Does the Use of Protease Inhibitors Further Improve in Vivo Distribution?
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(Apis Mellifera) ELISABETH P
J. Insect Ph.vsiol. Vol. 42, No. 9, pp. 823-828, 1996 Pergamon Copyright 0 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved PII: SOO22-1910(96)00045-5 0022-1910196 $15.00 + 0.00 Effects of Two Proteinase Inhibitors on the Digestive Enzymes and Survival of Honey Bees (Apis mellifera) ELISABETH P. J. BURGESS,*1 LOUISE A. MALONE,* JOHN T. CHRlSTELLERt Received I1 December 1995; revised und accepted 1 March 1996 Two endopeptidase inhibitors, BPTI (bovine pancreatic trypsin inhibitor) and SBTI (Kunitz soybean trypsin inhibitor), were found to significantly reduce the longevity of adult honey bees (&is mellifera L.) fed the inhibitors ad lib in sugar syrup at l.O%, 0.5% or O.l%, but not at 0.01% or 0.001% (w:v). Bees were taken from frames at emergence, kept in cages at 33”C, and provided with a pollen/protein diet, water and syrup. In vivo activity levels of three midgut endopeptidases (trypsin, chymotrypsin and elastase) and the exopeptidase leucine aminopeptidase (LAP) were determined in bees fed either BPTI or SBTI at l.O%, 0.3% or 0.1% (w:v) at two time points: the 8th day after emergence and when 75% of bees had died. LAP activity levels increased significantly in bees fed with either inhibitor at all concen- trations. At day 8, bees fed BPTI at all concentrations had significantly reduced levels of trypsin, chymotrypsin and elastase. At the time of 75% mortality, bees fed BPTI at each concentration had reduced trypsin levels, but only those fed the inhibitor at the highest dose level had reduced chymotrypsin or elastase activity. -
Treatment Protocol Copyright © 2018 Kostoff Et Al
Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL by Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc (a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA (b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA (c) Associate Professor, Department of Psychiatry, University of Michigan, USA KEYWORDS Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al CITATION TO MONOGRAPH Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311 COPYRIGHT AND CREATIVE COMMONS LICENSE COPYRIGHT Copyright © 2018 by Ronald N. Kostoff, Alan L. Porter, Henry A. Buchtel Printed in the United States of America; First Printing, 2018 CREATIVE COMMONS LICENSE This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License<http://creativecommons.org/licenses/by/4.0/>. DISCLAIMERS The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan. This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention. -
Combined Neprilysin and Renin–Angiotensin System Inhibition in Heart Failure with Reduced Ejection Fraction: a Meta-Analysis
European Journal of Heart Failure (2016) doi:10.1002/ejhf.603 Combined neprilysin and renin–angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis Scott D. Solomon1*, Brian Claggett1, John J.V. McMurray2, Adrian F. Hernandez3, and Gregg C. Fonarow4 1Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2University of Glasgow, Glasgow, UK; 3Duke University, Durham, NC, USA; and 4Ronald Reagan-UCLA Medical Center, Los Angeles, CA, USA Received 1 March 2016; revised 25 May 2016; accepted 3 June 2016 Aims The combined neprilysin/renin–angiotensin system (RAS) inhibitor sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization, cardiovascular death, and all-cause mortality in a large outcomes trial. While sacubitril/valsartan is the only currently available drug in its class, there are two prior clinical trials in heart failure with omapatrilat, another combined neprilysin/RAS inhibitor. Using all available evidence can inform clinicians and policy-makers. ..................................................................................................................................................................... Methods We performed a meta-analysis using data from three trials in heart failure with reduced EF that compared combined and results neprilysin/RAS inhibition with RAS inhibition alone and reported clinical outcomes: IMPRESS (n = 573), OVERTURE (n = 5770), and PARADIGM-HF (n = 8399). We assessed the pooled hazard ratio (HR) for all-cause death or heart failure hospitalization, and for all-cause mortality in random-effects models, comparing combined neprilysin/RAS inhibition with ACE inhibition alone. The composite outcome of death or heart failure hospitalization was reduced numerically in patients receiving combined neprilysin/RAS inhibition in all three trials, with a pooled HR of 0.86, 95% confidence interval (CI) 0.76–0.97, P = 0.013. -
Metabolic Actions of Natriuretic Peptides and Therapeutic Potential in the Metabolic Syndrome
Pharmacology & Therapeutics 144 (2014) 12–27 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: G. Eisenhofer Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome Nina Schlueter a,AnitadeSterkea, Diana M. Willmes a, Joachim Spranger a, Jens Jordan b,AndreasL.Birkenfelda,⁎ a Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité, University School of Medicine, Berlin, Germany b Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany article info abstract Available online 27 April 2014 Natriuretic peptides (NPs) are a group of peptide-hormones mainly secreted from the heart, signaling via c-GMP coupled receptors. NP are well known for their renal and cardiovascular actions, reducing arterial blood pressure Keywords: as well as sodium reabsorption. Novel physiological functions have been discovered in recent years, including Natriuretic peptides activation of lipolysis, lipid oxidation, and mitochondrial respiration. Together, these responses promote white ANP adipose tissue browning, increase muscular oxidative capacity, particularly during physical exercise, and protect BNP against diet-induced obesity and insulin resistance. Exaggerated NP release is a common finding in congestive Insulin resistance heart failure. In contrast, NP deficiency is observed in obesity and in type-2 diabetes, pointing to an involvement Diabetes fi Obesity of NP in the pathophysiology of metabolic disease. Based upon these ndings, the NP system holds the potential to be amenable to therapeutical intervention against pandemic diseases such as obesity, insulin resistance, and arterial hypertension. Various therapeutic approaches are currently under development. This paper reviews the current knowledge on the metabolic effects of the NP system and discusses potential therapeutic applications. -
Cathepsins and Their Involvement in Immune Responses
Review article: Medical intelligence | Published 20 July 2010, doi:10.4414/smw.2010.13042 Cite this as: Swiss Med Wkly. 2010;140:w13042 Cathepsins and their involvement in immune responses Sébastien Conus, Hans-Uwe Simon Institute of Pharmacology, University of Bern, Bern, Switzerland Correspondence to: cleaving proteases (= caspases) which cleave a wide range Sébastien Conus Ph.D. of cellular substrates [5]. Institute of Pharmacology Besides caspases, cathepsins have recently been shown University of Bern to be associated with cell death regulation [6–12] and vari- Friedbühlstrasse 49 3010 Bern ous other physiological and pathological processes, such as Switzerland maturation of the MHC class II complex, bone remodel- [email protected] ling, keratinocyte differentiation, tumour progression and metastasis, rheumatoid arthritis and osteoarthritis, as well Summary as atherosclerosis [13, 14] (table 1). Thus, cathepsins ap- pear to play a significant role in immune responses. In this The immune system is composed of an enormous variety of review we discuss recent advances addressing the role of cells and molecules that generate a collective and coordin- lysosomal proteases in the diverse aspects of the immune ated response on exposure to foreign antigens, called the response, and also the involvement of cathepsins in the immune response. Within the immune response, endo-lyso- pathogenesis of diseases in which these proteases seem not somal proteases play a key role. In this review we cover to be properly under control. specific roles of cathepsins in innate and adaptive immu- nity, as well as their implication in the pathogenesis of sev- The cathepsin family eral diseases. Lysosomes are membrane-bound organelles which repres- Key words: adaptive and innate immunity; apoptosis; ent the main degradative compartment in eukaryotic cells. -
A Cysteine Protease Inhibitor Blocks SARS-Cov-2 Infection of Human and Monkey Cells
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.23.347534; this version posted October 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. A cysteine protease inhibitor blocks SARS-CoV-2 infection of human and monkey cells Drake M. Mellott,1 Chien-Te Tseng,3 Aleksandra Drelich,3 Pavla Fajtová,4,5 Bala C. Chenna,1 Demetrios H. Kostomiris1, Jason Hsu,3 Jiyun Zhu,1 Zane W. Taylor,2,9 Vivian Tat,3 Ardala Katzfuss,1 Linfeng Li,1 Miriam A. Giardini,4 Danielle Skinner,4 Ken Hirata,4 Sungjun Beck4, Aaron F. Carlin,8 Alex E. Clark4, Laura Beretta4, Daniel Maneval6, Felix Frueh,6 Brett L. Hurst,7 Hong Wang,7 Klaudia I. Kocurek,2 Frank M. Raushel,2 Anthony J. O’Donoghue,4 Jair Lage de Siqueira-Neto,4 Thomas D. Meek1.*, and James H. McKerrow#4,* Departments of Biochemistry and Biophysics1 and Chemistry,2 Texas A&M University, 301 Old Main Drive, College Station, Texas 77843, 3Department of Microbiology and Immunology, University of Texas, Medical Branch, 3000 University Boulevard, Galveston, Texas, 77755-1001, 4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 5Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague, Czech Republic, 6Selva Therapeutics, and 7Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, Utah, 84322, 8Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92037, USA.9Current address: Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA 99353. -
The Evolution of Heart Failure with Reduced Ejection Fraction Pharmacotherapy: What Do We Have and Where Are We Going?
Pharmacology & Therapeutics 178 (2017) 67–82 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: M. Curtis The evolution of heart failure with reduced ejection fraction pharmacotherapy: What do we have and where are we going? Ahmed Selim, Ronald Zolty, Yiannis S. Chatzizisis ⁎ Division of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, NE, USA article info abstract Available online 21 March 2017 Cardiovascular diseases represent a leading cause of mortality and increased healthcare expenditure worldwide. Heart failure, which simply describes an inability of the heart to meet the body's needs, is the end point for many Keywords: other cardiovascular conditions. The last three decades have witnessed significant efforts aiming at the discovery Heart failure of treatments to improve the survival and quality of life of patients with heart failure; many were successful, Reduced ejection fraction while others failed. Given that most of the successes in treating heart failure were achieved in patients with re- Pharmacotherapy duced left ventricular ejection fraction (HFrEF), we constructed this review to look at the recent evolution of Novel drugs HFrEF pharmacotherapy. We also explore some of the ongoing clinical trials for new drugs, and investigate poten- tial treatment targets and pathways that might play a role in treating HFrEF in the future. © 2017 Elsevier Inc. All rights reserved. Contents 1. Introduction.............................................. -
Expression of POMC, Detection of Precursor Proteases, and Evidence
ORIGINAL ARTICLE See related commentary on page 1934 Human Mast Cells in the Neurohormonal Network: Expression of POMC, Detection of Precursor Proteases, and Evidence for IgE-Dependent Secretion of a-MSH Metin Artuc1, Markus Bo¨hm2, Andreas Gru¨tzkau1, Alina Smorodchenko1, Torsten Zuberbier1, Thomas Luger2 and Beate M. Henz1 Human mast cells have been shown to release histamine in response to the neuropeptide a-melanocyte- stimulating hormone (a-MSH), but it is unknown whether these cells express proopiomelanocortin (POMC) or POMC-derived peptides. We therefore examined highly purified human skin mast cells and a leukemic mast cell line-1 (HMC-1) for their ability to express POMC and members of the prohormone convertase (PC) family known to process POMC. Furthermore, we investigated whether these cells store and secrete a-MSH. Reverse transcriptase-PCR (RT-PCR) analysis revealed that both skin mast cells and HMC-1 cells express POMC mRNA and protein. Expression of the POMC gene at the RNA level in HMC-1 cells could be confirmed by Northern blotting. Transcripts for both PC1 and furin convertase were detectable in skin-derived mast cells and HMC-1 cells, as shown by RT-PCR. In contrast, PC2 transcripts were detected only in skin mast cells, whereas transcripts for paired basic amino acid converting enzyme 4 (PACE4) were present only in HMC-1 cells. Radio- immunoassays performed on cell lysates and cell culture supernatants from human skin-derived mast cells disclosed immunoreactive amounts of a-MSH in both fractions. Stimulation with an anti-IgE antibody significantly reduced intracellular a-MSH and increased extracellular levels, indicating IgE-mediated secretion of this neuropeptide. -
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 ........................................................................................ -
(12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub
US 20110263526A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub. Date: Oct. 27, 2011 (54) NITRICOXIDE RELEASING PRODRUGS OF CD7C 69/96 (2006.01) THERAPEUTICAGENTS C07C 319/22 (2006.01) CD7C 68/02 (2006.01) (75) Inventor: Apparao SATYAM, Mumbai (IN) A6IP 29/00 (2006.01) A6IP 9/00 (2006.01) (73) Assignee: PIRAMAL LIFE SCIENCES A6IP37/08 (2006.01) LIMITED, Mumbai (IN) A6IP35/00 (2006.01) A6IP 25/24 2006.O1 (21) Appl. No.: 13/092.245 A6IP 25/08 308: A6IP3L/04 2006.O1 (22) Filed: Apr. 22, 2011 A6IP3L/2 308: Related U.S. Application Data 39t. O 308: (60) Provisional application No. 61/327,175, filed on Apr. A6IP3/10 (2006.01) 23, 2010. A6IPL/04 (2006.01) A6IP39/06 (2006.01) Publication Classification A6IP3/02 (2006.01) (51) Int. Cl. A6IP 9/06 (2006.01) A 6LX 3L/7072 (2006.01) 39t. W 308: A6 IK3I/58 (2006.01) A6IP II/08 (2006.015 A6 IK3I/55 (2006.01) A63/62 (2006.015 A6 IK 3/495 (2006.01) A6 IK 3/4439 (2006.01) (52) U.S. Cl. ........... 514/50: 514/166; 514/172: 514/217; A6 IK 3L/455 (2006.01) 514/255.04: 514/338; 514/356; 514/412; A6 IK 3/403 (2006.01) 514/420; 514/423: 514/510,536/28.53:540/67; A6 IK 3/404 (2006.01) 540/591; 544/396; 546/273.7: 546/318: 548/452: A6 IK 3/40 (2006.01) 548/500: 548/537; 549/464; 558/275 A6 IK3I/265 (2006.01) C7H 9/06 (2006.01) (57) ABSTRACT CO7I 71/00 (2006.01) CO7D 22.3/26 (2006.01) The present invention relates to nitric oxide releasing pro C07D 295/14 (2006.01) drugs of known drugs or therapeutic agents which are repre CO7D 40/12 (2006.01) sented herein as compounds of formula (I) wherein the drugs CO7D 213/80 (2006.01) or therapeutic agents contain one or more functional groups C07D 209/52 (2006.01) independently selected from a carboxylic acid, an amino, a CO7D 209/26 (2006.01) hydroxyl and a sulfhydryl group. -
The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis
REVIEW published: 07 August 2015 doi: 10.3389/fimmu.2015.00387 The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis Yannick Waumans, Lesley Baerts, Kaat Kehoe, Anne-Marie Lambeir and Ingrid De Meester* Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium Edited by: Research from over the past 20 years has implicated dipeptidyl peptidase (DPP) IV and Heidi Noels, its family members in many processes and different pathologies of the immune system. RWTH Aachen University, Germany Jürgen Bernhagen, Most research has been focused on either DPPIV or just a few of its family members. It is, RWTH Aachen University, Germany however, essential to consider the entire DPP family when discussing any one of its mem- Reviewed by: bers. There is a substantial overlap between family members in their substrate specificity, Rafael Franco, University of Barcelona, Spain inhibitors, and functions. In this review, we provide a comprehensive discussion on the Catherine Anne Abbott, role of prolyl-specific peptidases DPPIV, FAP, DPP8, DPP9, dipeptidyl peptidase II, prolyl Flinders University, Australia carboxypeptidase, and prolyl oligopeptidase in the immune system and its diseases. We Mark Gorrell, University of Sydney, Australia highlight possible therapeutic targets for the prevention and treatment of atherosclerosis, *Correspondence: a condition that lies at the frontier between inflammation -
Death Penalty for Keratinocytes: Apoptosis Versus Cornification
Cell Death and Differentiation (2005) 12, 1497–1508 & 2005 Nature Publishing Group All rights reserved 1350-9047/05 $30.00 www.nature.com/cdd Review Death penalty for keratinocytes: apoptosis versus cornification S Lippens1,2, G Denecker1, P Ovaere1, P Vandenabeele*,1 and apoptosis, necrosis or autophagy ultimately result in the W Declercq*,1 elimination of particular cells from a tissue. However, in specialized forms of differentiation, dead cell corpses are not 1 Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical removed but maintained to fulfil a specific function. These Research, VIB (Flanders Interuniversity Institute for Biotechnology) and Ghent developmental cell death programs result in the production of University, Technologiepark 927, B-9052 Zwijnaarde, Belgium 2 differentiated ‘storage’ cells containing large amounts of Current address: Institute de Biochimie, Universite´ de Lausanne, Chemin des specific proteins or other substances. Examples of such Boveresses 155, CH-1066 Epalinges, Switzerland * Corresponding authors: W Declercq and P Vandenabeele, Molecular Signaling differentiation programs occur in the stalk of the slime mold and Cell Death Unit, Department of Molecular Biomedical Research, Dictyostelium, during xylogenesis in plants, erythrocyte Technologiepark 927, B-9052 Zwijnaarde, Belgium. differentiation, lens fiber formation and cornification of Tel: þ 32 9 33137 60 Fax: þ 32 9 3313609; keratinocytes in the skin. E-mails: [email protected], Both apoptosis and keratinocyte cornification share some [email protected] similarities at the cellular and molecular level, such as loss of an intact nucleus and other organelles, cytoskeleton and cell Received 17.6.04; revised 23.3.05; accepted 07.4.05 Edited by G Melino shape changes, involvement of proteolytic events and mitochondrial changes.