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Mokra D, Porvaznik I, Mokry J. N-Acetylcysteine in the Treatment of Acute Lung Injury: Perspectives and Limitations. Int J Mol Sci 2025; 26:2657. [PMID: 40141299 PMCID: PMC11942046 DOI: 10.3390/ijms26062657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/03/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies indicates that early administration of NAC may reduce markers of oxidative stress and alleviate inflammation in animal models of acute lung injury (ALI) and in patients suffering from distinct forms of acute respiratory distress syndrome (ARDS) or pulmonary infections including community-acquired pneumonia or Coronavirus Disease (COVID)-19. Besides low costs, easy accessibility, low toxicity, and rare side effects, NAC can also be combined with other drugs. This article provides a review of knowledge on the mechanisms of inflammation and oxidative stress in various forms of ALI/ARDS and critically discusses experience with the use of NAC in these disorders. For preparing the review, articles published in the English language from the PubMed database were used.
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Affiliation(s)
- Daniela Mokra
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, SK-03601 Martin, Slovakia
| | - Igor Porvaznik
- Department of Laboratory Medicine, Faculty of Health Sciences, Catholic University in Ružomberok, SK-03401 Ružomberok, Slovakia;
| | - Juraj Mokry
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, SK-03601 Martin, Slovakia;
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2
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González-Guzmán D, Andrade-Castellanos CA, Ponce-Gallegos MA, Mesina-Estarrón I, Mora-Almanza JG, Ruelas-Moreno HE, Rodríguez-González D, Eguia-Ortega O, Colunga-Lozano LE. N-acetyl-cysteine in Intensive Care Unit Patients with Acute Respiratory Distress Syndrome due to COVID-19: A Retrospective Cohort Study. J Intensive Care Med 2025; 40:284-293. [PMID: 39262205 DOI: 10.1177/08850666241281281] [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] [Indexed: 09/13/2024]
Abstract
COVID-19-related acute respiratory distress syndrome (ARDS) is linked to mortality, primarily due to a cytokine storm, oxidative stress imbalance, and pro-thrombotic state.PurposeWe assessed the potential association between N-acetyl-cysteine (NAC) and clinical outcomes in critically ill subjects with COVID-19-related ARDS.Material and MethodsWe included subjects with confirmed COVID-19 who were admitted to our ICU between March 1, 2020, and January 31, 2021, due to ARDS and necessitating invasive mechanical ventilation (IMV). Subjects who received standard of care (SOC) were compared with subjects who additionally received NAC 600 mg bid orally.ResultsA total of 243 subjects were included in this study. The results indicate significantly improved survival rates in the NAC plus SOC group, both in the unadjusted analysis and after adjusting for confounding factors such as ARDS severity (HR 0.48, 95% CI 0.32-0.70).ConclusionsWe found that oral administration of NAC was associated with reduced mortality in critically ill patients with COVID-19 related ARDS.
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Affiliation(s)
- Diego González-Guzmán
- Health science center, Universidad de Guadalajara, Guadalajara, Jalisco, México
- Department of Internal Medicine, Nuevo Hospital Civil de Guadalajara "Dr Juan I. Menchaca". Guadalajara, Jalisco, México
| | - Carlos A Andrade-Castellanos
- Department of Internal Medicine, Nuevo Hospital Civil de Guadalajara "Dr Juan I. Menchaca". Guadalajara, Jalisco, México
| | - Marco A Ponce-Gallegos
- Department of Clinical Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, México
| | | | - José G Mora-Almanza
- Health science center, Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Hugo E Ruelas-Moreno
- Department of Internal Medicine, Nuevo Hospital Civil de Guadalajara "Dr Juan I. Menchaca". Guadalajara, Jalisco, México
| | - Daniel Rodríguez-González
- Department of intensive care medicine, Nuevo Hospital Civil de Guadalajara "Dr Juan I. Menchaca", Guadalajara, Jalisco, México
| | - Omar Eguia-Ortega
- Department of intensive care medicine, Nuevo Hospital Civil de Guadalajara "Dr Juan I. Menchaca", Guadalajara, Jalisco, México
| | - Luis Enrique Colunga-Lozano
- Health science center, Universidad de Guadalajara, Guadalajara, Jalisco, México
- Department of intensive care medicine, Nuevo Hospital Civil de Guadalajara "Dr Juan I. Menchaca", Guadalajara, Jalisco, México
- Department of Health Research Methods, Evidence and Impact. McMaster University, Hamilton, Ontario, Canada
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Xie J, Yuan C, Yang S, Ma Z, Li W, Mao L, Jiao P, Liu W. The role of reactive oxygen species in severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection-induced cell death. Cell Mol Biol Lett 2024; 29:138. [PMID: 39516736 PMCID: PMC11549821 DOI: 10.1186/s11658-024-00659-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) represents the novel respiratory infectious disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by rapid spread throughout the world. Reactive oxygen species (ROS) account for cellular metabolic by-products, and excessive ROS accumulation can induce oxidative stress due to insufficient endogenous antioxidant ability. In the case of oxidative stress, ROS production exceeds the cellular antioxidant capacity, thus leading to cell death. SARS-CoV-2 can activate different cell death pathways in the context of infection in host cells, such as neutrophil extracellular trap (NET)osis, ferroptosis, apoptosis, pyroptosis, necroptosis and autophagy, which are closely related to ROS signalling and control. In this review, we comprehensively elucidated the relationship between ROS generation and the death of host cells after SARS-CoV-2 infection, which leads to the development of COVID-19, aiming to provide a reasonable basis for the existing interventions and further development of novel therapies against SARS-CoV-2.
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Affiliation(s)
- Jiufeng Xie
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Cui Yuan
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Sen Yang
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Zhenling Ma
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Wenqing Li
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Lin Mao
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Pengtao Jiao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Wei Liu
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China.
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Yu Y, Lin K, Wu H, Hu M, Yang X, Wang J, Grillari J, Chen J. Targeting senescent cells in aging and COVID-19: from cellular mechanisms to therapeutic opportunities. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:20. [PMID: 39358480 PMCID: PMC11447201 DOI: 10.1186/s13619-024-00201-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 09/10/2024] [Indexed: 10/04/2024]
Abstract
The COVID-19 pandemic has caused a global health crisis and significant social economic burden. While most individuals experience mild or non-specific symptoms, elderly individuals are at a higher risk of developing severe symptoms and life-threatening complications. Exploring the key factors associated with clinical severity highlights that key characteristics of aging, such as cellular senescence, immune dysregulation, metabolic alterations, and impaired regenerative potential, contribute to disruption of tissue homeostasis of the lung and worse clinical outcome. Senolytic and senomorphic drugs, which are anti-aging treatments designed to eliminate senescent cells or decrease the associated phenotypes, have shown promise in alleviating age-related dysfunctions and offer a novel approach to treating diseases that share certain aspects of underlying mechanisms with aging, including COVID-19. This review summarizes the current understanding of aging in COVID-19 progression, and highlights recent findings on anti-aging drugs that could be repurposed for COVID-19 treatment to complement existing therapies.
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Affiliation(s)
- Yuan Yu
- Center for Cell Lineage and Atlas, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Kaixuan Lin
- Center for Cell Lineage and Atlas, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
| | - Haoyu Wu
- Center for Cell Lineage and Atlas, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Mingli Hu
- Center for Cell Lineage and Atlas, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Xuejie Yang
- Center for Cell Lineage and Atlas, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jie Wang
- Center for Cell Lineage and Atlas, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Johannes Grillari
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Institute of Molecular Biotechnology, BOKU University, Vienna, Austria
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation With AUVA, 1200, Vienna, Austria
| | - Jiekai Chen
- Center for Cell Lineage and Atlas, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
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Zaid AB, Almady SK, Awad SM, Elabd MG, Saied SA, Saied AA, Elmalawany AM. Sofosbuvir (+) daclatasvir (+) ribavirin in Egyptian patients with hepatitis C virus: Therapeutic outcomes and the prognostic role of natural killer cells. Curr Res Transl Med 2024; 72:103443. [PMID: 38447269 DOI: 10.1016/j.retram.2024.103443] [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: 11/10/2023] [Revised: 02/02/2024] [Accepted: 02/29/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND One of the prominent causes of chronic liver disease worldwide is the hepatitis C virus (HCV). HCV believed that innate immunity contributes to a sustained virological response (SVR) to the treatment of Sofosbuvir (SOF) (+) Daclatasvir (DCV) (+) Ribavirin (RBV). This study aimed to evaluate the impact of SOF (+) DCV (+) RBV therapy and persistent HCV infection on the subset of natural killer cells (NK) in HCV genotype four patients from Egypt. MATERIALS AND METHODS One hundred and ten patients with persistent HCV infections requiring SOF (+) DCV (+) RBV therapy were grouped, and a flow cytometry (FCM) study of the NK cell subset in peripheral blood was performed. The assessment was performed before and after three and/or six months of the cessation of viral suppression therapy when a patient had a long-term viral response (SVR). One hundred and ten volunteers from the National Liver Institute's (NLI) blood bank were selected as controls. RESULTS Patients with chronic HCV infection before therapy had considerably lower CD16+ and CD3- CD56+ cells than controls. Their levels increase during SOF (+) DCV (+) RBV therapy. In patients with SVR during treatment, CD16+ and CD3- CD56+ cells increased significantly compared to those who did not get SVR. Furthermore, CD56+ cells were significantly higher in patients with persistent infection before treatment than controls but diminished with the response to treatment. CONCLUSION NK cell activation following SOF (+) DCV (+) RBV therapy and polarization to cytotoxicity occurred early in HCV antiviral therapy and was elevated in the respondents. Our data illustrated that establishing an inhibitory cytotoxic NK profile is related to therapeutic outcomes.
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Affiliation(s)
- Ahmed B Zaid
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | - Shimaa K Almady
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shibin-Elkom 32511, Egypt
| | - Samah M Awad
- Department of Clinical Microbiology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | - Mona G Elabd
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | - Sara A Saied
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
| | | | - Alshimaa M Elmalawany
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt.
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Abogunrin S, Adelakun A, Akinola T, Bashir U, Fagbohungbe B, Mueller E, Neeser K, Ogunnubi O, Parekh K. Challenges of consolidating evidence collected during a pandemic and lessons for the future. Curr Med Res Opin 2024; 40:1311-1322. [PMID: 38975733 DOI: 10.1080/03007995.2024.2377676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024]
Abstract
OBJECTIVE To illustrate the challenges encountered when gathering rapidly synthesized evidence in response to the coronavirus disease 2019 (COVID-19) pandemic. METHODS In this article, we describe the challenges encountered when we performed a systematic literature review (SLR) of randomized controlled trials (RCTs) on the efficacy and safety of treatments for severe COVID-19. The methods of the SLR are described in full, to show the context of our objectives. Then we use the results of the SLR to demonstrate the problems of producing synthesized evidence in this setting. RESULTS Various challenges were identified during this SLR. These were primarily a result of heterogeneity in the study methodology of eligible studies. Definitions of the patient populations and outcome measurements were highly variable and the majority of studies demonstrated a high risk of bias, preventing quantitative synthesis of the collated evidence. CONCLUSION Consolidating evidence from RCTs evaluating COVID-19 interventions was problematic. Guidance is needed for scenarios with high rapid output in primary research.
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Affiliation(s)
| | - Alex Adelakun
- Manchester University Foundation Trust, Manchester, UK
| | | | - Usman Bashir
- Community Medicine Department, Bayero University Kano, Kano, Nigeria
| | | | | | | | - Oluseun Ogunnubi
- Department of Psychiatry, College of Medicine of the University of Lagos, Lagos, Nigeria
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Liu TH, Wu JY, Huang PY, Tsai YW, Hsu WH, Chuang MH, Tang HJ, Lai CC. Clinical efficacy of N-acetylcysteine for COVID-19: A systematic review and meta-analysis of randomized controlled trials. Heliyon 2024; 10:e25179. [PMID: 38318025 PMCID: PMC10839595 DOI: 10.1016/j.heliyon.2024.e25179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 01/16/2024] [Accepted: 01/22/2024] [Indexed: 02/07/2024] Open
Abstract
Background The association between N-acetylcysteine (NAC) and COVID-19 remains undetermined; therefore, this meta-analysis assessed the clinical efficacy of NAC in the treatment of patients with COVID-19. Methods This study searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for studies published from their inception to December 17, 2022. Only randomized controlled trials (RCTs) that assessed the clinical efficacy of NAC for patients with COVID-19 were included. Results Five RCTs involving 651 patients were included. There was no significant difference in mortality between the study group receiving NAC and the control group (15.6 % [50/320] vs. 32.3 %, [107/331]; risk ratio [RR]: 0.58; 95 % confidence interval [CI]: 0.24-1.40). In addition, the two groups did not differ with respect to the incidence of invasive mechanical ventilation (RR: 0.93; 95 % CI: 0.65-1.33), the risk of intensive care unit (ICU) admission (RR: 0.86; 95 % CI: 0.62-1.21), the length of hospital stay (mean difference [MD]: 0.17 days; 95 % CI: -0.67-1.01), and the length of ICU stay (MD: -0.77 days; 95 % CI: -2.97-1.42). Conclusions The administration of NAC did not improve the clinical outcomes of patients with COVID-19; its routine use is not recommended for patients with SARS-CoV-2 infections.
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Affiliation(s)
- Ting-Hui Liu
- Department of Psychiatry, Chi Mei Medical Center, Tainan City, Taiwan
| | - Jheng-Yan Wu
- Department of Nutrition, Chi Mei Medical Center, Tainan City, Taiwan
| | - Po-Yu Huang
- Department of Internal Medicine, Chi Mei Medical Center, Tainan City, Taiwan
| | - Ya-Wen Tsai
- Center for Integrative Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Wan-Hsuan Hsu
- Department of Internal Medicine, Chi Mei Medical Center, Tainan City, Taiwan
| | - Min-Hsiang Chuang
- Department of Internal Medicine, Chi Mei Medical Center, Tainan City, Taiwan
| | - Hung-Jen Tang
- Department of Nutrition, Chi Mei Medical Center, Tainan City, Taiwan
| | - Chih-Cheng Lai
- Division of Hospital Medicine, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
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Zhou Q, Zhang L, Dong Y, Wang Y, Zhang B, Zhou S, Huang Q, Wu T, Chen G. The role of SARS-CoV-2-mediated NF-κB activation in COVID-19 patients. Hypertens Res 2024; 47:375-384. [PMID: 37872376 PMCID: PMC10838770 DOI: 10.1038/s41440-023-01460-2] [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: 07/10/2023] [Revised: 09/15/2023] [Accepted: 09/19/2023] [Indexed: 10/25/2023]
Abstract
The SARS-CoV-2 pandemic, now in its third year, has had a profound impact on public health and economics all over the world. Different populations showed varied susceptibility to this virus and mortality after infection. Clinical and laboratory data revealed that the uncontrolled inflammatory response plays an important role in their poor outcome. Herein, we summarized the role of NF-κB activation during SARS-CoV-2 invasion and replication, particularly the angiotensin-converting enzyme 2 (ACE2)-mediated NF-κB activation. Then we summarized the COVID-19 drugs' impact on NF-κB activation and their problems. A favorable prognosis is linked with timely treatment with NF-κB activation inhibitors, such as TNFα, IL-1β, and IL-6 monoclonal antibodies. However, further clinical researches are still required to clarify the time window, dosage of administration, contraindication, and potential side effects of these drugs, particularly for COVID-19 patients with hypertension, hyperglycemia, diabetes, or other chronic diseases.
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Affiliation(s)
- Qiaoqiao Zhou
- School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Key Laboratory of Purification and Application of Plant Anticancer Active Ingredients, School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
| | - Lei Zhang
- School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Key Laboratory of Purification and Application of Plant Anticancer Active Ingredients, School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Environmental Purification Material Science and Engineering Technology Research Center, Hubei University of Education, Wuhan, 430205, China
| | - Yanming Dong
- School of Life Sciences, Hubei University, Wuhan, 430062, China
| | - Yuan Wang
- School of Basic Medicine, Hubei University of Arts and Science, Xiangyang, 441053, China
| | - Bin Zhang
- School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Key Laboratory of Purification and Application of Plant Anticancer Active Ingredients, School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
| | - Shiyi Zhou
- School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Key Laboratory of Purification and Application of Plant Anticancer Active Ingredients, School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
| | - Qing Huang
- School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Key Laboratory of Purification and Application of Plant Anticancer Active Ingredients, School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Environmental Purification Material Science and Engineering Technology Research Center, Hubei University of Education, Wuhan, 430205, China
| | - Tian Wu
- School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China
- Hubei Environmental Purification Material Science and Engineering Technology Research Center, Hubei University of Education, Wuhan, 430205, China
| | - Gongxuan Chen
- School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China.
- Hubei Key Laboratory of Purification and Application of Plant Anticancer Active Ingredients, School of Chemistry and Life Sciences, Hubei University of Education, Wuhan, Hubei, 430205, PR China.
- Hubei Environmental Purification Material Science and Engineering Technology Research Center, Hubei University of Education, Wuhan, 430205, China.
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Huang Q, Le Y, Li S, Bian Y. Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS). Respir Res 2024; 25:30. [PMID: 38218783 PMCID: PMC10788036 DOI: 10.1186/s12931-024-02678-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities with refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advances, the mortality of ARDS remains unacceptably high, and there are still no effective targeted pharmacotherapeutic agents. With the outbreak of coronavirus disease 19 worldwide, the mortality of ARDS has increased correspondingly. Comprehending the pathophysiology and the underlying molecular mechanisms of ARDS may thus be essential to developing effective therapeutic strategies and reducing mortality. To facilitate further understanding of its pathogenesis and exploring novel therapeutics, this review provides comprehensive information of ARDS from pathophysiology to molecular mechanisms and presents targeted therapeutics. We first describe the pathogenesis and pathophysiology of ARDS that involve dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance and oxidative stress. Next, we summarize the molecular mechanisms and signaling pathways related to the above four aspects of ARDS pathophysiology, along with the latest research progress. Finally, we discuss the emerging therapeutic strategies that show exciting promise in ARDS, including several pharmacologic therapies, microRNA-based therapies and mesenchymal stromal cell therapies, highlighting the pathophysiological basis and the influences on signal transduction pathways for their use.
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Affiliation(s)
- Qianrui Huang
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jie Fang Avenue, Wuhan, 430030, China
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jie Fang Avenue, Wuhan, 430030, China
| | - Yue Le
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Shusheng Li
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jie Fang Avenue, Wuhan, 430030, China.
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jie Fang Avenue, Wuhan, 430030, China.
| | - Yi Bian
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jie Fang Avenue, Wuhan, 430030, China.
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jie Fang Avenue, Wuhan, 430030, China.
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10
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Fu Y, Yu B, Wang Q, Lu Z, Zhang H, Zhang D, Luo F, Liu R, Wang L, Chu Y. Oxidative stress-initiated one-carbon metabolism drives the generation of interleukin-10-producing B cells to resolve pneumonia. Cell Mol Immunol 2024; 21:19-32. [PMID: 38082147 PMCID: PMC10757717 DOI: 10.1038/s41423-023-01109-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 11/07/2023] [Indexed: 01/01/2024] Open
Abstract
The metabolic reprogramming underlying the generation of regulatory B cells during infectious diseases remains unknown. Using a Pseudomonas aeruginosa-induced pneumonia model, we reported that IL-10-producing B cells (IL-10+ B cells) play a key role in spontaneously resolving infection-mediated inflammation. Accumulated cytosolic reactive oxygen species (ROS) during inflammation were shown to drive IL-10+ B-cell generation by remodeling one-carbon metabolism. Depletion of the enzyme serine hydroxymethyltransferase 1 (Shmt1) led to inadequate one-carbon metabolism and decreased IL-10+ B-cell production. Furthermore, increased one-carbon flux elevated the levels of the methyl donor S-adenosylmethionine (SAM), altering histone H3 lysine 4 methylation (H3K4me) at the Il10 gene to promote chromatin accessibility and upregulate Il10 expression in B cells. Therefore, the one-carbon metabolism-associated compound ethacrynic acid (EA) was screened and found to potentially treat infectious pneumonia by boosting IL-10+ B-cell generation. Overall, these findings reveal that ROS serve as modulators to resolve inflammation by reprogramming one-carbon metabolism pathways in B cells.
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Affiliation(s)
- Ying Fu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Baichao Yu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Qi Wang
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Zhou Lu
- Zhongshan Hospital Institute of Clinical Science, Zhongshan Hospital, Shanghai, China
| | - Hushan Zhang
- Zhaotong Health Vocational College, Zhaotong, Yunnan, China
| | - Dan Zhang
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Feifei Luo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Ronghua Liu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Luman Wang
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
- Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, Shanghai Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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11
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Atefi N, Goodarzi A, Riahi T, Khodabandehloo N, Talebi Taher M, Najar Nobari N, Seirafianpour F, Mahdi Z, Baghestani A, Valizadeh R. Evaluation of the efficacy and safety of oral N-acetylcysteine in patients with COVID-19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial. Immun Inflamm Dis 2023; 11:e1083. [PMID: 38018602 PMCID: PMC10659758 DOI: 10.1002/iid3.1083] [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: 06/13/2023] [Revised: 10/25/2023] [Accepted: 10/31/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND The current absence of gold-standard or all-aspect favorable therapies for COVID-19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well-designed randomized controlled trial (RCT) sought to evaluate the efficacy and safety of N-acetylcysteine (NAC) as adjuvant therapy for 60 hospitalized Iranian patients with COVID-19. METHODS Two 30-person diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), were administered in the study. RESULTS At the end of the study, a further decrease in C-reactive protein was observed in the NAC group (P = 0.008), and no death occurred in the atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may reduce mortality. The atazanavir/ritonavir + HCQ and atazanavir/ritonavir + NAC groups exhibited the highest O2 saturation at the end of the study and a significant rise in O2 saturation following intervention commencement, including NAC (P > 0.05). Accordingly, oral or intravenous NAC, if indicated, may enhance O2 saturation, blunt the inflammation trend (by reducing C-reactive protein), and lower mortality in hospitalized patients with COVID-19. CONCLUSION The NAC could be more effective as prophylactic or adjuvant therapy in stable non-severe cases of COVID-19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation or could be effective for better controlling of COVID-19 or its therapy-related side effects.
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Affiliation(s)
- Najmolsadat Atefi
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of MedicineIran University of Medical SciencesTehranIran
| | - Azadeh Goodarzi
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of MedicineIran University of Medical SciencesTehranIran
| | - Taghi Riahi
- Department of Internal Medicine, School of MedicineIran University of Medical SciencesTehranIran
| | - Niloofar Khodabandehloo
- Department of Geriatric Medicine, School of MedicineIran University of Medical SciencesTehranIran
| | - Mahshid Talebi Taher
- Department of Infectious Disease, School of Medicine, Antimicrobial Resistance Research Center, Immunology and Infectious Disease Research InstituteIran University of Medical SciencesTehranIran
| | - Niloufar Najar Nobari
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of MedicineIran University of Medical SciencesTehranIran
| | | | - Zeinab Mahdi
- Department of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of MedicineIran University of Medical SciencesTehranIran
| | - Amir Baghestani
- Department of General Medicine, Rasool Akram Medical Complex, School of MedicineIran University of Medical SciencesTehranIran
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12
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Galindo-Andúgar MA, Arias Arias Á, Alfonso García Guerra J, Fernández Visier I, Manuel Fernández Ibáñez J, Bellido Maldonado A. Impact of N-Acetylcysteine in the mortality of patients hospitalized with COVID-19: a retrospective cohort study. Rev Clin Esp 2023; 223:479-485. [PMID: 37482215 DOI: 10.1016/j.rceng.2023.07.006] [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: 02/08/2023] [Accepted: 07/08/2023] [Indexed: 07/25/2023]
Abstract
INTRODUCTION AND AIM N-Acetylcysteine has been proposed for the treatment of COVID-19 thanks to its mucolytic, antioxidant and anti-inflammatory effects. Our aim is to evaluate its effect on patients admitted with COVID-19 in mortality terms. MATERIAL AND METHODS Retrospective single-center cohort study. All patients admitted to our hospital for COVID-19 from March to April 2020 have been considered. RESULTS A total of 378 patients were included, being 196 (51.9%) men, with an average age of 73.3±14.5 years. 52.6% (199) received treatment with N-Acetylcysteine. More than 70% presented coughs, fever, and/or dyspnea. The global hospital mortality was 26.7%. A multivariate analysis through logistic regression identified the age of patients [older than 80; OR: 8.4 (CI95%:3-23.4)], a moderate or severe radiologic affectation measured by the RALE score [OR:7.3 (CI95%:3.2-16.9)], the tobacco consumption [OR:2.8 (CI95%:1.3-6.1)] and previous arrhythmia [OR 2.8 (CI95%: 1.3-6.2)] as risk factor that were independently associated with mortality during the admission. The treatment with N-Acetylcysteine was identified as a protective factor [OR: 0.57 (CI95%: 0.31-0.99)]. Asthma also seems to have a certain protective factor although it was not statistically significant in our study [OR: 0.19 (CI95%: 0.03-1.06)]. CONCLUSIONS Patients with COVID-19 treated with N-acetylcysteine have presented a lower mortality and a better evolution in this study. Future prospective studies or randomized clinical trials must confirm the impact of N-Acetylcysteine on COVID-19 patients.
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Affiliation(s)
- M A Galindo-Andúgar
- Servicio de Medicina Interna. Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain.
| | - Á Arias Arias
- Unidad de Docencia, Investigación y Formación, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
| | - J Alfonso García Guerra
- Sección de Neumología, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
| | - I Fernández Visier
- Sección de Aparato Digestivo, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
| | | | - A Bellido Maldonado
- Sección de Neumología, Hospital General La Mancha Centro, Alcázar de San Juan (C. Real), Spain
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13
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Bellanti F, Kasperczyk S, Kasperczyk A, Dobrakowski M, Pacilli G, Vurchio G, Maddalena A, Quiete S, Lo Buglio A, Capurso C, Serviddio G, Vendemiale G. Alteration of circulating redox balance in coronavirus disease-19-induced acute respiratory distress syndrome. J Intensive Care 2023; 11:30. [PMID: 37408073 DOI: 10.1186/s40560-023-00679-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/27/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Mechanisms underpinning ARDS induced by COVID-19 are mostly immune-mediated, but need to be completely clarified. This study aimed to investigate redox balance in COVID-19 patients with ARDS, trying to recognize possible differences from typical ARDS related to the pathophysiology of severe disease. METHODS Patients affected by ARDS and positive for the SARS-CoV-2 virus (N = 40, COVID-19) were compared to ARDS patients negative to the molecular test (N = 42, No COVID-19). Circulating markers of redox balance were measured in serum and erythrocytes, and related to markers of inflammation and coagulability. RESULTS No differences in serum markers of oxidative damage were found between both groups, but a reduction in total antioxidant status and serum ceruloplasmin level was observed in COVID-19 rather than No COVID-19 patients. Redox balance alterations were described in erythrocytes from COVID-19 with respect to No COVID-19 group, characterized by increased lipofuscin and malondialdehyde concentration, and reduced glutathione S-transferase and glutathione reductase activity. These markers were associated with circulating indexes of respiratory disease severity (Horowitz index and alveolar-to-arterial oxygen gradient), inflammation (interleukin-6 and interleukin-10), and hypercoagulability (D-dimer) in COVID-19 patients with ARDS. CONCLUSIONS ARDS caused by COVID-19 is sustained by impairment of redox balance, particularly in erythrocytes. This alteration is associated with the pro-inflammatory and pro-coagulant status which characterizes severe COVID-19.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy.
| | - Sławomir Kasperczyk
- Department of Biochemistry, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, 41-808, Zabrze, Poland
| | - Aleksandra Kasperczyk
- Department of Biochemistry, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, 41-808, Zabrze, Poland
| | - Michał Dobrakowski
- Department of Biochemistry, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, 41-808, Zabrze, Poland
| | - Gabriella Pacilli
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
| | - Giuseppina Vurchio
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
| | - Alessandro Maddalena
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
| | - Stefano Quiete
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
| | - Aurelio Lo Buglio
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
| | - Cristiano Capurso
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto, 1, 71122, Foggia, Italy
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14
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Alam MS, Hasan MN, Maowa Z, Khatun F, Nazir KHMNH, Alam MZ. N-acetylcysteine reduces severity and mortality in COVID-19 patients: A systematic review and meta-analysis. J Adv Vet Anim Res 2023; 10:157-168. [PMID: 37534078 PMCID: PMC10390689 DOI: 10.5455/javar.2023.j665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/21/2023] [Accepted: 05/22/2023] [Indexed: 08/04/2023] Open
Abstract
Objectives Recent clinical studies suggest that oxidative stress is one of the key players in the pathogenesis of coronavirus disease 2019 (COVID-19), and N-acetylcysteine (NAC), a potent antioxidant, has been shown to improve clinical outcomes in COVID-19 patients. We conducted a systematic review and meta-analysis of the literature published on the therapeutic intervention of NAC on COVID-19 infection. Methods We searched PubMed, Google Scholar, and Science Direct. We identified and screened eight studies with 20,503 participants, including 2,852 in the NAC-treated group and 17,651 in the placebo group, which reported the effect of NAC on COVID-19 infection. A meta-analysis was performed using forest plots under fixed effect estimates based on the standardized mean difference (SMD) and risk ratio (RR). Results Pooled analysis showed that NAC was associated with lower mortality in patients with COVID-19 compared with the placebo group [RR, 0.65; (95% CI: 0.56 to 0.75); p < 0.0001]. Similarly, C-reactive protein (CRP) [SMD, -0.32; (95% CI: -56 to -0.09); p = 0.0070] and D-dimer [SMD, -0.35, (95% CI: -0.59 to -0.10; p = 0.0062] levels were significantly decreased, and the oxygenation marker, PaO2/FiO2 ratio, was increased in the NAC-treated group compared with the placebo group [SMD, 0.76; (95% CI: 0.48 to 1.03); p < 0.0001]. Conclusion Although the number of included studies was minimal, this meta-analysis suggests that NAC may have a positive effect on COVID-19 outcomes, specifically, a significant decrease in CRP and D-dimer levels and a significant increase in oxygen saturation, which decreased mortality. We have also presented a comprehensive review of the role and mechanisms of NAC in patients with COVID-19.
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Affiliation(s)
- Mohammad Shah Alam
- Department of Anatomy and Histology, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur, Bangladesh
| | - Mohammad Nazmol Hasan
- Department of Statistics, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur, Bangladesh
| | - Zannatul Maowa
- Department of Anatomy and Histology, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur, Bangladesh
| | - Fahima Khatun
- Department of Pathobiology, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur, Bangladesh
| | | | - Mohammad Zahangeer Alam
- Department of Environmental Science, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur, Bangladesh
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15
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Kuo CW, Su PL, Huang TH, Lin CC, Chen CW, Tsai JS, Liao XM, Chan TY, Shieh CC. Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression. Sci Rep 2023; 13:7894. [PMID: 37193781 DOI: 10.1038/s41598-023-34785-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/08/2023] [Indexed: 05/18/2023] Open
Abstract
Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb-/- mice; however, exogenous ROS increased the ACE2 in Cybb-/- AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.
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Affiliation(s)
- Chin-Wei Kuo
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Lan Su
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tang-Hsiu Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chien-Chung Lin
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chian-Wei Chen
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jeng-Shiuan Tsai
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Xin-Min Liao
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tzu-Yi Chan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Chang Shieh
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan.
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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16
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Gamarra-Morales Y, Herrera-Quintana L, Molina-López J, Vázquez-Lorente H, Machado-Casas JF, Castaño-Pérez J, Pérez-Villares JM, Planells E. Response to Intravenous N-Acetylcysteine Supplementation in Critically Ill Patients with COVID-19. Nutrients 2023; 15:2235. [PMID: 37405379 DOI: 10.3390/nu15092235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/01/2023] [Accepted: 05/07/2023] [Indexed: 07/06/2023] Open
Abstract
Administering N-acetylcysteine (NAC) could counteract the effect of free radicals, improving the clinical evolution of patients admitted to the Intensive Care Unit (ICU). This study aimed to investigate the clinical and biochemical effects of administering NAC to critically ill patients with COVID-19. A randomized controlled clinical trial was conducted on ICU patients (n = 140) with COVID-19 and divided into two groups: patients treated with NAC (NAC-treated group) and patients without NAC treatment (control group). NAC was administered as a continuous infusion with a loading dose and a maintenance dose during the study period (from admission until the third day of ICU stay). NAC-treated patients showed higher PaO2/FiO2 (p ≤ 0.014) after 3 days in ICU than their control group counterparts. Moreover, C-reactive protein (p ≤ 0.001), D-dimer (p ≤ 0.042), and lactate dehydrogenase (p ≤ 0.001) levels decreased on the third day in NAC-treated patients. Glutathione concentrations decreased in both NAC-treated (p ≤ 0.004) and control (p ≤ 0.047) groups after 3 days in ICU; whereas glutathione peroxidase did not change during the ICU stay. The administration of NAC manages to improve the clinical and analytical response of seriously ill patients with COVID-19 compared to the control group. NAC is able to stop the decrease in glutathione concentrations.
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Affiliation(s)
| | - Lourdes Herrera-Quintana
- Department of Physiology, School of Pharmacy, Institute of Nutrition and Food Technology "José Mataix", University of Granada, 18071 Granada, Spain
| | - Jorge Molina-López
- Faculty of Education, Psychology and Sports Sciences, University of Huelva, 21007 Huelva, Spain
| | - Héctor Vázquez-Lorente
- Department of Physiology, School of Pharmacy, Institute of Nutrition and Food Technology "José Mataix", University of Granada, 18071 Granada, Spain
| | | | - José Castaño-Pérez
- Intensive Care Unit, Virgen de las Nieves Hospital, Fuerzas Armadas Avenue, 18014 Granada, Spain
| | | | - Elena Planells
- Department of Physiology, School of Pharmacy, Institute of Nutrition and Food Technology "José Mataix", University of Granada, 18071 Granada, Spain
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17
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Schloss JV. Nutritional deficiencies that may predispose to long COVID. Inflammopharmacology 2023; 31:573-583. [PMID: 36920723 PMCID: PMC10015545 DOI: 10.1007/s10787-023-01183-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 02/28/2023] [Indexed: 03/16/2023]
Abstract
Multiple nutritional deficiencies (MND) confound studies designed to assess the role of a single nutrient in contributing to the initiation and progression of disease states. Despite the perception of many healthcare practitioners, up to 25% of Americans are deficient in five-or-more essential nutrients. Stress associated with the COVID-19 pandemic further increases the prevalence of deficiency states. Viral infections compete for crucial nutrients with immune cells. Viral replication and proliferation of immunocompetent cells critical to the host response require these essential nutrients, including zinc. Clinical studies have linked levels of more than 22 different dietary components to the likelihood of COVID-19 infection and the severity of the disease. People at higher risk of infection due to MND are also more likely to have long-term sequelae, known as Long COVID.
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Affiliation(s)
- John V Schloss
- Departments of Pharmaceutical Science and Biochemistry & Molecular Biology, Schools of Pharmacy and Medicine, American University of Health Sciences, 1600 East Hill St., Signal Hill, CA, 90755, USA.
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18
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Chen CH, Hung KF, Huang CY, Leong JL, Chu YC, Chang CY, Wang ML, Chiou SH, Cheng YF. Is N -acetylcysteine effective in treating patients with coronavirus disease 2019? A meta-analysis. J Chin Med Assoc 2023; 86:274-281. [PMID: 36728396 DOI: 10.1097/jcma.0000000000000869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has brought tremendous challenges to public health and medical systems around the world. The current strategy for drug repurposing has accumulated some evidence on the use of N -acetylcysteine (NAC) in treating patients with COVID-19. However, the evidence remains debated. METHODS We performed the systematic review and meta-analysis that complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five databases and reference lists were searched from inception to May 14, 2022. Studies evaluating the efficacy of NAC in treating patients with COVID-19 were regarded as eligible. The review was registered prospectively on PROSPERO (CRD42022332791). RESULTS Of 778 records identified from the preliminary search, four studies were enrolled in the final qualitative review and quantitative meta-analysis. A total of 355 patients were allocated into the NAC group and the control group. The evaluated outcomes included intubation rate, improvement, duration of intensive unit stay and hospital stay and mortality. The pooled results showed nonsignificant differences in intubation rate (OR, 0.55; 95% CI, 0.16-1.89; p = 0.34; I2 = 75%), improvement of oxygenation ([MD], 80.84; 95% CI, -38.16 to 199.84; p = 0.18; I2 = 98%), ICU stay (MD, -0.74; 95% CI, -3.19 to 1.71; p = 0.55; I2 = 95%), hospital stay (MD, -1.05; 95% CI, -3.02 to 0.92; p = 0.30; I2 = 90%), and mortality (OR, 0.58; 95% CI, 0.23-1.45; p = 0.24; I2 = 54%). Subsequent trial sequential analysis (TSA) showed conclusive nonsignificant results for mortality, while the TSA for the other outcomes suggested that a larger sample size is essential. CONCLUSIONS The current evidence reveals NAC is not beneficial for treating patients with COVID- 19 with regard to respiratory outcome, mortality, duration of ICU stay and hospital stay.
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Affiliation(s)
- Chih-Hao Chen
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Kai-Feng Hung
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chii-Yuan Huang
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Jing-Li Leong
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yuan-Chia Chu
- Information Management Office, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Medical AI Development Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Information Management, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, ROC
| | - Chun-Yu Chang
- Department of Anesthesiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, ROC
| | - Mong-Lien Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Anesthesiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, ROC
- Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yen-Fu Cheng
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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19
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Efficacy of N-acetyl Cysteine in Severe COVID-19 Patients: A Randomized Controlled Phase III Clinical Trial. Jundishapur J Nat Pharm Prod 2023. [DOI: 10.5812/jjnpp-129817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023] Open
Abstract
Background: Today, various drugs have been investigated as the primary or complementary treatment for coronavirus disease 2019 (COVID-19). N-acetylcysteine (NAC) has been used as a mucolytic in pulmonary diseases. This drug apparently contributes to the retrieval of the intracellular antioxidant system. Objectives: This study aimed to determine the efficacy of NAC in severe COVID-19 patients admitted to the intensive care unit (ICU). Methods: This single-blinded randomized controlled phase III clinical trial included 40 patients with confirmed COVID-19 (based on polymerase chain reaction) admitted to the Shahid Mohammadi Hospital’s ICU, Bandar Abbas, Iran, in 2020. All cases had severe COVID-19. They were allocated randomly to two equal groups. Patients in the control group received standard drug therapy based on the treatment protocol of the national COVID-19 committee, while those in the NAC group received a single dose of intravenous NAC (300 mg/kg) upon admission to the ICU in addition to standard drug treatment. Clinical status and laboratory tests were done on admission to the ICU and then 14 days later or at discharge without knowing the patient grouping. Results: The two groups were comparable regarding age, gender, and other baseline laboratory and clinical parameters. At the final evaluation, respiratory rate (21.25 ± 4.67 vs. 27.37 ± 6.99 /min) and D-dimer (186.37 ± 410.23 vs. 1339.04 ± 2183.87 ng/mL) were significantly lower in the NAC group (P = 0.004 and P = 0.030, respectively). Also, a lower percentage of patients in the NAC group had lactate dehydrogenase (LDH) ≤ 245 U/L (0% vs. 25%, P = 0.047). Although the length of ward and ICU stay was shorter in the NAC group than in controls, the difference was statistically insignificant (P = 0.598 and P = 0.629, respectively). Mortality, on the other hand, was 75% in the control group and 50% in the NAC group, with no statistically significant difference (P = 0.102). Concerning the change in the study parameters, only the decrease in diastolic blood pressure (DBP) was significantly higher with NAC (P = 0.042). The intubation and mechanical ventilation rates were higher, while oxygen with mask and nasal oxygen rates were lower with NAC, but the difference was statistically insignificant. Conclusions: Based on the current research, NAC is related to a significant decrease in RR, D-dimer, and DBP in severe COVID-19. Also, LDH was significantly lower in the NAC group than in the controls. More research with larger sample sizes is needed to validate the current study results.
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20
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Afaghi S, Moghimi N, Malekpour Alamdari N, Rahimi FS, Irilouzadian R, Esmaeili Tarki F, Moghimi M, Besharat S, Salehi Omran H, Karimi A. N-acetylcysteine as adjuvant therapy for hospitalized Covid-19 patients: A single-center prospective cohort study. CASPIAN JOURNAL OF INTERNAL MEDICINE 2023; 14:543-552. [PMID: 37520878 PMCID: PMC10379801 DOI: 10.22088/cjim.14.3.553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 09/18/2022] [Accepted: 10/29/2022] [Indexed: 08/01/2023]
Abstract
Background Whilst over two years have passed since the COVID-19 pandemic's emergence, the proper management of the disease remains challenging. N-acetylcysteine (NAC) as a potentially effective therapeutic option has been suggested by studies, while the exact clinical role of this agent is yet to be evaluated. Methods This prospective case-control study was conducted in a major referral respiratory center in Tehran, Iran. We enrolled 217 patients treated with an intravenous daily dose of 1500 mg NAC as a case group; and 245 control patients who did not receive NAC. Two groups were matched based on other treatments, socio-demographics, medical history, and comorbidities. Results After ten days of adjuvant therapy with NAC, patients in the NAC group and control group had median room-air SpO2 of 91% and 88%, respectively (P=0.02). Also, the SpO2 to FiO2 ratio had a median of 463 and 421 in the case and control groups, respectively (P=0.01). Furthermore, the case group's hospitalization period was three days shorter (P=0.002). Further, cough, dyspnea, and decreased appetite were reported to have a significantly lower incidence in the case group (P=0.03, 0.001, 0.008). Conclusion We showed that a daily intravenous dose of NAC in hospitalized COVID-19 patients could shorten the hospital stay and improve some clinical symptoms; however, it does not remarkably improve the risk of ICU admission and the 28 days in-hospital mortality rate.
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Affiliation(s)
- Siamak Afaghi
- Research Institute of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- : Co-first authors co-equally contributed to this study
| | - Negin Moghimi
- Research Institute of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- : Co-first authors co-equally contributed to this study
| | - Nasser Malekpour Alamdari
- Clinical Research and Development Center, Department of Surgery, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Sadat Rahimi
- Clinical Research and Development Center, Department of Surgery, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rana Irilouzadian
- Research Institute of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Esmaeili Tarki
- Clinical Research and Development Center, Department of Surgery, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Morvarid Moghimi
- School of Chemical Engineering, Faculty of Engineering, University of Tehran, Tehran, Iran
| | - Sara Besharat
- Department of Radiology, Shahid Labafi Nejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Salehi Omran
- Clinical Research and Development Center, Department of Surgery, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anita Karimi
- Research Institute of Internal Medicine, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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21
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Panahi Y, Ghanei M, Rahimi M, Samim A, Vahedian‐Azimi A, Atkin SL, Sahebkar A. Evaluation the efficacy and safety of N-acetylcysteine inhalation spray in controlling the symptoms of patients with COVID-19: An open-label randomized controlled clinical trial. J Med Virol 2023; 95:e28393. [PMID: 36495185 PMCID: PMC9878233 DOI: 10.1002/jmv.28393] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 10/07/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
The aim of this study was to evaluate the effect and safety of N-acetylcysteine (NAC) inhalation spray in the treatment of patients with coronavirus disease 2019 (COVID-19). This randomized controlled clinical trial study was conducted on patients with COVID-19. Eligible patients (n = 250) were randomly allocated into the intervention group (routine treatment + NAC inhaler spray one puff per 12 h, for 7 days) or the control group who received routine treatment alone. Clinical features, hemodynamic, hematological, biochemical parameters and patient outcomes were assessed and compared before and after treatment. The mortality rate was significantly higher in the control group than in the intervention group (39.2% vs. 3.2%, p < 0.001). Significant differences were found between the two groups (intervention and control, respectively) for white blood cell count (6.2 vs. 7.8, p < 0.001), hemoglobin (12.3 vs. 13.3, p = 0.002), C-reactive protein (CRP: 6 vs. 11.5, p < 0.0001) and aspartate aminotransferase (AST: 32 vs. 25.5, p < 0.0001). No differences were seen for hospital length of stay (11.98 ± 3.61 vs. 11.81 ± 3.52, p = 0.814) or the requirement for intensive care unit (ICU) admission (7.2% vs. 11.2%, p = 0.274). NAC was beneficial in reducing the mortality rate in patients with COVID-19 and inflammatory parameters, and a reduction in the development of severe respiratory failure; however, it did not affect the length of hospital stay or the need for ICU admission. Data on the effectiveness of NAC for Severe Acute Respiratory Syndrome Coronavirus-2 is limited and further research is required.
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Affiliation(s)
- Yunes Panahi
- Pharmacotherapy Department, School of PharmacyBaqiyatallah University of Medical SciencesTehranIran
| | - Mostafa Ghanei
- Chemical Injuries Center, Systems Biology and Poisoning InstituteBaqiyatallah University of Medical SciencesTehranIran
| | - Morteza Rahimi
- Chemical Injuries Center, Systems Biology and Poisoning InstituteBaqiyatallah University of Medical SciencesTehranIran
| | - Abbas Samim
- Chemical Injuries Center, Systems Biology and Poisoning InstituteBaqiyatallah University of Medical SciencesTehranIran
| | - Amir Vahedian‐Azimi
- Trauma Research Center, Nursing FacultyBaqiyatallah University of Medical SciencesTehranIran
| | - Stephen L. Atkin
- School of Postgraduate Studies and ResearchRCSI Medical University of BahrainBusaiteenKingdom of Bahrain
| | - Amirhossein Sahebkar
- Applied Biomedical Research CenterMashhad University of Medical SciencesMashhadIran,Biotechnology Research Center, Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran,Department of Biotechnology, School of PharmacyMashhad University of Medical SciencesMashhadIran
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22
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Izquierdo-Alonso JL, Pérez-Rial S, Rivera CG, Peces-Barba G. N-acetylcysteine for prevention and treatment of COVID-19: Current state of evidence and future directions. J Infect Public Health 2022; 15:1477-1483. [PMID: 36410267 PMCID: PMC9651994 DOI: 10.1016/j.jiph.2022.11.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 08/01/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19) and can be associated with serious complications, including acute respiratory distress syndrome. This condition is accompanied by a massive release of cytokines, also denominated cytokine storm, development of systemic oxidative stress and a prothrombotic state. In this context, it has been proposed a role for acetylcysteine (NAC) in the management of patients with COVID-19. NAC is a molecule classically known for its mucolytic effect, but it also has direct and indirect antioxidant activity as a precursor of reduced glutathione. Other effects of NAC have also been described, such as modulating the immune and inflammatory response, counteracting the thrombotic state, and having an antiviral effect. The pharmacological activities of NAC and its effects on the mechanisms of disease progression make it a potential therapeutic agent for COVID-19. NAC is safe, tolerable, affordable, and easily available. Moreover, the antioxidant effects of the molecule may even prevent infection and play an important role as a complement to vaccination. Although the clinical efficacy and dosing regimens of NAC have been evaluated in the clinical setting with small series of patients, the results are promising. In this article, we review the pathogenesis of SARS-CoV-2 infection and the current knowledge of the mechanisms of action of NAC across disease stages. We also propose NAC posology strategies to manage COVID-19 patients in different clinical scenarios.
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Affiliation(s)
- José Luis Izquierdo-Alonso
- Servicio de Neumología, Gerencia de Atención Integrada de Guadalajara, Spain,Correspondence to: Gerencia de Atención Integrada de Guadalajara, C/Donante de sangre, s/n, 19002 Guadalajara, Spain
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23
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Milara J, Martínez-Expósito F, Montero P, Roger I, Bayarri MA, Ribera P, Oishi-Konari MN, Alba-García JR, Zapater E, Cortijo J. N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro. Int J Mol Sci 2022; 23:ijms232314518. [PMID: 36498845 PMCID: PMC9738300 DOI: 10.3390/ijms232314518] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/17/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022] Open
Abstract
Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.
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Affiliation(s)
- Javier Milara
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain
- Pharmacy Unit, University General Hospital Consortium, 46014 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Health Institute Carlos III, 46014 Valencia, Spain
- Correspondence:
| | | | - Paula Montero
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain
- Faculty of Health Sciences, Universidad Europea de Valencia, 46010 Valencia, Spain
| | - Inés Roger
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Health Institute Carlos III, 46014 Valencia, Spain
- Faculty of Health Sciences, Universidad Europea de Valencia, 46010 Valencia, Spain
| | - Maria Amparo Bayarri
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain
| | - Pilar Ribera
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain
| | | | - Jose Ramón Alba-García
- ENT Department, Consorci Hospital General Universitari de Valencia, 46014 Valencia, Spain
| | - Enrique Zapater
- ENT Department, Consorci Hospital General Universitari de Valencia, 46014 Valencia, Spain
| | - Julio Cortijo
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Health Institute Carlos III, 46014 Valencia, Spain
- Research and Teaching Unit, University General Hospital Consortium, 46014 Valencia, Spain
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24
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Garbern SC, Relan P, O’Reilly GM, Bills CB, Schultz M, Trehan I, Kivlehan SM, Becker TK. A systematic review of acute and emergency care interventions for adolescents and adults with severe acute respiratory infections including COVID-19 in low- and middle-income countries. J Glob Health 2022; 12:05039. [DOI: 10.7189/jogh.12.05039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Stephanie Chow Garbern
- Department of Emergency Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Pryanka Relan
- Department of Emergency Medicine, Emory Healthcare Network, Atlanta, Georgia, USA
| | - Gerard M O’Reilly
- Emergency and Trauma Centre, The Alfred, Melbourne, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Corey B Bills
- Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Megan Schultz
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Indi Trehan
- Departments of Pediatrics, Global Health, and Epidemiology, University of Washington, Seattle, Washington, USA
| | - Sean M Kivlehan
- Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Humanitarian Initiative, Cambridge, Massachusetts, USA
| | - Torben K Becker
- Department of Emergency Medicine, University of Florida, Gainesville, Florida, USA
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25
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Cormier SA, Yamamoto A, Short KR, Vu L, Suk WA. Environmental Impacts on COVID-19: Mechanisms of Increased Susceptibility. Ann Glob Health 2022; 88:94. [PMID: 36348703 PMCID: PMC9585976 DOI: 10.5334/aogh.3907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/28/2022] [Indexed: 11/20/2022] Open
Abstract
Background Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in >554M cases and >6.3M deaths worldwide. The disease caused by SARS-CoV-2, COVID-19, has resulted in a broad range of clinical symptoms differing in severity. Initially, the elderly were identified as particularly susceptible to severe COVID-19, with children experiencing less severe disease. However, as new variants arise, the epidemiology of SARS-CoV-2 infection is changing, and the disease severity in children is increasing. While environmental impacts on COVID-19 have been described, the underlying mechanisms are poorly described. Objective The Pacific Basin Consortium for Environment and Health (PBC) held meeting on September 16, 2021, to explore environmental impacts on infectious diseases, including COVID-19. Methods The PBC is an international group of environmental scientists and those interested in health outcomes. The PBC met to present preliminary data and discuss the role of exposures to airborne pollutants in enhancing susceptibility to and severity of respiratory tract viral infections, including COVID-19. Findings Analysis of the literature and data presented identified age as an important factor in vulnerability to air pollution and enhanced COVID-19 susceptibility and severity. Mechanisms involved in increasing severity of COVID-19 were discussed, and gaps in knowledge were identified. Conclusions Exposure to particulate matter (PM) pollution enhanced morbidity and mortality to COVID-19 in a pediatric population associated with induction of oxidative stress. In addition, free radicals present on PM can induce rapid changes in the viral genome that can lead to vaccine escape, altered host susceptibility, and viral pathogenicity. Nutritional antioxidant supplements have been shown to reduce the severity of viral infections, inhibit the inflammatory cytokine storm, and boost host immunity and may be of benefit in combating COVID-19.
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Affiliation(s)
- Stephania A. Cormier
- Louisiana State University, Department of Biological Sciences, and Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Ayaho Yamamoto
- The University of Queensland, Child Health Research Centre, South Brisbane, QLD, Australia
| | - Kirsty R. Short
- The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, QLD, Australia
| | - Luan Vu
- Louisiana State University, Department of Biological Sciences, and Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - William A. Suk
- National Institute of Environmental Health Sciences, Superfund Research Program, 530 Davis Drive, Durham, NC, USA
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26
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Cheng Q, Zhao G, Chen J, Jia Q, Fang Z. Comparative efficacy and safety of pharmacological interventions for severe COVID-19 patients: An updated network meta-analysis of 48 randomized controlled trials. Medicine (Baltimore) 2022; 101:e30998. [PMID: 36254081 PMCID: PMC9575403 DOI: 10.1097/md.0000000000030998] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND To date, there has been little agreement on what drug is the "best" drug for treating severe COVID-19 patients. This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19. METHODS We searched databases for randomized controlled trials (RCTs) published up to February 28, 2022, with no language restrictions, of medications recommended for patients (aged 16 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). RESULTS We identified 4021 abstracts and of these included 48 RCTs comprising 9147 participants through database searches and other sources. For decrease in ACM, we found that ivermectin/doxycycline, C-IVIG (i.e., a hyperimmune anti-COVID-19 intravenous immunoglobulin), methylprednisolone, interferon-beta/standard-of-care (SOC), interferon-beta-1b, convalescent plasma, remdesivir, lopinavir/ritonavir, immunoglobulin gamma, high dosage sarilumab (HS), auxora, and imatinib were effective when compared with placebo or SOC group. We found that colchicine and interferon-beta/SOC were only associated with the TEAEs of severe COVID-19 patients. CONCLUSION This study suggested that ivermectin/doxycycline, C-IVIG, methylprednisolone, interferon-beta/SOC, interferon-beta-1b, convalescent plasma (CP), remdesivir, lopinavir/ritonavir, immunoglobulin gamma, HS, auxora, and imatinib were efficacious for treating severe COVID-19 patients. We found that most medications were safe in treating severe COVID-19. More large-scale RCTs are still needed to confirm the results of this study.
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Affiliation(s)
- Qinglin Cheng
- Hangzhou Center for Disease Control and Prevention, Hangzhou, China
- School of Medicine, Hangzhou Normal University, Hangzhou, China
- *Correspondence: Qinglin Cheng, Division of Infectious Diseases, Hangzhou Center for Disease Control and Prevention, 568 Mingshi Road, Hangzhou 310021, China (e-mail: )
| | - Gang Zhao
- Hangzhou Center for Disease Control and Prevention, Hangzhou, China
| | - Junfang Chen
- Hangzhou Center for Disease Control and Prevention, Hangzhou, China
| | - Qingjun Jia
- Hangzhou Center for Disease Control and Prevention, Hangzhou, China
| | - Zijian Fang
- Hangzhou Center for Disease Control and Prevention, Hangzhou, China
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27
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Ngo ATP, Gollomp K. Building a better
NET
: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders. Res Pract Thromb Haemost 2022. [DOI: 10.1002/rth2.12808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Affiliation(s)
- Anh T. P. Ngo
- Division of Hematology Children's Hospital of Philadelphia Philadelphia Pennsylvania USA
| | - Kandace Gollomp
- Division of Hematology Children's Hospital of Philadelphia Philadelphia Pennsylvania USA
- Department of Pediatrics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA
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28
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Avdeev SN. COVID-19: Opportunities to Improve Prognosis. HERALD OF THE RUSSIAN ACADEMY OF SCIENCES 2022; 92:404-411. [PMID: 36091855 PMCID: PMC9447977 DOI: 10.1134/s1019331622040025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/03/2022] [Accepted: 03/10/2022] [Indexed: 06/15/2023]
Abstract
COVID-19 is characterized by a severe course in approximately 5‒10% of patients, who require admittance to the intensive care unit and mechanical ventilation, which is associated with a very high risk of a poor prognosis. At present, in real clinical practice, in managing severe patients with COVID-19, noninvasive ventilation (NIV) is widely used (in some countries, up to 60% of all methods of respiratory support). In most studies on the effectiveness of NIV in hypoxemic acute respiratory failure in patients with COVID-19, the need for tracheal intubation and hospital mortality with the use of NIV averaged 20-30%, which suggests the rather high efficiency of this method. The COVID-19 pandemic has given a powerful impetus to the widespread use of prone positioning among nonintubated patients with acute respiratory failure caused by COVID-19. Several studies have shown that prone positioning can reduce the need for mechanical ventilation and hospital mortality. Medications that have proven effective in severe forms of COVID-19 include remdesivir, systemic glucocorticoids, tocilizumab, baricitinib, and anticoagulants. Among the new promising areas of drug therapy, noteworthy is the use of thiol-containing drugs (N-acetylcysteine), inhaled surfactant, and inhaled prostacyclin analogues.
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Affiliation(s)
- S. N. Avdeev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Pulmonology Research Institute, Federal Medical‒Biological Agency, Moscow, Russia
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29
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Tsermpini EE, Glamočlija U, Ulucan-Karnak F, Redenšek Trampuž S, Dolžan V. Molecular Mechanisms Related to Responses to Oxidative Stress and Antioxidative Therapies in COVID-19: A Systematic Review. Antioxidants (Basel) 2022; 11:1609. [PMID: 36009328 PMCID: PMC9405444 DOI: 10.3390/antiox11081609] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/25/2022] Open
Abstract
The coronavirus disease (COVID-19) pandemic is a leading global health and economic challenge. What defines the disease's progression is not entirely understood, but there are strong indications that oxidative stress and the defense against reactive oxygen species are crucial players. A big influx of immune cells to the site of infection is marked by the increase in reactive oxygen and nitrogen species. Our article aims to highlight the critical role of oxidative stress in the emergence and severity of COVID-19 and, more importantly, to shed light on the underlying molecular and genetic mechanisms. We have reviewed the available literature and clinical trials to extract the relevant genetic variants within the oxidative stress pathway associated with COVID-19 and the anti-oxidative therapies currently evaluated in the clinical trials for COVID-19 treatment, in particular clinical trials on glutathione and N-acetylcysteine.
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Affiliation(s)
- Evangelia Eirini Tsermpini
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Una Glamočlija
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Pharmacy, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina
- School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Fulden Ulucan-Karnak
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Department of Medical Biochemistry, Faculty of Medicine, Ege University, Bornova, 35100 İzmir, Turkey
| | - Sara Redenšek Trampuž
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Vita Dolžan
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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30
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du Preez HN, Aldous C, Kruger HG, Johnson L. N-Acetylcysteine and Other Sulfur-Donors as a Preventative and Adjunct Therapy for COVID-19. Adv Pharmacol Pharm Sci 2022; 2022:4555490. [PMID: 35992575 PMCID: PMC9385285 DOI: 10.1155/2022/4555490] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/07/2022] [Indexed: 12/11/2022] Open
Abstract
The airway epithelial glycocalyx plays an important role in preventing severe acute respiratory syndrome coronavirus 2 entry into the epithelial cells, while the endothelial glycocalyx contributes to vascular permeability and tone, as well as modulating immune, inflammatory, and coagulation responses. With ample evidence in the scientific literature that coronavirus disease 2019 (COVID-19) is related to epithelial and endothelial dysfunction, preserving the glycocalyx should be the main focus of any COVID-19 treatment protocol. The most studied functional unit of the glycocalyx is the glycosaminoglycan heparan sulfate, where the degree and position of the sulfate groups determine the biological activity. N-acetylcysteine (NAC) and other sulfur donors contribute to the inorganic sulfate pool, the rate-limiting molecule in sulfation. NAC is not only a precursor to glutathione but also converts to hydrogen sulfide, inorganic sulfate, taurine, Coenzyme A, and albumin. By optimising inorganic sulfate availability, and therefore sulfation, it is proposed that COVID-19 can be prevented or at least most of the symptoms attenuated. A comprehensive COVID-19 treatment protocol is needed to preserve the glycocalyx in both the prevention and treatment of COVID-19. The use of NAC at a dosage of 600 mg bid for the prevention of COVID-19 is proposed, but a higher dosage of NAC (1200 mg bid) should be administered upon the first onset of symptoms. In the severe to critically ill, it is advised that IV NAC should be administered immediately upon hospital admission, and in the late stage of the disease, IV sodium thiosulfate should be considered. Doxycycline as a protease inhibitor will prevent shedding and further degradation of the glycocalyx.
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Affiliation(s)
- Heidi N du Preez
- Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Westville Campus, Durban, South Africa
| | - Colleen Aldous
- College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Hendrik G Kruger
- Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Westville Campus, Durban, South Africa
| | - Lin Johnson
- School of Life Sciences, University of KwaZulu-Natal, Durban, South Africa
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Chen Y, Xu Y, Zhang K, Shen L, Deng M. Ferroptosis in COVID-19-related liver injury: A potential mechanism and therapeutic target. Front Cell Infect Microbiol 2022; 12:922511. [PMID: 35967872 PMCID: PMC9363633 DOI: 10.3389/fcimb.2022.922511] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/01/2022] [Indexed: 01/08/2023] Open
Abstract
The outbreak and worldwide spread of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a threat to global public health. SARS-CoV-2 infection not only impacts the respiratory system but also causes hepatic injury. Ferroptosis, a distinct iron-dependent form of non-apoptotic cell death, has been investigated in various pathological conditions, such as cancer, ischemia/reperfusion injury, and liver diseases. However, whether ferroptosis takes part in the pathophysiological process of COVID-19-related liver injury has not been evaluated yet. This review highlights the pathological changes in COVID-19-related liver injury and presents ferroptosis as a potential mechanism in the pathological process. Ferroptosis, as a therapeutic target for COVID-19-related liver injury, is also discussed. Discoveries in these areas will improve our understanding of strategies to prevent and treat hepatic injuries caused by COVID-19.
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Affiliation(s)
- Yunqing Chen
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
- *Correspondence: Yunqing Chen,
| | - Yan Xu
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Kan Zhang
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Liang Shen
- Department of Cardiology, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Min Deng
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, China
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Moslemi M, Hejazian SM, Shaddelan M, Javanali F, Mirghaffari A, Sadeghi A, Valizadeh H, Sharifi A, Haramshahi M, Ardalan M, Zununi Vahed S. Evaluating the effect of Edaravone on clinical outcome of patients with severe COVID-19 admitted to ICU: a randomized clinical trial. Inflammopharmacology 2022; 30:1277-1282. [PMID: 35723849 PMCID: PMC9207828 DOI: 10.1007/s10787-022-01001-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 11/11/2022]
Abstract
Cytokine storm is the most prominent hallmark in patients with coronavirus disease 2019 (COVID-19) that stimulates the free radical storm, both of which induce an overactive immune response during viral infection. We hypothesized that owning to its radical-scavenging and anti-inflammatory properties, Edaravone could reduce multi-organ injury, clinical complications, and mortality in severe COVID-19 cases. This single-center randomized clinical trial was accompanied in the intensive care units (ICUs) of the teaching hospital of Tabriz University of Medical Sciences to evaluate the effect of Edaravone on the outcome of patients with severe COVID-19. Thirty-eight patients admitted to ICU were included and randomized into two control and intervention arms. Patients in the intervention group received 30 mg Edaravone by slow intravenous infusion for three days in addition to receiving national therapy. The primary outcome was the need for intubation, the intubation length, and mortality rate. Secondary endpoints were clinical improvement. Edaravone administration improved the primary outcomes; it decreased the need for endotracheal intubation and mechanical ventilation [10.52% (n = 2) versus 42.1% (n = 8); p = 0.03] and intubation length [3 (1–7) versus 28 (4–28), p = 0.04] compared to control group. Baseline characteristics and laboratory tests were similar between the studied groups. No marked differences were observed in secondary endpoints (p > 0.05). Administration of Edaravone could decrease the need for mechanical ventilation and length of intubation in severe COVID-19 patients admitted to ICU.
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Affiliation(s)
- Mohammadreza Moslemi
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyedeh Mina Hejazian
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Molod Shaddelan
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Javanali
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Mirghaffari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Armin Sadeghi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Valizadeh
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Akbar Sharifi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Haramshahi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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Li X, Zhang Z, Wang Z, Gutiérrez-Castrellón P, Shi H. Cell deaths: Involvement in the pathogenesis and intervention therapy of COVID-19. Signal Transduct Target Ther 2022; 7:186. [PMID: 35697684 PMCID: PMC9189267 DOI: 10.1038/s41392-022-01043-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/18/2022] [Accepted: 05/26/2022] [Indexed: 02/06/2023] Open
Abstract
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has dramatically influenced various aspects of the world. It is urgent to thoroughly study pathology and underlying mechanisms for developing effective strategies to prevent and treat this threatening disease. It is universally acknowledged that cell death and cell autophagy are essential and crucial to maintaining host homeostasis and participating in disease pathogenesis. At present, more than twenty different types of cell death have been discovered, some parts of which have been fully understood, whereas some of which need more investigation. Increasing studies have indicated that cell death and cell autophagy caused by coronavirus might play an important role in virus infection and pathogenicity. However, the knowledge of the interactions and related mechanisms of SARS-CoV-2 between cell death and cell autophagy lacks systematic elucidation. Therefore, in this review, we comprehensively delineate how SARS-CoV-2 manipulates diverse cell death (including apoptosis, necroptosis, pyroptosis, ferroptosis, and NETosis) and cell autophagy for itself benefits, which is simultaneously involved in the occurrence and progression of COVID-19, aiming to provide a reasonable basis for the existing interventions and further development of novel therapies.
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Affiliation(s)
- Xue Li
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Ziqi Zhang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Zhenling Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Ke Yuan 4th Road, Gao Peng Street, Chengdu, Sichuan, 610041, People's Republic of China
| | - Pedro Gutiérrez-Castrellón
- Center for Translational Research on Health Science, Hospital General Dr. Manuel Gea Gonzalez. Ministry of Health, Calz. Tlalpan 4800, Col. Secc. XVI, 14080, Mexico city, Mexico.
| | - Huashan Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
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How to Restore Oxidative Balance That Was Disrupted by SARS-CoV-2 Infection. Int J Mol Sci 2022; 23:ijms23126377. [PMID: 35742820 PMCID: PMC9223498 DOI: 10.3390/ijms23126377] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/04/2022] [Accepted: 06/05/2022] [Indexed: 12/17/2022] Open
Abstract
Coronavirus 2019 disease (COVID-19) is caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December of 2019. COVID-19 pathogenesis is complex and involves a dysregulated renin angiotensin system. Severe courses of the disease are associated with a dysregulated immunological response known as cytokine storm. Many scientists have demonstrated that SARS-CoV-2 impacts oxidative homeostasis and stimulates the production of reactive oxygen species (ROS). In addition, the virus inhibits glutathione (GSH) and nuclear factor erythroid 2-related factor 2 (NRF2)-a major antioxidant which induces expression of protective proteins and prevents ROS damage. Furthermore, the virus stimulates NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes which play a significant role in inducing a cytokine storm. A variety of agents with antioxidant properties have shown beneficial effects in experimental and clinical studies of COVID-19. This review aims to present mechanisms of oxidative stress induced by SARS-CoV-2 and to discuss whether antioxidative drugs can counteract detrimental outcomes of a cytokine storm.
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Chen B, Raja K, Pierre-Louis F, Patel M, Patel R, Kang S, Daniel N, Attalla M, Philips M. Intravenous N-Acetylcysteine in Management of COVID-19: A Case Series. J Pharm Pract 2022:8971900221080283. [PMID: 35331045 PMCID: PMC8958286 DOI: 10.1177/08971900221080283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A novel coronavirus, severe acute respiratory syndrome coronavirus-2, was isolated from patients’ lower respiratory tracts in December 2019. As of May 19, 2021, there were over 33 million reported infections and almost 600,000 deaths in the United States. The infection, coronavirus disease-19 (COVID-19), can lead to cytokine storm, with elevations in interleukin-6 (IL-6), IL-10, tumor necrosis factor-α, nuclear factor-kappaB (NF-kappaB), and glutathione reductase. NF-kappaB activation is necessary for further transcription of other pro-inflammatory markers. Glutathione may play a role in modulation of NF-kappaB activation and elevated glutathione reductase may indicate glutathione depletion. Administration of N-acetylcysteine (NAC) may replenish spent glutathione and attenuate over-activation of NF-kappaB. This retrospective case series included 10 patients who were COVID-19 positive and received intravenous NAC in an attempt to attenuate the cytokine storm. Patients’ outcomes were graded based on the World Health Organization symptom severity scale from 0, no evidence of infection, to 8, death. Overall, the median WHO Scale prior to NAC was 6.5, and increased by day seven, which indicated clinical worsening. This retrospective case series showed no benefit of NAC; however, further studies are needed to elucidate if differences in drug regimens would lead to positive results.
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Affiliation(s)
- Brandon Chen
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Karan Raja
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | | | - Mitesh Patel
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Ruben Patel
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Soo Kang
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Nicole Daniel
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Mark Attalla
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
| | - Mona Philips
- Pharmacy Department, 24050Clara Maass Medical Center, Belleville, NJ, USA
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Bellanti F, Lo Buglio A, Vendemiale G. Redox Homeostasis and Immune Alterations in Coronavirus Disease-19. BIOLOGY 2022; 11:159. [PMID: 35205026 PMCID: PMC8869285 DOI: 10.3390/biology11020159] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 02/05/2023]
Abstract
The global Coronavirus Disease 2019 (COVID-19) pandemic is characterized by a wide variety of clinical features, from no or moderate symptoms to severe illness. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that first affects the respiratory tract. Other than being limited to lungs, SARS-CoV-2 may lead to a multisystem disease that can even be durable (long COVID). The clinical spectrum of COVID-19 depends on variability in the immune regulation. Indeed, disease progression is consequent to failure in the immune regulation, characterized by an intensification of the pro-inflammatory response. Disturbance of systemic and organ-related redox balance may be a further mechanism underlying variability in COVID-19 severity. Other than being determinant for SARS-CoV-2 entry and fusion to the host cell, reactive species and redox signaling are deeply involved in the immune response. This review sums up the present knowledge on the role of redox balance in the regulation of susceptibility to SARS-CoV-2 infection and related immune response, debating the effectiveness of antioxidant compounds in the management of COVID-19.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy; (A.L.B.); (G.V.)
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Liu J, Dean DA. Gene Therapy for Acute Respiratory Distress Syndrome. Front Physiol 2022; 12:786255. [PMID: 35111077 PMCID: PMC8801611 DOI: 10.3389/fphys.2021.786255] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome that leads to acute respiratory failure and accounts for over 70,000 deaths per year in the United States alone, even prior to the COVID-19 pandemic. While its molecular details have been teased apart and its pathophysiology largely established over the past 30 years, relatively few pharmacological advances in treatment have been made based on this knowledge. Indeed, mortality remains very close to what it was 30 years ago. As an alternative to traditional pharmacological approaches, gene therapy offers a highly controlled and targeted strategy to treat the disease at the molecular level. Although there is no single gene or combination of genes responsible for ARDS, there are a number of genes that can be targeted for upregulation or downregulation that could alleviate many of the symptoms and address the underlying mechanisms of this syndrome. This review will focus on the pathophysiology of ARDS and how gene therapy has been used for prevention and treatment. Strategies for gene delivery to the lung, such as barriers encountered during gene transfer, specific classes of genes that have been targeted, and the outcomes of these approaches on ARDS pathogenesis and resolution will be discussed.
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Affiliation(s)
- Jing Liu
- Department of Pediatrics, University of Rochester, Rochester, NY, United States
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, United States
| | - David A. Dean
- Department of Pediatrics, University of Rochester, Rochester, NY, United States
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, United States
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Dugbartey GJ, Alornyo KK, Ohene BO, Boima V, Antwi S, Sener A. Renal consequences of the novel coronavirus disease 2019 (COVID-19) and hydrogen sulfide as a potential therapy. Nitric Oxide 2022; 120:16-25. [PMID: 35032641 PMCID: PMC8755416 DOI: 10.1016/j.niox.2022.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 12/14/2022]
Abstract
The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H2S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H2S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H2S as a potential COVID-19 therapy.
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Affiliation(s)
- George J Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana.
| | - Karl K Alornyo
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Bright O Ohene
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Vincent Boima
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | - Sampson Antwi
- Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology and Komfo Anokye Teaching Hospital, Kumasi, Ghana
| | - Alp Sener
- Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, Ontario, Canada; Multi-organ Transplant Program, London Health Sciences Center, Ontario, Canada; Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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Mousapour P, Hamidi Farahani R, Mosaed R, Asgari A, Hazrati E. Efficacy and safety of acetylcysteine for the prevention of liver injury in COVID-19 intensive care unit patients under treatment with remdesivir. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2022; 15:241-248. [PMID: 36311968 PMCID: PMC9589135 DOI: 10.22037/ghfbb.v15i3.2565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/29/2022] [Indexed: 11/30/2022]
Abstract
AIM The present double-blinded placebo-controlled randomized clinical trial evaluated prophylactic use of acetylcysteine for the prevention of liver injury in patients with severe COVID-19 pneumonia under treatment with remdesivir. BACKGROUND Liver injury is reportedly common in patients with severe COVID-19 pneumonia and can occur not only as a result of disease progression, but as an iatrogenic reaction to remdesivir. METHODS A total of 83 adult patients with severe COVID-19 pneumonia were randomly assigned in parallel groups to receive either acetylcysteine or placebo. All the patients received standard care according to institutional protocols, including remdesivir for a total of five days. One gram acetylcysteine was administered intravenously every 12 hours for 42 patients, and 41 patients received the same volume of 0.9% sodium chloride as placebo (Trial Registration: www.irct.ir identifier, IRCT20210726051995N1). RESULTS After 5 days, median aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in the acetylcysteine than in the placebo group. Of those who received the placebo, 30 (73.2%), 4 (9.7%), and 3 (7.3%) patients had serum AST levels elevated between 1-2.5, 2.5-5, and over 5 times the upper limit of normal (ULN), respectively; while in the acetylcysteine group, 33 (78.6%) and 0 patients had AST levels between 1-2.5 and over 2.5 times ULN, respectively (p-value=0.037). In the acetylcysteine group, 23 (54.8%), 1 (2.4%), and 1 (2.4%) patient had serum ALT levels elevated between 1-2.5, 2.5-5, and over 5 times ULN, respectively; in the placebo group, however, 24 (58.5%), 7 (17.1%), and 1 (2.4%) patient had serum ALT levels between 1-2.5, 2.5-5, and over 5 times ULN, respectively (p-value=0.073). CONCLUSION Intravenous administration of acetylcysteine significantly prevents liver transaminases elevation and liver injury in seriously ill COVID-19 patients treated with remdesivir.
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Affiliation(s)
- Pouria Mousapour
- Department of Anesthesiology and Intensive Care, AJA University of Medical Sciences, Tehran, Iran
| | - Ramin Hamidi Farahani
- Department of Infectious Diseases, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Reza Mosaed
- Department of Clinical Pharmacy, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Ali Asgari
- Department of Infectious Diseases, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Ebrahim Hazrati
- Department of Anesthesiology and Intensive Care, AJA University of Medical Sciences, Tehran, Iran
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Di Girolamo FG, Fiotti N, Sisto UG, Nunnari A, Colla S, Mearelli F, Vinci P, Schincariol P, Biolo G. Skeletal Muscle in Hypoxia and Inflammation: Insights on the COVID-19 Pandemic. Front Nutr 2022; 9:865402. [PMID: 35529457 PMCID: PMC9072827 DOI: 10.3389/fnut.2022.865402] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/09/2022] [Indexed: 12/23/2022] Open
Abstract
SARS-CoV-2 infection is often associated with severe inflammation, oxidative stress, hypoxia and impaired physical activity. These factors all together contribute to muscle wasting and fatigue. In addition, there is evidence of a direct SARS-CoV-2 viral infiltration into skeletal muscle. Aging is often characterized by sarcopenia or sarcopenic obesity These conditions are risk factors for severe acute COVID-19 and long-COVID-19 syndrome. From these observations we may predict a strong association between COVID-19 and decreased muscle mass and functions. While the relationship between physical inactivity, chronic inflammation, oxidative stress and muscle dysfunction is well-known, the effects on muscle mass of COVID-19-related hypoxemia are inadequately investigated. The aim of this review is to highlight metabolic, immunity-related and redox biomarkers potentially affected by reduced oxygen availability and/or muscle fatigue in order to shed light on the negative impact of COVID-19 on muscle mass and function. Possible countermeasures are also reviewed.
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Affiliation(s)
- Filippo G. Di Girolamo
- Department of Medical Surgical ad Health Science, Clinica Medica, Cattinara Hospital, University of Trieste, Trieste, Italy
- SC Assistenza Farmaceutica, Cattinara Hospital, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
- *Correspondence: Filippo G. Di Girolamo
| | - Nicola Fiotti
- Department of Medical Surgical ad Health Science, Clinica Medica, Cattinara Hospital, University of Trieste, Trieste, Italy
| | - Ugo G. Sisto
- Department of Medical Surgical ad Health Science, Clinica Medica, Cattinara Hospital, University of Trieste, Trieste, Italy
| | - Alessio Nunnari
- Department of Medical Surgical ad Health Science, Clinica Medica, Cattinara Hospital, University of Trieste, Trieste, Italy
| | - Stefano Colla
- SC Assistenza Farmaceutica, Cattinara Hospital, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
| | - Filippo Mearelli
- Department of Medical Surgical ad Health Science, Clinica Medica, Cattinara Hospital, University of Trieste, Trieste, Italy
| | - Pierandrea Vinci
- Department of Medical Surgical ad Health Science, Clinica Medica, Cattinara Hospital, University of Trieste, Trieste, Italy
| | - Paolo Schincariol
- SC Assistenza Farmaceutica, Cattinara Hospital, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
| | - Gianni Biolo
- Department of Medical Surgical ad Health Science, Clinica Medica, Cattinara Hospital, University of Trieste, Trieste, Italy
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Faverio P, Rebora P, Rossi E, Del Giudice S, Montanelli F, Garzillo L, Busnelli S, Luppi F, Valsecchi MG, Pesci A. Impact of N-acetyl-l-cysteine on SARS-CoV-2 pneumonia and its sequelae: results from a large cohort study. ERJ Open Res 2021; 8:00542-2021. [PMID: 35136824 PMCID: PMC8646003 DOI: 10.1183/23120541.00542-2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/17/2021] [Indexed: 12/15/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may cause pneumonia and acute respiratory distress syndrome (ARDS), whose pathogenesis has been partially related to an increased systemic inflammatory response with great production of pro-inflammatory cytokines causing a “cytokine storm” and an oxidative stress imbalance [1]. Patients receiving N-acetyl-l-cysteine (NAC) during hospitalisation for #SARSCoV2 pneumonia and discharged alive present a significantly shorter length of hospital stay compared to those who did not receive NAChttps://bit.ly/3l1QsVo
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Sgalla G, Comes A, Lerede M, Richeldi L. COVID-related fibrosis: insights into potential drug targets. Expert Opin Investig Drugs 2021; 30:1183-1195. [PMID: 34842488 DOI: 10.1080/13543784.2021.2010188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and long-lasting impact on the quality of life of COVID-19 survivors. This is an emerging medical need, and it has been hypothesized that antifibrotic treatments could have a role in ameliorating the fibrotic process in the lungs of these patients. AREAS COVERED The safety and efficacy of available antifibrotic drugs (nintedanib and pirfenidone) and novel promising agents are being assessed in several ongoing clinical trials that were performed either in critically ill patients admitted to intensive care, or in discharged patients presenting fibrotic sequalae from COVID-19. Literature search was performed using Medline and Clinicaltrials.org databases (2001-2021). EXPERT OPINION Despite the strong rationale support the use of antifibrotic therapies in COVID-related fibrosis, there are several uncertainties regarding the timing for their introduction and the real risks/benefits ratio of antifibrotic treatment in the acute and the chronic phases of the disease. The findings of ongoing clinical trials and the long-term observation of longitudinal cohorts will eventually clarify the best management approach for these patients.
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Affiliation(s)
- Giacomo Sgalla
- UOC Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Alessia Comes
- Istituto di Medicina Interna Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Marialessia Lerede
- Istituto di Medicina Interna Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Luca Richeldi
- UOC Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.,Istituto di Medicina Interna Università Cattolica Del Sacro Cuore, Roma, Italy
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Xia H, Zhang Z, You F. Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection. Viruses 2021; 13:2383. [PMID: 34960652 PMCID: PMC8708337 DOI: 10.3390/v13122383] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 12/02/2022] Open
Abstract
Murine hepatitis virus strain A59 (MHV-A59) was shown to induce pyroptosis, apoptosis, and necroptosis of infected cells, especially in the murine macrophages. However, whether ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal infection model to address this. In primary macrophages, the ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 infection. To find how MHV-A59 infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel ferroptosis inducer. Using ferroptosis inhibitors and a TLR4 inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that ferroptosis inhibition protects hosts from MHV-A59 infection. Targeting ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus infection.
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Affiliation(s)
| | | | - Fuping You
- Department of Systems Biomedicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; (H.X.); (Z.Z.)
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Alam MS, Czajkowsky DM. SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities. Cytokine Growth Factor Rev 2021; 63:44-57. [PMID: 34836751 PMCID: PMC8591899 DOI: 10.1016/j.cytogfr.2021.11.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 01/08/2023]
Abstract
The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality.
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Affiliation(s)
- Mohammad Shah Alam
- Department of Anatomy and Histology, Bangabandhu Sheikh Mujibur Rahman Agricultural University, Gazipur 1706, Bangladesh.
| | - Daniel M Czajkowsky
- Bio-ID Centre, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
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Bourgonje AR, Offringa AK, van Eijk LE, Abdulle AE, Hillebrands JL, van der Voort PHJ, van Goor H, van Hezik EJ. N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019. Antioxid Redox Signal 2021; 35:1207-1225. [PMID: 33607929 DOI: 10.1089/ars.2020.8247] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Hydrogen sulfide (H2S) is one of the three main gasotransmitters that are endogenously produced in humans and are protective against oxidative stress. Recent findings from studies focusing on coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shifted our attention to a potentially modulatory role of H2S in this viral respiratory disease. Recent Advances: H2S levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant, and anti-inflammatory actions. Furthermore, many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H2S. Critical Issues: Combining H2S physiology and currently available knowledge of COVID-19, H2S is hypothesized to target three main vulnerabilities of SARS-CoV-2: (i) cell entry through interfering with functional host receptors, (ii) viral replication through acting on RNA-dependent RNA polymerase (RdRp), and (iii) the escalation of inflammation to a potentially lethal hyperinflammatory cytokine storm (toll-like receptor 4 [TLR4] pathway and NLR family pyrin domain containing 3 [NLRP3] inflammasome). Future Directions: Dissecting the breakdown of NAC reveals the possibility of increasing endogenous H2S levels, which may provide a convenient rationale for the application of H2S-targeted therapeutics. Further randomized-controlled trials are warranted to investigate its definitive role.
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Affiliation(s)
- Arno R Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Annette K Offringa
- Microbiology and System Biology, Netherlands Organisation for Applied Scientific Research, Zeist, the Netherlands
| | - Larissa E van Eijk
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Amaal E Abdulle
- Division of Vascular Medicine, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jan-Luuk Hillebrands
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Peter H J van der Voort
- Department of Critical Care Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Harry van Goor
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Ed J van Hezik
- Visiting Consultant Chest Physician, formerly Walcheren Hospital, Vlissingen, the Netherlands
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Honarmand K, Penn J, Agarwal A, Siemieniuk R, Brignardello-Petersen R, Bartoszko JJ, Zeraatkar D, Agoritsas T, Burns K, Fernando SM, Foroutan F, Ge L, Lamontagne F, Jimenez-Mora MA, Murthy S, Yepes-Nuñez JJ, Vandvik PO, Ye Z, Rochwerg B. Clinical trials in COVID-19 management & prevention: A meta-epidemiological study examining methodological quality. J Clin Epidemiol 2021; 139:68-79. [PMID: 34274489 PMCID: PMC8280397 DOI: 10.1016/j.jclinepi.2021.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/16/2021] [Accepted: 07/08/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect. STUDY DESIGN We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect. RESULTS We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled <50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect. CONCLUSIONS There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs. REGISTRATION CRD42020192095.
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Affiliation(s)
- Kimia Honarmand
- Division of Critical Care, Department of Medicine, Western University, 1151 Richmond Street London, Ontario, N6A 3K7, Canada.
| | - Jeremy Penn
- Faculty of Health Sciences, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Arnav Agarwal
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Medicine, University of Toronto, 27 King's College Circle, Toronto, Ontario, M5S 1A1, Canada
| | - Reed Siemieniuk
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Romina Brignardello-Petersen
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Jessica J Bartoszko
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Dena Zeraatkar
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Biomedical Informatics, Harvard Medical School, Boston, 25 Shattuck Street, Boston, MA, 02115, USA
| | - Thomas Agoritsas
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Division General Internal Medicine, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4 1205, Geneva, Switzerland
| | - Karen Burns
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Unity Health Toronto, St. Michael's Hospital, Li Ka Shing Knowledge Institute, 30 Bond St, Toronto, Ontario, M5B 1W8, Canada
| | - Shannon M Fernando
- Division of Critical Care, Department of Medicine, University of Ottawa, 75 Laurier Ave. E, Ottawa, Ontario, K1N 6N5, Canada
| | - Farid Foroutan
- Ted Rogers Centre for Heart Research, University Health Network, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada
| | - Long Ge
- Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, 222 Tianshui S Rd, Chengguan District, Lanzhou, Gansu, China
| | - Francois Lamontagne
- Department of Medicine and Centre de recherche du CHU de Sherbrooke, 12e Avenue N Porte 6, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Mario A Jimenez-Mora
- School of Medicine, Universidad de los Andes, Cra. 1 #18a-12, Bogotá D.C, Colombia
| | - Srinivas Murthy
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4, Canada
| | - Juan Jose Yepes-Nuñez
- School of Medicine, Universidad de los Andes, Cra. 1 #18a-12, Bogotá D.C, Colombia; Pulmonology Service, Internal Medicine Section, Fundación Santa Fe de Bogotá University Hospital, Cra. 7b (#)12390, Bogotá D.C, Colombia
| | - Per O Vandvik
- Department of Health and Society, Faculty of Medicine, University of Oslo, Problemveien 7, 0315, Oslo, Norway
| | - Zhikang Ye
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
| | - Bram Rochwerg
- Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada; Department of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, L8S 4L8, Canada
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Cheng Q, Chen J, Jia Q, Fang Z, Zhao G. Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: an updated network meta-analysis of randomized placebo-controlled trials. Aging (Albany NY) 2021; 13:21866-21902. [PMID: 34531332 PMCID: PMC8507270 DOI: 10.18632/aging.203522] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/31/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs). METHODS We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates. RESULTS From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96-393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21-30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients. CONCLUSION We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.
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Affiliation(s)
- Qinglin Cheng
- Hangzhou Center for Disease Control and Prevention, Hangzhou 310021, China
- School of Medicine, Hangzhou Normal University, Hangzhou 310021, China
| | - Junfang Chen
- Hangzhou Center for Disease Control and Prevention, Hangzhou 310021, China
| | - Qingjun Jia
- Hangzhou Center for Disease Control and Prevention, Hangzhou 310021, China
| | - Zijian Fang
- Hangzhou Center for Disease Control and Prevention, Hangzhou 310021, China
| | - Gang Zhao
- Hangzhou Center for Disease Control and Prevention, Hangzhou 310021, China
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Santos AF, Póvoa P, Paixão P, Mendonça A, Taborda-Barata L. Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19. Front Chem 2021; 9:685196. [PMID: 34568275 PMCID: PMC8461303 DOI: 10.3389/fchem.2021.685196] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/31/2021] [Indexed: 12/21/2022] Open
Abstract
COVID-19 is an infectious disease caused by Coronavirus 2 (SARS-CoV-2) that may lead to a severe acute respiratory syndrome. Such syndrome is thought to be related, at least in part, to a dysregulation of the immune system which involves three main components: hyperactivity of the innate immune system; decreased production of type 1 Interferons (IFN) by SARS-CoV-2-infected cells, namely respiratory epithelial cells and macrophages; and decreased numbers of both CD4+ and particularly CD8+ T cells. Herein, we describe how excessive activation of the innate immune system and the need for viral replication in several cells of the infected organism promote significant alterations in cells' energy metabolism (glucose metabolism), which may underlie the poor prognosis of the disease in severe situations. When activated, cells of the innate immune system reprogram their metabolism, and increase glucose uptake to ensure secretion of pro-inflammatory cytokines. Changes in glucose metabolism are also observed in pulmonary epithelial cells, contributing to dysregulation of cytokine synthesis and inflammation of the pulmonary epithelium. Controlling hyperglycolysis in critically ill patients may help to reduce the exaggerated production of pro-inflammatory cytokines and optimise the actions of the adaptive immune system. In this review, we suggest that the administration of non-toxic concentrations of 2-deoxy-D-glucose, the use of GLUT 1 inhibitors, of antioxidants such as vitamin C in high doses, as well as the administration of N-acetylcysteine in high doses, may be useful complementary therapeutic strategies for these patients, as suggested by some clinical trials and/ or reports. Overall, understanding changes in the glycolytic pathway associated with COVID-19 infection can help to find new forms of treatment for this disease.
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Affiliation(s)
- Adalberto Fernandes Santos
- Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
- CICS-UBI Health Sciences Research Centre, Universidade da Beira Interior, Lisbon, Portugal
- Department of Teaching and Research of Biochemistry, Faculty of Medicine, Agostinho Neto University, Luanda, Angola
| | - Pedro Póvoa
- Polyvalent Intensive Care Unit, Centro Hospitalar de Lisboa Ocidental, Hospital de Sao Francisco Xavier, Lisbon, Portugal
- Comprehensive Health Research Center–CHRC, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
- Center for Clinical Epidemiology and Research Unit of Clinical Epidemiology, OUH Odense University Hospital, Odense, Denmark
| | - Paulo Paixão
- Comprehensive Health Research Center–CHRC, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
- Laboratório de Patologia Clínica–SYNLAB, Hospital da Luz, Lisbon, Portugal
| | - António Mendonça
- CICS-UBI Health Sciences Research Centre, Universidade da Beira Interior, Lisbon, Portugal
- Department of Chemistry, Faculty of Sciences, University of Beira Interior, Covilhã, Portugal
| | - Luís Taborda-Barata
- Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
- CICS-UBI Health Sciences Research Centre, Universidade da Beira Interior, Lisbon, Portugal
- Department of Immunoallergology, Cova da Beira University Hospital Centre, Covilhã, Portugal
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Abstract
There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients
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50
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Avdeev SN, Gaynitdinova VV, Merzhoeva ZM, Berikkhanov ZGM. N-acetylcysteine for the treatment of COVID-19 among hospitalized patients. J Infect 2021; 84:94-118. [PMID: 34252497 PMCID: PMC8271031 DOI: 10.1016/j.jinf.2021.07.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Sergey N Avdeev
- Department of Pulmonology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
| | - Viliya V Gaynitdinova
- Department of Pulmonology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Zamira M Merzhoeva
- Department of Pulmonology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Zelimkhan G-M Berikkhanov
- Department of Pulmonology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
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