High-Throughput Screening Identifies Cardiac
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Digitoxin-Induced Cytotoxicity in Cancer Cells Is Mediated Through Distinct Kinase and Interferon Signaling Networks
Published OnlineFirst August 22, 2011; DOI: 10.1158/1535-7163.MCT-11-0421 Molecular Cancer Therapeutic Discovery Therapeutics Digitoxin-Induced Cytotoxicity in Cancer Cells Is Mediated through Distinct Kinase and Interferon Signaling Networks Ioannis Prassas1,2, George S. Karagiannis1,2, Ihor Batruch4, Apostolos Dimitromanolakis1,2, Alessandro Datti2,3,5, and Eleftherios P. Diamandis1,2,4 Abstract Cardiac glycosides (e.g., digoxin, digitoxin) constitute a diverse family of plant-derived sodium pump inhibitors that have been in clinical use for the treatment of heart-related diseases (congestive heart failure, atrial arrhythmia) for many years. Recently though, accumulating in vitro and in vivo evidence highlight potential anticancer properties of these compounds. Despite the fact that members of this family have advanced to clinical trial testing in cancer therapeutics, their cytotoxic mechanism is not yet elucidated. In this study, we investigated the cytotoxic properties of cardiac glycosides against a panel of pancreatic cancer cell lines, explored their apoptotic mechanism, and characterized the kinetics of cell death induced by these drugs. Furthermore, we deployed a high-throughput kinome screening approach and identified several kinases of the Na-K-ATPase-mediated signal transduction circuitry (epidermal growth factor receptor, Src, pkC, and mitogen-activated protein kinases) as important mediators downstream of cardiac glycoside cytotoxic action. To further extend our knowledge on their mode of action, we used mass-spectrometry–based quantitative proteomics (stable isotope labeling of amino acids in cell culture) coupled with bioinformatics to capture large-scale protein perturbations induced by a physiological dose of digitoxin in BxPC-3 pancreatic cancer cells and identified members of the interferon family as key regulators of the main protein/protein interactions downstream of digitoxin action. -
Chemistry, Spectroscopic Characteristics and Biological Activity of Natural Occurring Cardiac Glycosides
IOSR Journal of Biotechnology and Biochemistry (IOSR-JBB) ISSN: 2455-264X, Volume 2, Issue 6 Part: II (Sep. – Oct. 2016), PP 20-35 www.iosrjournals.org Chemistry, spectroscopic characteristics and biological activity of natural occurring cardiac glycosides Marzough Aziz DagerAlbalawi1* 1 Department of Chemistry, University college- Alwajh, University of Tabuk, Saudi Arabia Abstract:Cardiac glycosides are organic compounds containing two types namely Cardenolide and Bufadienolide. Cardiac glycosides are found in a diverse group of plants including Digitalis purpurea and Digitalis lanata (foxgloves), Nerium oleander (oleander),Thevetiaperuviana (yellow oleander), Convallariamajalis (lily of the valley), Urgineamaritima and Urgineaindica (squill), Strophanthusgratus (ouabain),Apocynumcannabinum (dogbane), and Cheiranthuscheiri (wallflower). In addition, the venom gland of cane toad (Bufomarinus) contains large quantities of a purported aphrodisiac substance that has resulted in cardiac glycoside poisoning.Therapeutic use of herbal cardiac glycosides continues to be a source of toxicity today. Recently, D.lanata was mistakenly substituted for plantain in herbal products marketed to cleanse the bowel; human toxicity resulted. Cardiac glycosides have been also found in Asian herbal products and have been a source of human toxicity.The most important use of Cardiac glycosides is its affects in treatment of cardiac failure and anticancer agent for several types of cancer. The therapeutic benefits of digitalis were first described by William Withering in 1785. Initially, digitalis was used to treat dropsy, which is an old term for edema. Subsequent investigations found that digitalis was most useful for edema that was caused by a weakened heart. Digitalis compounds have historically been used in the treatment of chronic heart failure owing to their cardiotonic effect. -
A Case Report of Accidental Intoxication Following Ingestion of Foxglove Confused with Borage: High Digoxinemia Without Major Complications
Hindawi Case Reports in Cardiology Volume 2019, Article ID 9707428, 6 pages https://doi.org/10.1155/2019/9707428 Case Report A Case Report of Accidental Intoxication following Ingestion of Foxglove Confused with Borage: High Digoxinemia without Major Complications Maria Silvia Negroni,1 Arianna Marengo,2 Donatella Caruso,3 Alessandro Tayar,1 Patrizia Rubiolo,2 Flavio Giavarini,3 Simone Persampieri,1 Enrico Sangiovanni,3 Franca Davanzo,4 Stefano Carugo,1 Maria Laura Colombo,2 and Mario Dell’Agli 3 1Division of Cardiology, San Paolo Hospital, Department of Health Sciences, University of Milan, Via A. Di Rudini 8, Milan, Italy 2Department of Drug Science and Technology, Università degli Studi di Torino, Via Pietro Giuria 9, Turin, Italy 3Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, Milan, Italy 4Poison Control Centre of Milan, Niguarda Ca’ Granda Hospital, Milan, Italy Correspondence should be addressed to Mario Dell’Agli; [email protected] Received 12 June 2019; Accepted 13 November 2019; Published 29 November 2019 Academic Editor: Kuan-Rau Chiou Copyright © 2019 Maria Silvia Negroni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Foxglove (Digitalis purpurea L.) leaves are frequently confused with borage (Borago officinalis L.), which is traditionally used as a food ingredient. Due to the presence of the cardiac glycosides, mostly digitoxin, foxglove leaves are poisonous to human and may be fatal if ingested. A 55-year-old Caucasian woman complaining weakness, fatigue, nausea, and vomiting was admitted to the Emergency Department. -
Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01 -
Multidose Evaluation of 6,710 Drug Repurposing Library Identifies Potent SARS-Cov-2 Infection Inhibitors in Vitro and in Vivo
bioRxiv preprint doi: https://doi.org/10.1101/2021.04.20.440626; this version posted April 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Multidose evaluation of 6,710 drug repurposing library identifies potent SARS-CoV-2 infection inhibitors In Vitro and In Vivo. JJ Patten1, P. T. Keiser 1, D. Gysi2,3, G. Menichetti 2,3, H. Mori 1, C. J. Donahue 1, X. Gan 2,3, I. Do Valle 2, , K. Geoghegan-Barek 1, M. Anantpadma 1,4, J. L. Berrigan 1, S. Jalloh1, T. Ayazika1, F. Wagner6, M. Zitnik 2, S. Ayehunie6, D. Anderson1, J. Loscalzo3, S. Gummuluru1, M. N. Namchuk7, A. L. Barabasi2,3,8, and R. A. Davey1. Addresses: 1. Department of Microbiology, Boston University School of Medicine and NEIDL, Boston University, Boston, MA, 02118, USA. 2. Center for Complex Network Research, Northeastern University, Boston, Massachusetts 02115, USA. 3. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 4. present address: Analytical Development, WuXi Advanced Therapies, Philadelphia, PA, 19112, USA. 5. Center for the Development of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. 6. MatTek Corporation, Ashland, MA 01721, USA. 7. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA. 02115, USA. 8. Department of Network and Data Science, Central European University, Budapest 1051, Hungary. Abstract The SARS-CoV-2 pandemic has caused widespread illness, loss of life, and socioeconomic disruption that is unlikely to resolve until vaccines are widely adopted, and effective therapeutic treatments become established. -
Natural and Synthetic Saponins As Vaccine Adjuvants
Review Natural and Synthetic Saponins as Vaccine Adjuvants Pengfei Wang Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA; [email protected] Abstract: Saponin adjuvants have been extensively studied for their use in veterinary and human vaccines. Among them, QS-21 stands out owing to its unique profile of immunostimulating activity, inducing a balanced Th1/Th2 immunity, which is valuable to a broad scope of applications in com- bating various microbial pathogens, cancers, and other diseases. It has recently been approved for use in human vaccines as a key component of combination adjuvants, e.g., AS01b in Shingrix® for herpes zoster. Despite its usefulness in research and clinic, the cellular and molecular mechanisms of QS-21 and other saponin adjuvants are poorly understood. Extensive efforts have been devoted to studies for understanding the mechanisms of QS-21 in different formulations and in different combi- nations with other adjuvants, and to medicinal chemistry studies for gaining mechanistic insights and development of practical alternatives to QS-21 that can circumvent its inherent drawbacks. In this review, we briefly summarize the current understandings of the mechanism underlying QS-21’s adjuvanticity and the encouraging results from recent structure-activity-relationship (SAR) studies. Keywords: adjuvant; saponin; mechanism; SAR; QS-21; VSA-1; VSA-2 1. Introduction Traditional vaccines are whole-organism-based, using live attenuated or inactivated Citation: Wang, P. Natural and viruses or bacteria. These vaccines are quite reactogenic due to the presence of numerous Synthetic Saponins as Vaccine pathogen-associated-molecular-patterns (PAMPs) that are responsible for activation, and Adjuvants. -
(12) Patent Application Publication (10) Pub. No.: US 2009/0246185 A1 Kishida Et Al
US 20090246185A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0246185 A1 Kishida et al. (43) Pub. Date: Oct. 1, 2009 (54) CARDIAC DYSFUNCTION-AMELIORATING (30) Foreign Application Priority Data AGENT OR CARDAC FUNCTION-MANTAININGAGENT Mar. 13, 2006 (JP) ................................. 2006-066992 Nov. 21, 2006 (JP) ................................. 2006-314034 (75) Inventors: Hideyuki Kishida, Hyogo (JP); O O Kenji Fujii, Hyogo (JP); Hiroshi Publication Classification Kubo, Hyogo (JP); Kazunori (51) Int. Cl. Hosoe, Hyogo (JP) A6II 3L/22 (2006.01) CD7C 43/23 (2006.01) Correspondence Address: A6IP 9/00 (2006.01) SUGHRUE MION, PLLC (52) U.S. Cl. ........................................ 424/94.1:568/651 2100 PENNSYLVANIA AVENUE, N.W., SUITE 8OO (57) ABSTRACT WASHINGTON, DC 20037 (US) An object of the present invention is to provide a highly safe oral composition Superior in a cardiac dysfunction-amelio (73) Assignee: KANEKA CORPORATION, rating or cardiac function-maintaining action. The present OSAKA-SHI, OSAKA (JP) inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that use of (21) Appl. No.: 12/282,448 particularly, reduced coenzyme Q10 from among highly safe coenzyme Q affords a composition useful for amelioration of (22) PCT Filed: Mar. 9, 2007 cardiac dysfunction and maintenance of cardiac function. Accordingly, the present invention provides a cardiac dys (86). PCT No.: PCT/UP2007/O54.643 function-ameliorating agent or cardiac function-maintaining agent containing reduced coenzyme Qas an active ingredient, S371 (c)(1), and a pharmaceutical product, a food, an animal drug, a feed (2), (4) Date: Dec. 23, 2008 and the like, which contain the agent. -
Eiichi Kimura, MD, Department of Internal Medicine, Nippon Medical
Effect of Metildigoxin (ƒÀ-Methyldigoxin) on Congestive Heart Failure as Evaluated by Multiclinical Double Blind Study Eiichi Kimura,* M.D. and Akira SAKUMA,** Ph.D. In Collaboration with Mitsuo Miyahara, M.D. (Sapporo Medi- cal School, Sapporo), Tomohiro Kanazawa, M.D. (Akita Uni- versity School of Medicine, Akita), Masato Hayashi, M.D. (Hiraga General Hospital, Akita), Hirokazu Niitani, M.D. (Showa Uni- versity School of Medicine, Tokyo), Yoshitsugu Nohara, M.D. (Tokyo Medical College, Tokyo), Satoru Murao, M.D. (Faculty of Medicine, University of Tokyo, Tokyo), Kiyoshi Seki, M.D. (Toho University School of Medicine, Tokyo), Michita Kishimoto, M.D. (National Medical Center Hospital, Tokyo), Tsuneaki Sugi- moto, M.D. (Faculty of Medicine, Kanazawa University, Kana- zawa), Masao Takayasu, M.D. (National Kyoto Hospital, Kyoto), Hiroshi Saimyoji, M.D. (Faculty of Medicine, Kyoto University, Kyoto), Yasuharu Nimura, M.D. (Medical School, Osaka Uni- versity, Osaka), Tatsuya Tomomatsu, M.D. (Kobe University, School of Medicine, Kobe), and Junichi Mise, M.D. (Yamaguchi University, School of Medicine, Ube). SUMMARY The efficacy on congestive heart failure of metildigoxin (ƒÀ-methyl- digoxin, MD), a derivative of digoxin (DX), which had a good absorp- tion rate from digestive tract, was examined in a double blind study using a group comparison method. After achieving digitalization with oral MD or intravenous deslanoside in the non-blind manner, mainte- nance treatment was initiated and the effects of orally administered MD and DX were compared. MD was administered in 44 cases , DX in 42. The usefulness of the drug was evaluated after 2 weeks , taking into account the condition of the patient and the ease of administration . -
Quo Vadis Cardiac Glycoside Research?
toxins Review Quo vadis Cardiac Glycoside Research? Jiˇrí Bejˇcek 1, Michal Jurášek 2 , VojtˇechSpiwok 1 and Silvie Rimpelová 1,* 1 Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, Prague 6, Czech Republic; [email protected] (J.B.); [email protected] (V.S.) 2 Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 3, Prague 6, Czech Republic; [email protected] * Correspondence: [email protected]; Tel.: +420-220-444-360 Abstract: AbstractCardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG’s toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG’s toxicity is inhibition of Na+/K+-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca2+ concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. -
Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0 -
(12) Patent Application Publication (10) Pub. No.: US 2012/0264810 A1 Lin Et Al
US 20120264810A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0264810 A1 Lin et al. (43) Pub. Date: Oct. 18, 2012 (54) COMPOSITIONS AND METHODS FOR 61/400,763, filed on Jul. 30, 2010, provisional appli ENHANCING CELLULARUPTAKE AND cation No. 61/400,758, filed on Jul. 30, 2010. INTRACELLULAR DELVERY OF LIPID PARTICLES Publication Classification (75) Inventors: Paulo J.C. Lin, Vancouver (CA); (51) Int. Cl. Yuen Yic. Tam, Vancouver (CA); C07. 4I/00 (2006.01) Srinivasulu Masuna, Edmonton A6II 47/24 (2006.01) (CA); Marco A. Ciufolini, CI2N 5/071 (2010.01) Vancouver (CA); Michel Roberge, A63L/73 (2006.01) Vancouver (CA); Pieter R. Cullis, A6II 47/22 (2006.01) Vancouver (CA) C07D 215/46 (2006.01) A 6LX 3L/705 (2006.01) (73) Assignee: The University of British (52) U.S. Cl. ............ 514/44A: 540/5: 546/163; 514/788: Columbia, Vancouver (CA) 514/44 R; 435/375 (21) Appl. No.: 13/497,395 (57) ABSTRACT (22) PCT Filed: Sep. 22, 2010 Compositions, methods and compounds useful for enhancing the uptake of a lipid particle b\ a cell are describedIn particu (86). PCT No.: PCT/B2O1O/OO2518 lar embodiments, the methods of the invention include con tacting a cell with a lipid particle and a compound that binds S371 (c)(1), a Na+/K+ ATPase to enhance uptake of the lipid particle b\the (2), (4) Date: Jul. 3, 2012 cell Related compositions useful in practicing methods include lipid particles comprising a conjugated compound Related U.S. Application Data that enhances uptake of the lipid particles b\ the cell The (60) Provisional application No. -
Wo 2008/127291 A2
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 23 October 2008 (23.10.2008) WO 2008/127291 A2 (51) International Patent Classification: Jeffrey, J. [US/US]; 106 Glenview Drive, Los Alamos, GOlN 33/53 (2006.01) GOlN 33/68 (2006.01) NM 87544 (US). HARRIS, Michael, N. [US/US]; 295 GOlN 21/76 (2006.01) GOlN 23/223 (2006.01) Kilby Avenue, Los Alamos, NM 87544 (US). BURRELL, Anthony, K. [NZ/US]; 2431 Canyon Glen, Los Alamos, (21) International Application Number: NM 87544 (US). PCT/US2007/021888 (74) Agents: COTTRELL, Bruce, H. et al.; Los Alamos (22) International Filing Date: 10 October 2007 (10.10.2007) National Laboratory, LGTP, MS A187, Los Alamos, NM 87545 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, (30) Priority Data: CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, 60/850,594 10 October 2006 (10.10.2006) US ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (71) Applicants (for all designated States except US): LOS LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, ALAMOS NATIONAL SECURITY,LLC [US/US]; Los MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, Alamos National Laboratory, Lc/ip, Ms A187, Los Alamos, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, NM 87545 (US).