Inhibition of Phosphodiesterase 11 (PDE11) Impacts on Sperm Quality

Total Page:16

File Type:pdf, Size:1020Kb

Inhibition of Phosphodiesterase 11 (PDE11) Impacts on Sperm Quality International Journal of Impotence Research (2005) 17, 385–386 & 2005 Nature Publishing Group All rights reserved 0955-9930/05 $30.00 www.nature.com/ijir Letter to the Editor Inhibition of phosphodiesterase 11 (PDE11) impacts on sperm quality Comment on ‘High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodies- terase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients.’ by Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Corbin JD. (Int J Impot Res 2004 Nov 11 [Epub ahead of print]). G Pomara1* and G Morelli1 1Section of Urology, Department of Surgery, S Chiara Hospital, Pisa University, Italy International Journal of Impotence Research (2005) 17, 385–386. doi:10.1038/sj.ijir.3901304 There is a growing interest worldwide in under- tadalafil is a nonspecific PDE11A4 inhibitor, we believe standing potential crossreaction of PDE5 inhibitors that for safety purpose we should consider the possible with other proteins and we agree with the authors crossreaction with all the four human PDE11 variants. that PDE11 is one of the obvious candidates, since it This global evaluation may provide the highest thera- is closely related to the PDE5. Weeks et al should be peutic benefits/undesirable side effects ratio. For these congratulated because, comparing the potencies of reasons, we do not believe that all safety issues on tadalafil, vardenafil and sildenafil for PDE11A4 and tadalafil crossreaction with PDE11 are satisfied. the fold selectivity of these inhibitors for PDE5A1 Within human PDE11A family, the alternatively over PDE11A4, they provide several important spliced isoforms display unique tissue expression information for safety issues. and specificity.3 We focused our attention on the conclusions of PDE11A4 is expressed in the prostate gland and the authors. Whereas we perfectly agree that ‘the unlikely it could be related to the tadalafil-related fold selectivity for PDE5 over PDE11A4 for sildenafil side effects, back-pain and alteration of sperm quality. (1000-fold selectivity) and vardenafil (9000-fold PDE11A1 is predominantly present in skeletal selectivity) reveals that these drugs are very unlikely muscle and, as the authors remember, there are to crossreact with PDE11A4 in patients treated with studies reporting a low selectivity (five-fold) of these medications’,1 on the contrary, we would tadalafil for PDE5 over PDE11A1.2 This enzyme suggest caution concerning the newest PDE-5 in- and its inhibition could account for the back pain, hibitor tadalafil. In fact, the 40-fold selectivity ratio reported by some men taking tadalafil. In our of tadalafil for PDE5 over PDE11A4, found in this opinion, the ‘back-pain’, ‘specific pain felt in the study, significantly lower than those reported with low or upper back’, should be considered a tadalafil- the other two drugs, is nearly the same of that specific-side effect, more than ‘myalgia’, ‘pain in a reported for sildenafil over PDE1 (41-fold). In this nonspecific muscle’, which has been reported even case, it has been suggested that the 41-fold selectiv- with sildenafil or vardenafil. ity of sildenafil for PDE5 over PDE1 may induce We have not many information on PDE11A2, but vasodilatation, flushing and tachycardia.2 its transcripts were detected in various tissues Moreover, Weeks et al studied and gave informa- including brain, lung, skeletal muscle, spleen, testis tion only on PDE11A4, which is one among four of and prostate.3 the identified human PDE11A splice variants. PDE11A3 is present predominantly in the testes Probably ‘PDE11A4, containing the most extensive and its inhibition could produce alteration in the regulatory domain structure, is highly regulated and quality of sperm of some patients taking tadalafil. plays an important physiological role’,1 but, since This hypothesis is consistent with the results of our preliminary report, which investigate for the first time the effect of tadalafil administration on men with fertility problems. Tadalafil, compared to the *Correspondence: G Pomara, Section of Urology, Depart- baseline, caused a statistically significant decrease ment of Surgery, S Chiara Hospital, Via Cervino, 6, 56100 of spermatozoa with rapid progressive motility 4 Pisa University, Italy. (12.3%72.2 vs 9%71.9 (Po0.05)). Moreover, E-mail: [email protected] surprisingly our results are comparable with those Letter to the Editor 386 reported in mice knock out for the PDE11. ‘Ejaculated (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross- sperm from PDE11KO mice had a reduced rate of for- reaction in patients. Int J Impot Res 2004 Nov 11 [Epub ahead ward progression compared with WT mice (range ¼ 1 of print]. 7 7 5 2 Bischoff E. Potency, selectivity, and consequences of non- (low) to 4 (high); 2.2 0.2 vs 2.9 0.1, Po0.05),’. selectivity of PDE inhibition. Int J Impot Res. 2004; 16(Suppl 1): In light of these findings, we believe that PDE11 S11–S14. inhibition impacts on sperm quality. Reasonable 3 Yuasa K et al. Identification of rat cyclic nucleotide phospho- caution should be suggested in patients taking the diesterase 11A (PDE11A). Comparison of rat and human PDE11A splicing variants. Eur J Biochem 2001; 268: prescribed dosages of tadalafil, the only PDE5 4440–4448. inhibitor to date which could crossreact with human 4 Pomara G et al. Effect of acute in vivo sildenafil or tadalafil PDE11A splicing variants. treatments on semen parameters in patients with fertility problem, a randomized, double-blind, crossover study. Oral Communication. 7th Congress of the European Society for References Sexual Medicine. London, December 2004. 5 Wayman C et al. Ablation of phosphodiesterase 11 (PDE11) impacts sperm physiology. Oral Communication. 7th Congress 1 Weeks JL et al. High biochemical selectivity of tadalafil, of the European Society for Sexual Medicine. London, sildenafil and vardenafil for human phosphodiesterase 5A1 December 2004. International Journal of Impotence Research.
Recommended publications
  • Activation and Phosphorylation of the 'Dense-Vesicle' High-Affinity Cyclic AMP Phosphodiesterase by Cyclic AMP-Dependent Protein Kinase
    Biochem. J. (1989) 260, 27-36 (Printed in Great Britain) 27 Activation and phosphorylation of the 'dense-vesicle' high-affinity cyclic AMP phosphodiesterase by cyclic AMP-dependent protein kinase Elaine KILGOUR, Neil G. ANDERSON and Miles D. HOUSLAY Molecular Pharmacology Group, Department of Biochemistry, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K. Incubation of a hepatocyte particulate fraction with ATP and the isolated catalytic unit of cyclic AMP- dependent protein kinase (A-kinase) selectively activated the high-affinity 'dense-vesicle' cyclic AMP phosphodiesterase. Such activation only occurred if the membranes had been pre-treated with Mg2". Mg2" pre-treatment appeared to function by stimulating endogenous phosphatases and did not affect phosphodiesterase activity. Using the antiserum DV4, which specifically immunoprecipitated the 51 and 57 kDa components of the 'dense-vesicle' phosphodiesterase from a detergent-solubilized membrane extract, we isolated a 32P-labelled phosphoprotein from 32P-labelled hepatocytes. MgCl2 treatment of such labelled membranes removed 32P from the immunoprecipitated protein. Incubation of the Mg2+-pre-treated membranes with [32P]ATP and A-kinase led to the time-dependent incorporation of label into the 'dense- vesicle' phosphodiesterase, as detected by specific immunoprecipitation with the antiserum DV4. The time- dependences of phosphodiesterase activation and incorporation of label were similar. It is suggested (i) that phosphorylation of the 'dense-vesicle' phosphodiesterase by A-kinase leads to its activation, and that such a process accounts for the ability of glucagon and other hormones, which increase intracellular cyclic AMP concentrations, to activate this enzyme, and (ii) that an as yet unidentified kinase can phosphorylate this enzyme without causing any significant change in enzyme activity but which prevents activation and phosphorylation of the phosphodiesterase by A-kinase.
    [Show full text]
  • Dissertation Characterization Of
    DISSERTATION CHARACTERIZATION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASES IN THE TRANSCRIPTOME OF THE CRUSTACEAN MOLTING GLAND Submitted by Nada Mukhtar Rifai Department of Biology In partial fulfillment of the requirements For the Degree of Doctor of Philosophy Colorado State University Fort Collins, Colorado Spring 2019 Doctoral Committee: Advisor: Donald L. Mykles Deborah Garrity Shane Kanatous Santiago Di-Pietro Copyright by Nada Mukhtar Rifai 2019 All Rights Reserved ABSTRACT CHARACTERIZATION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASES IN THE TRANSCRIPTOME OF THE CRUSTACEAN MOLTING GLAND Molting in crustaceans is a complex physiological process that has to occur in order for the animal to grow. The old exoskeleton must be discarded and a new one to be formed from the inside out. Molting is coordinated and regulated mainly by two hormones; steroid hormones named ecdysteroids, which are synthesized and secreted from a pair of Y- organs (YOs) that are located in the cephalothorax and a neuropeptide hormone, the molt inhibiting hormone (MIH), which is secreted from the X-organ/sinus gland complex located in the eyestalks. Molting is induced when MIH is decreased in the blood (hemolymph) which in turn stimulates the YOs to produce and secrete ecdysteroids (molting hormones). There are four distinctive physiological states that the YO can be in throughout the molt cycle; the transition of the YO from the “basal” to the “activated” state happens when the animal enters premolt. During mid-premolt, the YO transitions to the “committed” state, in which the YO becomes insensitive to MIH. In this state, the circulating hemolymph contains high levels of ecdysteroids, which increase to a peak before the actual molt (ecdysis) happens.
    [Show full text]
  • (PDE 1 B 1) Correlates with Brain Regions Having Extensive Dopaminergic Innervation
    The Journal of Neuroscience, March 1994, 14(3): 1251-l 261 Expression of a Calmodulin-dependent Phosphodiesterase lsoform (PDE 1 B 1) Correlates with Brain Regions Having Extensive Dopaminergic Innervation Joseph W. Polli and Randall L. Kincaid Section on Immunology, Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852 Cyclic nucleotide-dependent protein phosphorylation plays PDE implies an important physiological role for Ca2+-regu- a central role in neuronal signal transduction. Neurotrans- lated attenuation of CAMP-dependent signaling pathways mitter-elicited increases in cAMP/cGMP brought about by following dopaminergic stimulation. activation of adenylyl and guanylyl cyclases are downre- [Key words: CAMP, cyclase, striatum, dopamine, basal gulated by multiple phosphodiesterase (PDE) enzymes. In ganglia, DARPP-321 brain, the calmodulin (CaM)-dependent isozymes are the major degradative activities and represent a unique point of Cyclic nucleotides, acting as “second messengers”or via direct intersection between the cyclic nucleotide- and calcium effects, regulate a diverse array of neuronal functions, from ion (Ca*+)-mediated second messenger systems. Here we de- channel conductance to gene expression. Hydrolysis of 3’,5’- scribe the distribution of the PDEl Bl (63 kDa) CaM-depen- cyclic nucleotidesto 5’-nucleosidemonophosphates is the major dent PDE in mouse brain. An anti-peptide antiserum to this mechanismfor decreasingintracellular cyclic nucleotide levels. isoform immunoprecipitated -3O-40% of cytosolic PDE ac- This reaction is catalyzed by cyclic nucleotide phosphodiester- tivity, whereas antiserum to PDElA2 (61 kDa isoform) re- ase (PDE) enzymes that constitute a large superfamily (Beavo moved 60-70%, demonstrating that these isoforms are the and Reifsynder, 1990).
    [Show full text]
  • A Novel, Highly Potent and Selective Phosphodiesterase-9 Inhibitor for the Ferrata Storti Foundation Treatment of Sickle Cell Disease
    Red Cell Biology & its Disorders ARTICLE A novel, highly potent and selective phosphodiesterase-9 inhibitor for the Ferrata Storti Foundation treatment of sickle cell disease James G. McArthur,1 Niels Svenstrup,2 Chunsheng Chen,3 Aurelie Fricot,4 Caroline Carvalho,4 Julia Nguyen,3 Phong Nguyen,3 Anna Parachikova,2 Fuad Abdulla,3 Gregory M. Vercellotti,3 Olivier Hermine,4 Dave Edwards,5 Jean-Antoine Ribeil,6 John D. Belcher3 and Thiago T. Maciel4 1Imara Inc., 2nd Floor, 700 Technology Square, Cambridge, MA, USA; 2H. Lundbeck A/S, 3 Haematologica 2020 Ottiliavej 9, 2500 Valby, Denmark; Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; Volume 105(3):623-631 4INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Laboratory of Excellence GR-Ex, Paris Descartes - Sorbonne Paris Cité University, Paris, France; 5Kinexum, 8830 Glen Ferry Drive, Johns Creek, GA, USA and 6Departments of Biotherapy, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Descartes- Sorbonne Paris Cité University, Paris, France ABSTRACT he most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with Tpleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phospho- diesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of Correspondence: SCD.
    [Show full text]
  • Chemical Genetic Studies of Chemical Modulators of Mammalian Adenylyl Cyclases and Phosphodiesterases Expressed in Fission Yeast
    Chemical Genetic Studies of Chemical Modulators of Mammalian Adenylyl Cyclases and Phosphodiesterases Expressed in Fission Yeast Author: Ana Santos de Medeiros Persistent link: http://hdl.handle.net/2345/bc-ir:106786 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2016 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College Morrisey College of Arts and Sciences Graduate School Department of Biology CHEMICAL GENETIC STUDIES OF CHEMICAL MODULATORS OF MAMMALIAN ADENYLYL CYCLASES AND PHOSPHODIESTERASES EXPRESSED IN FISSION YEAST a dissertation by ANA SANTOS DE MEDEIROS Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2016 © copyright by ANA SANTOS DE MEDEIROS 2016 ABSTRACT Cyclic adenosine monophosphate (cAMP) and the second messengers that modulate several biological processes are regulated by adenylyl cyclase (AC) and cyclic nucleotide phosphodiesterases (PDEs). ACs and PDEs are comprised of superfamilies of enzymes that are viewed as druggable targets due to their many distinct biological roles and tissue-specific distribution. As such, small molecule regulators of ACs and PDEs are important as chemical probes to study the roles of individual ACs or PDEs and as potential therapeutics. In the past, our lab has expressed 15 mammalian PDE genes in S. pombe, replacing the endogenous Cgs2 PDE. High throughput screens for PDE inhibitors identified novel compounds that show relevant biological activity in mammalian cell culture assays. The aim of this thesis is to develop tools to understand the mechanism of interaction between key regulators of the cAMP pathway and small molecules.
    [Show full text]
  • Regulation of Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase (PDE1): Review
    95-105 5/6/06 13:44 Page 95 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 18: 95-105, 2006 95 Regulation of calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1): Review RAJENDRA K. SHARMA, SHANKAR B. DAS, ASHAKUMARY LAKSHMIKUTTYAMMA, PONNIAH SELVAKUMAR and ANURAAG SHRIVASTAV Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Cancer Research Division, Saskatchewan Cancer Agency, 20 Campus Drive, Saskatoon SK S7N 4H4, Canada Received January 16, 2006; Accepted March 13, 2006 Abstract. The response of living cells to change in cell 6. Differential inhibition of PDE1 isozymes and its environment depends on the action of second messenger therapeutic applications molecules. The two second messenger molecules cAMP and 7. Role of proteolysis in regulating PDE1A2 Ca2+ regulate a large number of eukaryotic cellular events. 8. Role of PDE1A1 in ischemic-reperfused heart Calmodulin-stimulated cyclic nucleotide phosphodiesterase 9. Conclusion (PDE1) is one of the key enzymes involved in the complex interaction between cAMP and Ca2+ second messenger systems. Some PDE1 isozymes have similar kinetic and 1. Introduction immunological properties but are differentially regulated by Ca2+ and calmodulin. Accumulating evidence suggests that the A variety of cellular activities are regulated through mech- activity of PDE1 is selectively regulated by cross-talk between anisms controlling the level of cyclic nucleotides. These Ca2+ and cAMP signalling pathways. These isozymes are mechanisms include synthesis, degradation, efflux and seque- also further distinguished by various pharmacological agents. stration of cyclic adenosine 3':5'-monophosphate (cAMP) and We have demonstrated a potentially novel regulation of PDE1 cyclic guanosine 3':5'- monophosphate (cGMP) within the by calpain.
    [Show full text]
  • Phosphodiesterase (PDE)
    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
    [Show full text]
  • Characterization of Contractile Machinery of Vascular Smooth Muscles in Hypertension
    life Review Characterization of Contractile Machinery of Vascular Smooth Muscles in Hypertension Qunhui Yang * and Masatoshi Hori Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-3-5841-7940; Fax: +81-3-5841-8183 Abstract: Hypertension is a key risk factor for cardiovascular disease and it is a growing public health problem worldwide. The pathophysiological mechanisms of vascular smooth muscle (VSM) contrac- tion contribute to the development of hypertension. Calcium (Ca2+)-dependent and -independent signaling mechanisms regulate the balance of the myosin light chain kinase and myosin light chain phosphatase to induce myosin phosphorylation, which activates VSM contraction to control blood pressure (BP). Here, we discuss the mechanism of the contractile machinery in VSM, especially RhoA/Rho kinase and PKC/CPI-17 of Ca2+ sensitization pathway in hypertension. The two signal- ing pathways affect BP in physiological and pathophysiological conditions and are highlighted in pulmonary, pregnancy, and salt-sensitive hypertension. Keywords: vascular smooth muscle contraction; hypertension; CPI-17 Citation: Yang, Q.; Hori, M. 1. Introduction Characterization of Contractile Three types of muscle tissues are found in vertebrates: skeletal muscle, cardiac muscle, Machinery of Vascular Smooth and smooth muscle [1]. Muscle contraction depends on the ATP-driven sliding of highly Muscles in Hypertension. Life 2021, organized arrays of actin filaments against arrays of myosin II filaments [2]. In smooth 11, 702. https://doi.org/10.3390/ muscle, phosphorylation at Thr18/Ser19 of the myosin regulatory light chain results in life11070702 myosin ATPase enzymatic activity that induces actin and myosin attachment to regulate smooth muscle contraction [3,4].
    [Show full text]
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................
    [Show full text]
  • Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19?
    International Journal of Molecular Sciences Review Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19? Mauro Giorgi 1,*, Silvia Cardarelli 2, Federica Ragusa 3, Michele Saliola 1, Stefano Biagioni 1, Giancarlo Poiana 1 , Fabio Naro 2 and Mara Massimi 3,* 1 Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; [email protected] (M.S.); [email protected] (S.B.); [email protected] (G.P.) 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University, 00185 Rome, Italy; [email protected] (S.C.); [email protected] (F.N.) 3 Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; [email protected] * Correspondence: [email protected] (M.G.); [email protected] (M.M.) Received: 10 July 2020; Accepted: 24 July 2020; Published: 27 July 2020 Abstract: In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets.
    [Show full text]
  • GRAS Notice No. GRN 000728, FDA Has No Questions, Phospholipase C
    .. .. Janet Oesterling Novozymes North America, Inc. 77 Perry Chapel Church Road Franklinton, NC 27525 Re: GRAS Notice No. GRN 000728 Dear Ms. Oesterling: The Food and Drug Administration (FDA, we) completed our evaluation of GRN 000728. We received Novozymes North America, Inc.’s (Novozymes’) notice on August 25, 2017, and filed it on September 8, 2017. We received an amendment containing additional safety information on October 11, 2017. The subject of the notice is phosphoinositide phospholipase C enzyme preparation produced by Bacillus licheniformis expressing a modified synthetic gene encoding a variant of the wild-type phosphoinositide phospholipase C from Pseudomonas sp. 62186 (phosphoinositide phospholipase C enzyme preparation) for use as an enzyme in the degumming of vegetable oils at a maximum level of 1.4 mg Total Organic Solids (TOS)/kg oil. The notice informs us of Novozymes’ view that this use of phosphoinositide phospholipase C enzyme preparation is GRAS through scientific procedures. Commercial enzyme preparations that are used in food processing typically contain an enzyme component that catalyzes the chemical reaction as well as substances used as stabilizers, preservatives, or diluents. Enzyme preparations may also contain components derived from the production organism and from the manufacturing process, e.g., constituents of the fermentation media or the residues of processing aids. Novozymes’ notice provides information about the components in the phosphoinositide phospholipase C enzyme preparation. Per the classification system of enzymes established by the International Union of Biochemistry and Molecular Biology, phosphoinositide phospholipase C is identified by the Enzyme Commission Number 3.1.4.11. The accepted name is phosphoinositide phospholipase C.
    [Show full text]
  • The Characterization of Oligonucleotides and Nucleic Acids Using Ribonuclease H and Mass Spectrometry
    Louisiana State University LSU Digital Commons LSU Historical Dissertations and Theses Graduate School 1999 The hC aracterization of Oligonucleotides and Nucleic Acids Using Ribonuclease H and Mass Spectrometry. Lenore Marie Polo Louisiana State University and Agricultural & Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_disstheses Recommended Citation Polo, Lenore Marie, "The hC aracterization of Oligonucleotides and Nucleic Acids Using Ribonuclease H and Mass Spectrometry." (1999). LSU Historical Dissertations and Theses. 6923. https://digitalcommons.lsu.edu/gradschool_disstheses/6923 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Historical Dissertations and Theses by an authorized administrator of LSU Digital Commons. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter free, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps.
    [Show full text]