DOCSLIB.ORG

Free PDF Download

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Free PDF Download European Review for Medical and Pharmacological Sciences 2020; 24: 9169-9171 SARS-CoV-2 infection: NLRP3 inflammasome as plausible target to prevent cardiopulmonary complications? V. QUAGLIARIELLO1, A. BONELLI1, A. CARONNA1, M.C. LOMBARI1, G. CONFORTI1, M. LIBUTTI2, R.V. IAFFAIOLI3, M. BERRETTA4, G. BOTTI5, N. MAUREA1 1Division of Cardiology, Istituto Nazionale Tumori – IRCCS- Fondazione G. Pascale, Naples, Italy 2Medical Oncology, A.S.L Naples 1, Naples, Italy 3Association for Multidisciplinary Studies in Oncology and Mediterranean Diet, Piazza Nicola Amore, Naples, Italy 4Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, Aviano, PN, Italy 5Scientific Direction, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Naples, Italy Abstract. – NLRP3 (NOD-, LRR- and pyrin therapeutic target, being upstream of cytokine domain-containing protein 3) inflammasome has storm causing multi-organ failure in COVID-19, recently become an intriguing target of several including myocarditis, venous thromboembolism chronic and viral diseases. Here, we argue that (VTE), hypertension and acute respiratory dis- targeting NLRP3 inflammasome could be a strat- tress syndrome (ARDS). SARS-CoV-2, an en- egy to prevent cardiovascular outcomes [fulmi- nant myocarditis, heart failure, venous thorom- veloped and non-segmented RNA based virus, boembolism (VTE)] and acute respiratory dis- is the etiological agent of Coronavirus disease tress syndrome (ARDS) in patients with SARS- 2019 (COVID-19)2. The main causes of death CoV-2 infection. We discuss the rational for NL- are cardiovascular diseases (mainly VTE, ful- RP3 targeting in clinical trials as an effective minant myocarditis, myocardial infarction) and therapeutic strategy aimed to improve progno- ARDS3. Clinical characteristics of patients with sis of COVID-19, analyzing the potential of two COVID-19 clearly identified a cytokine storm, therapeutic options (tranilast and OLT1177) cur- rently available in clinical practice. secondary to the interaction of SARS-CoV-2 with human cells expressing angiotensin converting Key Words: enzyme-2 (ACE2), an integral (type I) membrane NLRP3, COVID-19, SARS-CoV-2, Myocarditis, Cyto- zinc metallopeptidase widely expressed in heart, kines, Venous thoromboembolism. lungs, esophagus, kidneys, bladder and small intestine4. Introduction NLRP3 as Potential Target in COVID-19 NLRP3 (NOD-, LRR- and pyrin domain-con- Incidence and mortality of pandemic Coro- taining protein 3) is a macromolecular complex navirus disease 2019 (COVID-19) is constant- having a key role in the genesis of acute and ly growing globally. To date of writing, over chronic inflammatory processes, like cancer, dia- 13,6 million total cases are ascertained, with betes, virus infection, and cardiovascular diseas- over 593,000 deaths1. Pending the vaccine, many es5. Its role is based on the triggering of defense drugs are being used in clinical trials to reduce mechanisms against external agents and involves COVID-19 mortality, including cytokine-block- several pro-inflammatory cytokines modulating ing agents (monoclonal antibodies against Inter- cell metabolism and cell mediated immunity. leukin-1 or Interleukin-6), remdesivir, hydroxy- NLRP3 form a multi-molecular complex, termed chloroquine, azithromycin. Here, we highlight an “inflammasome”, that results in NOD-like re- on NLRP3 inflammasome as a considerable ceptor oligomerization, caspase-1 activation and Corresponding Author: Vincenzo Quagliariello, MD; e-mail: [email protected] 9169 V. Quagliariello, A. Bonelli, A. Caronna, M.C. Lombari, G. Conforti, et al. enzymatic release of IL-1β and IL-18, which con- orally available β-sulfonyl nitrile compound, re- tribute to T cell activity6. For several virus-relat- duced neutrophil infiltration and joint swelling in ed diseases and SARS-CoV-2, NLRP3, in concert preclinical models of arthritis15; it is recently stud- with MyD88 and NF-kB, drastically increased ied in phase 1 and 2 clinical trials for treatment of the production of pro-inflammatory and athero- degenerative arthritis, acute gout and myocardial genic cytokines inducing multi-organ failure, infarction16. Healthy humans receiving up to 1000 such as IL1-β, IL-6, IL-7, IL-8, IL-9, IL-10, basic mg daily for 8 days of dapansutrile did not show FGF, GCSF, GMCSF, IFNγ, IP10, MCP1, MIP1A, any organ or hematological toxicity, indicating a MIP1B, PDGF, TNF-α, and VEGF7. good safety and tolerance16. SARS-CoV-2 infection, as other viral-related Anti-cytokine treatments are currently un- diseases, leads to secondary haemophagocytic der investigation worldwide in patients with lymphohistiocytosis (sHLH), a multi organ hy- COVID-19 in pre-ICU and in ICU stages; ef- perinflammatory condition driven by cytokines8. fective targets involve IL-1 (canakimumab)17, sHLH induces hyperactivation of cytotoxic T IL-1receptor (anakinra)18, IL-6 (siltuximab)19, IL- lymphocytes, macrophages and natural killer 6 receptor (tocilizumab)20. By targeting NLRP3, cells, leading to multiorgan failure (including which activates upstream of many transcription- myocarditis and coronary artery aneurysm) and al factors (NF-kB, AP-1, p38-MAPK, JAK1/2- consequently to death. Although pathogenesis STAT3) and cytokines, most key players of direct of sHLH is not well understood, in patients with myocardial damages21, myocarditis22, VTE and sHLH monoallelic mutations or polymorphisms ARDS could be significantly disabled leading to they have been detected in genes involved in improvements in prognosis of COVID-1923,24. cytokine production and signaling, such as NL- RP3, other inflammasome proteins and toll like receptors9. Since sHLH is common in rheumatoid Conclusions arthritis and viral infections, target therapy with anti-cytokine agents and NLRP3 could be con- As insight is gained into the clinical pheno- siderable therapeutic strategies against SARS- types associated with COVID-19, we propose CoV-2-induced sHLH. NLRP3 as therapeutic target warranting rapid investigation in clinical trials highlighting car- NLRP3 Inhibitors: Therapeutic Options diovascular, immunological and pulmonary out- Currently Available in Clinical Practice comes. Inhibition of NLRP3 has been successfully studied in chronic inflammatory diseases, includ- ing rheumatoid arthritis, severe gout, cardiovascu- Conflict of Interest lar diseases and ARDS10. Activation of the NLRP3 The Authors declare that they have no conflict of interests. inflammasome exacerbates immunity response and mediates further cellular apoptosis, necro- Acknowledgements 11 sis and fibrosis, as well as events of VTE . Two We thank Dr. Grimaldi Immacolata, working in Division therapeutic options are currently available in clin- of Cardiology, Istituto Nazionale Tumori-IRCCS- Fonda- ical seeing: tranilast (N-[3′,4′-dimethoxycinnam- zione G. Pascale of Naples, for effective research support oyl]-anthranilic acid) and dapansutrile (OLT1177) activities. both acting as direct NLRP3 inhibitors. Tranilast, a tryptophan metabolite, has demonstrated signif- Funding icant therapeutic and preventive outcomes in mice This work was funded by “Ricerca Corrente” grant from the models of gout, Cryopyrin-Associated Periodic Italian Ministry of Health. “Cardiotossicità dei trattamenti Syndrome, and Type-2 diabetes12. In another pre- antineoplastici: identificazione precoce e strategie di cardi- clinical study13 in pigs tranilast reduced ARDS oprotezione” Project code: M1/5-C. and acute lung injury preventing pulmonary and airway vascular permeability and hypoxemia. In References clinical settings, it is already approved as an an- 14 ti-allergic drug and Matsumura et al indicate 1) ZHANG X. Epidemiology of Covid-19. N Engl J Med that tranilast reduces cardiomyopathy in patients 2020; 382: 1869. with muscular dystrophy after administration of 2) CÁRDENAS-CONEJO Y, LIÑAN-RICO A, GARCÍA-RODRÍGUEZ 300 mg/day for three months. Dapansutrile, an DA, CENTENO-LEIJA S, SERRANO-POSADA H. An ex- 9170 SARS-CoV-2 infection clusive 42 amino acid signature in pp1ab pro- 15) MARCHETTI C, SWARTZWELTER B, GAMBONI F, NEFF CP, tein provides insights into the evolutive history of RICHTER K, AZAM T, CARTA S, TENGESDAL I, NEmkOV T, the 2019 novel human-pathogenic coronavirus D’ALESSANDRO A, HENRY C, JONES GS, GOODRICH SA, (SARS-CoV2). J Med Virol 2020; 92: 688-692. ST LAURENT JP, JONES TM, SCRIBNER CL, BARROW RB, AL- TMAN RD, SKOURAS DB, GATTORNO M, GRAU V, JANCI- 3) MAHAllAWI WH, KHABOUR OF, ZHANG Q, MAKHDOUM AUSKIENE S, RUBARTEllI A, JOOSTEN LAB, DINAREllO CA HM, SULIMAN BA. MERS-CoV infection in humans . is associated with a pro-inflammatory Th1 and OLT1177, a β-sulfonyl nitrile compound, safe in Th17 cytokine profile. Cytokine 2018; 104: 8-13. humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc ZOU X, CHEN K, ZOU J, HAN P, HAO J, HAN Z 4) . Sin- Natl Acad Sci U S A 2018; 115: E1530-E1539. gle-cell RNA-seq data analysis on the receptor TOLDO S, ABBATE A ACE2 expression reveals the potential risk of dif- 16) . The NLRP3 inflammasome ferent human organs vulnerable to 2019-nCoV in- in acute myocardial infarction. Nat Rev Cardiol fection. Front Med 2020; 14: 185-192. 2018; 15: 203-214. RUSSEll B, MOSS C, GEORGE G, SANTAOLAllA A, COPE 5) KEllEY N, JELTEMA D, DUAN Y, HE Y. The NLRP3 In- 17) A, PAPA S, VAN HEMELRIJck M. flammasome: an overview of mechanisms of ac- Associations between tivation and regulation. Int J Mol Sci 2019; 20: immune-suppressive and stimulating drugs and 3328. novel
Load more

Recommended publications
  • PRODUCT INFORMATION Dapansutrile Item No
    PRODUCT INFORMATION Dapansutrile Item No. 24671 CAS Registry No.: 54863-37-5 Formal Name: 3-(methylsulfonyl)-propanenitrile Synonym: 3-methanesulfonyl Propanenitrile OO MF: C H NO S 4 7 2 S FW: 133.2 CN Purity: ≥98% Supplied as: A crystalline solid Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Dapansutrile is supplied as a crystalline solid. A stock solution may be made by dissolving the dapansutrilein the solvent of choice. Dapansutrile is soluble in the organic solvent DMSO, which should be purged with an inert gas at a concentration of approximately 2 mg/ml. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. Organic solvent-free aqueous solutions of dapansutrile can be prepared by directly dissolving the crystalline solid in aqueous buffers. The solubility of dapansutrile in PBS, pH 7.2, is approximately 3 mg/ml. We do not recommend storing the aqueous solution for more than one day. Description Dapansutrile is a β-sulfonyl nitrile inhibitor of the NLRP3 inflammasome that inhibits the release of IL-1β and decreases caspase-1 levels in LPS-stimulated J774A.1 murine macrophages, human monocyte derived macrophages (HMDMs), and primary human blood neutrophils without affecting TNF-α release.1 It is selective for NLRP3 over NLRP4 and AIM2 inflammasomes at concentrations up to 100 μM.
    [Show full text]
  • ATP-Binding and Hydrolysis in Inflammasome Activation
    molecules Review ATP-Binding and Hydrolysis in Inflammasome Activation Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald * Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; [email protected] (C.F.S.); [email protected] (B.K.Z.) * Correspondence: [email protected]; Tel.: +1-403-210-8433 Academic Editor: Massimo Bertinaria Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure.
    [Show full text]
  • Modulation of the Inflammatory Response After Spinal Cord Injury
    ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en MODULATION OF THE INFLAMMATORY RESPONSE AFTER SPINAL CORD INJURY Presented by Jesús Amo Aparicio ACADEMIC DISSERTATION To obtain the degree of PhD in Neuroscience by the Universitat Autònoma de Barcelona 2019 Directed by Dr. Rubèn López Vales Tutorized by Dr. Xavier Navarro Acebes INDEX SUMMARY Page 7 INTRODUCTION Page 13 - Spinal cord Page 15 - Spinal cord injury Page 17 - Incidence and causes Page 18 - Types of SCI Page 18 - Biological events after SCI Page 20 - Studying SCI Page 24 - Animal models Page 24 - Lesion models Page 24 - Current therapies for SCI Page 25 - Basic principles of the immune system Page 27 - Innate immune response Page 27 - Adaptive immune response Page 28 - Inflammatory response Page 29 - Inflammatory response after SCI Page 30 - Modulation of injury environment Page 36 - Interleukin 1 Page 36 - Interleukin 37 Page 40 - Interleukin 13 Page 44 OBJECTIVES Page 47 MATERIALS AND METHODS Page 51
    [Show full text]
  • Charles A. Dinarello, MD
    Acute Respiratory Distress Syndrome, NLRP3 and IL-1β Activation Induced by COVID-19 Grand Rounds Presentation by Charles A. Dinarello, MD 08 April 2020 Randy Cron:…” the cytokine storm keeps raging long after the virus is no longer a threat” What is a cytokine storm? Unusually high circulating levels of pro-inflammatory cytokines associated with organ damage Pharmacologic blockade or neutralization of specific cytokines can reduce organ damage, particularly when treatment is initiated early in the disease Therapeutic options to reduce the cytokine storm Blocking IL-1α and IL-1β with anakinra Blocking IL-6R with tocilizumab Blocking Upstream early with oral NLRP3 inhibitor The first reports from China established the cytokine storm in CVID-19 pneumonia Increased chemokines and IL-18 from PBMC, but not IL-6. IL-6 is from Epithelial cells. The authors concluded: One view of the evolving Cytokine Storm in COVID-19 infection adherence to endothelium Lung opening of endothelial junctions Lung Primary Infection Inflammation infiltration of damaging MDSC; cytokine production: IL-1β, IL- Virus infects type 2 6, IL-12, IL-18, TNFα, epithelial cells. Death of cells. chemokines Release of IL-1α processing of IL-1β and IL-18 and cell contents by the NLRP3 inflammasome IL-1α inducesViru chemokines and other cytokines from resident macrophages in the lungs. cytokine storm G-CSF and IL-1β enters β, circulation IL-6 (IL-1 TNFα, IL-8) G-CSF; IL-1β Liver IL-18I IL-12 + IL-18 hepatitis release of immature neutrophil and monocytes (MDSC) IFNγ IFNγ Bone marrow
    [Show full text]
  • Development of Covalent NLRP3 Inflammasome Inhibitors: Chemistry and Biological Activity
    AperTO - Archivio Istituzionale Open Access dell'Università di Torino Development of covalent NLRP3 inflammasome inhibitors: chemistry and biological activity This is the author's manuscript Original Citation: Availability: This version is available http://hdl.handle.net/2318/1720025 since 2019-12-23T10:06:07Z Published version: DOI:10.1016/j.abb.2018.11.013 Terms of use: Open Access Anyone can freely access the full text of works made available as "Open Access". Works made available under a Creative Commons license can be used according to the terms and conditions of said license. Use of all other works requires consent of the right holder (author or publisher) if not exempted from copyright protection by the applicable law. (Article begins on next page) 05 October 2021 This is the author's final version of the contribution published as: Massimo Bertinaria, Simone Gastaldi, Elisabetta Marini, Marta Giorgis, Development of covalent NLRP3 inflammasome inhibitors: chemistry and biological activity, Archives of Biochemistry and Biophysics, 670, 2019, 116-139. doi: 10.1016/j.abb.2018.11.013. The publisher's version is available at: https://www.sciencedirect.com/science/article/pii/S0003986118305575?via%3Dihub #! When citing, please refer to the published version. Link to this full text: https://www.sciencedirect.com/science/article/pii/S0003986118305575?via%3Dihub #! 1 This full text was downloaded from iris-Aperto: https://iris.unito.it/ 2 Development of covalent NLRP3 inflammasome inhibitors: chemistry and biological activity Massimo Bertinaria,* Simone Gastaldi, Elisabetta Marini, Marta Giorgis Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9 – 10125 Torino, Italy Keywords: NLRP3 inflammasome; NLRP3 inhibitors; covalent drugs; irreversible inhibitors, drug design.
    [Show full text]
  • Inhibitory Effects of Shiitake-Derived Exosome-Like Nanoparticles on NLRP3 Inflammasome Activation" (2019)
    University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Nutrition & Health Sciences Dissertations & Theses Nutrition and Health Sciences, Department of 8-2019 Inhibitory Effects Of Shiitake-derived Exosome- like Nanoparticles On NLRP3 Inflammasome Activation Yizhu Lu University of Nebraska-Lincoln, [email protected] Follow this and additional works at: https://digitalcommons.unl.edu/nutritiondiss Part of the Molecular, Genetic, and Biochemical Nutrition Commons Lu, Yizhu, "Inhibitory Effects Of Shiitake-derived Exosome-like Nanoparticles On NLRP3 Inflammasome Activation" (2019). Nutrition & Health Sciences Dissertations & Theses. 84. https://digitalcommons.unl.edu/nutritiondiss/84 This Article is brought to you for free and open access by the Nutrition and Health Sciences, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Nutrition & Health Sciences Dissertations & Theses by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. INHIBITORY EFFECTS OF SHIITAKE-DERIVED EXOSOME-LIKE NANOPARTICLES ON NLRP3 INFLAMMASOME ACTIVATION By Yizhu Lu A THESIS Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Master of Science Major: Nutrition Under the Supervision of Professor Jiujiu Yu Lincoln, Nebraska August, 2019 INHIBITORY EFFECTS OF SHIITAKE-DERIVED EXOSOME-LIKE NANOPARTICLES ON NLRP3 INFLAMMASOME ACTIVATION Yizhu Lu, M.S. University of Nebraska, 2019 Advisor: Jiujiu Yu The NLRP3 inflammasome is a critical mediator of inflammation and consists of the sensor NOD-like receptor family, pyrin domain containing 3 (NLRP3), the adaptor apoptotic speck protein containing a caspase recruitment domain (ASC), and the effector caspase-1. Dysregulated or excessive activation of the NLRP3 inflammasome contributes to pathogenesis of diverse inflammatory diseases such as Type 2 diabetes and atherosclerosis.
    [Show full text]
  • NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases
    molecules Review NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases Eleonora Mezzaroma 1,2, Antonio Abbate 1 and Stefano Toldo 1,* 1 VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA; [email protected] (E.M.); [email protected] (A.A.) 2 Pharmacotherapy and Outcomes Sciences, Virginia Commonwealth University, Richmond, VA 23298, USA * Correspondence: [email protected]; Tel.: +1-804-628-3396 Abstract: Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)- containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases. Keywords: NLRP3; inflammasome; caspase-1; ASC; IL-1; IL-18; cardiovascular disease; ischemia; heart failure; inhibitor Citation: Mezzaroma, E.; Abbate, A.; 1. Introduction Toldo, S. NLRP3 Inflammasome The innate immune system comprehends a genetically coded and inherited set of Inhibitors in Cardiovascular Diseases.
    [Show full text]
  • Product Data Sheet
    Product data sheet MedKoo Cat#: 319577 Name: Dapansutrile CAS#: 54863-37-5 Chemical Formula: C4H7NO2S Exact Mass: 133.0197 Molecular Weight: 133.17 Product supplied as: Powder Purity (by HPLC): ≥ 98% Shipping conditions Ambient temperature Storage conditions: Powder: -20°C 3 years; 4°C 2 years. In solvent: -80°C 3 months; -20°C 2 weeks. 1. Product description: Dapansutrile, also known as OLT1177, is an anti-inflammatory, analgesic drug candidate. Dapansutrile is a β-sulfonyl nitrile inhibitor of the NLRP3 inflammasome that inhibits the release of IL-1β and decreases caspase-1 levels in LPS-stimulated J774A. murine macrophages, human monocyte derived macrophages (HMDMs), and primary human blood neutrophils without affecting TNF-α release. 2. CoA, QC data, SDS, and handling instruction SDS and handling instruction, CoA with copies of QC data (NMR, HPLC and MS analytical spectra) can be downloaded from the product web page under “QC And Documents” section. Note: copies of analytical spectra may not be available if the product is being supplied by MedKoo partners. Whether the product was made by MedKoo or provided by its partners, the quality is 100% guaranteed. 3. Solubility data Solvent Max Conc. mg/mL Max Conc. mM DMSO 60.0 450.55 H2O 68.0 510.63 4. Stock solution preparation table: Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg 1 mM 7.51 mL 37.55 mL 75.09 mL 5 mM 1.50 mL 7.51 mL 15.02 mL 10 mM 0.75 mL 3.75 mL 7.51 mL 50 mM 0.15 mL 0.75 mL 1.50 mL 5.
    [Show full text]
  • Current and Pipeline NLRP3 Inhibitors
    ISSN: 2693-4965 DOI: 10.33552/OJCR.2019.03.000556 Online Journal of Cardiology Research & Reports Review Article Copyright © All rights are reserved by Victoria McGilligan The NLRP3 Inflammasome as a promising target for Coronary Artery Disease: Current and Pipeline NLRP3 Inhibitors Shauna Donnelly1, Roisin McAllister1, Melody Chemaly1, Tony Bjourson1, Aaron Peace2 and Victoria McGilligan1* 1Ulster University, Centre for Personalised Medicine, C-TRIC Clinical Translational Research and Innovation Centre, Altnagelvin Area Hospital, UK 2Department of Cardiology, Altnagelvin Area Hospital, UK *Corresponding author: Victoria McGilligan, Ulster University, Centre for Personalised Received Date: November 06, 2019 Medicine, C-TRIC Clinical Translational Research and Innovation Centre, Altnagelvin Area Hospital, UK. Published Date: November 13, 2019 Abstract Coronary Artery Disease (CAD) represents a major health burden worldwide. It is driven by chronic inflammation of the arterial vasculature supplying the heart, in response to pro-inflammatory assaults such as high LDL cholesterol. The resultant atherosclerosis can cause occlusive disease and acute cardiovascular events. The pro-inflammatory cytokine, IL-1β is a central component of this inflammatory response and signalling is activated and amplified by the NLRP3 inflammasome. Rational therapeutic targeting of these mediators could modify atherosclerotic disease progression; myocardial remodelling and CAD patient outcomes. Here we discuss promising current and pipeline inhibitors of the NLRP3
    [Show full text]
  • Implications for Circadian Medicine
    REVIEW published: 31 July 2020 doi: 10.3389/fimmu.2020.01630 Circadian Control of Inflammasome Pathways: Implications for Circadian Medicine Benoit Pourcet and Hélène Duez* University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France The innate immune system senses “non-self” molecules derived from pathogens (PAMPs) as well as endogenous damage-associated molecular patterns (DAMPs) and promotes sterile inflammation that is necessary for injury resolution, tissue repair/regeneration, and homeostasis. The NOD-, LRR- and pyrin domain containing protein 3 (NLRP3) is an innate immune signaling complex whose assembly and activation can be triggered by various signals ranging from microbial molecules to ATP or the abnormal accumulation of crystals, thus leading to IL-1β and IL-18 maturation and secretion. Deregulation of the NLRP3 signaling cascade is associated with numerous inflammatory and metabolic diseases including rheumatoid arthritis, gout, atherosclerosis or type 2 diabetes. Interestingly, the circadian clock controls numerous inflammatory processes while clock disruption leads to or exacerbates inflammation. Recently, the Edited by: biological clock was demonstrated to control NLRP3 expression and activation, thereby Christoph Scheiermann, controlling IL-1β and IL-18 secretion in diverse tissues and immune cells, particularly Ludwig Maximilian University of Munich, Germany macrophages. Circadian oscillations of NLRP3 signaling is lost in models of clock Reviewed by: disruption, contributing to the development of peritonitis, hepatitis, or colitis. Sterile Je-Wook Yu, inflammation is also an important driver of atherosclerosis, and targeting the production Yonsei University, South Korea of IL-1β has proven to be a promising approach for atherosclerosis management in Chiara Agostinis, IRCCS Materno Infantile Burlo humans.
    [Show full text]
  • Inflammasome Activation at the Crux of Severe COVID-19
    PROGRESS based on RNA sequencing, often of thawed cells, and infected, activated or dying cells do Inflammasome activation at the crux not survive freeze–thaw well, which could skew results. Moreover, inflammasome of severe COVID-19 activation does not directly induce tran- scriptional responses, and its detection is less straightforward than that of most other Setu M. Vora, Judy Lieberman and Hao Wu signalling pathways. Nonetheless, several Abstract | The COVID-19 pandemic, caused by severe acute respiratory syndrome studies are now accumulating that support coronavirus 2 (SARS- CoV-2), results in life- threatening disease in a minority of direct (infection-induced) and indirect inflammasome activation and the critical patients, especially elderly people and those with co- morbidities such as obesity role of inflammasomes in severe COVID-19. and diabetes. Severe disease is characterized by dysregulated cytokine release, Here we discuss the available evidence, pneumonia and acute lung injury, which can rapidly progress to acute respiratory potential mechanisms and the implications distress syndrome, disseminated intravascular coagulation, multisystem failure and for therapy. death. However, a mechanistic understanding of COVID-19 progression remains Inflammasomes unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates Key to inflammation and innate immunity, inflammasomes, which are large multiprotein assemblies that are broadly inflammasomes are large, micrometre- responsive to pathogen- associated and stress- associated cellular insults, leading scale multiprotein cytosolic complexes to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and that assemble in response to pathogen- pyroptosis, an inflammatory form of cell death. We further discuss potential associated molecular patterns (PAMPs) mechanisms of inflammasome activation and clinical efforts currently under way or damage-associated molecular patterns (DAMPs) and trigger proinflammatory to suppress inflammation to prevent or ameliorate severe COVID-19.
    [Show full text]
  • The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia
    International Journal of Molecular Sciences Review The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia Laura Urwanisch 1 , Michela Luciano 1,2 and Jutta Horejs-Hoeck 1,2,* 1 Department of Biosciences, University of Salzburg, 5020 Salzburg, Austria; [email protected] (L.U.); [email protected] (M.L.) 2 Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria * Correspondence: [email protected] Abstract: Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1β is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia- promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia. Keywords: NLRP3 inflammasome; IL-1β; autophagy; leukemia Citation: Urwanisch, L.; Luciano, M.; Horejs-Hoeck, J. The NLRP3 Inflammasome and Its Role in the 1.
    [Show full text]