DOCSLIB.ORG

WO 2010/024852 Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
WO 2010/024852 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 4 March 2010 (04.03.2010) WO 2010/024852 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (2006.01) C07H 21/02 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US2009/004582 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 10 August 2009 (10.08.2009) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/190,369 28 August 2008 (28.08.2008) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, NESTEC S.A. [CH/CH]; Avenue Nestle 55, CH-1800 ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Vevey (CH). TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors; and MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (75) Inventors/Applicants (for US only): PAN, Yuanlong TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, [US/US]; 2743 Quail Valley Drive, Chesterfield, MO ML, MR, NE, SN, TD, TG). 6301 7 (US). HANNAH, Steven [US/US]; 293 High Ridge Court, Chesterfield, MO 63017 (US). MIDDLE- Published: TON, Rondo [US/US]; 12366 Country Glen Lane, Creve — with international search report (Art. 21(3)) Coeur, MO 63 141 (US). (74) Agent: GUFFEY, Wendell, Ray; Nestle Purina Petcare Global Resources, Inc., Checkerboard Square, St. Louis, MO 63 164 (US). (54) Title: GENE EXPRESSION PROFILES ASSOCIATED WITH LEAN PHENOTYPE AND USES THEREOF (57) Abstract: Gene expression profiles associated with improved or maintained lean body mass or reduced body fat are dis- closed. The gene expression profiles were determined in adipose, liver, and muscle tissue of animals subjected to lean-promoting regimens such as consumption of a high protein diet, ingestion of conjugated linolenic acid, and/or increased exercise. Methods of using such profiles for the identification of pharmaceutical substances, nutraceutical substances, dietary substances, or treatment regimens that modulate or contribute to desired phenotypes in animals are also disclosed GENE EXPRESSION PROFILES ASSOCIATED WITH LEAN PHENOTYPE AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Serial No. 61/190369 filed August 28, 2008, the disclosure of which is incorporated herein by reference. BACKGROUND OF THE INVENTION Field of the Invention [0002] The invention relates generally to nutritional or pharmaceutical modulation of body composition and particularly to gene expression profiles associated with improved or maintained lean body mass or reduced body fat and the use of such profiles for the identification of pharmaceutical, nutraceutical, or dietary substances that modulate or contribute to desired phenotypes in animals. Description of the Related Art [0003] Body weight is primarily a function of lean body mass and fat mass in an individual. Lean body mass is the weight of bones, muscles, organs, body water, and all other non-fat constituents of the body. Fat mass is the weight of the body's storage lipids. Disproportionate or excessive fat mass is a hallmark for an individual being overweight or obese. [0004] Excess fat mass and obesity are recognized as a worldwide health problem among humans. The World Health Organization estimates that there are over 1 billion overweight adults, with just under one third of them classified as obese. In addition, obesity is also increasingly recognized as a problem for animals, particularly for companion animals such as dogs and cats. According to the Centers for Disease Control (CDC), obesity is closely associated with at least a risk of other health problems, including hypertension, dyslipidemia, Type II diabetes, heart disease, stroke, sleep apnea, and certain cancers such as breast, endometrial, and colon cancers. Risk factors for an individual becoming obese include genetics, emotions/stress, overeating, and a sedentary lifestyle. [0005] Enhancing lean body mass can enhance the body's basal metabolic rate. Enhancing metabolic rate can facilitate the loss of excess fat mass when dietary caloric intake is insufficient to meet the body's energy needs or can reduce the accumulation of fat mass when dietary caloric intake exceeds the body's maintenance energy requirement. Various approaches to increase lean body mass have been described. One such approach is dietary supplementation with conjugated linoleic acid (CLA). CLA is a term used to describe isomers of octadecdienoic acid that are found in many foods such as dairy products (Terpstra AHM (2004) Am. J. Clin. Nutr. 79:352-61). CLA has been shown to reduce fat mass in mice and humans and has been implicated in an increase in lean body mass (Bhattacharya A et al. (2005) J. Nutr. 135: 1124- 30; Gaullier J-M et al. (2004) Am. J. Clin. Nutr. 79:1 118-25; Blankson H et al. (2000) J. Nutr. 130:2943- 8; and, Park Y et al. (1997) Lipids 32:853-8). Another approach to increase lean body mass is consumption of a high protein diet. Studies suggest that diets with higher protein content, coupled with reduced carbohydrate consumption and/or regular exercise, can enhance the loss of fat mass and reduce the loss of lean body mass (Layman DK et al. (2005) J. Nutr. 135:1903-10; Layman DK et al. (2004) J. Nutr. 134:968S-73S; Marsset-Baglieri A et al. (2004) J. Nutr. 134:2646-52; and, Due A et al. (2004) Int. J. Obes. Relat. Metab. Disord. 28:1283-90). A third approach to increase lean body mass and decrease fat mass is regular exercise (Bhattacharya A et al. (2005) J. Nutr. 135:1 124-30; Layman DK et al. (2005) J. Nutr. 135:1903-10; and, Tsai AC et al. (2003) J. Nutr. Biochem. 14:541-9). [0006] Various studies have evaluated different aspects of the genetics of lean body mass and obesity. Association studies have revealed links between bodyweight, overweight, and obesity and polymorphisms in various genes (Chagnon YC et al. (2003) Obesity Res. 11:313-67). Similarly, association studies have identified genes relating to body fat mass, percentage of body fat, and skin folds, body fat distribution (waist-to-hip ratio, waist circumference, etc.), resting energy expenditure, and adipocyte lipolysis (Chagnon YC et al. (2003) Obesity Res. 11:313-67). In addition, studies have evaluated associations between candidate genes and changes in body weight, including genes associated with spontaneous weight gain over time, genes associated with endurance training-induced changes in fat mass, and genes associated with weight loss during a three year lifestyle change (Chagnon YC et al. (2003) Obesity Res. 11:313-67). A listing of all such genes can be found in the prior art (Chagnon YC et al. (2003) Obesity Res. 11:313-67). Studies have also analyzed the genetic aspects of lean body mass. Lean body mass studies have linked polymorphisms in Type 1 Deiodinase with higher lean body mass and muscle strength (Peeters RP et al. (2005) J. Clin. Endocrinol. 90:256-63), and polymorphisms in the glucocorticoid receptor with higher muscle mass and muscle strength (van Rossum EFC et al. (2004) J. Clin. Endocrinol. 89:4004-9). [0007] Although lean body mass and fat mass are directly related, few studies have attempted to explore the genetic mechanisms that mediate a higher proportion of one type relative to the other. A detailed knowledge of these mechanisms would provide a better understanding of the conditions that favor a high level of lean body mass and/or reduced body fat and would provide a better understanding of how to promote a lean phenotype in an animal. Because a higher proportion of lean body mass, especially relative to fat mass, has positive implications for improved health and decreased risk for obesity-related ailments, it is desirable for an individual to increase the ratio of lean body mass to fat mass, either by increasing lean body mass and/or by reducing body fat. SUMMARY OF THE INVENTION [0008] It is, therefore, an object of the invention to provide one or more genes or gene segments that are differentially expressed in animals exhibiting a lean phenotype resulting from one or more lean phenotype- promoting treatments comprising (1) administration of CLA, (2) consumption of a high protein diet, and (3) increased exercise. [0009] It is another object of the invention to provide a combination comprising a plurality of polynucleotides that are differentially expressed in animals exhibiting a lean phenotype resulting from one or more lean phenotype-promoting treatments comprising (1) administration of CLA, (2) consumption of a high protein diet, and (3) increased exercise. [0010] It is another object of the invention to provide compositions of two or more polynucleotide or polypeptide probes suitable for detecting the expression of genes differentially expressed in animals exhibiting a lean phenotype resulting from one or more lean phenotype-promoting treatments comprising (1) administration of CLA, (2) consumption of a high protein diet, and (3) increased exercise, and devices such as substrate arrays containing the probes.
Load more

Recommended publications
  • In Vitro Differentiation of Bone Marrow Mesenchymal Stem Cells Into Endometrial Epithelial Cells in Mouse: a Proteomic Analysis
    Int J Clin Exp Pathol 2014;7(7):3662-3672 www.ijcep.com /ISSN:1936-2625/IJCEP0000322 Original Article In vitro differentiation of bone marrow mesenchymal stem cells into endometrial epithelial cells in mouse: a proteomic analysis Qing Cong1,2, Bin Li1,2, Yisheng Wang1,2, Wenbi Zhang1,2, Mingjun Cheng1,2, Zhiyong Wu1,2, Xiaoyan Zhang1,2, Wei Jiang1,2, Congjian Xu1,2,3,4 1Obstetrics and Gynecology Hospital of Fudan University, 2Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 3Department of Obstetrics and Gynecology of Shanghai Medical School, 4Institute of Biomedical Sciences, Fudan University, Shanghai, P.R. China Received March 24, 2014; Accepted June 23, 2014; Epub June 15, 2014; Published July 1, 2014 Abstract: Objective: Mouse bone marrow mesenchymal stem cells (BMSCs) have been demonstrated to differenti- ate into female endometrial epithelial cells (EECs) in vivo. Our previous studies demonstrated that BMSCs can differentiate in the direction of EECs when co-cultured with endometrial stromal cells in vitro. Here, we obtain and analyse differential proteins and their relevant pathways in the process of BMSCs differentiating into EECs by iso- baric tags for relative and absolute quantitation (iTRAQ) proteomic analysis. Methods: A 0.4-µm pore size indirect co- culture system was established with female mice endometrial stromal cells (EStCs) restricted in the upper Transwell chamber and BMSCs in the lower well plate. After indirect co-culture for several days, the BMSCs were revealed to progressively differentiate towards EECs in vitro. Then, four groups were divided according to different co-culture days with single culture groups of BMSCs as controls.
    [Show full text]
  • Effect of a Caloric Restriction Based On
    UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE CIENCIAS DEPARTAMENTO DE BIOLOGÍA DOCTORAL THESIS Biology PhD “Effect of a caloric restriction based on the Mediterranean diet and intake of traditional Mediterranean foods on the expression of microRNAs regulating molecular processes associated with aging” INSTITUTO MADRILEÑO DE ESTUDIOS AVANZADOS EN ALIMENTACIÓN (IMDEA FOOD INSTITUTE) VÍCTOR MICÓ MORENO Madrid, 2018 UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE CIENCIAS DEPARTAMENTO DE BIOLOGÍA DOCTORAL THESIS Biology PhD “Effect of a caloric restriction based on the Mediterranean diet and intake of traditional Mediterranean foods on the expression of microRNAs regulating molecular processes associated with aging” INSTITUTO MADRILEÑO DE ESTUDIOS AVANZADOS EN ALIMENTACIÓN (IMDEA FOOD INSTITUTE) Memoria presentada por: Víctor Micó Moreno Para optar al grado de: DOCTOR EN BIOLOGÍA Doña Lidia Ángeles Daimiel Ruíz, Doctora en Biología Celular y Genética por la Universidad Autónoma de Madrid, investigadora del Instituto IMDEA Alimentación, informa favorablemente la solicitud de autorización de defensa de la tesis doctoral con el Título: “Effect of a caloric restriction based on the Mediterranean diet and intake of traditional Mediterranean foods on the expression of microRNAs regulating molecular processes associated with aging”, presentada por Don Víctor Micó Moreno para optar al grado de Doctor en Biología. Este trabajo ha sido realizado en el Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA Alimentación) bajo su dirección, y cumple satisfactoriamente las condiciones requeridas por el Departamento de Biología de la Universidad Autónoma de Madrid para optar al Título de Doctor. Ha actuado como tutor académico, y presenta su conformidad el Dr. Carlos Francisco Sentís Castaño, vicedecano de Personal Docente e Investigador y profesor titular del Departamento de Biología de la Facultad de Ciencias de la Universidad Autónoma de Madrid.
    [Show full text]
  • Searching for Novel Peptide Hormones in the Human Genome Olivier Mirabeau
    Searching for novel peptide hormones in the human genome Olivier Mirabeau To cite this version: Olivier Mirabeau. Searching for novel peptide hormones in the human genome. Life Sciences [q-bio]. Université Montpellier II - Sciences et Techniques du Languedoc, 2008. English. tel-00340710 HAL Id: tel-00340710 https://tel.archives-ouvertes.fr/tel-00340710 Submitted on 21 Nov 2008 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE MONTPELLIER II SCIENCES ET TECHNIQUES DU LANGUEDOC THESE pour obtenir le grade de DOCTEUR DE L'UNIVERSITE MONTPELLIER II Discipline : Biologie Informatique Ecole Doctorale : Sciences chimiques et biologiques pour la santé Formation doctorale : Biologie-Santé Recherche de nouvelles hormones peptidiques codées par le génome humain par Olivier Mirabeau présentée et soutenue publiquement le 30 janvier 2008 JURY M. Hubert Vaudry Rapporteur M. Jean-Philippe Vert Rapporteur Mme Nadia Rosenthal Examinatrice M. Jean Martinez Président M. Olivier Gascuel Directeur M. Cornelius Gross Examinateur Résumé Résumé Cette thèse porte sur la découverte de gènes humains non caractérisés codant pour des précurseurs à hormones peptidiques. Les hormones peptidiques (PH) ont un rôle important dans la plupart des processus physiologiques du corps humain.
    [Show full text]
  • The EMILIN/Multimerin Family
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE REVIEW ARTICLE published: 06 Januaryprovided 2012 by Frontiers - Publisher Connector doi: 10.3389/fimmu.2011.00093 The EMILIN/multimerin family Alfonso Colombatti 1,2,3*, Paola Spessotto1, Roberto Doliana1, Maurizio Mongiat 1, Giorgio Maria Bressan4 and Gennaro Esposito2,3 1 Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico, Aviano, Italy 2 Department of Biomedical Science and Technology, University of Udine, Udine, Italy 3 Microgravity, Ageing, Training, Immobility Excellence Center, University of Udine, Udine, Italy 4 Department of Histology Microbiology and Medical Biotechnologies, University of Padova, Padova, Italy Edited by: Elastin microfibrillar interface proteins (EMILINs) and Multimerins (EMILIN1, EMILIN2, Uday Kishore, Brunel University, UK Multimerin1, and Multimerin2) constitute a four member family that in addition to the Reviewed by: shared C-terminus gC1q domain typical of the gC1q/TNF superfamily members contain a Uday Kishore, Brunel University, UK Kenneth Reid, Green Templeton N-terminus unique cysteine-rich EMI domain. These glycoproteins are homotrimeric and College University of Oxford, UK assemble into high molecular weight multimers. They are predominantly expressed in *Correspondence: the extracellular matrix and contribute to several cellular functions in part associated with Alfonso Colombatti, Division of the gC1q domain and in part not yet assigned nor linked to other specific regions of the Experimental Oncology 2, Centro di sequence. Among the latter is the control of arterial blood pressure, the inhibition of Bacil- Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico, lus anthracis cell cytotoxicity, the promotion of cell death, the proangiogenic function, and 33081 Aviano, Italy.
    [Show full text]
  • Down Regulation of Membrane-Bound Neu3 Constitutes a New
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Publications of the IAS Fellows IJC International Journal of Cancer Down regulation of membrane-bound Neu3 constitutes a new potential marker for childhood acute lymphoblastic leukemia and induces apoptosis suppression of neoplastic cells Chandan Mandal1, Cristina Tringali2, Susmita Mondal1, Luigi Anastasia2, Sarmila Chandra3, Bruno Venerando2 and Chitra Mandal1 1 Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, A Unit of Council of Scientific and Industrial Research, Govt of India, 4, Raja S. C. Mullick Road, Kolkata 700032, India 2 Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, and IRCCS Policlinico San Donato, San Donato, Milan, Italy 3 Department of Hematology, Kothari Medical Centre, Kolkata 700027, India Membrane-linked sialidase Neu3 is a key enzyme for the extralysosomal catabolism of gangliosides. In this respect, it regulates pivotal cell surface events, including trans-membrane signaling, and plays an essential role in carcinogenesis. In this report, we demonstrated that acute lymphoblastic leukemia (ALL), lymphoblasts (primary cells from patients and cell lines) are characterized by a marked down-regulation of Neu3 in terms of both gene expression (230 to 40%) and enzymatic activity toward ganglioside GD1a (225.6 to 30.6%), when compared with cells from healthy controls. Induced overexpression of Neu3 in the ALL-cell line, MOLT-4, led to a significant increase of ceramide (166%) and to a parallel decrease of lactosylceramide (255%). These events strongly guided lymphoblasts to apoptosis, as we assessed by the decrease in Bcl2/ Bax ratio, the accumulation of Neu3 transfected cells in the sub G0–G1 phase of the cell cycle, the enhanced annexin-V positivity, the higher cleavage of procaspase-3.
    [Show full text]
  • (HMGB1) Deletion Leads to Small Heart and Glycolipid Metabolic
    Yu et al. Cell Death Discovery (2020) 6:106 https://doi.org/10.1038/s41420-020-00340-9 Cell Death Discovery ARTICLE Open Access Cardiomyocyte-restricted high-mobility group box 1 (HMGB1) deletion leads to small heart and glycolipid metabolic disorder through GR/PGC-1α signalling Peng Yu 1, Ming Liu2,BaoliZhang3,YingYu2,EnyongSu3,ShiyaoXie3,LeiZhang3,XueYang3,HongJiang 3, Ruizhen Chen3, Yunzeng Zou3 and Junbo Ge3 Abstract Cardiac growth and remodelling are key biological processes influencing the physiological performance of the heart, and a previous study showed a critical role for intracellular HMGB1 in vitro. However, the in vivo study, which used conditional Hmgb1 ablation, did not show a significant effect on cellular or organic function. We have demonstrated the extracellular effect of HMGB1 as a pro-inflammatory molecule on cardiac remodelling. In this study, we found that HMGB1 deletion by cTnT-Cre in mouse hearts altered glucocorticoid receptor (GR) function and glycolipid metabolism, eventually leading to growth retardation, small heart and heart failure. The subcellular morphology did not show a significant change caused by HMGB1 knockout. The heart showed significant elevation of glycolysis, free fatty acid deposition and related enzyme changes. Transcriptomic analysis revealed a list of differentially expressed genes that coincide with glucocorticoid receptor function in neonatal mice and a significant increase in inflammatory genes in 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; adult mice. Cardiac HMGB1 knockout led to a series of changes in PGC-1α, UCP3 and GyK, which were the cause of metabolic changes and further impacted cardiac function. Ckmm-Cre Hmgb1fl/fl mice did not show a specific phenotype, which was consistent with the reported negative result of cardiomyocyte-specific Hmgb1 deletion via MHC-Cre.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Multimerin-2 Is a Ligand for Group 14 Family C-Type Lectins CLEC14A, CD93 and CD248 Spanning the Endothelial Pericyte Interface
    OPEN Oncogene (2017) 36, 6097–6108 www.nature.com/onc ORIGINAL ARTICLE Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface KA Khan1, AJ Naylor2, A Khan1, PJ Noy1, M Mambretti1, P Lodhia1, J Athwal1, A Korzystka1, CD Buckley2, BE Willcox3, F Mohammed3 and R Bicknell1 TheC-typelectindomaincontaininggroup14familymembers CLEC14A and CD93 are proteins expressed by endothelium and are implicated in tumour angiogenesis. CD248 (alternatively known as endosialin or tumour endothelial marker-1) is also a member of this family and is expressed by tumour-associated fibroblasts and pericytes. Multimerin-2 (MMRN2) is a unique endothelial specific extracellular matrix protein that has been implicated in angiogenesis and tumour progression. We show that the group 14 C-type lectins CLEC14A, CD93 and CD248 directly bind to MMRN2 and only thrombomodulin of the family does not. Binding to MMRN2 is dependent on a predicted long-loop region in the C-type lectin domainandisabrogatedbymutationwithinthedomain. CLEC14A and CD93 bind to the same non-glycosylated coiled-coil region of MMRN2, but the binding of CD248 occurs on a distinct non-competing region. CLEC14A and CD248 can bind MMRN2 simultaneously and this occurs at the interface between endothelium and pericytes in human pancreatic cancer. A recombinant peptide of MMRN2 spanning the CLEC14A and CD93 binding region blocks CLEC14A extracellular domain binding to the endothelial cellsurfaceaswellasincreasingadherenceofhumanumbilical vein endothelial cells to the active peptide. This MMRN2 peptide is anti-angiogenic in vitro and reduces tumour growth in mouse models. These findings identify novel protein interactions involving CLEC14A, CD93 and CD248 with MMRN2 as targetable components of vessel formation.
    [Show full text]
  • Looking for New Classes of Bronchodilators
    REVIEW BRONCHODILATORS The future of bronchodilation: looking for new classes of bronchodilators Mario Cazzola1, Paola Rogliani 1 and Maria Gabriella Matera2 Affiliations: 1Dept of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy. 2Dept of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy. Correspondence: Mario Cazzola, Dept of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy. E-mail: [email protected] @ERSpublications There is a real interest among researchers and the pharmaceutical industry in developing novel bronchodilators. There are several new opportunities; however, they are mostly in a preclinical phase. They could better optimise bronchodilation. http://bit.ly/2lW1q39 Cite this article as: Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators. Eur Respir Rev 2019; 28: 190095 [https://doi.org/10.1183/16000617.0095-2019]. ABSTRACT Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes. At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.
    [Show full text]
  • (KPNA7), a Divergent Member of the Importin a Family of Nuclear Import
    Kelley et al. BMC Cell Biology 2010, 11:63 http://www.biomedcentral.com/1471-2121/11/63 RESEARCH ARTICLE Open Access Karyopherin a7 (KPNA7), a divergent member of the importin a family of nuclear import receptors Joshua B Kelley1, Ashley M Talley1, Adam Spencer1, Daniel Gioeli2, Bryce M Paschal1,3* Abstract Background: Classical nuclear localization signal (NLS) dependent nuclear import is carried out by a heterodimer of importin a and importin b. NLS cargo is recognized by importin a, which is bound by importin b. Importin b mediates translocation of the complex through the central channel of the nuclear pore, and upon reaching the nucleus, RanGTP binding to importin b triggers disassembly of the complex. To date, six importin a family members, encoded by separate genes, have been described in humans. Results: We sequenced and characterized a seventh member of the importin a family of transport factors, karyopherin a 7 (KPNA7), which is most closely related to KPNA2. The domain of KPNA7 that binds Importin b (IBB) is divergent, and shows stronger binding to importin b than the IBB domains from of other importin a family members. With regard to NLS recognition, KPNA7 binds to the retinoblastoma (RB) NLS to a similar degree as KPNA2, but it fails to bind the SV40-NLS and the human nucleoplasmin (NPM) NLS. KPNA7 shows a predominantly nuclear distribution under steady state conditions, which contrasts with KPNA2 which is primarily cytoplasmic. Conclusion: KPNA7 is a novel importin a family member in humans that belongs to the importin a2 subfamily. KPNA7 shows different subcellular localization and NLS binding characteristics compared to other members of the importin a family.
    [Show full text]
  • Salmonella Degrades the Host Glycocalyx Leading to Altered Infection and Glycan Remodeling
    UC Davis UC Davis Previously Published Works Title Salmonella Degrades the Host Glycocalyx Leading to Altered Infection and Glycan Remodeling. Permalink https://escholarship.org/uc/item/0nk8n7xb Journal Scientific reports, 6(1) ISSN 2045-2322 Authors Arabyan, Narine Park, Dayoung Foutouhi, Soraya et al. Publication Date 2016-07-08 DOI 10.1038/srep29525 Peer reviewed eScholarship.org Powered by the California Digital Library University of California www.nature.com/scientificreports OPEN Salmonella Degrades the Host Glycocalyx Leading to Altered Infection and Glycan Remodeling Received: 09 February 2016 Narine Arabyan1, Dayoung Park2, Soraya Foutouhi1, Allison M. Weis1, Bihua C. Huang1, Accepted: 17 June 2016 Cynthia C. Williams2, Prerak Desai1,†, Jigna Shah1,‡, Richard Jeannotte1,3,§, Nguyet Kong1, Published: 08 July 2016 Carlito B. Lebrilla2,4 & Bart C. Weimer1 Complex glycans cover the gut epithelial surface to protect the cell from the environment. Invasive pathogens must breach the glycan layer before initiating infection. While glycan degradation is crucial for infection, this process is inadequately understood. Salmonella contains 47 glycosyl hydrolases (GHs) that may degrade the glycan. We hypothesized that keystone genes from the entire GH complement of Salmonella are required to degrade glycans to change infection. This study determined that GHs recognize the terminal monosaccharides (N-acetylneuraminic acid (Neu5Ac), galactose, mannose, and fucose) and significantly (p < 0.05) alter infection. During infection, Salmonella used its two GHs sialidase nanH and amylase malS for internalization by targeting different glycan structures. The host glycans were altered during Salmonella association via the induction of N-glycan biosynthesis pathways leading to modification of host glycans by increasing fucosylation and mannose content, while decreasing sialylation.
    [Show full text]
  • Human Erythrocyte Acetylcholinesterase in Health and Disease
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Universidade de Lisboa: Repositório.UL molecules Review Human Erythrocyte Acetylcholinesterase in Health and Disease Carlota Saldanha Instituto de Bioquímica, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal; [email protected] Received: 10 August 2017; Accepted: 4 September 2017; Published: 8 September 2017 Abstract: The biochemical properties of erythrocyte or human red blood cell (RBC) membrane acetylcholinesterase (AChE) and its applications on laboratory class and on research are reviewed. Evidence of the biochemical and the pathophysiological properties like the association between the RBC AChE enzyme activity and the clinical and biophysical parameters implicated in several diseases are overviewed, and the achievement of RBC AChE as a biomarker and as a prognostic factor are presented. Beyond its function as an enzyme, a special focus is highlighted in this review for a new function of the RBC AChE, namely a component of the signal transduction pathway of nitric oxide. Keywords: acetylcholinesterase; red blood cells; nitric oxide 1. Introduction Erythrocytes or red blood cells (RBC) are more than sacks of oxyhemoglobin or deoxyhemoglobin during the semi-life of 120 days in blood circulation [1]. Erythrocytes comport different signaling pathways which includes the final stage of apoptosis, also called eryptosis [2,3]. Exovesicules enriched with acetylcholinesterase (AChE) originated from membranes of aged erythrocytes appear in plasma [4]. Kinetic changes of the AChE enzyme have been observed in old erythrocytes [5]. Previously, AChE in erythrocytes was evidenced as a biomarker of membrane integrity [6].
    [Show full text]