacteria. aspP was cloned into an expression vector and introduced into E. coli. Transformed cells were shown to contain a dramatically reduced amount of glycogen, as compared with the untransformed bacteria. No pleiotropic changes in the bacterial growth occurred in both the aspP-overexpressing and aspP-deficient strains. The overall results pinpoint the reaction catalyzed by ASPPase as a potential step of regulating glycogen biosynthesis in E. coli. PMID:11416161
The actin family protein ARP6 contributes to the structure and the function of the nucleolus.

Science.gov (United States)

Kitamura, Hiroshi; Matsumori, Haruka; Kalendova, Alzbeta; Hozak, Pavel; Goldberg, Ilya G; Nakao, Mitsuyoshi; Saitoh, Noriko; Harata, Masahiko

2015-08-21

The actin family members, consisting of actin and actin-related proteins (ARPs), are essential components of chromatin remodeling complexes. ARP6, one of the nuclear ARPs, is part of the Snf-2-related CREB-binding protein activator protein (SRCAP) chromatin remodeling complex, which promotes the deposition of the histone variant H2A.Z into the chromatin. In this study, we showed that ARP6 influences the structure and the function of the nucleolus. ARP6 is localized in the central region of the nucleolus, and its knockdown induced a morphological change in the nucleolus. We also found that in the presence of high concentrations of glucose ARP6 contributed to the maintenance of active ribosomal DNA (rDNA) transcription by placing H2A.Z into the chromatin. In contrast, under starvation, ARP6 was required for cell survival through the repression of rDNA transcription independently of H2A.Z. These findings reveal novel pleiotropic roles for the actin family in nuclear organization and metabolic homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.

The Role of Stress and Stress Adaptations in Determining the Fate of the Bacterial Pathogen Listeria monocytogenes in the Food Chain.

Science.gov (United States)

NicAogáin, Kerrie; O'Byrne, Conor P

2016-01-01

The foodborne pathogen Listeria monocytogenes is a highly adaptable organism that can persist in a wide range of environmental and food-related niches. The consumption of contaminated ready-to-eat foods can cause infections, termed listeriosis, in vulnerable humans, particularly those with weakened immune systems. Although these infections are comparatively rare they are associated with high mortality rates and therefore this pathogen has a significant impact on food safety. L. monocytogenes can adapt to and survive a wide range of stress conditions including low pH, low water activity, and low temperature, which makes it problematic for food producers who rely on these stresses for preservation. Stress tolerance in L. monocytogenes can be explained partially by the presence of the general stress response (GSR), a transcriptional response under the control of the alternative sigma factor sigma B (σ B ) that reconfigures gene transcription to provide homeostatic and protective functions to cope with the stress. Within the host σ B also plays a key role in surviving the harsh conditions found in the gastrointestinal tract. As the infection progresses beyond the GI tract L. monocytogenes uses an intracellular infectious cycle to propagate, spread and remain protected from the host's humoral immunity. Many of the virulence genes that facilitate this infectious cycle are under the control of a master transcriptional regulator called PrfA. In this review we consider the environmental reservoirs that enable L. monocytogenes to gain access to the food chain and discuss the stresses that the pathogen must overcome to survive and grow in these environments. The overlap that exists between stress tolerance and virulence is described. We review the principal measures that are used to control the pathogen and point to exciting new approaches that might provide improved means of control in the future.
The Role of Stress and Stress Adaptations in Determining the Fate of the Bacterial Pathogen Listeria monocytogenes in the Food Chain

Science.gov (United States)

NicAogáin, Kerrie; O’Byrne, Conor P.

2016-01-01

The foodborne pathogen Listeria monocytogenes is a highly adaptable organism that can persist in a wide range of environmental and food-related niches. The consumption of contaminated ready-to-eat foods can cause infections, termed listeriosis, in vulnerable humans, particularly those with weakened immune systems. Although these infections are comparatively rare they are associated with high mortality rates and therefore this pathogen has a significant impact on food safety. L. monocytogenes can adapt to and survive a wide range of stress conditions including low pH, low water activity, and low temperature, which makes it problematic for food producers who rely on these stresses for preservation. Stress tolerance in L. monocytogenes can be explained partially by the presence of the general stress response (GSR), a transcriptional response under the control of the alternative sigma factor sigma B (σB) that reconfigures gene transcription to provide homeostatic and protective functions to cope with the stress. Within the host σB also plays a key role in surviving the harsh conditions found in the gastrointestinal tract. As the infection progresses beyond the GI tract L. monocytogenes uses an intracellular infectious cycle to propagate, spread and remain protected from the host’s humoral immunity. Many of the virulence genes that facilitate this infectious cycle are under the control of a master transcriptional regulator called PrfA. In this review we consider the environmental reservoirs that enable L. monocytogenes to gain access to the food chain and discuss the stresses that the pathogen must overcome to survive and grow in these environments. The overlap that exists between stress tolerance and virulence is described. We review the principal measures that are used to control the pathogen and point to exciting new approaches that might provide improved means of control in the future. PMID:27933042
A Quantitative RNAi Screen for JNK Modifiers Identifies Pvr as a Novel Regulator of Drosophila Immune Signaling

Science.gov (United States)

Bond, David; Foley, Edan

2009-01-01

Drosophila melanogaster responds to gram-negative bacterial challenges through the IMD pathway, a signal transduction cassette that is driven by the coordinated activities of JNK, NF-κB and caspase modules. While many modifiers of NF-κB activity were identified in cell culture and in vivo assays, the regulatory apparatus that determines JNK inputs into the IMD pathway is relatively unexplored. In this manuscript, we present the first quantitative screen of the entire genome of Drosophila for novel regulators of JNK activity in the IMD pathway. We identified a large number of gene products that negatively or positively impact on JNK activation in the IMD pathway. In particular, we identified the Pvr receptor tyrosine kinase as a potent inhibitor of JNK activation. In a series of in vivo and cell culture assays, we demonstrated that activation of the IMD pathway drives JNK-dependent expression of the Pvr ligands, Pvf2 and Pvf3, which in turn act through the Pvr/ERK MAP kinase pathway to attenuate the JNK and NF-κB arms of the IMD pathway. Our data illuminate a poorly understood arm of a critical and evolutionarily conserved innate immune response. Furthermore, given the pleiotropic involvement of JNK in eukaryotic cell biology, we believe that many of the novel regulators identified in this screen are of interest beyond immune signaling. PMID:19893628
Genes involved in translation of Mycoplasma hyopneumoniae and Mycoplasma synoviae

Directory of Open Access Journals (Sweden)

Mônica de Oliveira Santos

2007-01-01

Full Text Available This is a report on the analysis of genes involved in translation of the complete genomes of Mycoplasma hyopneumoniae strain J and 7448 and Mycoplasma synoviae. In both genomes 31 ORFs encoding large ribosomal subunit proteins and 19 ORFs encoding small ribosomal subunit proteins were found. Ten ribosomal protein gene clusters encoding 42 ribosomal proteins were found in M. synoviae, while 8 clusters encoding 39 ribosomal proteins were found in both M. hyopneumoniae strains. The L33 gene of the M. hyopneumoniae strain 7448 presented two copies in different locations. The genes encoding initiation factors (IF-1, IF-2 and IF-3, elongation factors (EF-G, EF-Tu, EF-Ts and EF-P, and the genes encoding the ribosome recycling factor (frr and one polypeptide release factor (prfA were present in the genomes of M. hyopneumoniae and M. synoviae. Nineteen aminoacyl-tRNA synthases had been previously identified in both mycoplasmas. In the two strains of M. hyopneumoniae, J and 7448, only one set of 5S, 16S and 23S rRNAs had been identified. Two sets of 16S and 23S rRNA genes and three sets of 5S rRNA genes had been identified in the M. synoviae genome.
Systematic Review of Radiofrequency Ablation and Pulsed Radiofrequency for Management of Cervicogenic Headaches.

Science.gov (United States)

Grandhi, Ravi K; Kaye, Alan David; Abd-Elsayed, Alaa

2018-02-23

Cervicogenic headache (CHA) is a secondary headache which has a source in the upper cervical spine. Many traditional analgesic choices lack good efficacy in managing the associated pain. As a result, in management of CHA, radiofrequency ablation (RFA) or pulse radiofrequency (PRF) has been tried with success. Our study investigated the use of RFA and PRF for the management of CHA. In the present investigation, a review of the literature was conducted using PubMed (1966 to February 2017). The quality assessment was determined using The Cochrane Risk of Bias. After initial search and consultation with experts, 34 articles were identified for initial review and 10 articles met inclusion for review. Criteria for inclusion were primarily based on identification of articles discussing cervicogenic headaches which were previously treatment resistant and occurred without any other pathology of the craniofacial region or inciting event such as trauma. This systematic review demonstrated that RFA and PRFA provide very limited benefit in the management of CHA. At present, there is no high-quality RCT and/or strong non-RCTs to support the use of these techniques, despite numerous case reports which have demonstrated benefit. This review is one of the first to provide a comprehensive overview of the use of RFA and PRF in the management of CHA.
The biofilm formation ability of Listeria monocytogenes isolated from meat, poultry, fish and processing plant environments is related to serotype and pathogenic profile of the strains

Directory of Open Access Journals (Sweden)

Domenico Meloni

2012-10-01

Full Text Available In the present study, the relationships between serotype, pathogenic profile and in vitro biofilm formation of 106 Listeria monocytogenes strains, having no epidemiological correlation and isolated from different environmental and food sources, were analyzed. The quantitative assessment of the in vitro biofilm formation was carried out by using a microtiter plate assay with spectrophotometric reading (OD620. The isolates were also submitted to serogrouping using the target genes lmo0737, lmo1118, ORF2819, ORF2110, prs, and to the evaluation of the presence of the following virulence genes: prfA, hlyA, rrn, inlA, inlB, iap, plcA, plcB, actA and mpl, by multiplex PCRs. The 62% of the strains showed weak or moderate in vitro ability in biofilm formation, in particular serotypes 1/2b and 4b, frequently associated with sporadic or epidemic listeriosis cases. The 25% of these isolates showed polymorphism for the actA gene, producing a fragment of 268-bp instead of the expected 385-bp. The deletion of nucleotides in this gene seems to be related to enhanced virulence properties among these strains. Strains belonging to serotypes associated with human infections and characterized by pathogenic potential are capable to persist within the processing plants forming biofilm.
The pathogenic potential of different pulsed-field gel electrophoresis types of Listeria monocytogenes strains isolated from food in Northeast Bosnia and Herzegovina.

Science.gov (United States)

Hodžić, Snjezana; Hukić, Mirsada; Franciosa, Giovanna; Aureli, Paolo

2011-09-01

Listeria monocytogenes is often present in meat and meat products that are sold in the area of northeast Bosnia and Herzegovina. The major objective of this study was to examine the virulence of L. monocytogenes strains isolated from these types of food in that geographic area. Polymerase chain reaction was used to detect eight genes responsible for virulence of this pathogen, namely, prfA, inlA, inlB, hly, plcA, plcB, actA, and mpl. All examined isolates were confirmed to possess the eight virulence genes. Ten different pulsed-field gel electrophoresis (PFGE) macrorestriction profiles were recognized among 19 L. monocytogenes strains after restriction with two different endonucleases (ApaI and AscI). The pathogenicity of three different PFGE types of L. monocytogenes was confirmed through in vivo tests, which were performed on female white mice (Pasteur strain), and it ranged from 3.55 × 10(8) LD50 to 1.58 × 10(10) LD50. All of the three different PFGE types of L. monocytogenes were regarded as moderately virulent in relation to the reference strain L. monocytogenes Scott A. This result might be one of the reasons for the absence of reported listeriosis in northeast Bosnia and Herzegovina, despite the high degree of food contamination with this pathogen.
Mesenchymal stromal cells express GARP/LRRC32 on their surface: effects on their biology and immunomodulatory capacity.

Science.gov (United States)

Carrillo-Galvez, Ana Belén; Cobo, Marién; Cuevas-Ocaña, Sara; Gutiérrez-Guerrero, Alejandra; Sánchez-Gilabert, Almudena; Bongarzone, Pierpaolo; García-Pérez, Angélica; Muñoz, Pilar; Benabdellah, Karim; Toscano, Miguel G; Martín, Francisco; Anderson, Per

2015-01-01

Mesenchymal stromal cells (MSCs) represent a promising tool for therapy in regenerative medicine, transplantation, and autoimmune disease due to their trophic and immunomodulatory activities. However, we are still far from understanding the mechanisms of action of MSCs in these processes. Transforming growth factor (TGF)-β1 is a pleiotropic cytokine involved in MSC migration, differentiation, and immunomodulation. Recently, glycoprotein A repetitions predominant (GARP) was shown to bind latency-associated peptide (LAP)/TGF-β1 to the cell surface of activated Foxp3(+) regulatory T cells (Tregs) and megakaryocytes/platelets. In this manuscript, we show that human and mouse MSCs express GARP which presents LAP/TGF-β1 on their cell surface. Silencing GARP expression in MSCs increased their secretion and activation of TGF-β1 and reduced their proliferative capacity in a TGF-β1-independent manner. Importantly, we showed that GARP expression on MSCs contributed to their ability to inhibit T-cell responses in vitro. In summary, we have found that GARP is an essential molecule for MSC biology, regulating their immunomodulatory and proliferative activities. We envision GARP as a new target for improving the therapeutic efficacy of MSCs and also as a novel MSC marker. © 2014 AlphaMed Press.
CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.

Science.gov (United States)

Scudiero, Ivan; Mazzone, Pellegrino; D'Andrea, Luca E; Ferravante, Angela; Zotti, Tiziana; Telesio, Gianluca; De Rubis, Gabriele; Reale, Carla; Pizzulo, Maddalena; Muralitharan, Shanmugakonar; Vito, Pasquale; Stilo, Romania

2017-02-23

The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.
Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice

OpenAIRE

Ven, Marieke; Andressoo, Jaan-Olle; Holcomb, Valerie; Lindern, Marieke; Jong, Willeke; Zeeuw, Chris; Suh, Yousin; Hasty, Paul; Hoeijmakers, Jan; Horst, Gijsbertus; Mitchell, James

2006-01-01

textabstractHow congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cul...
cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

International Nuclear Information System (INIS)

Bhattacharjee, Rajesh; Xiang, Wenpei; Wang, Yinna; Zhang, Xiaoying; Billiar, Timothy R.

2012-01-01

Highlights: ► cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. ► cAMP blocks NF-κB activation induced by TNF and actinomycin D. ► cAMP blocks DISC formation following TNF and actinomycin D exposure. ► cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor α (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found that cAMP exerts its affect at the proximal level of TNF signaling by inhibiting the formation of the DISC
cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

Energy Technology Data Exchange (ETDEWEB)

Bhattacharjee, Rajesh [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Xiang, Wenpei [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People' s Republic of China (China); Wang, Yinna [Vascular Medicine Institute, University of Pittsburgh School of Medicine, 10051-5A BST 3, 3501 Fifth Avenue, Pittsburgh, PA 15261 (United States); Zhang, Xiaoying [Department of Medicine/Endocrinology Division, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213 (United States); Billiar, Timothy R., E-mail: billiartr@upmc.edu [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States)

2012-06-22

Highlights: Black-Right-Pointing-Pointer cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. Black-Right-Pointing-Pointer cAMP blocks NF-{kappa}B activation induced by TNF and actinomycin D. Black-Right-Pointing-Pointer cAMP blocks DISC formation following TNF and actinomycin D exposure. Black-Right-Pointing-Pointer cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor {alpha} (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found
Characterization of recombinant human HBP/CAP37/azurocidin, a pleiotropic mediator of inflammation-enhancing LPS-induced cytokine release from monocytes.

Science.gov (United States)

Rasmussen, P B; Bjørn, S; Hastrup, S; Nielsen, P F; Norris, K; Thim, L; Wiberg, F C; Flodgaard, H

1996-07-15

Neutrophil-derived heparin-binding protein (HBP) is a strong chemoattractant for monocytes. We report here for the first time the expression of recombinant HBP. A baculovirus containing the human HBP cDNA mediated in insect cells the secretion of a 7-residue N-terminally extended HBP form (pro-HBP). Deletion of the pro-peptide-encoding cDNA sequence resulted in correctly processed HBP at the N-terminus. Electrospray mass spectrum analysis of recombinant HBP yielded a molecular weight of 27.237 +/- 3 amu. Consistent with this mass is a HBP form of 225 amino acids (mature part +3 amino acid C-terminal extension). The biological activity of recombinant HBP was confirmed by its chemotactic action towards monocytes. Furthermore, we have shown that recombinant HBP stimulates in a dose-dependent manner the lipopolysaccharide (LPS)-induced cytokine release from human monocytes.
The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks.

Science.gov (United States)

Adan, Aysun; Baran, Yusuf

2015-11-01

Fisetin and hesperetin, flavonoids from various plants, have several pharmaceutical activities including antioxidative, anti-inflammatory, and anticancer effects. However, studies elucidating the role and the mechanism(s) of action of fisetin and hesperetin in acute promyelocytic leukemia are absent. In this study, we investigated the mechanism of the antiproliferative and apoptotic actions exerted by fisetin and hesperetin on human HL60 acute promyelocytic leukemia cells. The viability of HL60 cells was evaluated using the MTT assay, apoptosis by annexin V/propidium iodide (PI) staining and cell cycle distribution using flow cytometry, and changes in caspase-3 enzyme activity and mitochondrial transmembrane potential. Moreover, we performed whole-genome microarray gene expression analysis to reveal genes affected by fisetin and hesperetin that can be important for developing of future targeted therapy. Based on data obtained from microarray analysis, we also described biological networks modulated after fisetin and hesperetin treatment by KEGG and IPA analysis. Fisetin and hesperetin treatment showed a concentration- and time-dependent inhibition of proliferation and induced G2/M arrest for both agents and G0/G1 arrest for hesperetin at only the highest concentrations. There was a disruption of mitochondrial membrane potential together with increased caspase-3 activity. Furthermore, fisetin- and hesperetin-triggered apoptosis was confirmed by annexin V/PI analysis. The microarray gene profiling analysis revealed some important biological pathways including mitogen-activated protein kinases (MAPK) and inhibitor of DNA binding (ID) signaling pathways altered by fisetin and hesperetin treatment as well as gave a list of genes modulated ≥2-fold involved in cell proliferation, cell division, and apoptosis. Altogether, data suggested that fisetin and hesperetin have anticancer properties and deserve further investigation.
Interleukin-10 and posttransplant lymphoproliferative disorder after kidney transplantation

DEFF Research Database (Denmark)

Birkeland, S.A.; Bendtzen, K.; Moller, B.

1999-01-01

, and the type and duration of immunosuppression. Interleukin-10 (IL-10) is a pleiotropic cytokine, produced primarily by T-helper 2 (Th2) lymphocytes in the later stages of T-cell activation, suggested to play a role in EBV-associated PTLD, We recently reported preliminary findings on IL-10 in relation...... human recombinant IL-10 was employed; the assay is specific for human natural and viral IL-10, Results, Three patients experienced primary EBV infection, five reactivated EBV infections, and one did not change EBV status. Three patients had a fulminant course and died with EBV-associated PTLD; confirmed...... immunosuppression and are now in a state of operational tolerance. In three of four cases with initial lymphoma, EBV infection (primary or reactivation) preceded the increase in IL-10, In all four cases, the IL-10 increase preceded the PTLD diagnosis. In six cases, IL-10 could be followed after treatment showing...
Genomics meets ethology: a new route to understanding domestication, behavior, and sustainability in animal breeding.

Science.gov (United States)

Jensen, Per; Andersson, Leif

2005-06-01

Animal behavior is a central part of animal welfare, a keystone in sustainable animal breeding. During domestication, animals have adapted with respect to behavior and an array of other traits. We compared the behavior of junglefowl and White Leghorn layers, selected for egg production (and indirectly for growth). Jungle-fowl had a more active behavior in social, exploratory, anti-predatory, and feeding tests. A genome scan for Quantitative Trait Loci (QTLs) in a junglefowl x White Leghorn intercross revealed several significant or suggestive QTLs for different traits. Some production QTLs coincided with QTLs for behavior, suggesting that pleiotropic effects may be important for the development of domestication phenotypes. One gene has been located, which has a strong effect on the risk of being a victim of feather pecking, a detrimental behavior disorder. Modern genomics paired with analysis of behavior may help in designing more sustainable and robust breeding in the future.
Management Strategies in Advanced Uterine Leiomyosarcoma: Focus on Trabectedin

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Frédéric Amant

2015-01-01

Full Text Available The treatment of advanced uterine leiomyosarcomas (U-LMS represents a considerable challenge. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made postoperatively. Whilst a total abdominal hysterectomy is the cornerstone of management of early disease, the role of routine adjuvant pelvic radiotherapy and adjuvant chemotherapy is less clear, since they may improve local tumor control in high risk patients but are not associated with an overall survival benefit. For recurrent or disseminated U-LMS, cytotoxic chemotherapy remains the mainstay of treatment. There have been few active chemotherapy drugs approved for advanced disease, although newer drugs such as trabectedin with its pleiotropic mechanism of actions represent an important addition to the standard front-line systemic therapy with doxorubicin and ifosfamide. In this review, we outline the therapeutic potential and in particular the emerging evidence-based strategy of therapy with trabectedin in patients with advanced U-LMS.
Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death

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Hiroto Kambara

2018-03-01

Full Text Available Summary: Gasdermin D (GSDMD is considered a proinflammatory factor that mediates pyroptosis in macrophages to protect hosts from intracellular bacteria. Here, we reveal that GSDMD deficiency paradoxically augmented host responses to extracellular Escherichia coli, mainly by delaying neutrophil death, which established GSDMD as a negative regulator of innate immunity. In contrast to its activation in macrophages, in which activated inflammatory caspases cleave GSDMD to produce an N-terminal fragment (GSDMD-cNT to trigger pyroptosis, GSDMD cleavage and activation in neutrophils was caspase independent. It was mediated by a neutrophil-specific serine protease, neutrophil elastase (ELANE, released from cytoplasmic granules into the cytosol in aging neutrophils. ELANE-mediated GSDMD cleavage was upstream of the caspase cleavage site and produced a fully active ELANE-derived NT fragment (GSDMD-eNT that induced lytic cell death as efficiently as GSDMD-cNT. Thus, GSDMD is pleiotropic, exerting both pro- and anti-inflammatory effects that make it a potential target for antibacterial and anti-inflammatory therapies. : Kambara et al. find that GSDMD deficiency augments host responses to extracellular Escherichia coli, mainly by delaying neutrophil death, establishing GSDMD as a negative regulator of innate immunity. GSDMD cleavage and activation in neutrophils is mediated by ELANE, released from cytoplasmic granules into the cytosol in aging neutrophils. Keywords: GSDMD, neutrophil death, neutrophil elastase, innate immunity, host defense
Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat.

Science.gov (United States)

Meunier, Alice; Latrémolière, Alban; Dominguez, Elisa; Mauborgne, Annie; Philippe, Stéphanie; Hamon, Michel; Mallet, Jacques; Benoliel, Jean-Jacques; Pohl, Michel

2007-04-01

Neuropathic pain developing after peripheral nerve injury is associated with altered neuronal and glial cell functions in the spinal cord. Activated glia produces algogenic mediators, exacerbating pain. Among the different intracellular pathways possibly involved in the modified glial function, the nuclear factor kappaB (NF-kappaB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-kappaB is a pleiotropic factor also involved in central nervous system homeostasy. To study its role in chronic pain, it is thus essential to inhibit the NF-kappaB pathway selectively in activated spinal glial cells. Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-kappaB super- repressor IkappaBalpha resulted in an inhibition of the NF-kappaB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IkappaBalpha overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects. These data show that targeted blockade of NF-kappaB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-kappaB pathway in the development of neuropathic pain after peripheral nerve injury.
Towards the concept of disease-modifier in post-stroke or vascular cognitive impairment: a consensus report.

Science.gov (United States)

Bordet, Régis; Ihl, Ralf; Korczyn, Amos D; Lanza, Giuseppe; Jansa, Jelka; Hoerr, Robert; Guekht, Alla

2017-05-24

Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier. Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline. Disease-modifying strategies should integrate both pharmacological and non-pharmacological multimodal approaches, with pleiotropic effects targeting (1) endothelial and brain-blood barrier dysfunction; (2) neuronal death and axonal loss; (3) cerebral plasticity and compensatory mechanisms; and (4) degenerative-related protein misfolding. Moreover, pharmacological and non-pharmacological treatment in PSCI or VCI requires valid study designs clearly stating the definition of basic methodological issues, such as the instruments that should be used to measure eventual changes, the biomarker-based stratification of participants to be investigated, and statistical tests, as well as the inclusion and exclusion criteria that should be applied. A consensus emerged to propose the development of a disease-modifying strategy in VCI and PSCI based on pleiotropic pharmacological and non-pharmacological approaches.

Implications of pleiotropy: Challenges and opportunities for mining Big Data in Biomedicine

Directory of Open Access Journals (Sweden)

Can eYang

2015-06-01

Full Text Available Pleiotropy arises when a locus influences multiple traits. Rich GWAS findings of various traits in the past decade reveal many examples of this phenomenon, suggesting the wide existence of pleiotropic effects. What underlies this phenomenon is the biological connection among seemingly unrelated traits/diseases. Characterizing the molecular mechanisms of pleiotropy not only helps to explain the relationship between diseases, but may also contribute to novel insights concerning the pathological mechanism of each specific disease, leading to better disease prevention, diagnosis and treatment. However, most pleiotropic effects remain elusive because their functional roles have not been systematically examined. A systematic investigation requires availability of qualified measurements at multilayered biological processes (e.g., transcription and translation.The rise of Big Data in biomedicine, such as high-quality multi-omics data, biomedical imaging data and electronic medical records of patients, offers us an unprecedented opportunity to investigate pleiotropy. There will be a great need of computationally efficient and statistically rigorous methods for integrative analysis of these Big Data in biomedicine. In this review, we outline many opportunities and challenges in methodology developments for systematic analysis of pleiotropy, and highlight its implications on disease prevention, diagnosis and treatment.
A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers.

Science.gov (United States)

Ji, Fei; Lee, Dayoung; Mendell, Nancy Role

2005-12-30

Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes they consider individuals as affected if they have either the disease or the DRT, or both. We propose instead to consider the joint distribution of the disease and the DRT and do a linkage analysis assuming a pleiotropic model. We evaluated our results through analysis of the simulated datasets provided by Genetic Analysis Workshop 14. We first conducted univariate linkage analysis of the simulated disease, Kofendrerd Personality Disorder and one of its simulated associated traits, phenotype b (fear/discomfort with strangers). Subsequently, we considered the bivariate phenotype, which combined the information on Kofendrerd Personality Disorder and fear/discomfort with strangers. We developed a program to perform bivariate linkage analysis using an extension to the Elston-Stewart peeling method of likelihood calculation. Using this program we considered the microsatellites within 30 cM of the gene pleiotropic for this simulated disease and DRT. Based on 100 simulations of 300 families we observed excellent power to detect linkage within 10 cM of the disease locus using the DRT and the bivariate trait.
Identification of Redox and Glucose-Dependent Txnip Protein Interactions

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Benjamin J. Forred

2016-01-01

Full Text Available Thioredoxin-interacting protein (Txnip acts as a negative regulator of thioredoxin function and is a critical modulator of several diseases including, but not limited to, diabetes, ischemia-reperfusion cardiac injury, and carcinogenesis. Therefore, Txnip has become an attractive therapeutic target to alleviate disease pathologies. Although Txnip has been implicated with numerous cellular processes such as proliferation, fatty acid and glucose metabolism, inflammation, and apoptosis, the molecular mechanisms underlying these processes are largely unknown. The objective of these studies was to identify Txnip interacting proteins using the proximity-based labeling method, BioID, to understand differential regulation of pleiotropic Txnip cellular functions. The BioID transgene fused to Txnip expressed in HEK293 identified 31 interacting proteins. Many protein interactions were redox-dependent and were disrupted through mutation of a previously described reactive cysteine (C247S. Furthermore, we demonstrate that this model can be used to identify dynamic Txnip interactions due to known physiological regulators such as hyperglycemia. These data identify novel Txnip protein interactions and demonstrate dynamic interactions dependent on redox and glucose perturbations, providing clarification to the pleiotropic cellular functions of Txnip.
Quantitative trait loci for fertility traits in Finnish Ayrshire cattle

Directory of Open Access Journals (Sweden)

Viitala Sirja M

2008-03-01

Full Text Available Abstract A whole genome scan was carried out to detect quantitative trait loci (QTL for fertility traits in Finnish Ayrshire cattle. The mapping population consisted of 12 bulls and 493 sons. Estimated breeding values for days open, fertility treatments, maternal calf mortality and paternal non-return rate were used as phenotypic data. In a granddaughter design, 171 markers were typed on all 29 bovine autosomes. Associations between markers and traits were analysed by multiple marker regression. Multi-trait analyses were carried out with a variance component based approach for the chromosomes and trait combinations, which were observed significant in the regression method. Twenty-two chromosome-wise significant QTL were detected. Several of the detected QTL areas were overlapping with milk production QTL previously identified in the same population. Multi-trait QTL analyses were carried out to test if these effects were due to a pleiotropic QTL affecting fertility and milk yield traits or to linked QTL causing the effects. This distinction could only be made with confidence on BTA1 where a QTL affecting milk yield is linked to a pleiotropic QTL affecting days open and fertility treatments.
Implications of pleiotropy: challenges and opportunities for mining Big Data in biomedicine.

Science.gov (United States)

Yang, Can; Li, Cong; Wang, Qian; Chung, Dongjun; Zhao, Hongyu

2015-01-01

Pleiotropy arises when a locus influences multiple traits. Rich GWAS findings of various traits in the past decade reveal many examples of this phenomenon, suggesting the wide existence of pleiotropic effects. What underlies this phenomenon is the biological connection among seemingly unrelated traits/diseases. Characterizing the molecular mechanisms of pleiotropy not only helps to explain the relationship between diseases, but may also contribute to novel insights concerning the pathological mechanism of each specific disease, leading to better disease prevention, diagnosis and treatment. However, most pleiotropic effects remain elusive because their functional roles have not been systematically examined. A systematic investigation requires availability of qualified measurements at multilayered biological processes (e.g., transcription and translation). The rise of Big Data in biomedicine, such as high-quality multi-omics data, biomedical imaging data and electronic medical records of patients, offers us an unprecedented opportunity to investigate pleiotropy. There will be a great need of computationally efficient and statistically rigorous methods for integrative analysis of these Big Data in biomedicine. In this review, we outline many opportunities and challenges in methodology developments for systematic analysis of pleiotropy, and highlight its implications on disease prevention, diagnosis and treatment.
The functional DRD3 Ser9Gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement.

Science.gov (United States)

Savitz, Jonathan; Hodgkinson, Colin A; Martin-Soelch, Chantal; Shen, Pei-Hong; Szczepanik, Joanna; Nugent, Allison; Herscovitch, Peter; Grace, Anthony A; Goldman, David; Drevets, Wayne C

2013-01-01

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [(11)C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.
The functional DRD3 Ser9Gly polymorphism (rs6280 is pleiotropic, affecting reward as well as movement.

Directory of Open Access Journals (Sweden)

Jonathan Savitz

Full Text Available Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3 gene (ser9gly, rs6280 on reward-associated dopamine (DA release in the striatum. Twenty-six healthy controls (HCs and 10 unmedicated subjects with major depressive disorder (MDD completed two positron emission tomography (PET scans with [(11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition and on another occasion subjects completed a gambling task (reward condition. A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release in the middle (anterior caudate (p<0.01 and the ventral striatum (p<0.05. The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.
Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

Directory of Open Access Journals (Sweden)

Abeer M Mahmoud

Full Text Available Blocking the androgen receptor (AR activity is the main goal of therapies for advanced prostate cancer (PCa. However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.
Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a

OpenAIRE

Schiering, Nikolaus; Knapp, Stefan; Marconi, Marina; Flocco, Maria M.; Cui, Jean; Perego, Rita; Rusconi, Luisa; Cristiani, Cinzia

2003-01-01

The protooncogene c-met codes for the hepatocyte growth factor receptor tyrosine kinase. Binding of its ligand, hepatocyte growth factor/scatter factor, stimulates receptor autophosphorylation, which leads to pleiotropic downstream signaling events in epithelial cells, including cell growth, motility, and invasion. These events are mediated by interaction of cytoplasmic effectors, generally through Src homology 2 (SH2) domains, with two phosphotyrosine-containing sequence motifs in the unique...
Lr67/Yr46 confers adult plant resistance to stem rust and powdery mildew in wheat.

Science.gov (United States)

Herrera-Foessel, Sybil A; Singh, Ravi P; Lillemo, Morten; Huerta-Espino, Julio; Bhavani, Sridhar; Singh, Sukhwinder; Lan, Caixia; Calvo-Salazar, Violeta; Lagudah, Evans S

2014-04-01

We demonstrate that Lr67/Yr46 has pleiotropic effect on stem rust and powdery mildew resistance and is associated with leaf tip necrosis. Genes are designated as Sr55, Pm46 and Ltn3 , respectively. Wheat (Triticum aestivum) accession RL6077, known to carry the pleiotropic slow rusting leaf and yellow rust resistance genes Lr67/Yr46 in Thatcher background, displayed significantly lower stem rust (P. graminis tritici; Pgt) and powdery mildew (Blumeria graminis tritici; Bgt) severities in Kenya and in Norway, respectively, compared to its recurrent parent Thatcher. We investigated the resistance of RL6077 to stem rust and powdery mildew using Avocet × RL6077 F6 recombinant inbred lines (RILs) derived from two photoperiod-insensitive F3 families segregating for Lr67/Yr46. Greenhouse seedling tests were conducted with Mexican Pgt race RTR. Field evaluations were conducted under artificially initiated stem rust epidemics with Pgt races RTR and TTKST (Ug99 + Sr24) at Ciudad Obregon (Mexico) and Njoro (Kenya) during 2010-2011; and under natural powdery mildew epiphytotic in Norway at Ås and Hamar during 2011 and 2012. In Mexico, a mean reduction of 41 % on stem rust severity was obtained for RILs carrying Lr67/Yr46, compared to RILs that lacked the gene, whereas in Kenya the difference was smaller (16 %) but significant. In Norway, leaf tip necrosis was associated with Lr67/Yr46 and RILs carrying Lr67/Yr46 showed a 20 % reduction in mean powdery mildew severity at both sites across the 2 years of evaluation. Our study demonstrates that Lr67/Yr46 confers partial resistance to stem rust and powdery mildew and is associated with leaf tip necrosis. The corresponding pleiotropic, or tightly linked, genes, designated as Sr55, Pm46, and Ltn3, can be utilized to provide broad-spectrum durable disease resistance in wheat.
Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells

Directory of Open Access Journals (Sweden)

Butrous Ghazwan S

2011-10-01

Full Text Available Abstract Background Recent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. In this study we explored the molecular effects of statins on distal human pulmonary artery smooth muscle cells (PASMCs and their relevance to proliferation and apoptosis in pulmonary arterial hypertension. Methods Primary distal human PASMCs from patients and controls were treated with lipophilic (simvastatin, atorvastatin, mevastatin and fluvastatin, lipophobic (pravastatin and nitric-oxide releasing statins and studied in terms of their DNA synthesis, proliferation, apoptosis, matrix metalloproteinase-9 and endothelin-1 release. Results Treatment of human PASMCs with selected statins inhibited DNA synthesis, proliferation and matrix metalloproteinase-9 production in a concentration-dependent manner. Statins differed in their effectiveness, the rank order of anti-mitogenic potency being simvastatin > atorvastatin > > pravastatin. Nevertheless, a novel nitric oxide-releasing derivative of pravastatin (NCX 6550 was effective. Lipophilic statins, such as simvastatin, also enhanced the anti-proliferative effects of iloprost and sildenafil, promoted apoptosis and inhibited the release of the mitogen and survival factor endothelin-1. These effects were reversed by mevalonate and the isoprenoid intermediate geranylgeranylpyrophosphate and were mimicked by inhibitors of the Rho and Rho-kinase. Conclusions Lipophilic statins exert direct effects on distal human PASMCs and are likely to involve inhibition of Rho GTPase signalling. These findings compliment some of the recently documented effects in patients with pulmonary arterial hypertension.
Pleiotropic effects of type 2 diabetes management strategies on renal risk factors

NARCIS (Netherlands)

Muskiet, Marcel H. A.; Tonneijck, Lennart; Smits, Mark M.; Kramer, Mark H. H.; Lambers Heerspink, Hiddo; van Raalte, Danil H.

In parallel with the type 2 diabetes pandemic, diabetic kidney disease has become the leading cause of end-stage renal disease worldwide, and is associated with high cardiovascular morbidity and mortality. As established in landmark randomised trials and recommended in clinical guidelines,
Pleiotropic effects of a methyl donor diet in a novel animal model.

Directory of Open Access Journals (Sweden)

Kimberly R Shorter

Full Text Available Folate and other methyl-donor pathway components are widely supplemented due to their ability to prevent prenatal neural tube defects. Several lines of evidence suggest that these supplements act through epigenetic mechanisms (e.g. altering DNA methylation. Primary among these are the experiments on the mouse viable yellow allele of the agouti locus (A(vy. In the Avy allele, an Intracisternal A-particle retroelement has inserted into the genome adjacent to the agouti gene and is preferentially methylated. To further test these effects, we tested the same diet used in the Avy studies on wild-derived Peromyscus maniculatus, a native North American rodent. We collected tissues from neonatal offspring whose parents were fed the high-methyl donor diet as well as controls. In addition, we assayed coat-color of a natural variant (wide-band agouti = A(Nb that overexpresses agouti as a phenotypic biomarker. Our data indicate that these dietary components affected agouti protein production, despite the lack of a retroelement at this locus. Surprisingly, the methyl-donor diet was associated with defects (e.g. ovarian cysts, cataracts and increased mortality. We also assessed the effects of the diet on behavior: We scored animals in open field and social interaction tests. We observed significant increases in female repetitive behaviors. Thus these data add to a growing number of studies that suggest that these ubiquitously added nutrients may be a human health concern.
Assessment of pleiotropic transcriptome perturbations in Arabidopsis engineered for indirect insect defence

NARCIS (Netherlands)

Houshyani Hassanzadeh, B.; Krol, van der A.R.; Bino, R.J.; Bouwmeester, H.J.

2014-01-01

Background: Molecular characterization is an essential step of risk/safety assessment of genetically modified (GM) crops. Holistic approaches for molecular characterization using omics platforms can be used to confirm the intended impact of the genetic engineering, but can also reveal the unintended
Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia.

NARCIS (Netherlands)

Paznekas, W.A.; Boyadjiev, S.A.; Shapiro, R.E.; Daniëls, O.; Wollnik, B.; Keegan, C.E.; Innis, J.W.; Dinulos, M.B.; Christian, C.; Hannibal, M.C.; Jabs, E.W.

2003-01-01

Gap junctions are assemblies of intercellular channels that regulate a variety of physiologic and developmental processes through the exchange of small ions and signaling molecules. These channels consist of connexin family proteins that allow for diversity of channel composition and conductance
HDACi: cellular effects, opportunities for restorative dentistry.

LENUS (Irish Health Repository)

Duncan, H F

2011-12-01

Acetylation of histone and non-histone proteins alters gene expression and induces a host of cellular effects. The acetylation process is homeostatically balanced by two groups of cellular enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HAT activity relaxes the structure of the human chromatin, rendering it transcriptionally active, thereby increasing gene expression. In contrast, HDAC activity leads to gene silencing. The enzymatic balance can be \\'tipped\\' by histone deacetylase inhibitors (HDACi), leading to an accumulation of acetylated proteins, which subsequently modify cellular processes including stem cell differentiation, cell cycle, apoptosis, gene expression, and angiogenesis. There is a variety of natural and synthetic HDACi available, and their pleiotropic effects have contributed to diverse clinical applications, not only in cancer but also in non-cancer areas, such as chronic inflammatory disease, bone engineering, and neurodegenerative disease. Indeed, it appears that HDACi-modulated effects may differ between \\'normal\\' and transformed cells, particularly with regard to reactive oxygen species accumulation, apoptosis, proliferation, and cell cycle arrest. The potential beneficial effects of HDACi for health, resulting from their ability to regulate global gene expression by epigenetic modification of DNA-associated proteins, also offer potential for application within restorative dentistry, where they may promote dental tissue regeneration following pulpal damage.
Phytoceuticals in Acute Pancreatitis: Targeting the Balance between Apoptosis and Necrosis

Science.gov (United States)

Gaman, Laura; Robu, Georgiana Catalina; Radoi, Mugurel Petrinel; Stroica, Laura; Badea, Mihaela

2018-01-01

Despite recent advances in understanding the complex pathogenesis of pancreatitis, the management of the disease remains suboptimal. The use of phytoceuticals (plant-derived pleiotropic multitarget molecules) represents a new research trend in pancreatology. The purpose of this review is to discuss the phytoceuticals with pancreatoprotective potential in acute pancreatitis and whose efficacy is based, at least in part, on their capacity to modulate the acinar cell death. The phytochemicals selected, belonging to such diverse classes as polyphenols, flavonoids, lignans, anthraquinones, sesquiterpene lactones, nitriles, and alkaloids, target the balance between apoptosis and necrosis. Activation of apoptosis via various mechanisms (e.g., inhibition of X-linked inhibitor of apoptosis proteins by embelin, upregulation of FasL gene expression by resveratrol) and/or inhibition of necrosis seem to represent the essential key for decreasing the severity of the disease. Apart from targeting the apoptosis/necrosis balance, the phytochemicals displayed other specific protective activities: inhibition of inflammasome (e.g., rutin), suppression of neutrophil infiltration (e.g., ligustrazine, resveratrol), and antioxidant activity. Even though many of the selected phytoceuticals represent a promising therapeutic alternative, there is a shortage of human evidence, and further studies are required to provide solid basis to justify their use in the treatment of pancreatitis. PMID:29686719
PPARs and the Cardiovascular System

Science.gov (United States)

Hamblin, Milton; Chang, Lin; Fan, Yanbo; Zhang, Jifeng

2009-01-01

Abstract Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone-receptor superfamily. Originally cloned in 1990, PPARs were found to be mediators of pharmacologic agents that induce hepatocyte peroxisome proliferation. PPARs also are expressed in cells of the cardiovascular system. PPARγ appears to be highly expressed during atherosclerotic lesion formation, suggesting that increased PPARγ expression may be a vascular compensatory response. Also, ligand-activated PPARγ decreases the inflammatory response in cardiovascular cells, particularly in endothelial cells. PPARα, similar to PPARγ, also has pleiotropic effects in the cardiovascular system, including antiinflammatory and antiatherosclerotic properties. PPARα activation inhibits vascular smooth muscle proinflammatory responses, attenuating the development of atherosclerosis. However, PPARδ overexpression may lead to elevated macrophage inflammation and atherosclerosis. Conversely, PPARδ ligands are shown to attenuate the pathogenesis of atherosclerosis by improving endothelial cell proliferation and survival while decreasing endothelial cell inflammation and vascular smooth muscle cell proliferation. Furthermore, the administration of PPAR ligands in the form of TZDs and fibrates has been disappointing in terms of markedly reducing cardiovascular events in the clinical setting. Therefore, a better understanding of PPAR-dependent and -independent signaling will provide the foundation for future research on the role of PPARs in human cardiovascular biology. Antioxid. Redox Signal. 11, 1415–1452. PMID:19061437
Role of JAK/STAT signaling in neuroepithelial stem cell maintenance and proliferation in the Drosophila optic lobe

Energy Technology Data Exchange (ETDEWEB)

Wang, Wei; Li, Yonggang; Zhou, Liya; Yue, Haitao [School of Life Sciences, Tsinghua University, Beijing 100084 (China); Luo, Hong, E-mail: luohong@mail.tsinghua.edu.cn [School of Life Sciences, Tsinghua University, Beijing 100084 (China)

2011-07-15

Highlights: {yields} JAK/STAT activity is graded in the Drosophila optic lobe neuroepithelium. {yields} Inactivation of JAK signaling causes disintegration of the optic lobe neuroepithelium and depletion of the neuroepithelial stem cells. {yields} JAK pathway overactivation promotes neuroepithelial overgrowth. {yields} Notch signaling acts downstream of JAK/STAT to promote neuroepithelial growth and expansion. -- Abstract: During Drosophila optic lobe development, proliferation and differentiation must be tightly modulated to reach its normal size for proper functioning. The JAK/STAT pathway plays pleiotropic roles in Drosophila development and in the larval brain, has been shown to inhibit medulla neuroblast formation. In this study, we find that JAK/STAT activity is required for the maintenance and proliferation of the neuroepithelial stem cells in the optic lobe. In loss-of-function JAK/STAT mutant brains, the neuroepithelial cells lose epithelial cell characters and differentiate prematurely while ectopic activation of this pathway is sufficient to induce neuroepithelial overgrowth in the optic lobe. We further show that Notch signaling acts downstream of JAK/STAT to control the maintenance and growth of the optic lobe neuroepithelium. Thus, in addition to its role in suppression of neuroblast formation, the JAK/STAT pathway is necessary and sufficient for optic lobe neuroepithelial growth.
Interactions between prolactin and kisspeptin to control reproduction.

Science.gov (United States)

Donato, Jose; Frazão, Renata

2016-01-01

Prolactin is best known for its effects of stimulating mammary gland development and lactogenesis. However, prolactin is a pleiotropic hormone that is able to affect several physiological functions, including fertility. Prolactin receptors (PRLRs) are widely expressed in several tissues, including several brain regions and reproductive tract organs. Upon activation, PRLRs may exert prolactin's functions through several signaling pathways, although the recruitment of the signal transducer and activator of transcription 5 causes most of the known effects of prolactin. Pathological hyperprolactinemia is mainly due to the presence of a prolactinoma or pharmacological effects induced by drugs that interact with the dopamine system. Notably, hyperprolactinemia is a frequent cause of reproductive dysfunction and may lead to infertility in males and females. Recently, several studies have indicated that prolactin may modulate the reproductive axis by acting on specific populations of hypothalamic neurons that express the Kiss1 gene. The Kiss1 gene encodes neuropeptides known as kisspeptins, which are powerful activators of gonadotropin-releasing hormone neurons. In the present review, we will summarize the current knowledge about prolactin's actions on reproduction. Among other aspects, we will discuss whether the interaction between prolactin and the Kiss1-expressing neurons can affect reproduction and how kisspeptins may become a novel therapeutic approach to treat prolactin-induced infertility.

Four-tiered π interaction at the dimeric interface of HIV-1 integrase critical for DNA integration and viral infectivity

International Nuclear Information System (INIS)

Al-Mawsawi, Laith Q.; Hombrouck, Anneleen; Dayam, Raveendra; Debyser, Zeger; Neamati, Nouri

2008-01-01

HIV-1 integrase (IN) is an essential enzyme for viral infection. Here, we report an extensive π electron orbital interaction between four amino acids, W132, M178, F181 and F185, located at the dimeric interface of IN that is critical for the strand transfer activity alone. Catalysis of nine different mutant IN proteins at these positions were evaluated. Whereas the 3'-processing activity is predominantly strong, the strand transfer activity of each enzyme was completely dependent on an intact π electron orbital interaction at the dimeric interface. Four representative IN mutants were constructed in the context of the infectious NL4.3 HIV-1 viral clone. Whereas viruses with an intact π electron orbital interaction at the IN dimeric interface replicated comparable to wild type, viruses containing an abolished π interaction were non-infectious. Q-PCR analysis of viral DNA forms during viral replication revealed pleiotropic effects of most mutations. We hypothesize that the π interaction is a critical contact point for the assembly of functional IN multimeric complexes, and that IN multimerization is required for a functional pre-integration complex. The rational design of small molecule inhibitors targeting the disruption of this π-π interaction should lead to powerful anti-retroviral drugs
Chronic mitragynine (kratom) enhances punishment resistance in natural reward seeking and impairs place learning in mice.

Science.gov (United States)

Ismail, Nurul Iman W; Jayabalan, Nanthini; Mansor, Sharif Mahsufi; Müller, Christian P; Muzaimi, Mustapha

2017-07-01

Kratom (Mitragyna speciosa) is a widely abused herbal drug preparation in Southeast Asia. It is often consumed as a substitute for heroin, but imposing itself unknown harms and addictive burdens. Mitragynine is the major psychostimulant constituent of kratom that has recently been reported to induce morphine-like behavioural and cognitive effects in rodents. The effects of chronic consumption on non-drug related behaviours are still unclear. In the present study, we investigated the effects of chronic mitragynine treatment on spontaneous activity, reward-related behaviour and cognition in mice in an IntelliCage® system, and compared them with those of morphine and Δ-9-tetrahydrocannabinol (THC). We found that chronic mitragynine treatment significantly potentiated horizontal exploratory activity. It enhanced spontaneous sucrose preference and also its persistence when the preference had aversive consequences. Furthermore, mitragynine impaired place learning and its reversal. Thereby, mitragynine effects closely resembled that of morphine and THC sensitisation. These findings suggest that chronic mitragynine exposure enhances spontaneous locomotor activity and the preference for natural rewards, but impairs learning and memory. These findings confirm pleiotropic effects of mitragynine (kratom) on human lifestyle, but may also support the recognition of the drug's harm potential. © 2016 Society for the Study of Addiction.
Expression of phenazine biosynthetic genes during the arbuscular mycorrhizal symbiosis of Glomus intraradices

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Dionicia Gloria León-Martínez

2012-06-01

Full Text Available To explore the molecular mechanisms that prevail during the establishment of the arbuscular mycorrhiza symbiosis involving the genus Glomus, we transcriptionally analysed spores of Glomus intraradices BE3 during early hyphal growth. Among 458 transcripts initially identified as being expressed at presymbiotic stages, 20% of sequences had homology to previously characterized eukaryotic genes, 30% were homologous to fungal coding sequences, and 9% showed homology to previously characterized bacterial genes. Among them, GintPbr1a encodes a homolog to Phenazine Biosynthesis Regulator (Pbr of Burkholderia cenocepacia, an pleiotropic regulatory protein that activates phenazine production through transcriptional activation of the protein D isochorismatase biosynthetic enzyme phzD (Ramos et al., 2010. Whereas GintPbr1a is expressed during the presymbiotic phase, the G. intraradices BE3 homolog of phzD (BGintphzD is transcriptionally active at the time of the establishment of the arbuscular mycorrhizal symbiosis. DNA from isolated bacterial cultures found in spores of G. intraradices BE3 confirmed that both BGintPbr1a and BGintphzD are present in the genome of its potential endosymbionts. Taken together, our results indicate that spores of G. intraradices BE3 express bacterial phenazine biosynthetic genes at the onset of the fungal-plant symbiotic interaction.
Influence of Background Genome on Enzymatic Characteristics of Yellow (Ay/-, Avy/-) Mice

Science.gov (United States)

Wolff, George L.; Pitot, Henry C.

1973-01-01

Identification of the fundamental polypeptide difference between yellow (Ay/-, Avy/-) and non-yellow mice is important for biomedical research because of the influence of the yellow genotype on normal and neoplastic growth and obesity. The complexity of the "yellow mouse syndrome" makes attainment of this objective dependent on the separation of those pleiotropic enzyme differences which are secondary, and depend on the background genome, from those which are primary, and depend primarily on the agouti locus genotype.—Four of nine hepatic enzyme activities assayed simultaneously differed between eight-week-old yellow (Ay/-, Avy/-) and non-yellow (A/-, a/a) male inbred and F1 hybrid mice. Among these four, only cytoplasmic malic enzyme activity was elevated in all yellow mice, as compared with the non-yellow sibs, regardless of background genome. Glucokinase, serine dehydratase, and tyrosine α-ketoglutarate transaminase activities were also changed in yellow mice, but these alterations depended on the background genome.—The ratio of malic enzyme activity to citrate-cleavage enzyme activity, possibly related to the altered fat metabolism of yellow mice, was influenced by background genome as well as by the yellow genotype.——Significant deviations of enzyme activities from mid-parent values among F1 hybrids were associated with particular background genomes; the number of such deviations was larger among yellow mice than among non-yellows and this difference was greater among C3H F1 hybrids than among C57BL/6 F1 hybrids. PMID:4405752
The neuropeptide catestatin promotes vascular smooth muscle cell proliferation through the Ca{sup 2+}-calcineurin-NFAT signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Guo, Xiaoxia [Department of Cardiology, People' s Hospital, Peking University, No. 11 South Avenue, Xi Zhi Men Xicheng District, Beijing 100044 (China); Zhou, Chunyan, E-mail: chunyanzhou@bjmu.edu.cn [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191 (China); Sun, Ningling, E-mail: nlsun@263.net [Department of Cardiology, People' s Hospital, Peking University, No. 11 South Avenue, Xi Zhi Men Xicheng District, Beijing 100044 (China)

2011-04-22

Highlights: {yields} Catestatin stimulates proliferation of vascular smooth muscle cells in a dose-dependent manner. {yields} Catestatin provokes sustained increase in intracellular Ca{sup 2+}. {yields} Catestatin produces increased activation of calcineurin and promotes NFATc1 translocation into the nucleus. -- Abstract: The Chromogranin A-derived neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone. Since catestatin shares several functions with other members derived from the chromogranin/secretogranin protein family and other neuropeptides which exert proliferative effects on vascular smooth muscle cells (VSMCs), we therefore hypothesized that catestatin would regulate VSMC proliferation. The present study demonstrates that catestatin caused a dose-dependent induction of proliferation in rat aortic smooth muscle cells and furthermore evoked a sustained increase in intracellular calcium. This subsequently leaded to enhanced activation of the Ca{sup 2+}/calmodulin-dependent phosphatase, calcineurin and resulted in an activation of the Ca{sup 2+}-dependent transcription factor, nuclear factor of activated T cells (NFAT), initiating transcription of proliferative genes. In addition, cyclosporin A (CsA), a potent inhibitor of calcineurin, abrogated catestatin-mediated effect on VSMCs, indicating that the calcineurin-NFAT signaling is strongly required for catestatin-induced growth of VSMCs. The present study establishes catestatin as a novel proliferative cytokine on vascular smooth muscle cells and this effect is mediated by the Ca{sup 2+}-calcineurin-NFAT signaling pathway.
WRKY Transcription Factors: Key Components in Abscisic Acid Signaling

Science.gov (United States)

2011-01-01

networks that take inputs from numerous stimuli and that they are involved in mediating responses to numerous phytohormones including salicylic acid ... jasmonic acid , ABA and GA. These roles in multiple signalling pathways may in turn partly explain the pleiotropic effects commonly seen when TF genes are...Review article WRKY transcription factors: key components in abscisic acid signalling Deena L. Rushton1, Prateek Tripathi1, Roel C. Rabara1, Jun Lin1
To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents

OpenAIRE

Arbel?ez-Quintero, Isaac; Palacios, Mauricio

2017-01-01

Ischemic strokes are major causes of death and disability. Searching for potential therapeutic strategies to prevent and treat stroke is necessary, given the increase in overall life expectancy. Epidemiological reports indicate that metformin is an oral antidiabetic medication that can reduce the incidence of ischemic events in patients with diabetes mellitus. Its mechanism of action has not been elucidated, but metformin pleiotropic effects involve actions in addition to glycemic control. AM...
Convergent Synthesis of Two Fluorescent Ebselen-Coumarin Heterodimers

OpenAIRE

K?ppers, Jim; Schulz-Fincke, Anna Christina; Palus, Jerzy; Giurg, Miros?aw; Skar?ewski, Jacek; G?tschow, Michael

2016-01-01

The organo-seleniumdrug ebselen exhibits a wide range of pharmacological effects that are predominantly due to its interference with redox systems catalyzed by seleno enzymes, e.g., glutathione peroxidase and thioredoxin reductase. Moreover, ebselen can covalently interact with thiol groups of several enzymes. According to its pleiotropic mode of action, ebselen has been investigated in clinical trials for the prevention and treatment of different ailments. Fluorescence-labeled probes contain...
Curcumin induces human cathelicidin antimicrobial peptide gene expression through a vitamin D receptor-independent pathway

DEFF Research Database (Denmark)

Guo, Chunxiao; Rosoha, Elena; Lowry, Malcolm B

2013-01-01

The vitamin D receptor (VDR) mediates the pleiotropic biologic effects of 1α,25 dihydroxy-vitamin D(3). Recent in vitro studies suggested that curcumin and polyunsaturated fatty acids (PUFAs) also bind to VDR with low affinity. As potential ligands for the VDR, we hypothesized that curcumin...... cancer cell line HT-29 and keratinocyte cell line HaCaT. We demonstrated that PUFAs failed to induce CAMP or CYP24A1 mRNA expression in all three cell lines, but curcumin up-regulated CAMP mRNA and protein levels in U937 cells. Curcumin treatment induced CAMP promoter activity from a luciferase reporter...... construct lacking the VDR binding site and did not increase binding of the VDR to the CAMP promoter as determined by chromatin immunoprecipitation assays. These findings indicate that induction of CAMP by curcumin occurs through a vitamin D receptor-independent manner. We conclude that PUFAs and curcumin do...
Plasticity-related genes in brain development and amygdala-dependent learning.

Science.gov (United States)

Ehrlich, D E; Josselyn, S A

2016-01-01

Learning about motivationally important stimuli involves plasticity in the amygdala, a temporal lobe structure. Amygdala-dependent learning involves a growing number of plasticity-related signaling pathways also implicated in brain development, suggesting that learning-related signaling in juveniles may simultaneously influence development. Here, we review the pleiotropic functions in nervous system development and amygdala-dependent learning of a signaling pathway that includes brain-derived neurotrophic factor (BDNF), extracellular signaling-related kinases (ERKs) and cyclic AMP-response element binding protein (CREB). Using these canonical, plasticity-related genes as an example, we discuss the intersection of learning-related and developmental plasticity in the immature amygdala, when aversive and appetitive learning may influence the developmental trajectory of amygdala function. We propose that learning-dependent activation of BDNF, ERK and CREB signaling in the immature amygdala exaggerates and accelerates neural development, promoting amygdala excitability and environmental sensitivity later in life. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
1,25-Dihydroxyvitamin D3 regulates genes responsible for detoxification in intestine

International Nuclear Information System (INIS)

Kutuzova, Galina D.; DeLuca, Hector F.

2007-01-01

1α,25-Dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), the biologically active form of vitamin D 3 , not only plays a major role in mammalian calcium and phosphorous homeostasis but also exerts pleiotropic effects on cell proliferation, differentiation and the immune system. Further, vitamin D is believed to play a significant role in the prevention of colon, prostate, and breast cancer and in reducing the risk of autoimmune diseases. To gain insight into the mechanism whereby vitamin D can have such diverse actions, we have employed microarray technology. We studied the effect of a single dose of 1,25-(OH) 2 D 3 on gene expression in the intestine of vitamin D-deficient rats. Within 6 h, 1,25-(OH) 2 D 3 stimulates the expression of several phase I and phase II biotransformation genes. There is also an increased expression of antioxidant genes. These results support the idea that vitamin D is a significant factor in detoxification and protection against environmental toxins
Glutaminolysis: A Hallmark of Cancer Metabolism.

Science.gov (United States)

Yang, Lifeng; Venneti, Sriram; Nagrath, Deepak

2017-06-21

Glutamine is the most abundant circulating amino acid in blood and muscle and is critical for many fundamental cell functions in cancer cells, including synthesis of metabolites that maintain mitochondrial metabolism; generation of antioxidants to remove reactive oxygen species; synthesis of nonessential amino acids (NEAAs), purines, pyrimidines, and fatty acids for cellular replication; and activation of cell signaling. In light of the pleiotropic role of glutamine in cancer cells, a comprehensive understanding of glutamine metabolism is essential for the development of metabolic therapeutic strategies for targeting cancer cells. In this article, we review oncogene-, tumor suppressor-, and tumor microenvironment-mediated regulation of glutamine metabolism in cancer cells. We describe the mechanism of glutamine's regulation of tumor proliferation, metastasis, and global methylation. Furthermore, we highlight the therapeutic potential of glutamine metabolism and emphasize that clinical application of in vivo assessment of glutamine metabolism is critical for identifying new ways to treat patients through glutamine-based metabolic therapy.
Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity.

Science.gov (United States)

Quarta, Carmelo; Clemmensen, Christoffer; Zhu, Zhimeng; Yang, Bin; Joseph, Sini S; Lutter, Dominik; Yi, Chun-Xia; Graf, Elisabeth; García-Cáceres, Cristina; Legutko, Beata; Fischer, Katrin; Brommage, Robert; Zizzari, Philippe; Franklin, Bernardo S; Krueger, Martin; Koch, Marco; Vettorazzi, Sabine; Li, Pengyun; Hofmann, Susanna M; Bakhti, Mostafa; Bastidas-Ponce, Aimée; Lickert, Heiko; Strom, Tim M; Gailus-Durner, Valerie; Bechmann, Ingo; Perez-Tilve, Diego; Tuckermann, Jan; Hrabě de Angelis, Martin; Sandoval, Darleen; Cota, Daniela; Latz, Eicke; Seeley, Randy J; Müller, Timo D; DiMarchi, Richard D; Finan, Brian; Tschöp, Matthias H

2017-10-03

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity. Copyright © 2017 Elsevier Inc. All rights reserved.
Rab39a interacts with phosphatidylinositol 3-kinase and negatively regulates autophagy induced by lipopolysaccharide stimulation in macrophages.

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Shintaro Seto

Full Text Available Rab39a has pleiotropic functions in phagosome maturation, inflammatory activation and neuritogenesis. Here, we characterized Rab39a function in membrane trafficking of phagocytosis and autophagy induction in macrophages. Rab39a localized to the periphery of LAMP2-positive vesicles and showed the similar kinetics on the phagosome to that of LAMP1. The depletion of Rab39a did not influence the localization of LAMP2 to the phagosome, but it augments the autophagosome formation and LC3 processing by lipopolysaccharide (LPS stimulation. The augmentation of autophagosome formation in Rab39a-knockdown macrophages was suppressed by Atg5 depletion or an inhibitor for phosphatidylinostol 3-kinase (PI3K. Immunoprecipitation analysis revealed that Rab39a interacts with PI3K and that the amino acid residues from 34(th to 41(st in Rab39a were indispensable for this interaction. These results suggest that Rab39a negatively regulates the LPS-induced autophagy in macrophages.
Methyl Jasmonate: An Alternative for Improving the Quality and Health Properties of Fresh Fruits

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Marjorie Reyes-Díaz

2016-05-01

Full Text Available Methyl jasmonate (MeJA is a plant growth regulator belonging to the jasmonate family. It plays an important role as a possible airborne signaling molecule mediating intra- and inter-plant communications and modulating plant defense responses, including antioxidant systems. Most assessments of this compound have dealt with post-harvest fruit applications, demonstrating induced plant resistance against the detrimental impacts of storage (chilling injuries and pathogen attacks, enhancing secondary metabolites and antioxidant activity. On the other hand, the interactions between MeJA and other compounds or technological tools for enhancing antioxidant capacity and quality of fruits were also reviewed. The pleiotropic effects of MeJA have raisen numerous as-yet unanswered questions about its mode of action. The aim of this review was endeavored to clarify the role of MeJA on improving pre- and post-harvest fresh fruit quality and health properties. Interestingly, the influence of MeJA on human health will be also discussed.
Hypercholesterolemia, Stroke And Statins

Directory of Open Access Journals (Sweden)

Prabhakar S

2005-01-01

Full Text Available The link between serum cholesterol levels and the incidence of stroke still remain to be established. There are conflicting reports from a series of observational cohort studies. However, clinical trials with HMG CoA reductase inhibitors (also called statins have shown that cholesterol lowering therapy used in the primary and secondary prevention of myocardial infarction significantly reduced cardiovascular events including strokes. Meta analysis of trials with statins have shown a relative risk reduction in stroke of 12 to 48% in patients with coronary heart disease after MI. It has been postulated that the clinical action of statins is the result of pleiotropic / antiatherogenic effects rather than simply a reduction in cholesterol. The putative beneficial effect of statins in stroke involve blocking of macrophage and platelet activation, improvement of endothelial cell vasomotor function, enhancement of endothelial fibrinolytic function, immunosuppressive and anti-inflammatory action, inhibition of smooth muscle cell proliferation and particularly enhancement of endothelial nitric oxide synthase (eNOS.
Psd1 Effects on Candida albicans Planktonic Cells and Biofilms

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Sónia Gonçalves

2017-06-01

Full Text Available Candida albicans is an important human pathogen, causing opportunistic infections. The adhesion of planktonic cells to a substrate is the first step for biofilm development. The antimicrobial peptide (AMP Psd1 is a defensin isolated from Pisum sativum seeds. We tested the effects of this AMP on C. albicans biofilms and planktonic cells, comparing its activity with amphotericin B and fluconazole. Three C. albicans variants were studied, one of them a mutant deficient in glucosylceramide synthase, conferring resistance to Psd1 antifungal action. Atomic force microscopy (AFM was used to assess morphological and biomechanical changes on fungal cells. Surface alterations, with membrane disruption and leakage of cellular contents, were observed. Cytometry assays and confocal microscopy imaging showed that Psd1 causes cell death, in a time and concentration-dependent manner. These results demonstrate Psd1 pleiotropic action against a relevant fungal human pathogen, suggesting its use as natural antimycotic agent.
Aging, tumor suppression and cancer: High-wire act!

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Campisi, Judith

2004-08-15

Evolutionary theory holds that aging is a consequence of the declining force of natural selection with age. We discuss here the evidence that among the causes of aging in complex multicellular organisms, such as mammals, is the antagonistically pleiotropic effects of the cellular responses that protect the organism from cancer. Cancer is relatively rare in young mammals, owing in large measure to the activity of tumor suppressor mechanisms. These mechanisms either protect the genome from damage and/or mutations, or they elicit cellular responses--apoptosis or senescence--that eliminate or prevent the proliferation of somatic cells at risk for neoplastic transformation.We focus here on the senescence response, reviewing its causes, regulation and effects. In addition, we describe recent data that support the idea that both senescence and apoptosis may indeed be the double-edged swords predicted by the evolutionary hypothesis of antagonistic pleiotropy--protecting organisms from cancer early in life, but promoting aging phenotypes, including late life cancer, in older organisms.
New Insight into Adiponectin Role in Obesity and Obesity-Related Diseases

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Ersilia Nigro

2014-01-01

Full Text Available Obesity is a major health problem strongly increasing the risk for various severe related complications such as metabolic syndrome, cardiovascular diseases, respiratory disorders, diabetic retinopathy, and cancer. Adipose tissue is an endocrine organ that produces biologically active molecules defined “adipocytokines,” protein hormones with pleiotropic functions involved in the regulation of energy metabolism as well as in appetite, insulin sensitivity, inflammation, atherosclerosis, cell proliferation, and so forth. In obesity, fat accumulation causes dysregulation of adipokine production that strongly contributes to the onset of obesity-related diseases. Several advances have been made in the treatment and prevention of obesity but current medical therapies are often unsuccessful even in compliant patients. Among the adipokines, adiponectin shows protective activity in various processes such as energy metabolism, inflammation, and cell proliferation. In this review, we will focus on the current knowledge regarding the protective properties of adiponectin and its receptors, AdipoRs (“adiponectin system”, on metabolic complications in obesity and obesity-related diseases. Adiponectin, exhibiting antihyperglycemic, antiatherogenic, and anti-inflammatory properties, could have important clinical benefits in terms of development of therapies for the prevention and/or for the treatment of obesity and obesity-related diseases.
Essential role of Stat6 in IL-4 signalling.

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Takeda, K; Tanaka, T; Shi, W; Matsumoto, M; Minami, M; Kashiwamura, S; Nakanishi, K; Yoshida, N; Kishimoto, T; Akira, S

1996-04-18

Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.

Metabolic actions of FGF21: molecular mechanisms and therapeutic implications

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Xuan Ge

2012-08-01

Full Text Available Fibroblast growth factor 21 (FGF21 is an atypical member of the FGF family that functions as an endocrine factor. In obese animals, elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight, decreases hyperglycemia and hyperlipidemia, alleviates fatty liver and increases insulin sensitivity. FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets, including adipose tissue, liver, brain and pancreas. The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma (PPARγ and peroxisome proliferator-activated receptor alpha (PPARα. A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21. In humans, plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes, but are reduced in patients with autoimmune diabetes. This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions, and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.
Chocolate protects a heart and vessels

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Małgorzata Chudzińska

2017-08-01

Full Text Available A healthy diet plays a key role in the prevention and management of cardiovascular diseases. Atherosclerosis and its complications are nowadays one of the leading causes of death in the western population. Among numerous factors known for slowing down the progression of the disease is the consumption of vegetables, fruits and chocolate rich in multiring compounds called polyphenols. Chocolate is a source of catechins, epicatechins and procyanidins. Recently, several studies have demonstrated the beneficial effects of dark chocolate in management of hypertension by hypotensive effect associated with vasorelaxation mediated most likely by the stimulation of nitric oxide production in the vascular wall. Cocoa and its derivatives have also strong antioxidative properties resulting in enhancement of the total antioxidant potential and inhibition of lipid peroxidation. It was also demonstrated that cocoa polyphenols have a favourable antithrombotic effect connected with the inhibition of platelet activation. Chocolate may diminish insulin resistance and inhibit inflammatory process. Cocoa improves also psychical well being. This pleiotropic activity of cocoa results in slowing down the progression and limiting the complications of atherosclerosis in regular chocolate consumers.
Functional analysis of apf1 mutation causing defective amino acid transport in Saccharomyces cerevisiae.

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Horák, J; Kotyk, A

1993-04-01

Mutation in the Apf1 locus causes a pleiotropic effect of H(+)-driven active amino acid transport in baker's yeast Saccharomyces cerevisiae. The uptake of other, presumably H(+)-driven, substances, e.g. of purine and pyrimidine bases, maltose and phosphate ions, is not significantly influenced by this mutation. The apf1 mutation decreases not only the initial rates of amino acid uptake but also the accumulation ratios of amino acids taken up but has virtually no effect on the membrane potential or on the delta pH which constitute the thermodynamically relevant source of energy for their transport. Similarly, no changes in intracellular ATP content, in ATP-hydrolyzing and H(+)-extruding H(+)-ATPase activities, in the efflux of intracellularly accumulated amino acids, or in rates of endogenous respiration, were observed in the apf1 mutant phenotype. Hence, all these data are in accordance with the experiments showing that the Apf1 protein, an integral protein of the endoplasmic reticulum, is required exclusively for efficient processing and translocation of transport proteins specific for amino acids from the endoplasmic reticulum to their final destination, the plasma membrane.
Procyanidins from evening primrose (Oenothera paradoxa) defatted seeds inhibit invasiveness of breast cancer cells and modulate the expression of selected genes involved in angiogenesis, metastasis, and apoptosis.

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Lewandowska, Urszula; Szewczyk, Karolina; Owczarek, Katarzyna; Hrabec, Zbigniew; Podsędek, Anna; Sosnowska, Dorota; Hrabec, Elżbieta

2013-01-01

There is a growing interest in plant polyphenols (including flavanols) that exhibit pleiotropic biological activities such as antiinflammatory, antioxidant, and anticancer effects. Here, we report for the first time the inhibition of MDA-MB-231 breast cancer cell viability and invasiveness by an evening primrose flavanol preparation (EPFP). We observed a decrease in MDA-MB-231 viability of 50% vs. a control after 72 h of incubation with EPFP at a concentration of 58 μM gallic acid equivalents (GAE) and an inhibition of their invasiveness of 65% vs. a control at 75 μM GAE after 48 h of incubation. EPFP caused a 10-fold reduction in matrix metalloproteinase-9 (MMP-9) activity at 100 μM GAE. Furthermore, through modulation of mRNA expression, EPFP reduced the expression levels of the following proteins: antiapoptotic Bcl-2, angiogenic vascular endothelial growth factor (VEGF), and 2 transcription factors (c-Jun, c-Fos). Moreover, analysis by flow cytometry revealed that EPFP induced apoptosis in MDA-MB-231 cells. In conclusion, our data shows that EPFP inhibits cell viability by increasing apoptosis and decreases cell invasiveness by decreasing angiogenesis.
Prevalence and characteristics of Listeria monocytogenes in bovine colostrum in Japan.

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Hasegawa, Megumi; Iwabuchi, Eriko; Yamamoto, Shiori; Esaki, Hidetake; Kobayashi, Kazuhiko; Ito, Masahiko; Hirai, Katsuya

2013-02-01

This study was conducted to determine the prevalence and characteristics of Listeria monocytogenes in bovine colostrum in Japan. We collected bovine colostrum samples from 210 dams from 21 dairy farms in Hokkaido prefecture (Japan) between March and June 2009. L. monocytogenes was detected in samples from 6 (28.6%) of the 21 farms. Of the 210 samples, 16 (7.6%) were positive for L. monocytogenes. We recovered 80 L. monocytogenes isolates; 44 (55%) isolates were classified as serotype 1/2b and 36 (45%) were classified as serotype 4b. The isolates were susceptible to penicillin, ampicillin, amoxicillin, gentamicin, kanamycin, streptomycin, erythromycin, vancomycin, tetracycline, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole. Pulsed-field gel electrophoresis (PFGE) characterization of the 80 isolates revealed six PFGE types. Two PFGE types corresponded to human listeriosis cases. Most L. monocytogenes isolates possessed virulence-associated genes (actA, hly, iap, inlA, inlC, mpl, plcA, plcB, opuCA, prfA, and clpC). One PFGE type isolate possessed an epidemic clone II marker. Our findings suggest that isolates from bovine colostrum have the potential to cause human and animal listeriosis. This is the first study on the prevalence and characteristics of L. monocytogenes isolated from bovine colostrum obtained from dairy farms. Our results have important implications for improving public health and elucidating the epidemiology of L. monocytogenes in bovine colostrum.
Roles of a novel Crp/Fnr family transcription factor Lmo0753 in soil survival, biofilm production and surface attachment to fresh produce of Listeria monocytogenes.

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Joelle K Salazar

Full Text Available Listeria monocytogenes is a foodborne bacterial pathogen and the causative agent of an infectious disease, listeriosis. L. monocytogenes is ubiquitous in nature and has the ability to persist in food processing environments for extended periods of time by forming biofilms and resisting industrial sanitization. Human listeriosis outbreaks are commonly linked to contaminated dairy products, ready-to-eat meats, and in recent years, fresh produce such as lettuce and cantaloupes. We identified a putative Crp/Fnr family transcription factor Lmo0753 that is highly specific to human-associated genetic lineages of L. monocytogenes. Lmo0753 possesses two conserved functional domains similar to the major virulence regulator PrfA in L. monocytogenes. To determine if Lmo0753 is involved in environmental persistence-related mechanisms, we compared lmo0753 deletion mutants with respective wild type and complementation mutants of two fully sequenced L. monocytogenes genetic lineage II strains 10403S and EGDe for the relative ability of growth under different nutrient availability and temperatures, soil survival, biofilm productivity and attachment to select fresh produce surfaces including romaine lettuce leaves and cantaloupe rinds. Our results collectively suggested that Lmo0753 plays an important role in L. monocytogenes biofilm production and attachment to fresh produce, which may contribute to the environmental persistence and recent emergence of this pathogen in human listeriosis outbreaks linked to fresh produce.
The occurrence, transmission, virulence and antibiotic resistance of Listeria monocytogenes in fish processing plant.

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Skowron, Krzysztof; Kwiecińska-Piróg, Joanna; Grudlewska, Katarzyna; Świeca, Agnieszka; Paluszak, Zbigniew; Bauza-Kaszewska, Justyna; Wałecka-Zacharska, Ewa; Gospodarek-Komkowska, Eugenia

2018-06-13

The aim of this research was to investigate the occurrence of Listeria monocytogenes in fish and fish processing plant and to determine their transmission, virulence and antibiotic resistance. L. monocytogenes was isolated according to the ISO 11290-1. The identification of L. monocytogenes was confirmed by multiplex PCR method. Genetic similarity of L. monocytogenes strains was determined with the Pulsed-Filed Gene Electrophoresis (PFGE) method. The multiplex PCR was used for identification of L. monocytogenes serogroups and detection of selected virulence genes (actA, fbpA, hlyA, iap, inlA, inlB, mpl, plcA, plcB, prfA). The L. monocytogens isolates susceptibility to penicillin, ampicillin, meropenem, erythromycin, trimethoprim/sulfamethoxazole was evaluated with disc diffusion method according to EUCAST v. 7.1. The presence of 237 L. monocytogenes isolates (before genetic similarity assessment) in 614 examined samples was confirmed. After strain differentiation by PFGE techniques the presence of 161 genetically different strains were confirmed. The genetic similarity of the examined isolates suggested that the source of the L. monocytogenes strains were fishes originating from farms. All tested strains possessed all detected virulence genes. Among examined strains, the most (26, 38.6%) belonged to the group 1/2a-3a. The most of tested strains were resistant to erythromycin (47.1%) and trimethoprim/sulfamethoxazole (47.1%). Copyright © 2018. Published by Elsevier B.V.
Listeria monocytogenes en alimentos: ¿son todos los aislamientos igual de virulentos?

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V. López

Full Text Available Listeria monocytogenes es un patógeno humano que se transmite a través de los alimentos y que causa infecciones graves, con una alta tasa de mortalidad. A pesar de la ubicuidad del microorganismo, la tasa real de la enfermedad es bastante baja y se asocia casi siempre a condiciones predisponentes. Tradicionalmente se consideraba que los aislamientos presentes en los alimentos y en el ambiente tenían la misma capacidad patogénica que los aislamientos de origen clínico. Pero el análisis de mutaciones en los genes de determinados factores de virulencia (internalina, hemolisina, fosfolipasas, proteína de superficie ActA y proteína reguladora PrfA, los estudios cuantitativos realizados con cultivos celulares y la genética de poblaciones, están replanteando la discusión sobre la variabilidad de la virulencia de L. monocytogenes. A pesar de todos estos avances, no existe un único marcador que permita comprobar la virulencia de los aislamientos naturales de esta especie. Probablemente en el futuro, la combinación de diferentes marcadores moleculares permitirá detectar los alimentos contaminados sólo por los clones virulentos de L. monocytogenes, con lo que se mejorará la prevención de la listeriosis humana transmitida por alimentos.
Electrochemical genosensing of Salmonella, Listeria and Escherichia coli on silica magnetic particles.

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Liébana, Susana; Brandão, Delfina; Cortés, Pilar; Campoy, Susana; Alegret, Salvador; Pividori, María Isabel

2016-01-21

A magneto-genosensing approach for the detection of the three most common pathogenic bacteria in food safety, such as Salmonella, Listeria and Escherichia coli is presented. The methodology is based on the detection of the tagged amplified DNA obtained by single-tagging PCR with a set of specific primers for each pathogen, followed by electrochemical magneto-genosensing on silica magnetic particles. A set of primers were selected for the amplification of the invA (278 bp), prfA (217 bp) and eaeA (151 bp) being one of the primers for each set tagged with fluorescein, biotin and digoxigenin coding for Salmonella enterica, Listeria monocytogenes and E. coli, respectively. The single-tagged amplicons were then immobilized on silica MPs based on the nucleic acid-binding properties of silica particles in the presence of the chaotropic agent as guanidinium thiocyanate. The assessment of the silica MPs as a platform for electrochemical magneto-genosensing is described, including the main parameters to selectively attach longer dsDNA fragments instead of shorter ssDNA primers based on their negative charge density of the sugar-phosphate backbone. This approach resulted to be a promising detection tool with sensing features of rapidity and sensitivity very suitable to be implemented on DNA biosensors and microfluidic platforms. Copyright © 2015 Elsevier B.V. All rights reserved.
Biochemical and molecular characteristics of Listeria monocytogenes isolates from a prosthetic mitral heart valve-bearing patient´s blood cultures

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Nilma Cintra Leal

2013-09-01

Full Text Available Background: In Brazil, listeriosis is not a notifiable disease; thus, the incidence of Brazilian cases remains unknown. Listeria monocytogenes is not always included in automated systems, and its detection depends on the high skill level of microbiology laboratory professionals. This paper describes the characteristics of L. monocytogenes isolates fortuitously obtained from an endocarditis case in Recife, PE, Brazil. Methods: Six bacterial isolates obtained from six blood cultures from a 28-year-old male bearing a prosthetic mitral heart valve were analyzed by PCR using primers specific of L. monocytogenes to confirm a presumptive identification, determine the serotype and presence of the virulence genes (inlA, inlB, inlC, inlJ, hly, plcA, actA, prfA in an attempt to determine the Listeria genotype by PCR-ribotyping. Results: The samples were identified as L. monocytogenes 4b. All investigated virulence genes were amplified by PCR, and the identity of the amplified segments was confirmed by sequencing. A deletion of 105 base pairs was detected in the actA gene. All of the samples generated the same PCR-ribotype pattern, clustered into a single ribotype, and were considered a single strain. Conclusion: L. monocytogenes infection should be considered in endocarditis differential diagnoses, especially among high-risk groups, due to its high pathogenicity and the environmental ubiquity.
BIOCHEMICAL AND MOLECULAR CHARACTERISTICS OF LISTERIA MONOCYTOGENES ISOLATES FROM A PROSTHETIC MITRAL HEART VALVE-BEARING PATIENT´S BLOOD CULTURES

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Nilma Cintra Lea

2013-09-01

Full Text Available Background: In Brazil, listeriosis is not a notifiable disease; thus, the incidence of Brazilian cases remains unknown. Listeria monocytogenes is not always included in automated systems, and its detection depends on the high skill level of microbiology laboratory professionals. This paper describes the characteristics of L. monocytogenes isolates fortuitously obtained from an endocarditis case in Recife, PE, Brazil. Methods: Six bacterial isolates obtained from six blood cultures from a 28-year-old male bearing a prosthetic mitral heart valve were analyzed by PCR using primers specific of L. monocytogenes to confirm a presumptive identification, determine the serotype and presence of the virulence genes (inlA, inlB, inlC, inlJ, hly, plcA, actA, prfA in an attempt to determine the Listeria genotype by PCR-ribotyping. Results: The samples were identified as L. monocytogenes 4b. All investigated virulence genes were amplified by PCR, and the identity of the amplified segments was confirmed by sequencing. A deletion of 105 base pairs was detected in the actA gene. All of the samples generated the same PCR-ribotype pattern, clustered into a single ribotype, and were considered a single strain. Conclusion: L. monocytogenes infection should be considered in endocarditis differential diagnoses, especially among high-risk groups, due to its high pathogenicity and the environmental ubiquity.
Effects of EPSPS Copy Number Variation (CNV and Glyphosate Application on the Aromatic and Branched Chain Amino Acid Synthesis Pathways in Amaranthus palmeri

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Manuel Fernández-Escalada

2017-11-01

Full Text Available A key enzyme of the shikimate pathway, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS; EC 2.5.1.19, is the known target of the widely used herbicide glyphosate. Glyphosate resistance in Amaranthus palmeri, one of the most troublesome weeds in agriculture, has evolved through increased EPSPS gene copy number. The aim of this work was to study the pleiotropic effects of (i EPSPS increased transcript abundance due to gene copy number variation (CNV and of (ii glyphosate application on the aromatic amino acid (AAA and branched chain amino acid (BCAA synthesis pathways. Hydroponically grown glyphosate sensitive (GS and glyphosate resistant (GR plants were treated with glyphosate 3 days after treatment. In absence of glyphosate treatment, high EPSPS gene copy number had only a subtle effect on transcriptional regulation of AAA and BCAA pathway genes. In contrast, glyphosate treatment provoked a general accumulation of the transcripts corresponding to genes of the AAA pathway leading to synthesis of chorismate in both GS and GR. After chorismate, anthranilate synthase transcript abundance was higher while chorismate mutase transcription showed a small decrease in GR and remained stable in GS, suggesting a regulatory branch point in the pathway that favors synthesis toward tryptophan over phenylalanine and tyrosine after glyphosate treatment. This was confirmed by studying enzyme activities in vitro and amino acid analysis. Importantly, this upregulation was glyphosate dose dependent and was observed similarly in both GS and GR populations. Glyphosate treatment also had a slight effect on the expression of BCAA genes but no general effect on the pathway could be observed. Taken together, our observations suggest that the high CNV of EPSPS in A. palmeri GR populations has no major pleiotropic effect on the expression of AAA biosynthetic genes, even in response to glyphosate treatment. This finding supports the idea that the fitness cost associated
Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice.

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Miranda, Hugo F; Noriega, Viviana; Olavarria, Loreto; Zepeda, Ramiro J; Sierralta, Fernando; Prieto, Juan C

2011-12-01

Statins, belonging to a well-known drug class used for lowering cholesterol through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also have other pleiotropic properties, such as anti-inflammatory action. The purpose of this study was to evaluate the antinociceptive and anti-inflammatory effects of simvastatin in five models of nociceptive behaviour. Oral gavage administration of simvastatin induced a dose-dependent inhibition of nociception for 1 day in the acetic acid writhing (ED(50) = 5.59 ± 0.07), tail-flick (ED(50) = 112.96 ± 8.00), hot-plate (ED(50) = 134.87 ± 2.20), formalin hind paw (ED(50) = 19.86 ± 1.12 in phase I and 23.30 ± 2.05 in phase II) and orofacial formalin (ED(50) = 5.54 ± 2.74 in phase I and 11.48 ± 1.88 in phase II) tests. However, after 3 days, the values were in the acetic acid writhing (ED(50) = 6.14 ± 0.51), tail-flick (ED(50) = 154 ± 8.88), hot-plate (ED(50) = 136.14 ± 2.94), formalin hind paw (ED(50) = 15.93 ± 0.42 in phase I and 17.10 ± 1.80 in phase II) and orofacial formalin (ED(50) = 6.79 ± 0.66 in phase I and 5.80 ± 1.49 in phase II) tests. This study demonstrated the antinociceptive and anti-inflammatory activities of simvastatin in five models of tonic or phasic pain. These actions seem to be related to the inhibition of cytokine and prostanoid release and stimulation of nitric oxide synthesis. A possible clinical role of simvastatin could be related to the potentially beneficial effects in the neuropathic pain, and by their pleiotropic properties, they could play a clinical role in anti-inflammatory disease. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.
DELLA genes restrict inflorescence meristem function independently of plant height.

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Serrano-Mislata, Antonio; Bencivenga, Stefano; Bush, Max; Schiessl, Katharina; Boden, Scott; Sablowski, Robert

2017-09-01

DELLA proteins associate with transcription factors to control plant growth in response to gibberellin 1 . Semi-dwarf DELLA mutants with improved harvest index and decreased lodging greatly improved global food security during the 'green revolution' in the 1960-1970s 2 . However, DELLA mutants are pleiotropic and the developmental basis for their effects on plant architecture remains poorly understood. Here, we show that DELLA proteins have genetically separable roles in controlling stem growth and the size of the inflorescence meristem, where flowers initiate. Quantitative three-dimensional image analysis, combined with a genome-wide screen for DELLA-bound loci in the inflorescence tip, revealed that DELLAs limit meristem size in Arabidopsis by directly upregulating the cell-cycle inhibitor KRP2 in the underlying rib meristem, without affecting the canonical WUSCHEL-CLAVATA meristem size regulators 3 . Mutation of KRP2 in a DELLA semi-dwarf background restored meristem size, but not stem growth, and accelerated flower production. In barley, secondary mutations in the DELLA gain-of-function mutant Sln1d 4 also uncoupled meristem and inflorescence size from plant height. Our work reveals an unexpected and conserved role for DELLA genes in controlling shoot meristem function and suggests how dissection of pleiotropic DELLA functions could unlock further yield gains in semi-dwarf mutants.
d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology.

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De Gregorio, Danilo; Comai, Stefano; Posa, Luca; Gobbi, Gabriella

2016-11-23

d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles' reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD's mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT 2A receptor as a partial agonist and 5-HT 1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D₂, Trace Amine Associate receptor 1 (TAAR₁) and 5-HT 2A . More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD's effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR₁ receptors.
The Architecture of the Pollen Hoarding Syndrome in Honey Bees: Implications for Understanding Social Evolution, Behavioral Syndromes, and Selective Breeding.

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Rueppell, Olav

2014-05-01

Social evolution has influenced every aspect of contemporary honey bee biology, but the details are difficult to reconstruct. The reproductive ground plan hypothesis of social evolution proposes that central regulators of the gonotropic cycle of solitary insects have been coopted to coordinate social complexity in honey bees, such as the division of labor among workers. The predicted trait associations between reproductive physiology and social behavior have been identified in the context of the pollen hoarding syndrome, a larger suite of interrelated traits. The genetic architecture of this syndrome is characterized by a partially overlapping genetic architecture with several consistent, pleiotropic QTL. Despite these central QTL and an integrated hormonal regulation, separate aspects of the pollen hoarding syndrome may evolve independently due to peripheral QTL and additionally segregating genetic variance. The characterization of the pollen hoarding syndrome has also demonstrated that this syndrome involves many non-behavioral traits, which may be the case for numerous "behavioral" syndromes. Furthermore, the genetic architecture of the pollen hoarding syndrome has implications for breeding programs for improving honey health and other desirable traits: If these traits are comparable to the pollen hoarding syndrome, consistent pleiotropic QTL will enable marker assisted selection, while sufficient additional genetic variation may permit the dissociation of trade-offs for efficient multiple trait selection.
Effects of Hd2 in the presence of the photoperiod-insensitive functional allele of Hd1 in rice

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Zhen-Hua Zhang

2016-11-01

Full Text Available The role of photoperiod sensitivity (PS of flowering genes have become well recognized in rice, whereas little attention has been drawn to the non-PS component of these genes, especially to their influence on gene-by-gene interactions. Rice populations in which the photoperiod-sensitive allele at Hd1 has become insensitive to photoperiod but continued to affect heading date (HD were used in this study to fine-map a quantitative trait locus (QTL for HD and analyze its genetic relationship to Hd1. The QTL was delimitated to a 96.3-kb region on the distal end of the long arm of chromosome 7. Sequence comparison revealed that this QTL is identical to Hd2. In the near-isogenic line (NIL populations analyzed, Hd1 and Hd2 were shown to be photoperiod insensitive and have pleiotropic effects for HD, plant height and yield traits. The two genes were found to largely act additively in regulating HD and yield traits. The results indicate that non-PS components of flowering genes involved in photoperiod response play an important role in controlling flowering time and grain yield in rice, which should allow breeders to better manipulate pleiotropic genes for balancing adaptability and high-yielding accumulation.
The evolutionary role of modularity and integration in the hominoid cranium.

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Mitteroecker, Philipp; Bookstein, Fred

2008-04-01

Patterns of morphological integration and modularity among shape features emerge from genetic and developmental factors with varying pleiotropic effects. Factors or processes affecting morphology only locally may respond to selection more easily than common factors that may lead to deleterious side effects and hence are expected to be more conserved. We briefly review evidence for such global factors in primate cranial development as well as for local factors constrained to either the face or the neurocranium. In a sample comprising 157 crania of Homo sapiens, Pan troglodytes, and Gorilla gorilla, we statistically estimated common and local factors of shape variation from Procrustes coordinates of 347 landmarks and semilandmarks. Common factors with pleiotropic effects on both the face and the neurocranium account for a large amount of shape variation, but mainly by extension or truncation of otherwise conserved developmental pathways. Local factors (modular shape characteristics) have more degrees of freedom for evolutionary change than mere ontogenetic scaling. Cranial shape is similarly integrated during development in all three species, but human evolution involves dissociation among several characteristics. The dissociation has probably been achieved by evolutionary alterations and by the novel emergence of local factors affecting characteristics that are controlled at the same time by the common factors.
Reduced genetic variance among high fitness individuals: inferring stabilizing selection on male sexual displays in Drosophila serrata.

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Sztepanacz, Jacqueline L; Rundle, Howard D

2012-10-01

Directional selection is prevalent in nature, yet phenotypes tend to remain relatively constant, suggesting a limit to trait evolution. However, the genetic basis of this limit is unresolved. Given widespread pleiotropy, opposing selection on a trait may arise from the effects of the underlying alleles on other traits under selection, generating net stabilizing selection on trait genetic variance. These pleiotropic costs of trait exaggeration may arise through any number of other traits, making them hard to detect in phenotypic analyses. Stabilizing selection can be inferred, however, if genetic variance is greater among low- compared to high-fitness individuals. We extend a recently suggested approach to provide a direct test of a difference in genetic variance for a suite of cuticular hydrocarbons (CHCs) in Drosophila serrata. Despite strong directional sexual selection on these traits, genetic variance differed between high- and low-fitness individuals and was greater among the low-fitness males for seven of eight CHCs, significantly more than expected by chance. Univariate tests of a difference in genetic variance were nonsignificant but likely have low power. Our results suggest that further CHC exaggeration in D. serrata in response to sexual selection is limited by pleiotropic costs mediated through other traits. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.
Statistical power and utility of meta-analysis methods for cross-phenotype genome-wide association studies.

Science.gov (United States)

Zhu, Zhaozhong; Anttila, Verneri; Smoller, Jordan W; Lee, Phil H

2018-01-01

Advances in recent genome wide association studies (GWAS) suggest that pleiotropic effects on human complex traits are widespread. A number of classic and recent meta-analysis methods have been used to identify genetic loci with pleiotropic effects, but the overall performance of these methods is not well understood. In this work, we use extensive simulations and case studies of GWAS datasets to investigate the power and type-I error rates of ten meta-analysis methods. We specifically focus on three conditions commonly encountered in the studies of multiple traits: (1) extensive heterogeneity of genetic effects; (2) characterization of trait-specific association; and (3) inflated correlation of GWAS due to overlapping samples. Although the statistical power is highly variable under distinct study conditions, we found the superior power of several methods under diverse heterogeneity. In particular, classic fixed-effects model showed surprisingly good performance when a variant is associated with more than a half of study traits. As the number of traits with null effects increases, ASSET performed the best along with competitive specificity and sensitivity. With opposite directional effects, CPASSOC featured the first-rate power. However, caution is advised when using CPASSOC for studying genetically correlated traits with overlapping samples. We conclude with a discussion of unresolved issues and directions for future research.

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