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Bhimraj A, Morgan RL, Shumaker AH, Baden L, Cheng VCC, Edwards KM, Gallagher JC, Gandhi RT, Muller WJ, Nakamura MM, O’Horo JC, Shafer RW, Shoham S, Murad MH, Mustafa RA, Sultan S, Falck-Ytter Y. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19 (September 2022). Clin Infect Dis 2024; 78:e250-e349. [PMID: 36063397 PMCID: PMC9494372 DOI: 10.1093/cid/ciac724] [Citation(s) in RCA: 99] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 02/07/2023] Open
Abstract
There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials. The objective was to develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Based on the most recent search conducted on 31 May 2022, the IDSA guideline panel has made 32 recommendations for the treatment and management of the following groups/populations: pre- and postexposure prophylaxis, ambulatory with mild-to-moderate disease, and hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines. At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were conducted that provided much-needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved, which we hope future trials can answer.
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Affiliation(s)
- Adarsh Bhimraj
- Division of Infectious Diseases, Houston Methodist Hospital, Houston, Texas
| | - Rebecca L Morgan
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Amy Hirsch Shumaker
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio
- VA Northeast Ohio Healthcare System, Cleveland, Ohio
| | | | - Vincent Chi Chung Cheng
- Queen Mary Hospital, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Kathryn M Edwards
- Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center,Nashville, Tennessee
| | - Jason C Gallagher
- Department of Pharmacy Practice, Temple University, Philadelphia, Pennsylvania
| | - Rajesh T Gandhi
- Infectious Diseases Division, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts
| | - William J Muller
- Division of Pediatric Infectious Diseases, Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University, Chicago, Illinois
| | - Mari M Nakamura
- Antimicrobial Stewardship Program and Division of Infectious Diseases, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - John C O’Horo
- Division of Infectious Diseases, Joint Appointment Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
| | - Robert W Shafer
- Division of Infectious Diseases, Department of Medicine, Stanford University, Palo Alto, California
| | - Shmuel Shoham
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - M Hassan Murad
- Division of Public Health, Infectious Diseases and Occupational Medicine, Mayo Clinic, Rochester, Minnesota
| | - Reem A Mustafa
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | - Shahnaz Sultan
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis VA Healthcare System, Minneapolis, Minnesota
| | - Yngve Falck-Ytter
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio
- VA Northeast Ohio Healthcare System, Cleveland, Ohio
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2
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Tarique AA, Tuladhar N, Kelk D, Begum N, Lucas RM, Luo L, Stow JL, Wainwright CE, Bell SC, Sly PD, Fantino E. Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis. Cells 2024; 13:166. [PMID: 38247856 PMCID: PMC10813867 DOI: 10.3390/cells13020166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/12/2024] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF. METHODS Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs), were differentiated into monocyte-derived macrophages (MDMs) and subsequently infected with P. aeruginosa. P. aeruginosa uptake and killing by MDMs in the presence or absence of AZM was studied. M1 and M2 macrophage polarizations were induced and their functions and cytokine release were analyzed. RESULTS Following AZM treatment, both HC and CF MDMs exhibited a significant increase in P. aeruginosa uptake and killing, however, lysosomal acidification remained unchanged. AZM treatment led to higher activation of ERK1/2 in both HC and CF MDMs. Pharmacological inhibition of ERK1/2 using U0126 significantly reduced P. aeruginosa uptake in HC MDMs. M1 macrophage polarization remained unaffected; however, AZM treatment led to increased IL-6 and IL-10 release in both HC and CF M1 macrophages. AZM also significantly increased the phagocytic index for both pHrodo E. coli and S. aureus in CF M1 macrophages. In CF, AZM treatment promoted anti-inflammatory M2 macrophage polarization, with an increased percentage of CD209+ M2 macrophages, induction of the M2 gene CCL18, along with its secretion in the culture supernatant. However, AZM d'd not restore endocytosis in CF, another essential feature of M2 macrophages. CONCLUSIONS This study highlights the cellular functions and molecular targets of AZM which may involve an improved uptake of both Gram-positive and Gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.
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Affiliation(s)
- Abdullah A. Tarique
- Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia (P.D.S.); (E.F.)
| | - Neeraj Tuladhar
- Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia
| | - Dean Kelk
- Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia (P.D.S.); (E.F.)
| | - Nelufa Begum
- Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia (P.D.S.); (E.F.)
| | - Richard M. Lucas
- Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia
| | - Lin Luo
- Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia
| | - Jennifer L. Stow
- Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD 4067, Australia
| | - Claire E. Wainwright
- Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia (P.D.S.); (E.F.)
- Respiratory and Sleep Medicine, Queensland Children’s Hospital, Brisbane, QLD 4101, Australia
| | - Scott C. Bell
- Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia (P.D.S.); (E.F.)
- Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD 4032, Australia
| | - Peter D. Sly
- Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia (P.D.S.); (E.F.)
| | - Emmanuelle Fantino
- Child Health Research Centre (CHRC), The University of Queensland, Brisbane, QLD 4101, Australia (P.D.S.); (E.F.)
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3
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Lu G, Wang Y, Shi Y, Zhang Z, Huang C, He W, Wang C, Shen H. Autophagy in health and disease: From molecular mechanisms to therapeutic target. MedComm (Beijing) 2022; 3:e150. [PMID: 35845350 PMCID: PMC9271889 DOI: 10.1002/mco2.150] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.
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Affiliation(s)
- Guang Lu
- Department of Physiology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yu Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yin Shi
- Department of BiochemistryZhejiang University School of MedicineHangzhouChina
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn ResearchSouthwest HospitalArmy Medical UniversityChongqingChina
| | - Chuang Wang
- Department of Pharmacology, Provincial Key Laboratory of PathophysiologyNingbo University School of MedicineNingboZhejiangChina
| | - Han‐Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision OncologyUniversity of MacauMacauChina
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He W, Gao Y, Zhou J, Shi Y, Xia D, Shen HM. Friend or Foe? Implication of the autophagy-lysosome pathway in SARS-CoV-2 infection and COVID-19. Int J Biol Sci 2022; 18:4690-4703. [PMID: 35874956 PMCID: PMC9305279 DOI: 10.7150/ijbs.72544] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/24/2022] [Indexed: 12/14/2022] Open
Abstract
There is increasing amount of evidence indicating the close interplays between the replication cycle of SARS-CoV-2 and the autophagy-lysosome pathway in the host cells. While autophagy machinery is known to either assist or inhibit the viral replication process, the reciprocal effects of the SARS-CoV-2 on the autophagy-lysosome pathway have also been increasingly appreciated. More importantly, despite the disappointing results from the clinical trials of chloroquine and hydroxychloroquine in treatment of COVID-19, there is still ongoing effort in discovering new therapeutics targeting the autophagy-lysosome pathway. In this review, we provide an update-to-date summary of the interplays between the autophagy-lysosome pathway in the host cells and the pathogen SARS-CoV-2 at the molecular level, to highlight the prognostic value of autophagy markers in COVID-19 patients and to discuss the potential of developing novel therapeutic strategies for COVID-19 by targeting the autophagy-lysosome pathway. Thus, understanding the nature of such interactions between SARS-CoV-2 and the autophagy-lysosome pathway in the host cells is expected to provide novel strategies in battling against this global pandemic.
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Affiliation(s)
- Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yuan Gao
- Faculty of Health Sciences, University of Macau, Macau, China
- Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Jing Zhou
- Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Yi Shi
- Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China
| | - Dajing Xia
- Department of Toxicology of School of Public Health, Department of Gynecologic Oncology of Women's Hospital; Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Han-Ming Shen
- Faculty of Health Sciences, University of Macau, Macau, China
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5
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Sunkak S, Argun M, Celik B, Tasci O, Ozturk AB, Inan DB, Dogan M. Effects of azithromycin on ventricular repolarization in children with COVID-19. Rev Port Cardiol 2022; 41:551-556. [PMID: 35221464 PMCID: PMC8858685 DOI: 10.1016/j.repc.2021.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/18/2021] [Indexed: 11/29/2022] Open
Abstract
Introduction Azithromycin is used to treat pediatric COVID-19 patients. It can also prolong the QT interval in adults. This study assessed the effects of azithromycin on ventricular repolarization in children with COVID-19. Method The study prospectively enrolled children with COVID-19 who received azithromycin between July and August 2020. An electrocardiogram was performed before, one, three, and five days post-treatment. Using ImageJ®, the following parameters were measured: QT max, QT min, Tp-e max, and Tp-e min. The parameters QTc max, QTc min, Tp-ec max, Tp-ec min, QTcd, Tp-ecd, and the QTc/Tp-ec ratio were calculated using Bazett's formula. Results The study included 105 pediatric patients (mean age 9.8±5.3 years). The pretreatment heart rate was higher than after treatment (before 92 [79–108]/min vs. Day 1 82 [69–108)]/min vs. Day 3 80 [68–92.2]/min vs. Day 5 81 [70–92]/min; p=0.05). Conclusion Azithromycin does not affect the ventricular repolarization parameters on ECG in pediatric COVID-19 cases.
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Khan MA, Bin Islam S, Rakib MU, Alam D, Hossen MM, Tania M, Asad A. Major Drugs Used in COVID-19 Treatment: Molecular Mechanisms, Validation
and Current Progress in Trials. CORONAVIRUSES 2022; 3. [DOI: 10.2174/2666796701999201204122819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/16/2020] [Accepted: 11/11/2020] [Indexed: 07/28/2024]
Abstract
Background:
Currently, the present world is facing a new deadly challenge against a pandemic disease called
COVID-19, which is caused by a coronavirus, named SARS-CoV-2. To date, there is no drug or vaccine that can treat
COVID-19 completely, but some drugs have been used primarily, and they are in different stages of clinical trials. This
review article discussed and compared those drugs which are running ahead in COVID-19 treatments.
Methods:
We have explored PUBMED, SCOPUS, WEB OF SCIENCE, as well as press release of WHO, NIH and FDA for
articles about COVID-19, and reviewed them.
Results:
Drugs like favipiravir, remdesivir, lopinavir/ritonavir, hydroxychloroquine, azithromycin, ivermectin,
corticosteroids and interferons have been found effective in some extents, and partially approved by FDA and WHO to treat
COVID-19 at different phases of pandemic. However, some of these drugs have been disapproved later, although clinical
trials are going on. In parallel, plasma therapy has been found fruitful in some extents too, and a number of vaccine trails are
going on.
Conclusions:
This review article discussed the epidemiologic and mechanistic characteristics of SARS-CoV-2, and how
drugs could act on this virus with the comparative discussion on progress and backwards of major drugs used till date,
which might be beneficial for choosing therapies against COVID-19 in different countries.
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Affiliation(s)
- Md. Asaduzzaman Khan
- The Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical
University, Luzhou, Sichuan 646000, China
| | - Shad Bin Islam
- Bachelor in Medicine and Surgery Program, Affiliated hospital of Southwest
Medical University, Luzhou, Sichuan 646000, China
| | - Mejbah Uddin Rakib
- Bachelor in Medicine and Surgery Program, Affiliated hospital of Southwest
Medical University, Luzhou, Sichuan 646000, China
| | - Didarul Alam
- Bachelor in Medicine and Surgery Program, Affiliated hospital of Southwest
Medical University, Luzhou, Sichuan 646000, China
| | - Md. Munnaf Hossen
- Department of Immunology, Health Science Center, Shenzhen,
University, Shenzhen, Guangdong 518060, China
| | - Mousumi Tania
- Division of Molecular Cancer, Red Green Research Center,
Dhaka, Bangladesh
| | - Asaduzzaman Asad
- Department of Biochemistry and Molecular Biology, Jahangirnagar University; and International
Center for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
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7
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Marro FC, Abad L, Blocker AJ, Laurent F, Josse J, Valour F. In vitro antibiotic activity against intraosteoblastic Staphylococcus aureus: a narrative review of the literature. J Antimicrob Chemother 2021; 76:3091-3102. [PMID: 34459881 PMCID: PMC8598303 DOI: 10.1093/jac/dkab301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Staphylococcus aureus – a major aetiological agent of bone and joint infection (BJI) – is associated with a high risk of relapse and chronicity, in part due to its ability to invade and persist in non-professional phagocytic bone cells such as osteoblasts. This intracellular reservoir protects S. aureus from the action of the immune system and most antibiotics. To date, the choice of antimicrobial strategies for BJI treatment mostly relies on standard susceptibility testing, bone penetration of antibiotics and their ‘antibiofilm’ activity. Despite the role of intracellular persistent S. aureus in the development of chronic infection, the ability of antibiotics to target the S. aureus intraosteoblastic reservoir is not considered in therapeutic choices but might represent a key determinant of treatment outcome. This review provides an overview of the intracellular pharmacokinetics of antistaphylococcal drugs used in the treatment of BJI and of their ability to target intraosteoblastic S. aureus. Thirteen studies focusing on the intraosteoblastic activity of antibiotics against S. aureus were reviewed, all relying on in vitro models of osteoblast infection. Despite varying incubation times, multiplicities of infection, bacterial strains, and the types of infected cell lines, rifamycins and fluoroquinolones remain the two most potent antimicrobial classes for intraosteoblastic S. aureus eradication, consistent with clinical data showing a superiority of this combination therapy in S. aureus orthopaedic device-related infections.
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Affiliation(s)
- Florian C Marro
- CIRI-Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France.,Evotec ID Lyon, In Vitro Biology, Infectious Diseases and Antibacterials Unit, Gerland, 69007 Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Lélia Abad
- CIRI-Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France.,Laboratoire de bactériologie, Institut des Agents Infectieux, French National Reference Center for Staphylococci, Hospices Civils de Lyon, Lyon, France
| | - Ariel J Blocker
- Evotec ID Lyon, In Vitro Biology, Infectious Diseases and Antibacterials Unit, Gerland, 69007 Lyon, France
| | - Frédéric Laurent
- CIRI-Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France.,Laboratoire de bactériologie, Institut des Agents Infectieux, French National Reference Center for Staphylococci, Hospices Civils de Lyon, Lyon, France.,Centre de Référence pour la prise en charge des Infections ostéo-articulaires complexes (CRIOAc) Lyon, Hospices Civils de Lyon, Lyon, France
| | - Jérôme Josse
- CIRI-Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France.,Centre de Référence pour la prise en charge des Infections ostéo-articulaires complexes (CRIOAc) Lyon, Hospices Civils de Lyon, Lyon, France
| | - Florent Valour
- CIRI-Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France.,Centre de Référence pour la prise en charge des Infections ostéo-articulaires complexes (CRIOAc) Lyon, Hospices Civils de Lyon, Lyon, France.,Service des maladies infectieuses et tropicales, Hospices Civils de Lyon, Lyon, France
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Biswas P, Hasan MM, Dey D, Dos Santos Costa AC, Polash SA, Bibi S, Ferdous N, Kaium MA, Rahman MDH, Jeet FK, Papadakos S, Islam K, Uddin MS. Candidate antiviral drugs for COVID-19 and their environmental implications: a comprehensive analysis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:59570-59593. [PMID: 34510341 PMCID: PMC8435122 DOI: 10.1007/s11356-021-16096-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/18/2021] [Indexed: 05/27/2023]
Abstract
Emerging from Wuhan, China, SARS-CoV-2 is the new global threat that killed millions of people, and many are still suffering. This pandemic has not only affected people but also caused economic crisis throughout the world. Researchers have shown good progress in revealing the molecular insights of SARS-CoV-2 pathogenesis and developing vaccines, but effective treatment against SARS-CoV-2-infected patients are yet to be found. Several vaccines are available and used in many countries, while many others are still in clinical or preclinical studies. However, this involves a long-term process, considering the safety procedures and requirements and their long-term protection capacity and in different age groups are still questionable. Therefore, at present, the drug repurposing of the existing therapeutics previously designed against other viral diseases seems to be the only practical approach to mitigate the current situation. The safety of most of these therapeutic agents has already been tested. Recent clinical reports revealed promising therapeutic efficiency of several drugs such as remdesivir, tenofovir disoproxil fumarate, azithromycin, lopinavir/ritonavir, chloroquine, baricitinib, and cepharanthine. Besides, plasma therapies were used to treat patients and prevent fatal outcomes. Thus, in this article, we have summarized the epidemiological and clinical data from several clinical trials conducted since the beginning of the pandemic, emphasizing the efficiency of the known agents against SARS-CoV-2 and their harmful side effects on the human body as well as their environmental implications. This review shows a clear overview of the current pharmaceutical perspective on COVID-19 treatment.
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Affiliation(s)
- Partha Biswas
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
| | - Mohammad Mehedi Hasan
- Department of Biochemistry and Molecular Biology, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail, 1902, Bangladesh
| | - Dipta Dey
- Department of Biochemistry and Molecular Biology, Faculty of Life Science, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | | | | | - Shabana Bibi
- Yunnan Herbal Laboratory, School of Ecology and Environmental Sciences, Yunnan University, Kunming, 650091, Yunnan, China
| | - Nadim Ferdous
- Department of Biotechnology and Genetic Engineering, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail, 1902, Bangladesh
| | - Md Abu Kaium
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh
| | - M D Hasanur Rahman
- Department of Biotechnology and Genetic Engineering, Faculty of Life Science, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
| | - Fardin Kamal Jeet
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh
| | - Stavros Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens (NKUA), Athens, Greece
| | - Khairul Islam
- Department of Biochemistry and Molecular Biology, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail, 1902, Bangladesh
| | - Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh.
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.
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9
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Seabra G, Ventura Mendes RF, Dos Santos Amorim LFV, Peregrino IV, Branquinha MH, Dos Santos ALS, Nunes APF. Azithromycin Use in COVID-19 Patients: Implications on the Antimicrobial Resistance. Curr Top Med Chem 2021; 21:677-683. [PMID: 34028347 DOI: 10.2174/156802662108210319145317] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Gabriela Seabra
- Laboratorio de Resistencia Bacteriana (RESBAC), Departamento de Microbiologia, Centro de Ciencias da Saude (CCS), Universidade Federal do Espirito Santo (UFES), Vitoria, Brazil
| | - Roberta Ferreira Ventura Mendes
- Laboratorio de Resistencia Bacteriana (RESBAC), Departamento de Microbiologia, Centro de Ciencias da Saude (CCS), Universidade Federal do Espirito Santo (UFES), Vitoria, Brazil
| | - Luiz Felipe Vieira Dos Santos Amorim
- Laboratorio de Resistencia Bacteriana (RESBAC), Departamento de Microbiologia, Centro de Ciencias da Saude (CCS), Universidade Federal do Espirito Santo (UFES), Vitoria, Brazil
| | - Ingrid Vianez Peregrino
- Laboratorio de Resistencia Bacteriana (RESBAC), Departamento de Microbiologia, Centro de Ciencias da Saude (CCS), Universidade Federal do Espirito Santo (UFES), Vitoria, Brazil
| | - Marta Helena Branquinha
- Laboratorio de Estudos Avancados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - André Luis Souza Dos Santos
- Laboratorio de Estudos Avancados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes (IMPG), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Ana Paula Ferreira Nunes
- Laboratorio de Resistencia Bacteriana (RESBAC), Departamento de Microbiologia, Centro de Ciencias da Saude (CCS), Universidade Federal do Espirito Santo (UFES), Vitoria, Brazil
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10
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Yacouba A, Olowo-Okere A, Yunusa I. Repurposing of antibiotics for clinical management of COVID-19: a narrative review. Ann Clin Microbiol Antimicrob 2021; 20:37. [PMID: 34020659 PMCID: PMC8139224 DOI: 10.1186/s12941-021-00444-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 05/11/2021] [Indexed: 12/22/2022] Open
Abstract
Background Drug repurposing otherwise known as drug repositioning or drug re-profiling is a time-tested approach in drug discovery through which new medical uses are being established for already known drugs. Antibiotics are among the pharmacological agents being investigated for potential anti-SARS-COV-2 activities. The antibiotics are used either to resolve bacterial infections co-existing with COVID-19 infections or exploitation of their potential antiviral activities. Herein, we aimed to review the various antibiotics that have been repositioned for the management of COVID-19. Methods This literature review was conducted from a methodical search on PubMed and Web of Science regarding antibiotics used in patients with COVID-19 up to July 5, 2020. Results Macrolide and specifically azithromycin is the most common antibiotic used in the clinical management of COVID-19. The other antibiotics used in COVID-19 includes teicoplanin, clarithromycin, doxycycline, tetracyclines, levofloxacin, moxifloxacin, ciprofloxacin, and cefuroxime. In patients with COVID-19, antibiotics are used for their immune-modulating, anti-inflammatory, and antiviral properties. The precise antiviral mechanism of most of these antibiotics has not been determined. Moreover, the use of some of these antibiotics against SARS-CoV-2 infection remains highly controversial and not widely accepted. Conclusion The heavy use of antibiotics during the COVID-19 pandemic would likely worsen antibiotic resistance crisis. Consequently, antibiotic stewardship should be strengthened in order to prevent the impacts of COVID-19 on the antibiotic resistance crisis.
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Affiliation(s)
- Abdourahamane Yacouba
- Faculté des Sciences de la Santé, Université Abdou Moumouni, P.M.B. 10896, Niamey, Niger.
| | - Ahmed Olowo-Okere
- Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, P.M.B. 2346, Sokoto, Nigeria
| | - Ismaeel Yunusa
- Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina College of Pharmacy, Columbia, SC, USA
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11
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Brief review on repurposed drugs and vaccines for possible treatment of COVID-19. Eur J Pharmacol 2021; 898:173977. [PMID: 33639193 PMCID: PMC7905377 DOI: 10.1016/j.ejphar.2021.173977] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/06/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic coronavirus disease 2019 (Covid-19) has claimed more than a million lives. Various in silico, in vitro, and in vivo studies are being conducted to understand the effect of SARS-CoV-2 on the cellular metabolism of humans and the various drugs and drug-targets that may be used. In this review, we discuss protein-protein interactions (PPIs) between viral and human proteins as well as viral targets like proteases. We try to understand the molecular mechanism of various repurposed antiviral drugs against SARS-CoV-2, their combination therapies, drug dosage regimens, and their adverse effects along with possible alternatives like non-toxic antiviral phytochemicals. Ultimately, randomized controlled trials are needed to identify which of these compounds has the required balance of efficacy and safety. We also focus on the recent advancements in diagnostic methods and vaccine candidates developed around the world to fight against Covid-19.
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12
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Galvez J, Zanni R, Galvez-Llompart M, Benlloch JM. Macrolides May Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Entry into Cells: A Quantitative Structure Activity Relationship Study and Experimental Validation. J Chem Inf Model 2021; 61:2016-2025. [PMID: 33734704 PMCID: PMC7986980 DOI: 10.1021/acs.jcim.0c01394] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Indexed: 02/07/2023]
Abstract
The global pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening the health and economic systems worldwide. Despite the enormous efforts of scientists and clinicians around the world, there is still no drug or vaccine available worldwide for the treatment and prevention of the infection. A rapid strategy for the identification of new treatments is based on repurposing existing clinically approved drugs that show antiviral activity against SARS-CoV-2 infection. In this study, after developing a quantitative structure activity relationship analysis based on molecular topology, several macrolide antibiotics are identified as promising SARS-CoV-2 spike protein inhibitors. To confirm the in silico results, the best candidates were tested against two human coronaviruses (i.e., 229E-GFP and SARS-CoV-2) in cell culture. Time-of-addition experiments and a surrogate model of viral cell entry were used to identify the steps in the virus life cycle inhibited by the compounds. Infection experiments demonstrated that azithromycin, clarithromycin, and lexithromycin reduce the intracellular accumulation of viral RNA and virus spread as well as prevent virus-induced cell death, by inhibiting the SARS-CoV-2 entry into cells. Even though the three macrolide antibiotics display a narrow antiviral activity window against SARS-CoV-2, it may be of interest to further investigate their effect on the viral spike protein and their potential in combination therapies for the coronavirus disease 19 early stage of infection.
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Affiliation(s)
- Jorge Galvez
- Molecular Topology and Drug Design
Unit, Department of Physical Chemistry, Universitat de
Valencia, Burjassot 46100,
Spain
| | - Riccardo Zanni
- Molecular Topology and Drug Design
Unit, Department of Physical Chemistry, Universitat de
Valencia, Burjassot 46100,
Spain
| | - Maria Galvez-Llompart
- Molecular Topology and Drug Design
Unit, Department of Physical Chemistry, Universitat de
Valencia, Burjassot 46100,
Spain
- Instituto de Tecnología
Química, UPV-CSIC, Universidad Politícnica
de Valencia, Valencia 46022,
Spain
| | - Jose Maria Benlloch
- Instituto de Instrumentación para
Imagen Molecular, Centro Mixto CSIC—Universitat
Politècnica de València, Valencia
46022, Spain
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13
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Oliver ME, Hinks TSC. Azithromycin in viral infections. Rev Med Virol 2021; 31:e2163. [PMID: 32969125 PMCID: PMC7536932 DOI: 10.1002/rmv.2163] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 12/18/2022]
Abstract
Azithromycin (AZM) is a synthetic macrolide antibiotic effective against a broad range of bacterial and mycobacterial infections. Due to an additional range of anti-viral and anti-inflammatory properties, it has been given to patients with the coronaviruses SARS-CoV or MERS-CoV. It is now being investigated as a potential candidate treatment for SARS-CoV-2 having been identified as a candidate therapeutic for this virus by both in vitro and in silico drug screens. To date there are no randomised trial data on its use in any novel coronavirus infection, although a large number of trials are currently in progress. In this review, we summarise data from in vitro, murine and human clinical studies on the anti-viral and anti-inflammatory properties of macrolides, particularly AZM. AZM reduces in vitro replication of several classes of viruses including rhinovirus, influenza A, Zika virus, Ebola, enteroviruses and coronaviruses, via several mechanisms. AZM enhances expression of anti-viral pattern recognition receptors and induction of anti-viral type I and III interferon responses. Of relevance to severe coronavirus-19 disease (COVID-19), which is characterised by an over-exuberant innate inflammatory response, AZM also has anti-inflammatory properties including suppression of IL-1beta, IL-2, TNF and GM-CSF. AZM inhibits T cells by inhibiting calcineurin signalling, mammalian target of rapamycin activity and NFκB activation. AZM particularly targets granulocytes where it concentrates markedly in lysosomes, particularly affecting accumulation, adhesion, degranulation and apoptosis of neutrophils. Given its proven safety, affordability and global availability, tempered by significant concerns about antimicrobial stewardship, there is an urgent mandate to perform well-designed and conducted randomised clinical trials.
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Affiliation(s)
| | - Timothy S. C. Hinks
- Nuffield Department of Medicine Experimental Medicine, Respiratory Medicine Unit and National Institute for Health Research (NIHR), Oxford Biomedical Research Centre (BRC)University of OxfordOxfordUK
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14
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Venditto VJ, Haydar D, Abdel-Latif A, Gensel JC, Anstead MI, Pitts MG, Creameans J, Kopper TJ, Peng C, Feola DJ. Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19. Front Immunol 2021; 12:574425. [PMID: 33643308 PMCID: PMC7906979 DOI: 10.3389/fimmu.2021.574425] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 01/22/2021] [Indexed: 12/14/2022] Open
Abstract
The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.
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Affiliation(s)
- Vincent J. Venditto
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United States
| | - Dalia Haydar
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Ahmed Abdel-Latif
- Gill Heart Institute and Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - John C. Gensel
- Department of Physiology, Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Michael I. Anstead
- Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Michelle G. Pitts
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United States
| | - Jarrod Creameans
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, United States
| | - Timothy J. Kopper
- Department of Physiology, Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Chi Peng
- Gill Heart Institute and Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - David J. Feola
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, United States
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15
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Firth A, Prathapan P. Broad-spectrum therapeutics: A new antimicrobial class. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2020; 2:100011. [PMID: 34870144 PMCID: PMC8035643 DOI: 10.1016/j.crphar.2020.100011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/30/2020] [Accepted: 12/03/2020] [Indexed: 01/29/2023] Open
Abstract
There are currently no emergency treatments for pandemics, yet drug repositioning has emerged as the foremost treatment development strategy for COVID-19, with an aim to identify successful antiviral therapeutics from safe, non-antiviral candidates. These therapeutics include antibiotics such as azithromycin and the antiparasitic nitazoxanide, both of which exhibit antiviral activity. Broad-spectrum therapeutics (BSTs) are a class of antimicrobials active against multiple pathogen types. Establishment of a developmental framework for BSTs will markedly improve global preparedness for future health emergencies.
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Affiliation(s)
- Anton Firth
- New Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Praveen Prathapan
- New Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
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16
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Firth A, Prathapan P. Azithromycin: The First Broad-spectrum Therapeutic. Eur J Med Chem 2020; 207:112739. [PMID: 32871342 PMCID: PMC7434625 DOI: 10.1016/j.ejmech.2020.112739] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/15/2022]
Abstract
The Strategic Plan for Biodefense Research by the U.S. Department of Health and Human Services demarcates the need for drugs which target multiple types of pathogens to prepare for infectious threats. Azithromycin is one such broad-spectrum therapeutic that is both included in the University of Oxford's RECOVERY and excluded from the World Health Organization's SOLIDARITY trials. Here we review azithromycin's broad antibiotic, antimalarial, antiviral pharmacology and contextualise it against a broader history as the most repositioned therapeutic of the macrolide class; we further evaluate azithromycin's clinical and socio-economic propriety for respiratory pandemics and delineate a model for its combinatorial mechanism of action against COVID-19 pneumonia.
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Affiliation(s)
| | - Praveen Prathapan
- New Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
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17
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Carrière F, Longhi S, Record M. The endosomal lipid bis(monoacylglycero) phosphate as a potential key player in the mechanism of action of chloroquine against SARS-COV-2 and other enveloped viruses hijacking the endocytic pathway. Biochimie 2020; 179:237-246. [PMID: 32485205 PMCID: PMC7261073 DOI: 10.1016/j.biochi.2020.05.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023]
Abstract
The anti-malarial drug Chloroquine (CQ) and its derivative hydroxychloroquine have shown antiviral activities in vitro against many viruses, including coronaviruses, dengue virus and the biosafety level 4 Nipah and Hendra paramyxoviruses. The in vivo efficacy of CQ in the treatment of COVID-19 is currently a matter of debate. CQ is a lysosomotrophic compound that accumulates in lysosomes, as well as in food vacuoles of Plasmodium falciparum. In the treatment of malaria, CQ impairs the digestion and growth of the parasite by increasing the pH of the food vacuole. Similarly, it is assumed that the antiviral effects of CQ results from the increase of lysosome pH and the inhibition of acidic proteases involved in the maturation of virus fusion protein. CQ has however other effects, among which phospholipidosis, characterized by the accumulation of multivesicular bodies within the cell. The increase in phospholipid species particularly concerns bis(monoacylglycero)phosphate (BMP), a specific lipid of late endosomes involved in vesicular trafficking and pH-dependent vesicle budding. It was shown previously that drugs like progesterone, the cationic amphiphile U18666A and the phospholipase inhibitor methyl arachidonyl fluoro phosphonate (MAFP) induce the accumulation of BMP in THP-1 cells and decrease cell infection by human immunodeficiency virus. HIV viral particles were found to be retained into large endosomal-type vesicles, preventing virus spreading. Since BMP was also reported to favour virus entry through hijacking of the endocytic pathway, we propose here that BMP could play a dual role in viral infection, with its antiviral effects triggered by lysosomotropic drugs like CQ.
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Affiliation(s)
- Frédéric Carrière
- Aix Marseille Univ, CNRS, BIP, UMR7281, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 9, France.
| | - Sonia Longhi
- Aix Marseille Univ, CNRS, AFMB, UMR7257, 163 Avenue de Luminy, 13288, Marseille cedex 09, France
| | - Michel Record
- UMR INSERM 1037-CRCT (Cancer Research Center of Toulouse), University of Toulouse III Paul Sabatier, Team "Cholesterol Metabolism and Therapeutic Innovations,", 2 Avenue Hubert Curien, 31037, Toulouse cedex 1, France.
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18
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Alkotaji M. Azithromycin and ambroxol as potential pharmacotherapy for SARS-CoV-2. Int J Antimicrob Agents 2020; 56:106192. [PMID: 33045350 PMCID: PMC7546948 DOI: 10.1016/j.ijantimicag.2020.106192] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/10/2020] [Accepted: 09/26/2020] [Indexed: 12/23/2022]
Abstract
Knowing the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind to the angiotensin-converting enzyme 2 (ACE2) receptor and to enter cells via endocytosis paved the way for repositioning of old drugs as potential treatment of COVID-19, the disease caused by SARS-CoV-2 infection. This paper highlights the potential of azithromycin and ambroxol to treat COVID-19. Azithromycin and ambroxol share lysosomotropic characteristics, i.e. they penetrate and accumulate inside the late endosomes and lysosomes and may possibly interfere with multiplication of the virus inside cells. In addition, both of these drugs have anti-inflammatory effects. Ambroxol has a proven antiviral effect and a unique stimulatory action on the secretion of surfactant by alveolar type II cells, the main target of SARS-CoV-2. Surfactant may form a fundamental defence mechanism against the virus. Involvement of nasal epithelial cells in SARS-CoV-2 entry suggested advantageous use of inhaled drug delivery of these two drugs over the use of systemic administration. Inhaled drug delivery could aid in targeting the drug to the exact site of action with little or no side effects. To conclude, administration of these two drugs using a special drug delivery system provides two kinds of drug targeting: (i) tissue targeting through using an inhaled drug delivery system to achieve high drug concentrations at the respiratory epithelial tissue that overexpress the ACE2 receptor for virus binding; and (ii) cellular targeting of the virus in the acidic vesicles (late endosomes and lysosomes), which represent the fate of endocytic viruses.
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Affiliation(s)
- Myasar Alkotaji
- Department of Pharmaceutics, College of Pharmacy, University of Mosul, Mosul, Iraq.
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19
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Echeverría-Esnal D, Martin-Ontiyuelo C, Navarrete-Rouco ME, De-Antonio Cuscó M, Ferrández O, Horcajada JP, Grau S. Azithromycin in the treatment of COVID-19: a review. Expert Rev Anti Infect Ther 2020; 19:147-163. [DOI: 10.1080/14787210.2020.1813024] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Daniel Echeverría-Esnal
- Service of Pharmacy, Hospital Del Mar, Hospital Del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital Del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
| | | | - María Eugenia Navarrete-Rouco
- Service of Pharmacy, Hospital Del Mar, Hospital Del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital Del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Marta De-Antonio Cuscó
- Service of Pharmacy, Hospital Del Mar, Hospital Del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital Del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Olivia Ferrández
- Service of Pharmacy, Hospital Del Mar, Hospital Del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital Del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Juan Pablo Horcajada
- Service of Infectious Diseases, Hospital Del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital Del Mar d’Investigacions Mèdiques (IMIM), Spain
- Department of Pharmacy, Universitat Autònoma De Barcelona, Barcelona, Spain
| | - Santiago Grau
- Service of Pharmacy, Hospital Del Mar, Hospital Del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital Del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain
- Department of Pharmacy, Universitat Autònoma De Barcelona, Barcelona, Spain
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20
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Taştemur Ş, Ataseven H. Is it possible to use Proton Pump Inhibitors in COVID-19 treatment and prophylaxis? Med Hypotheses 2020; 143:110018. [PMID: 32679422 PMCID: PMC7834647 DOI: 10.1016/j.mehy.2020.110018] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022]
Abstract
Coronaviruses (CoV), discovered after 1960, caused human life-threatening outbreaks. SARS-CoV2, which appeared in Wuhan, China in December 2019, causing Severe Acute Respiratory Syndrome and has different features than other coronaviruses, has been determined and the disease caused by the virus has been called "Coronavirus Disease-2019" (COVID-19). This disease activates both the natural and acquired immune system. The cytokin storm, in which blood levels of proinflammatory cytokines are detected excessively high is developing and the uncontrolled inflammatory response causes local and systemic tissue damages. Although a spesific drug has not been found yet, the medications currently in use for other indications, whose pharmacokinetic- pharmacodynamic properties and toxic doses are already known; are included in the treatment practice of COVID-19. These drugs affect the entry of the virus into the cell and its intracellular distribution. They also have anti-inflammatory and immunomodulating effects too. Therefore, we think that Proton Pump Inhibitors (PPI's) with similar mechanisms of action may also be involved in COVID-19 treatment and prophylaxis.
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Affiliation(s)
- Şeyma Taştemur
- Department of Internal Medicine, Sivas Numune Hospital, Sivas, Turkey.
| | - Hilmi Ataseven
- Department of Internal Medicine, Discipline of Gastroenterology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey.
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21
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Di Franco S, Alfieri A, Petrou S, Damiani G, Passavanti MB, Pace MC, Leone S, Fiore M. Current status of COVID-19 treatment: An opinion review. World J Virol 2020; 9:27-37. [PMID: 33024717 PMCID: PMC7520874 DOI: 10.5501/wjv.v9.i3.27] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/07/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has garnered the attention of scientists worldwide in the search for an effective treatment while also focusing on vaccine development. Several drugs have been used for the management of coronavirus disease 2019 (COVID-19), which has affected many hospitals and health centers worldwide. Statistically significant results are lacking on the effectiveness of the experimented drugs in reducing COVID-19 morbidity or mortality, as there are very few published randomized clinical trials. Despite this, the literature offers some material for study and reflection. This opinion review attempts to address three burning questions on COVID-19 treatment options. (1) What kind of studies are currently published or ongoing in the treatment of patients with COVID-19? (2) What drugs are currently described in the literature as options of treatment for patients affected by the infection? And (3) Are there specific clinical manifestations related to COVID-19 that can be treated with a customized and targeted therapy? By answering these questions, we wish to create a summary of current COVID-19 treatments and the anti-COVID-19 treatments proposed in the recent clinical trials developed in the last 3 mo, and to describe examples of clinical manifestations of the SARS-CoV-2 infection with a cause-related treatment.
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Affiliation(s)
- Sveva Di Franco
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Aniello Alfieri
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Stephen Petrou
- Department of Emergency Medicine, Good Samaritan Hospital Medical Center, New York, NY 11795, United States
| | - Giovanni Damiani
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan 20122, Italy
- Clinical Dermatology, IRCCS Instituto Ortopedico Galeazzi, Milan 20122, Italy
| | - Maria Beatrice Passavanti
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Maria Caterina Pace
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Sebastiano Leone
- Division of Infectious Diseases, “San Giuseppe Moscati” Hospital, Avellino 83100, Italy
| | - Marco Fiore
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
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22
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Pandey A, Nikam AN, Shreya AB, Mutalik SP, Gopalan D, Kulkarni S, Padya BS, Fernandes G, Mutalik S, Prassl R. Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements. Life Sci 2020; 256:117883. [PMID: 32497632 PMCID: PMC7263255 DOI: 10.1016/j.lfs.2020.117883] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/27/2020] [Accepted: 05/28/2020] [Indexed: 12/31/2022]
Abstract
The present pandemic of SARS-CoV-2 has been a tough task for the whole world to deal with. With the absence of specific drugs or vaccines against SARS-CoV-2, the situation is very difficult to control. Apart from the absence of specific therapies, the lack of knowledge about potential therapeutic targets and individual perception is adding to the complications. The present review describes the novel SARS-CoV-2 structure, surface proteins, asymptomatic and symptomatic transmission in addition to the genotype and phenotype of SARS-CoV-2 along with genetic strains and similarity between SARS, MERS and SARS-CoV-2. Therapeutic strategies such as inhibition of the endocytic pathway and suppressing RNA polymerase activity by metal ions, which could be quite beneficial for controlling COVID-19, are outlined. The drug repurposing for SARS-CoV-2 is discussed in detail along with therapeutic classes such as antivirals, antibiotics, and amino quinolones and their probable role in suppressing SARS-CoV-2 with reference to case studies. The ongoing clinical trials both with respect to drug repurposing and vaccines are summarized along with a brief description. The recent advancements and future perspective of ongoing research for therapy and detection of SARS-CoV-2 are provided. The review, in brief, summarizes epidemiology, therapy and the current scenario for combating SARS-CoV-2.
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Affiliation(s)
- Abhjieet Pandey
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India; Gottfried Schatz Research Centre for Cell Signalling, Metabolism and Aging, Medical University of Graz, Graz, Austria
| | - Ajinkya Nitin Nikam
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India
| | - Ajjappla Basavaraj Shreya
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India
| | - Sadhana P Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India
| | - Divya Gopalan
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India
| | - Sanjay Kulkarni
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India
| | - Bharath Singh Padya
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India
| | - Gasper Fernandes
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576106, Karnataka State, India.
| | - Ruth Prassl
- Gottfried Schatz Research Centre for Cell Signalling, Metabolism and Aging, Medical University of Graz, Graz, Austria..
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Lane TR, Massey C, Comer JE, Freiberg AN, Zhou H, Dyall J, Holbrook MR, Anantpadma M, Davey RA, Madrid PB, Ekins S. Pyronaridine tetraphosphate efficacy against Ebola virus infection in guinea pig. Antiviral Res 2020; 181:104863. [PMID: 32682926 PMCID: PMC8194506 DOI: 10.1016/j.antiviral.2020.104863] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/15/2020] [Accepted: 06/16/2020] [Indexed: 12/22/2022]
Abstract
The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 μM against three strains of EBOV and IC50 range of 1.01-2.72 μM against two strains of Marburg virus (MARV)) which is an approved drug in the European Union and used in combination with artesunate. To date, no small molecule drugs have shown statistically significant efficacy in the guinea pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs directed us to a single 300 mg/kg or 600 mg/kg oral dose of pyronaridine 1hr after infection. Pyronaridine resulted in statistically significant survival of 40% at 300 mg/kg and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 mg/kg dosed once a day) had 43.5% survival. All animals in the vehicle treatment group succumbed to disease by study day 12 (100% mortality). The in vitro metabolism and metabolite identification of pyronaridine and another of our EBOV active molecules, tilorone, suggested significant species differences which may account for the efficacy or lack thereof, respectively in guinea pig. In summary, our studies with pyronaridine demonstrates its utility for repurposing as an antiviral against EBOV and MARV.
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Affiliation(s)
- Thomas R. Lane
- Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA
| | - Christopher Massey
- Institutional Office of Regulated Nonclinical Studies, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Jason E. Comer
- Institutional Office of Regulated Nonclinical Studies, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Alexander N. Freiberg
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
- Department of Pathology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
| | - Huanying Zhou
- Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Julie Dyall
- Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Michael R. Holbrook
- Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Manu Anantpadma
- Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Robert A. Davey
- Texas Biomedical Research Institute, San Antonio, TX 78227, USA
| | - Peter B. Madrid
- SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA
| | - Sean Ekins
- Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA
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Kruger D, Prathapan P. Azithromycin: The First Broad-spectrum Therapeutic. J Transl Autoimmun 2020:100062. [PMID: 32839756 PMCID: PMC7439010 DOI: 10.1016/j.jtauto.2020.100062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/01/2020] [Accepted: 08/05/2020] [Indexed: 01/03/2023] Open
Abstract
The Strategic Plan for Biodefense Research by the U.S. Department of Health and Human Services demarcates the need for drugs which target multiple types of pathogens to prepare for infectious threats. Azithromycin is one such broad-spectrum therapeutic that is both included in the University of Oxford's RECOVERY and excluded from the World Health Organization's SOLIDARITY trials. Here we review azithromycin's broad antibiotic, antimalarial, antiviral pharmacology and contextualise it against a broader history as the most disease-repositioned therapeutic of the macrolide class; we further evaluate azithromycin's clinical and socio-economic propriety for respiratory pandemics and delineate a model for its combinatorial mechanism of action against COVID-19 pneumonia.
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Affiliation(s)
- Donna Kruger
- New Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Praveen Prathapan
- New Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
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Saber-Ayad M, Saleh MA, Abu-Gharbieh E. The Rationale for Potential Pharmacotherapy of COVID-19. Pharmaceuticals (Basel) 2020; 13:E96. [PMID: 32423024 PMCID: PMC7281404 DOI: 10.3390/ph13050096] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022] Open
Abstract
On 11 March 2020, the coronavirus disease (COVID-19) was defined by the World Health Organization as a pandemic. Severe acute respiratory syndrome-2 (SARS-CoV-2) is the newly evolving human coronavirus infection that causes COVID-19, and it first appeared in Wuhan, China in December 2019 and spread rapidly all over the world. COVID-19 is being increasingly investigated through virology, epidemiology, and clinical management strategies. There is currently no established consensus on the standard of care in the pharmacological treatment of COVID-19 patients. However, certain medications suggested for other diseases have been shown to be potentially effective for treating this infection, though there has yet to be clear evidence. Therapies include new agents that are currently tested in several clinical trials, in addition to other medications that have been repurposed as antiviral and immune-modulating therapies. Previous high-morbidity human coronavirus epidemics such as the 2003 SARS-CoV and the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) prompted the identification of compounds that could theoretically be active against the emerging coronavirus SARS-CoV-2. Moreover, advances in molecular biology techniques and computational analysis have allowed for the better recognition of the virus structure and the quicker screening of chemical libraries to suggest potential therapies. This review aims to summarize rationalized pharmacotherapy considerations in COVID-19 patients in order to serve as a tool for health care professionals at the forefront of clinical care during this pandemic. All the reviewed therapies require either additional drug development or randomized large-scale clinical trials to be justified for clinical use.
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Affiliation(s)
- Maha Saber-Ayad
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE; (M.A.S.); (E.A.-G.)
- College of Medicine, Cairo University, Cairo 12613, Egypt
| | - Mohamed A. Saleh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE; (M.A.S.); (E.A.-G.)
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Eman Abu-Gharbieh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE; (M.A.S.); (E.A.-G.)
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Damle B, Vourvahis M, Wang E, Leaney J, Corrigan B. Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19. Clin Pharmacol Ther 2020; 108:201-211. [PMID: 32302411 PMCID: PMC7262099 DOI: 10.1002/cpt.1857] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 04/15/2020] [Indexed: 12/19/2022]
Abstract
Azithromycin (AZ) is a broad-spectrum macrolide antibiotic with a long half-life and a large volume of distribution. It is primarily used for the treatment of respiratory, enteric, and genitourinary bacterial infections. AZ is not approved for the treatment of viral infections, and there is no well-controlled, prospective, randomized clinical evidence to support AZ therapy in coronavirus disease 2019 (COVID-19). Nevertheless, there are anecdotal reports that some hospitals have begun to include AZ in combination with hydroxychloroquine or chloroquine (CQ) for treatment of COVID-19. It is essential that the clinical pharmacology (CP) characteristics of AZ be considered in planning and conducting clinical trials of AZ alone or in combination with other agents, to ensure safe study conduct and to increase the probability of achieving definitive answers regarding efficacy of AZ in the treatment of COVID-19. The safety profile of AZ used as an antibacterial agent is well established.1 This work assesses published in vitro and clinical evidence for AZ as an agent with antiviral properties. It also provides basic CP information relevant for planning and initiating COVID-19 clinical studies with AZ, summarizes safety data from healthy volunteer studies, and safety and efficacy data from phase II and phase II/III studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of AZ and CQ in combination. This paper may also serve to facilitate the consideration and use of a priori-defined control groups for future research.
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Affiliation(s)
- Bharat Damle
- Pfizer Global Research and Development, New York, New York, USA
| | | | - Erjian Wang
- Pfizer Global Research and Development, San Diego, California, USA
| | - Joanne Leaney
- Pfizer Global Research and Development, Sandwich, Kent, UK
| | - Brian Corrigan
- Pfizer Global Research and Development, Groton, Connecticut, USA
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Derendorf H. Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin. Int J Antimicrob Agents 2020; 55:106007. [PMID: 32389720 PMCID: PMC7204663 DOI: 10.1016/j.ijantimicag.2020.106007] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 02/08/2023]
Abstract
A recent report identified significant reductions or disappearance of viral load in COVID-19 patients given a combination of hydroxychloroquine and azithromycin. The present communication discusses some common pharmacokinetic properties of these two drugs that may be linked to a potential underlying mechanism of action for these antiviral effects. The physicochemical properties of both hydroxychloroquine and azithromycin are consistent with particularly high affinity for the intracellular lysosomal space, which has been implicated as a target site for antiviral activity. The properties of both drugs predict dramatic accumulation in lysosomes, with calculated lysosomal drug concentrations that exceed cytosolic and extracellular concentrations by more than 50 000-fold. These predictions are consistent with previously reported experimentally measured cellular and extracellular concentrations of azithromycin. This is also reflected in the very large volumes of distribution of these drugs, which are among the highest of all drugs currently in use. The combination of hydroxychloroquine and azithromycin produces very high local concentrations in lysosomes. The clinical significance of this observation is unclear; however, the magnitude of this mechanism of drug accumulation via ion-trapping in lysosomes could be an important factor for the pharmacodynamic effects of this drug combination.
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Nowroozi F, Dadashzadeh S, Soleimanjahi H, Haeri A, Shahhosseini S, Javidi J, Karimi H. Theranostic niosomes for direct intratumoral injection: marked enhancement in tumor retention and anticancer efficacy. Nanomedicine (Lond) 2018; 13:2201-2219. [PMID: 29993311 DOI: 10.2217/nnm-2018-0091] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
AIM For simultaneous bioimaging and drug delivery via direct intratumoral injection, doxorubicin and Ag2S quantum dots co-loaded multifunctional niosomes were prepared and fully characterized. MATERIALS & METHODS Various theranostic niosomes were prepared and investigated regarding cytotoxicity, in vivo imaging, drug accumulation in breast cancer tumor and antitumor activity. RESULTS Niosomes composed of Tween-60, Tween-80 or Span 60 produced strong and more durable detectable fluorescence signals. Despite a higher accumulation of Tween-60 niosomes in tumor, the Span 60 formulation showed the highest antitumor efficacy when compared with the free drug (71.7 and 20.3% inhibition in tumor growth, respectively). CONCLUSION Direct intratumoral injection of theranostic niosomes with appropriate composition could be a powerful tool for combined multimodal imaging and therapy.
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Affiliation(s)
- Fatemeh Nowroozi
- Department of Pharmaceutics, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, 14115-6153, Iran
| | - Simin Dadashzadeh
- Department of Pharmaceutics, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, 14115-6153, Iran.,Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, 14155-6153, Iran
| | - Hoorieh Soleimanjahi
- Department of Virology, Faculty of Medical Sciences Tarbiat Modares University Tehran, 331-14115, Iran
| | - Azadeh Haeri
- Department of Pharmaceutics, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, 14115-6153, Iran
| | - Soraya Shahhosseini
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, 14155-6153, Iran
| | - Jaber Javidi
- Department of Pharmaceutics, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, 14115-6153, Iran
| | - Hesam Karimi
- Department of Virology, Faculty of Medical Sciences Tarbiat Modares University Tehran, 331-14115, Iran
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Tyteca D, Nishino T, Debaix H, Van Der Smissen P, N'Kuli F, Hoffmann D, Cnops Y, Rabolli V, van Loo G, Beyaert R, Huaux F, Devuyst O, Courtoy PJ. Regulation of macrophage motility by the water channel aquaporin-1: crucial role of M0/M2 phenotype switch. PLoS One 2015; 10:e0117398. [PMID: 25719758 PMCID: PMC4342038 DOI: 10.1371/journal.pone.0117398] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 12/22/2014] [Indexed: 12/21/2022] Open
Abstract
The water channel aquaporin-1 (AQP1) promotes migration of many cell types. Although AQP1 is expressed in macrophages, its potential role in macrophage motility, particularly in relation with phenotype polarization, remains unknown. We here addressed these issues in peritoneal macrophages isolated from AQP1-deficient mice, either undifferentiated (M0) or stimulated with LPS to orientate towards pro-inflammatory phenotype (classical macrophage activation; M1). In non-stimulated macrophages, ablation of AQP1 (like inhibition by HgCl2) increased by 2-3 fold spontaneous migration in a Src/PI3K/Rac-dependent manner. This correlated with cell elongation and formation of lamellipodia/ruffles, resulting in membrane lipid and F4/80 recruitment to the leading edge. This indicated that AQP1 normally suppresses migration of resting macrophages, as opposed to other cell types. Resting Aqp1-/- macrophages exhibited CD206 redistribution into ruffles and increased arginase activity like IL4/IL13 (alternative macrophage activation; M2), indicating a M0-M2 shift. In contrast, upon M1 orientation by LPS in vitro or peritoneal inflammation in vivo, migration of Aqp1-/- macrophages was reduced. Taken together, these data indicate that AQP1 oppositely regulates macrophage migration, depending on stimulation or not by LPS, and that macrophage phenotypic and migratory changes may be regulated independently of external cues.
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Affiliation(s)
- Donatienne Tyteca
- CELL Unit, de Duve Institute (DDUV), Université catholique de Louvain, Brussels, Belgium
| | - Tomoya Nishino
- Pôle de Néphrologie (NEFR), Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain, Brussels, Belgium
- Division of Nephrology, Nagasaki University, Nagasaki, Japan
| | - Huguette Debaix
- Pôle de Néphrologie (NEFR), Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain, Brussels, Belgium
| | | | - Francisca N'Kuli
- CELL Unit, de Duve Institute (DDUV), Université catholique de Louvain, Brussels, Belgium
| | - Delia Hoffmann
- CELL Unit, de Duve Institute (DDUV), Université catholique de Louvain, Brussels, Belgium
| | - Yvette Cnops
- Pôle de Néphrologie (NEFR), Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain, Brussels, Belgium
| | - Virginie Rabolli
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain, Brussels, Belgium
| | - Geert van Loo
- Inflammation Research Center, VIB, Department of Biomedical Molecular Biology, University of Ghent, Ghent, Belgium
| | - Rudi Beyaert
- Inflammation Research Center, VIB, Department of Biomedical Molecular Biology, University of Ghent, Ghent, Belgium
| | - François Huaux
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain, Brussels, Belgium
| | - Olivier Devuyst
- Pôle de Néphrologie (NEFR), Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain, Brussels, Belgium
| | - Pierre J. Courtoy
- CELL Unit, de Duve Institute (DDUV), Université catholique de Louvain, Brussels, Belgium
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Relationship between azithromycin susceptibility and administration efficacy for nontypeable Haemophilus influenzae respiratory infection. Antimicrob Agents Chemother 2015; 59:2700-12. [PMID: 25712355 DOI: 10.1128/aac.04447-14] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 02/14/2015] [Indexed: 12/21/2022] Open
Abstract
Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.
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Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther 2014; 143:225-45. [PMID: 24631273 DOI: 10.1016/j.pharmthera.2014.03.003] [Citation(s) in RCA: 406] [Impact Index Per Article: 36.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 03/04/2014] [Indexed: 01/02/2023]
Abstract
Azithromycin is a macrolide antibiotic which inhibits bacterial protein synthesis, quorum-sensing and reduces the formation of biofilm. Accumulating effectively in cells, particularly phagocytes, it is delivered in high concentrations to sites of infection, as reflected in rapid plasma clearance and extensive tissue distribution. Azithromycin is indicated for respiratory, urogenital, dermal and other bacterial infections, and exerts immunomodulatory effects in chronic inflammatory disorders, including diffuse panbronchiolitis, post-transplant bronchiolitis and rosacea. Modulation of host responses facilitates its long-term therapeutic benefit in cystic fibrosis, non-cystic fibrosis bronchiectasis, exacerbations of chronic obstructive pulmonary disease (COPD) and non-eosinophilic asthma. Initial, stimulatory effects of azithromycin on immune and epithelial cells, involving interactions with phospholipids and Erk1/2, are followed by later modulation of transcription factors AP-1, NFκB, inflammatory cytokine and mucin release. Delayed inhibitory effects on cell function and high lysosomal accumulation accompany disruption of protein and intracellular lipid transport, regulation of surface receptor expression, of macrophage phenotype and autophagy. These later changes underlie many immunomodulatory effects of azithromycin, contributing to resolution of acute infections and reduction of exacerbations in chronic airway diseases. A sub-group of post-transplant bronchiolitis patients appears to be sensitive to azithromycin, as may be patients with severe sepsis. Other promising indications include chronic prostatitis and periodontitis, but weak activity in malaria is unlikely to prove crucial. Long-term administration of azithromycin must be balanced against the potential for increased bacterial resistance. Azithromycin has a very good record of safety, but recent reports indicate rare cases of cardiac torsades des pointes in patients at risk.
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Affiliation(s)
- Michael J Parnham
- Fraunhofer Institute for Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology, Frankfurt am Main, Germany; Institute of Pharmacology for Life Scientists, Goethe University Frankfurt, Frankfurt am Main, Germany; Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt am Main, Germany.
| | | | - Evangelos J Giamarellos-Bourboulis
- 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
| | - Gianpaolo Perletti
- Biomedical Research Division, Department of Theoretical and Applied Sciences, University of Insubria, Busto A., Varese, Italy; Department of Basic Medical Sciences, Ghent University, Ghent, Belgium.
| | - Geert M Verleden
- Respiratory Division, Lung Transplantation Unit, University Hospitals Leuven and Department of Clinical and Experimental Medicine, KU Leuven, Belgium.
| | - Robin Vos
- Respiratory Division, Lung Transplantation Unit, University Hospitals Leuven and Department of Clinical and Experimental Medicine, KU Leuven, Belgium.
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Study of macrophage functions in murine J774 cells and human activated THP-1 cells exposed to oritavancin, a lipoglycopeptide with high cellular accumulation. Antimicrob Agents Chemother 2014; 58:2059-66. [PMID: 24449768 DOI: 10.1128/aac.02475-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Oritavancin, a lipoglycopeptide antibiotic in development, accumulates to high levels in the lysosomes of eukaryotic cells. We examined specific functions of macrophages (phagocytic capacity, lysosomal integrity, metabolic activity, and production of reactive oxygen species [ROS]) in correlation with the cellular accumulation of the drug, using J774 mouse macrophages and THP-1 human monocytes differentiated into macrophages using phorbol 12-myristate 13-acetate. Oritavancin did not affect Pseudomonas aeruginosa phagocytosis, lysosomal integrity, or metabolic activity in cells incubated for 3 h with extracellular concentrations ranging from 5 to 50 μg/ml. At extracellular concentrations of ≥25 μg/ml, oritavancin reduced latex bead phagocytosis by approximately 50% and doubled ROS production in J774 macrophages only. This may result from the fact that the cellular accumulation of oritavancin was 15 times higher in J774 cells than in activated THP-1 cells at 3 h. Human pharmacokinetic studies estimate that the concentration of oritavancin in alveolar macrophages could reach approximately 560 μg/ml after administration of a cumulative dose of 4 g, which is below the cellular concentration needed in the present study to impair latex bead phagocytosis (1,180 μg/ml) or to stimulate ROS production (15,000 μg/ml) by J774 cells. The data, therefore, suggest that, in spite of its substantial cellular accumulation, oritavancin is unlikely to markedly affect macrophage functions under the conditions of use investigated in current phase III trials (a single dose of 1,200 mg).
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Carpentier S, N'Kuli F, Grieco G, Van Der Smissen P, Janssens V, Emonard H, Bilanges B, Vanhaesebroeck B, Gaide Chevronnay HP, Pierreux CE, Tyteca D, Courtoy PJ. Class III phosphoinositide 3-kinase/VPS34 and dynamin are critical for apical endocytic recycling. Traffic 2013; 14:933-48. [PMID: 23621784 DOI: 10.1111/tra.12079] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 04/23/2013] [Accepted: 04/26/2013] [Indexed: 12/27/2022]
Abstract
Recycling is a limiting step for receptor-mediated endocytosis. We first report three in vitro or in vivo evidences that class III PI3K/VPS34 is the key PI3K isoform regulating apical recycling. A substractive approach, comparing in Opossum Kidney (OK) cells a pan-class I/II/III PI3K inhibitor (LY294002) with a class I/II PI3K inhibitor (ZSTK474), suggested that class III PI3K/VPS34 inhibition induced selective apical endosome swelling and sequestration of the endocytic receptor, megalin/LRP-2, causing surface down-regulation. GFP-(FYVE)x2 overexpression to sequester PI(3)P caused undistinguishable apical endosome swelling. In mouse kidney proximal tubular cells, conditional Vps34 inactivation also led to vacuolation and intracellular megalin redistribution. We next report that removal of LY294002 from LY294002-treated OK cells induced a spectacular burst of recycling tubules and restoration of megalin surface pool. Acute triggering of recycling tubules revealed recruitment of dynamin-GFP and dependence of dynamin-GTPase, guidance directionality by microtubules, and suggested that a microfilamentous net constrained endosomal swelling. We conclude that (i) besides its role in endosome fusion, PI3K-III is essential for endosome fission/recycling; and (ii) besides its role in endocytic entry, dynamin also supports tubulation of recycling endosomes. The unleashing of recycling upon acute reversal of PI3K inhibition may help study its dynamics and associated machineries.
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Affiliation(s)
- Sarah Carpentier
- CELL Unit, Université catholique de Louvain & de Duve Institute, Brussels, Belgium
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Anti-inflammatory mechanism of action of azithromycin in LPS-stimulated J774A.1 cells. Pharmacol Res 2012; 66:357-62. [DOI: 10.1016/j.phrs.2012.06.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 06/20/2012] [Accepted: 06/20/2012] [Indexed: 11/24/2022]
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Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype. Cell Immunol 2012; 279:78-86. [PMID: 23099154 DOI: 10.1016/j.cellimm.2012.09.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 09/11/2012] [Accepted: 09/12/2012] [Indexed: 11/23/2022]
Abstract
Azithromycin and chloroquine have been shown to exhibit anti-inflammatory activities in a number of cellular systems, but the mechanisms of these activities have still not been clarified unequivocally. Since both drugs are cationic, accumulate in acidic cellular compartments and bind to phospholipids with a consequent increase in lysosomal pH and induce phospholipidosis, we examined the relevance of these common properties to their anti-inflammatory activities. We compared also these effects with effects of concanamycin A, compound which inhibits acidification of lysosomes. All three compounds increased lysosomal pH, accumulation of autophagic vacuoles and ubiquitinated proteins and impaired recycling of TLR4 receptor with consequences in downstream signaling in LPS-stimulated J774A.1 cells. Azithromycin and chloroquine additionally inhibited arachidonic acid release and prostaglandin E2 synthesis. Therefore, impairment of lysosomal functions by azithromycin and chloroquine deregulate TLR4 recycling and signaling and phospholipases activation and lead to anti-inflammatory phenotype in LPS-stimulated J774A.1 cells.
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Persson HL, Vainikka LK, Sege M, Wennerström U, Dam-Larsen S, Persson J. Leaky lysosomes in lung transplant macrophages: azithromycin prevents oxidative damage. Respir Res 2012; 13:83. [PMID: 23006592 PMCID: PMC3511206 DOI: 10.1186/1465-9921-13-83] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 09/14/2012] [Indexed: 01/31/2023] Open
Abstract
Background Lung allografts contain large amounts of iron (Fe), which inside lung macrophages may promote oxidative lysosomal membrane permeabilization (LMP), cell death and inflammation. The macrolide antibiotic azithromycin (AZM) accumulates 1000-fold inside the acidic lysosomes and may interfere with the lysosomal pool of Fe. Objective Oxidative lysosomal leakage was assessed in lung macrophages from lung transplant recipients without or with AZM treatment and from healthy subjects. The efficiency of AZM to protect lysosomes and cells against oxidants was further assessed employing murine J774 macrophages. Methods Macrophages harvested from 8 transplant recipients (5 without and 3 with ongoing AZM treatment) and 7 healthy subjects, and J774 cells pre-treated with AZM, a high-molecular-weight derivative of the Fe chelator desferrioxamine or ammonium chloride were oxidatively stressed. LMP, cell death, Fe, reduced glutathione (GSH) and H-ferritin were assessed. Results Oxidant challenged macrophages from transplants recipients without AZM exhibited significantly more LMP and cell death than macrophages from healthy subjects. Those macrophages contained significantly more Fe, while GSH and H-ferritin did not differ significantly. Although macrophages from transplant recipients treated with AZM contained both significantly more Fe and less GSH, which would sensitize cells to oxidants, these macrophages resisted oxidant challenge well. The preventive effect of AZM on oxidative LMP and J774 cell death was 60 to 300 times greater than the other drugs tested. Conclusions AZM makes lung transplant macrophages and their lysososomes more resistant to oxidant challenge. Possibly, prevention of obliterative bronchiolitis in lung transplants by AZM is partly due to this action.
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Affiliation(s)
- H Lennart Persson
- Division of Pulmonary Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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Vrančić M, Banjanac M, Nujić K, Bosnar M, Murati T, Munić V, Stupin Polančec D, Belamarić D, Parnham MJ, Eraković Haber V. Azithromycin distinctively modulates classical activation of human monocytes in vitro. Br J Pharmacol 2012; 165:1348-60. [PMID: 21726210 DOI: 10.1111/j.1476-5381.2011.01576.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Azithromycin has been reported to modify activation of macrophages towards the M2 phenotype. Here, we have sought to identify the mechanisms underlying this modulatory effect of azithromycin on human monocytes, classically activated in vitro. EXPERIMENTAL APPROACH Human blood monocytes were primed with IFN-γ for 24 h and activated with LPS for 24 h. Azithromycin, anti-inflammatory and lysosome-affecting agents were added 2 h before IFN-γ. Cytokine and chemokine expression was determined by quantitative PCR and protein release by ELISA. Signalling molecules were determined by Western blotting and transcription factor activation quantified with a DNA-binding ELISA kit. KEY RESULTS Azithromycin (1.5-50 µM) dose-dependently inhibited gene expression and/or release of M1 macrophage markers (CCR7, CXCL 11 and IL-12p70), but enhanced CCL2, without altering TNF-α or IL-6. Azithromycin also enhanced the gene expression and/or release of M2 macrophage markers (IL-10 and CCL18), and the pan-monocyte marker CD163, but inhibited that of CCL22. The Toll-like receptor (TLR) 4 signalling pathway was modulated, down-regulating NF-κB and STAT1 transcription factors. The inhibitory profile of azithromycin differed from that of dexamethasone, the phosphodiesterase-4 inhibitor roflumilast and the p38 kinase inhibitor SB203580 but was similar to that of the lysosomotropic drug chloroquine. Effects of concanamycin and NH4Cl, which also act on lysosomes, differed significantly. CONCLUSIONS AND IMPLICATIONS Azithromycin modulated classical activation of human monocytes by inhibition of TLR4-mediated signalling and possible effects on lysosomal function, and generated a mediator expression profile that differs from that of monocyte/macrophage phenotypes so far described.
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Affiliation(s)
- M Vrančić
- GlaxoSmithKline Research Centre Zagreb Limited, Zagreb, Croatia.
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Polančec DS, Munić Kos V, Banjanac M, Vrančić M, Čužić S, Belamarić D, Parnham MJ, Polančec D, Haber VE. Azithromycin drives in vitro GM-CSF/IL-4-induced differentiation of human blood monocytes toward dendritic-like cells with regulatory properties. J Leukoc Biol 2011; 91:229-43. [DOI: 10.1189/jlb.1210655] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis. Pharmacol Res 2011; 64:298-307. [DOI: 10.1016/j.phrs.2011.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Revised: 03/25/2011] [Accepted: 03/27/2011] [Indexed: 11/19/2022]
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Gregas MK, Yan F, Scaffidi J, Wang HN, Vo-Dinh T. Characterization of nanoprobe uptake in single cells: spatial and temporal tracking via SERS labeling and modulation of surface charge. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2011; 7:115-22. [PMID: 20817123 PMCID: PMC5453314 DOI: 10.1016/j.nano.2010.07.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2009] [Revised: 03/01/2010] [Accepted: 07/23/2010] [Indexed: 01/27/2023]
Abstract
A critical aspect for use of nanoprobes in biomedical research and clinical applications involves fundamental spatial and temporal characterization of their uptake and distribution in cells. Raman spectroscopy and two-dimensional Raman imaging were used to identify and locate nanoprobes in single cells using surface-enhanced Raman scattering detection. To study the efficiency of cellular uptake, silver nanoparticles functionalized with three different positive-, negative-, and neutrally charged Raman labels were co-incubated with cell cultures and internalized via normal cellular processes. The surface charge on the nanoparticles was observed to modulate uptake efficiency, demonstrating a dual function of the surface modifications as tracking labels and as modulators of cell uptake. These results indicate that the functionalized nanoparticle construct has potential for sensing and delivery in single living cells and that use of surface-enhanced Raman scattering for tracking and detection is a practical and advantageous alternative to traditional fluorescence methods. FROM THE CLINICAL EDITOR Cell labeling and tracking methods are commonly required in biomedical research. This paper presents specific functionalized nanoparticle constructs with potential for sensing and delivery in single living cells. The use of surface-enhanced Raman scattering enables tracking and detection of these cells as a practical alternative to traditional fluorescence methods.
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Affiliation(s)
- Molly K. Gregas
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA
- Fitzpatrick Institute for Photonics, Duke University, Durham, North Carolina, USA
| | - Fei Yan
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA
- Fitzpatrick Institute for Photonics, Duke University, Durham, North Carolina, USA
| | - Jonathan Scaffidi
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA
- Fitzpatrick Institute for Photonics, Duke University, Durham, North Carolina, USA
| | - Hsin-Neng Wang
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA
- Fitzpatrick Institute for Photonics, Duke University, Durham, North Carolina, USA
| | - Tuan Vo-Dinh
- Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA
- Fitzpatrick Institute for Photonics, Duke University, Durham, North Carolina, USA
- Department of Chemistry, Duke University, Durham, North Carolina, USA
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Tyteca D, D'Auria L, Der Smissen PV, Medts T, Carpentier S, Monbaliu J, de Diesbach P, Courtoy P. Three unrelated sphingomyelin analogs spontaneously cluster into plasma membrane micrometric domains. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2010; 1798:909-27. [DOI: 10.1016/j.bbamem.2010.01.021] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2009] [Revised: 01/22/2010] [Accepted: 01/27/2010] [Indexed: 01/01/2023]
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Fahrer JÃ, Kuban J, Heine K, Rupps G, Kaiser E, Felder E, Benz R, Barth H. Selective and specific internalization of clostridial C3 ADP-ribosyltransferases into macrophages and monocytes. Cell Microbiol 2010; 12:233-47. [DOI: 10.1111/j.1462-5822.2009.01393.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Reed AAC, Loh NY, Terryn S, Lippiat JD, Partridge C, Galvanovskis J, Williams SE, Jouret F, Wu FTF, Courtoy PJ, Nesbit MA, Rorsman P, Devuyst O, Ashcroft FM, Thakker RV. CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease. Am J Physiol Renal Physiol 2009; 298:F365-80. [PMID: 19940036 PMCID: PMC2822520 DOI: 10.1152/ajprenal.00038.2009] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Renal tubular reabsorption is important for extracellular fluid homeostasis and much of this occurs via the receptor-mediated endocytic pathway. This pathway is disrupted in Dent’s disease, an X-linked renal tubular disorder that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Dent's disease is due to mutations of CLC-5, a chloride/proton antiporter, expressed in endosomes and apical membranes of renal tubules. Loss of CLC-5 function alters receptor-mediated endocytosis and trafficking of megalin and cubilin, although the underlying mechanisms remain to be elucidated. Here, we report that CLC-5 interacts with kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles. Using yeast two-hybrid, glutathione-S-transferase pull-down and coimmunoprecipitation assays, the COOH terminus of CLC-5 and the coiled-coil and globular domains of KIF3B were shown to interact. This was confirmed in vivo by endogenous coimmunoprecipitation of CLC-5 and KIF3B and codistribution with endosomal markers in mouse kidney fractions. Confocal live cell imaging in kidney cells further demonstrated association of CLC-5 and KIF3B, and transport of CLC-5-containing vesicles along KIF3B microtubules. KIF3B overexpression and underexpression, using siRNA, had reciprocal effects on whole cell chloride current amplitudes, CLC-5 cell surface expression, and endocytosis of albumin and transferrin. Clcn5Y/− mouse kidneys and isolated proximal tubular polarized cells showed increased KIF3B expression, whose effects on albumin endocytosis were dependent on CLC-5 expression. Thus, the CLC-5 and KIF3B interaction is important for CLC-5 plasma membrane expression and for facilitating endocytosis and microtubular transport in the kidney.
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Affiliation(s)
- Anita A C Reed
- Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford, United Kingdom
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Cooperation between prokaryotic (Lde) and eukaryotic (MRP) efflux transporters in J774 macrophages infected with Listeria monocytogenes: studies with ciprofloxacin and moxifloxacin. Antimicrob Agents Chemother 2008; 52:3040-6. [PMID: 18573933 DOI: 10.1128/aac.00105-08] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Antibiotic efflux is observed in both eukaryotic and prokaryotic cells, modulating accumulation and resistance. The present study examines whether eukaryotic and prokaryotic fluoroquinolone transporters can cooperate in the context of an intracellular infection. We have used (i) J774 macrophages (comparing a ciprofloxacin-resistant cell line overexpressing an MRP-like transporter with wild-type cells with basal expression), (ii) Listeria monocytogenes (comparing a clinical isolate [CLIP21369] displaying ciprofloxacin resistance associated with overexpression of the Lde efflux system with a wild-type strain [EGD]), (iii) ciprofloxacin (substrate of both Lde and MRP) and moxifloxacin (nonsubstrate), and (iv) probenecid and reserpine (preferential inhibitors of MRP and Lde, respectively). The ciprofloxacin MICs for EGD were unaffected by reserpine, while those for CLIP21369 were decreased approximately fourfold (and made similar to those of EGD). Neither probenecid nor reserpine affected the moxifloxacin MICs against EGD or CLIP21369. In dose-response studies (0.01x to 100x MIC) in broth, reserpine fully restored the susceptibility of CLIP21369 to ciprofloxacin (no effect on EGD) but did not influence the activity of moxifloxacin. In studies with intracellular bacteria, reserpine, probenecid, and their combination increased the activity of ciprofloxacin in wild-type and ciprofloxacin-resistant macrophages in parallel with an increase in ciprofloxacin accumulation in macrophages for EGD and an increase in accumulation and decrease in MIC (in broth) for CLIP21369. Moxifloxacin accumulation and intracellular activity were consistently not affected by the inhibitors. A bacterial efflux pump may thus actively cooperate with a eukaryotic efflux transporter to reduce the activity of a common substrate (ciprofloxacin) toward an intracellular bacterial target.
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Barcia-Macay M, Mouaden F, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F. Cellular pharmacokinetics of telavancin, a novel lipoglycopeptide antibiotic, and analysis of lysosomal changes in cultured eukaryotic cells (J774 mouse macrophages and rat embryonic fibroblasts). J Antimicrob Chemother 2008; 61:1288-94. [PMID: 18375379 PMCID: PMC2386079 DOI: 10.1093/jac/dkn120] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Background Telavancin is a lipoglycopeptide with multiple mechanisms of action that include membrane-destabilizing effects towards bacterial cells. It shows bactericidal activity against forms of Staphylococcus aureus (phagolysosomal infection) with different resistance phenotypes [methicillin-resistant S. aureus, vancomycin-intermediate S. aureus or vancomycin-resistant S. aureus]. We examine here the uptake, efflux and intracellular distribution of telavancin in eukaryotic cells as well as its potential to induce lysosomal changes (in comparison with vancomycin and oritavancin). Methods J774 macrophages and rat embryo fibroblasts were exposed for up to 24 and 72 h to telavancin (5–90 mg/L). The following studies were performed: measurement of 14C-labelled telavancin cellular uptake and subcellular distribution (cell fractionation), determination of pericellular membrane integrity (lactate dehydrogenase release), electron microscopy with morphometric analysis of changes in lysosome size and determination of total phospholipid and cholesterol content. Results The uptake of telavancin proceeded linearly as a function of time and concentration in both cell types (clearance rate of ∼10 mL/g of protein/h). Efflux (macrophages) was ∼5.7-fold slower. Telavancin subcellular distribution was superimposable on that of a lysosomal marker (N-acetyl-β-hexosaminidase). It did not cause an increase in the release of lactate dehydrogenase and did not induce significant increases in total phospholipid or cholesterol content. It caused only mild morphological lysosomal alterations (similar to vancomycin and much less than oritavancin by morphometric analysis). Conclusions Telavancin is taken up by eukaryotic cells and localizes in lysosomes, causing mild morphological alterations without evidence of lipid metabolism alterations. These data support our observations that telavancin is active against intracellular S. aureus.
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Mathot F, des Rieux A, Ariën A, Schneider YJ, Brewster M, Préat V. Transport mechanisms of mmePEG750P(CL-co-TMC) polymeric micelles across the intestinal barrier. J Control Release 2007; 124:134-43. [DOI: 10.1016/j.jconrel.2007.09.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2007] [Revised: 08/29/2007] [Accepted: 09/03/2007] [Indexed: 11/30/2022]
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Mettlen M, Platek A, Van Der Smissen P, Carpentier S, Amyere M, Lanzetti L, de Diesbach P, Tyteca D, Courtoy PJ. Src triggers circular ruffling and macropinocytosis at the apical surface of polarized MDCK cells. Traffic 2007; 7:589-603. [PMID: 16643281 DOI: 10.1111/j.1600-0854.2006.00412.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
We addressed the role of Src on cortical actin dynamics and polarized endocytosis in MDCK cells harboring a thermosensitive v-src mutant. Shifting monolayers established at 40 degrees C (non-permissive temperature) to 34 degrees C (permissive temperature) rapidly reactivated v-Src kinase, but tight junctions and cell polarity resisted for >6 h. At this interval, activated v-src was recruited on apical vesicles, induced cortactin-associated apical circular ruffles productive of macropinosomes, thereby accelerating apical pinocytosis by approximately fivefold. Ruffling and macropinosome formation were selectively abrogated by inhibitors of actin polymerization, phosphoinositide 3-kinase, phospholipase C, and phospholipase D, which all returned apical pinocytosis to the level observed at 40 degrees C, underscoring the distinct control of apical micropinocytosis and macropinocytosis. Src promoted microtubule-dependent fusion of macropinosomes to the apical recycling endosome (ARE), causing its strong vacuolation. However, preservation of tubulation and apical polarity indicated that its function was not affected. The ARE was labeled for v-src, Rab11, and rabankyrin-5 but not early endosome antigen 1, thus distinguishing two separate Rab5-dependent apical pathways. The mechanisms of Src-induced apical ruffling and macropinocytosis could shed light on the triggered apical enteroinvasive pathogens entry and on the apical differentiation of osteoclasts.
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Affiliation(s)
- Marcel Mettlen
- CELL Unit, Université catholique de Louvain and Christian de Duve Institute of Cellular Pathology, 1200 Brussels, Belgium
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Guest CB, Hartman ME, O'Connor JC, Chakour KS, Sovari AA, Freund GG. Phagocytosis of cholesteryl ester is amplified in diabetic mouse macrophages and is largely mediated by CD36 and SR-A. PLoS One 2007; 2:e511. [PMID: 17551591 PMCID: PMC1876806 DOI: 10.1371/journal.pone.0000511] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2007] [Accepted: 05/09/2007] [Indexed: 11/19/2022] Open
Abstract
Type 2 diabetes (T2D) is associated with accelerated atherosclerosis, which accounts for approximately 75% of all diabetes-related deaths. Here we investigate the link between diabetes and macrophage cholesteryl ester accumulation. When diabetic (db/db) mice are given cholesteryl ester intraperitoneally (IP), peritoneal macrophages (PerMΦs) recovered from these animals showed a 58% increase in intracellular cholesteryl ester accumulation over PerMΦs from heterozygote control (db/+) mice. Notably, PerMΦ fluid-phase endocytosis and large particle phagocytosis was equivalent in db/+and db/db mice. However, IP administration of CD36 and SR-A blocking antibodies led to 37% and 25% reductions in cholesteryl ester accumulation in PerMΦ. Finally, in order to determine if these scavenger receptors (SRs) were part of the mechanism responsible for the increased accumulation of cholesteryl esters observed in the diabetic mouse macrophages, receptor expression was quantified by flow cytometry. Importantly, db/db PerMΦs showed a 43% increase in CD36 expression and an 80% increase in SR-A expression. Taken together, these data indicate that direct cholesteryl ester accumulation in mouse macrophages is mediated by CD36 and SR-A, and the magnitude of accumulation is increased in db/db macrophages due to increased scavenger receptor expression.
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Affiliation(s)
- Christopher B. Guest
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Matthew E. Hartman
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Jason C. O'Connor
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Kenneth S. Chakour
- College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Ali A. Sovari
- College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Gregory G. Freund
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- Department of Pathology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- * To whom correspondence should be addressed. E-mail:
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Lemaire S, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM. Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytized Staphylococcus aureus by the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and madin-darby canine kidney cells. Antimicrob Agents Chemother 2007; 51:2748-57. [PMID: 17548493 PMCID: PMC1932525 DOI: 10.1128/aac.00090-07] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
P-glycoprotein (P-gp; MDR1), a major efflux transporter, recognizes various antibiotics and is present in macrophages. We have examined its effect on the modulation of the intracellular accumulation and activity of daptomycin towards phagocytized Staphylococcus aureus (ATCC 25923) in human THP-1 macrophages, in comparison with MDCK epithelial cells (wild type and MDCK-MDR1 overexpressing P-gp; the bulk of the protein was immunodetected at the surface of all three cell types). Daptomycin displayed concentration-dependent intracellular activity (Hill equation pattern) in THP-1 and MDCK cells with (i) 50% effective drug extracellular concentration (EC(50); relative potency) and static concentrations at 9 to 10 times the MIC and (ii) maximal efficacy (E(max); CFU decrease at infinite extracellular drug concentration) at 1.6 to 2 log compared to that of the postphagocytosis inoculum. Verapamil (100 microM) and elacridar (GF 120918; 0.5 microM), two known inhibitors of P-gp, decreased daptomycin EC(50) (about threefold) in THP-1 and MDCK cells without affecting E(max). Daptomycin EC(50) was about three- to fourfold higher and accumulation in MDCK-MDR1 commensurately lower than in wild-type cells. In THP-1 macrophages, (i) verapamil and ATP depletion increased, and ouabain (an inducer of mdr1 [the gene encoding P-gp] expression) decreased the accumulation of daptomycin in parallel with that of DiOC(2) (a known substrate of P-gp); (ii) silencing mdr1 with duplex human mdr1 siRNAs reduced the cell content in immunoreactive P-gp to 15 to 30% of controls and caused an eight- to 13-fold increase in daptomycin accumulation. We conclude that daptomycin is subject to efflux from THP-1 macrophages and MDCK cells by P-gp, which reduces its intracellular activity against phagocytized S. aureus.
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Affiliation(s)
- Sandrine Lemaire
- Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Mounier 73, Brussels, Belgium
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Zifarelli G, Pusch M. CLC chloride channels and transporters: a biophysical and physiological perspective. Rev Physiol Biochem Pharmacol 2007; 158:23-76. [PMID: 17729441 DOI: 10.1007/112_2006_0605] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Chloride-transporting proteins play fundamental roles in many tissues in the plasma membrane as well as in intracellular membranes. They have received increasing attention in the last years because crucial, and often unexpected and novel, physiological functions have been disclosed with gene-targeting approaches, X-ray crystallography, and biophysical analysis. CLC proteins form a gene family that comprises nine members in mammals, at least four of which are involved in human genetic diseases. The X-ray structure of the bacterial CLC homolog, ClC-ec1, revealed a complex fold and confirmed the anticipated homodimeric double-barreled architecture of CLC-proteins with two separate Cl-ion transport pathways, one in each subunit. Four of the mammalian CLC proteins, ClC-1, ClC-2, ClC-Ka, and ClC-Kb, are chloride ion channels that fulfill their functional roles-stabilization of the membrane potential, transepithelial salt transport, and ion homeostasisin the plasma membrane. The other five CLC proteins are predominantly expressed in intracellular organelles like endosomes and lysosomes, where they are probably important for a proper luminal acidification, in concert with the V-type H+-ATPase. Surprisingly, ClC-4, ClC-5, and probably also ClC-3, are not Cl- ion channels but exhibit significant Cl-/H+ antiporter activity, as does the bacterial homolog ClC-ec1 and the plant homolog AtCLCa. The physiological significance of the Cl-/H+ antiport activity remains to be established.
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Affiliation(s)
- G Zifarelli
- CNR, Istituto di Biofisica, Via De Marini 6, 16149 Genova, Italy
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