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Duarte LF, Carbone-Schellman J, Bueno SM, Kalergis AM, Riedel CA, González PA. Tackling cutaneous herpes simplex virus disease with topical immunomodulators-a call to action. Clin Microbiol Rev 2025; 38:e0014724. [PMID: 39982077 PMCID: PMC11917526 DOI: 10.1128/cmr.00147-24] [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] [Indexed: 02/22/2025] Open
Abstract
SUMMARYAntivirals play important roles in restricting viral diseases. Nevertheless, they act on a relatively limited number of viruses and occasionally display partial effectiveness in some tissues or against escape variants. Although vaccination remains the most cost-effective approach for preventing microbial diseases, developing prophylactic or therapeutic solutions for pathogens, such as herpes simplex viruses (HSVs), that effectively reduce their clinical manifestations in the skin has proven exceptionally challenging despite extensive research. Alternatively, a less explored approach for tackling HSV skin infection involves using topical immunomodulatory molecules to potentiate the host's innate antiviral immune responses. When applied directly to herpetic skin lesions where viral antigen is present, this strategy has the potential to elicit virus-specific adaptive immunity. Based on currently available data, we foresee substantial potential for this approach in addressing HSV skin infections, along with additional prospects to advance understanding of skin biology and apply relevant new findings to other dermatological conditions. However, due to the limited number of case studies evaluating this method and its safety profile, particularly in immunocompromised individuals and pregnant women, further research is crucial, especially to assess the effects of immunomodulators in these vulnerable populations. Here, we revisit and discuss the use of immunomodulatory molecules for potentiating the host immune response against HSV skin infection and call for action for increased research and clinical trials regarding the possible benefits of this latter strategy for treating HSV cutaneous disease and recurrences. We also revisit and discuss antivirals and vaccine candidates against HSVs.
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Affiliation(s)
- Luisa F. Duarte
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana – Universidad del Desarrollo, Santiago, Chile
| | - Javier Carbone-Schellman
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M. Bueno
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia A. Riedel
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Centro de Investigación para la Resilencia a Pandemias, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Santiago, Chile
- Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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2
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Poudineh M, Darweesh O, Mokhtari M, Zolfaghari O, Khaledi A, Piroozmand A. Expression of microRNAs in the detection and therapeutic roles of viral infections: Mechanisms and applications. J Virus Erad 2025; 11:100586. [PMID: 40296890 PMCID: PMC12034616 DOI: 10.1016/j.jve.2025.100586] [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: 08/25/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 04/30/2025] Open
Abstract
In recent years, microRNAs (miRNAs) are potential diagnostic and therapeutic agents for viral infections. Here, we aimed to investigate the expression of microRNAs in the identification and treatment of viral infections. MiRNAs are non-coding molecules that control gene expression and participate in numerous biological processes, including host immunity and pathogen duplication. MiRNAs have played a role in the pathogenesis of various viral infections, such as HIV and HCV. Their presence in the tissues and serum of infected patients has been demonstrated to help predict disease progression, identify disease subtypes, and evaluate treatment responses. Research has shown that miRNAs can detect viral infections by identifying specific miRNAs in serum. For example, miRNA expression profiling was recently used to distinguish between hepatitis C and hepatitis B viral infections precisely. Furthermore, miRNAs can be used to detect the presence of multiple viral infections simultaneously by assessing the expression levels of these miRNAs. Also, miRNAs can differentiate between different genetic variants of the same virus, which is useful for identifying emerging viral strains or drug-resistant ones. MiRNAs have been identified as being a factor in treating viral infections. For example, miRNA mimics have decreased gene expression and halted viral replication in HIV, HCV, and EBV. Moreover, microRNA antagonists have been utilized to inhibit pro-inflammatory cytokines, thereby modulating the immune response and the severity of infections.
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Affiliation(s)
- Mohsen Poudineh
- Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Omeed Darweesh
- College of Pharmacy, Al-Kitab University, Kirkuk, 36015, Iraq
| | - Mohsen Mokhtari
- Laboratory Department, Paramedical School, Kashan University of Medical Sciences, Kashan, Iran
| | - Omid Zolfaghari
- Laboratory Department, Paramedical School, Kashan University of Medical Sciences, Kashan, Iran
| | - Azad Khaledi
- Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Ahmad Piroozmand
- Autoimmune Diseases Research Center, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
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Tworig J, Grafton F, Fisher K, Hörer M, Reid CA, Mandegar MA. Transcriptomics-informed pharmacology identifies epigenetic and cell cycle regulators that enhance AAV production. Mol Ther Methods Clin Dev 2024; 32:101384. [PMID: 39687728 PMCID: PMC11647610 DOI: 10.1016/j.omtm.2024.101384] [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: 06/24/2024] [Accepted: 11/14/2024] [Indexed: 12/18/2024]
Abstract
Recombinant adeno-associated virus (rAAV) is a widely used viral vector for gene therapy. However, these vectors have limited availability due to manufacturing challenges with productivity and quality. These challenges can be addressed by better understanding the mechanisms that influence cellular responses during rAAV production. In this study, we aimed to identify targets that may enhance rAAV production using transcriptomic analyses of five cell lines with variable capacities for rAAV production. Using an intersectional approach, we measured the transcriptional responses of these cells during rAAV production and compared transcriptional profiles between high and base producers to identify possible targets for enhancing production. During rAAV production, we found transcriptional differences in cell cycle and nucleosome components contributed to proliferative capacity and DNA replication. We also saw upregulation of several core functions, including transcription, stress response, and Golgi and endoplasmic reticulum organization. Conversely, we saw consistent downregulation of other factors, including inhibitors of DNA-binding proteins and mitochondrial components. With a drug-connectivity analysis, we identified five classes of drugs that were predicted to enhance rAAV production. We also validated the efficacy of histone deacetylase and microtubule inhibitors. Our data uncover novel and previously identified pathways that may enhance rAAV production and quality to expand availability of rAAV for gene therapies.
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Affiliation(s)
- Joshua Tworig
- Ascend Advanced Therapies CA, Inc, Alameda, CA 94501, USA
| | | | - Kaylin Fisher
- Ascend Advanced Therapies CA, Inc, Alameda, CA 94501, USA
| | - Markus Hörer
- Ascend Advanced Therapies GmbH, 82152 Planegg, Germany
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Abioye AI, Sudfeld CR, Noor RA, Ulenga N, Sando D, Fawzi WW. Anemia and Iron Supplementation in Relation to Viral Load and Mortality among 70,442 People Living with Human Immunodeficiency Virus in Tanzania. J Nutr 2024; 154:1927-1935. [PMID: 38615735 PMCID: PMC11217031 DOI: 10.1016/j.tjnut.2024.04.019] [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: 01/27/2024] [Revised: 04/02/2024] [Accepted: 04/10/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Anemia may be associated with poor clinical outcomes among people living with human immunodeficiency virus (HIV) (PLHIV) despite highly active antiretroviral therapy (HAART). There are concerns that iron supplementation may be unsafe to prevent and treat anemia among PLHIV. OBJECTIVE The objective of the study was to evaluate the associations of anemia and iron supplementation with mortality and viral load among PLHIV in Tanzania. METHODS We analyzed data from a cohort of 70,442 nonpregnant adult PLHIV in Tanzania conducted between 2015 and 2019. Regression models evaluated the relationships between anemia severity and iron supplement use with mortality and unsuppressed HIV-1 viral load among all participants and stratified by whether participants were initiating or continuing HAART. RESULTS Anemia was associated with an increased risk of mortality and unsuppressed viral load for participants who initiated or continued HAART. Iron supplement use was associated with reduced mortality risk but also had a greater risk of an unsuppressed viral load among participants continuing HAART. There was no association of iron supplement use with mortality, and unsuppressed viral load among PLHIV that were initiating HAART. There was a stronger negative association between iron supplement use and the risk of having an unsuppressed viral load among participants with stage III/IV disease compared with stage I/II disease. CONCLUSIONS Anemia is associated with increased risk of mortality and unsuppressed viral load, but the benefits and safety of iron supplements appear to differ for those initiating compared with continuing ART as well as by HIV disease severity.
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Affiliation(s)
- Ajibola Ibraheem Abioye
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
| | - Christopher R Sudfeld
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Ramadhani Abdallah Noor
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Nzovu Ulenga
- Management and Development for Health, Dar es Salaam, Tanzania
| | - David Sando
- Management and Development for Health, Dar es Salaam, Tanzania
| | - Wafaie W Fawzi
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
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Murtaza B, Li X, Nawaz MY, Saleemi MK, Li G, Jin B, Wang L, Xu Y. Toxicodynamic of combined mycotoxins: MicroRNAs and acute-phase proteins as diagnostic biomarkers. Compr Rev Food Sci Food Saf 2024; 23:e13338. [PMID: 38629461 DOI: 10.1111/1541-4337.13338] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/18/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024]
Abstract
Mycotoxins, ubiquitous contaminants in food, present a global threat to human health and well-being. Mitigation efforts, such as the implementation of sound agricultural practices, thorough food processing, and the advancement of mycotoxin control technologies, have been instrumental in reducing mycotoxin exposure and associated toxicity. To comprehensively assess mycotoxins and their toxicodynamic implications, the deployment of effective and predictive strategies is imperative. Understanding the manner of action, transformation, and cumulative toxic effects of mycotoxins, moreover, their interactions with food matrices can be gleaned through gene expression and transcriptome analyses at cellular and molecular levels. MicroRNAs (miRNAs) govern the expression of target genes and enzymes that play pivotal roles in physiological, pathological, and toxicological responses, whereas acute phase proteins (APPs) exert regulatory control over the metabolism of therapeutic agents, both endogenously and posttranscriptionally. Consequently, this review aims to consolidate current knowledge concerning the regulatory role of miRNAs in the initiation of toxicological pathways by mycotoxins and explores the potential of APPs as biomarkers following mycotoxin exposure. The findings of this research highlight the potential utility of miRNAs and APPs as indicators for the detection and management of mycotoxins in food through biological processes. These markers offer promising avenues for enhancing the safety and quality of food products.
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Affiliation(s)
- Bilal Murtaza
- School of Bioengineering, Dalian University of Technology, Dalian, China
- Dalian SEM Bioengineering Technology Co., Ltd, Dalian, China
| | - Xiaoyu Li
- School of Bioengineering, Dalian University of Technology, Dalian, China
- MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, China
| | | | | | - Gen Li
- School of Bioengineering, Dalian University of Technology, Dalian, China
| | - Bowen Jin
- School of Bioengineering, Dalian University of Technology, Dalian, China
| | - Lili Wang
- School of Bioengineering, Dalian University of Technology, Dalian, China
- MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, China
| | - Yongping Xu
- School of Bioengineering, Dalian University of Technology, Dalian, China
- Dalian SEM Bioengineering Technology Co., Ltd, Dalian, China
- MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, China
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Wang T, Li S, Hu X, Geng Y, Chen L, Liu W, Zhao J, Tian W, Wang C, Li Y, Li L. Heme oxygenase-1 is an equid alphaherpesvirus 8 replication restriction host protein and suppresses viral replication via the PKCβ/ERK1/ERK2 and NO/cGMP/PKG pathway. Microbiol Spectr 2024; 12:e0322023. [PMID: 38441979 PMCID: PMC10986571 DOI: 10.1128/spectrum.03220-23] [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: 08/29/2023] [Accepted: 02/14/2024] [Indexed: 03/07/2024] Open
Abstract
Equid alphaherpesvirus 8 (EqHV-8) is one of the most economically important viruses that is known to cause severe respiratory disease, abortion, and neurological syndromes in equines. However, no effective vaccines or therapeutic agents are available to control EqHV-8 infection. Heme oxygenase-1 (HO-1) is an antioxidant defense enzyme that displays significant cytoprotective effects against different viral infections. However, the literature on the function of HO-1 during EqHV-8 infection is little. We explored the effects of HO-1 on EqHV-8 infection and revealed its potential mechanisms. Our results demonstrated that HO-1 induced by cobalt-protoporphyrin (CoPP) or HO-1 overexpression inhibited EqHV-8 replication in susceptible cells. In contrast, HO-1 inhibitor (zinc protoporphyria) or siRNA targeting HO-1 reversed the anti-EqHV-8 activity. Furthermore, biliverdin, a metabolic product of HO-1, mediated the anti-EqHV-8 effect of HO-1 via both the protein kinase C (PKC)β/extracellular signal-regulated kinase (ERK)1/ERK2 and nitric oxide (NO)-dependent cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathways. In addition, CoPP protected the mice by reducing the EqHV-8 infection in the lungs. Altogether, these results indicated that HO-1 can be developed as a promising therapeutic strategy to control EqHV-8 infection.IMPORTANCEEqHV-8 infections have threatened continuously donkey and horse industry worldwide, which induces huge economic losses every year. However, no effective vaccination strategies or drug against EqHV-8 infection until now. Our present study found that one host protien HO-1 restrict EqHV-8 replication in vitro and in vivo. Furthermore, we demonstrate that HO-1 and its metabolite biliverdin suppress EqHV-8 relication via the PKCβ/ERK1/ERK2 and NO/cGMP/PKG pathways. Hence, we believe that HO-1 can be developed as a promising therapeutic strategy to control EqHV-8 infection.
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Affiliation(s)
- Tongtong Wang
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
| | - Shuwen Li
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Xinyao Hu
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
| | - Yiqing Geng
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Li Chen
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
| | - Wenqiang Liu
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
| | - Juan Zhao
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Wenxia Tian
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Changfa Wang
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
| | - Yubao Li
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
| | - Liangliang Li
- College of Agronomy, Liaocheng University, Liaocheng, Shandong, China
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Naidu AS, Wang CK, Rao P, Mancini F, Clemens RA, Wirakartakusumah A, Chiu HF, Yen CH, Porretta S, Mathai I, Naidu SAG. Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID. NPJ Sci Food 2024; 8:19. [PMID: 38555403 PMCID: PMC10981760 DOI: 10.1038/s41538-024-00261-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/15/2024] [Indexed: 04/02/2024] Open
Abstract
SARS-CoV-2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is critical for the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. This single-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates a plethora of virus-host protein-protein interactions in the human body. These extensive viral protein interactions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as altered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectious process, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii) hyperferritinemia ('cytokine storm'), and (iii) thrombocytosis (coagulopathy). The mean incubation period for COVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The mean viral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients, respectively. However, about 25-70% of virus-free COVID-19 survivors continue to sustain virus-induced HMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new 'onset' clinical incidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patients experience several debilitating clinical condition(s) with >200 different and overlapping symptoms that may last for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-related pathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innate host responses. Based on HMRD and virus-free clinical impairments of different human organs/systems, PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%) with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viral hijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage to multiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. We have also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precision nutrients to reset HMRD for health recovery of PASC patients.
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Affiliation(s)
- A Satyanarayan Naidu
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA.
- N-terminus Research Laboratory, 232659 Via del Rio, Yorba Linda, CA, 92887, USA.
| | - Chin-Kun Wang
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- School of Nutrition, Chung Shan Medical University, 110, Section 1, Jianguo North Road, Taichung, 40201, Taiwan
| | - Pingfan Rao
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- College of Food and Bioengineering, Fujian Polytechnic Normal University, No.1, Campus New Village, Longjiang Street, Fuqing City, Fujian, China
| | - Fabrizio Mancini
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- President-Emeritus, Parker University, 2540 Walnut Hill Lane, Dallas, TX, 75229, USA
| | - Roger A Clemens
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- University of Southern California, Alfred E. Mann School of Pharmacy/D. K. Kim International Center for Regulatory & Quality Sciences, 1540 Alcazar St., CHP 140, Los Angeles, CA, 90089, USA
| | - Aman Wirakartakusumah
- International Union of Food Science and Technology (IUFoST), Guelph, ON, Canada
- IPMI International Business School Jakarta; South East Asian Food and Agriculture Science and Technology, IPB University, Bogor, Indonesia
| | - Hui-Fang Chiu
- Department of Chinese Medicine, Taichung Hospital, Ministry of Health & Well-being, Taichung, Taiwan
| | - Chi-Hua Yen
- Department of Family and Community Medicine, Chung Shan Medical University Hospital; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Sebastiano Porretta
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- President, Italian Association of Food Technology (AITA), Milan, Italy
- Experimental Station for the Food Preserving Industry, Department of Consumer Science, Viale Tanara 31/a, I-43121, Parma, Italy
| | - Issac Mathai
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- Soukya International Holistic Health Center, Whitefield, Bengaluru, India
| | - Sreus A G Naidu
- Global Nutrition Healthcare Council (GNHC) Mission-COVID, Yorba Linda, CA, USA
- N-terminus Research Laboratory, 232659 Via del Rio, Yorba Linda, CA, 92887, USA
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Wu M, Fan Y, Li L, Yuan J. Bi-directional regulation of type I interferon signaling by heme oxygenase-1. iScience 2024; 27:109185. [PMID: 38420586 PMCID: PMC10901085 DOI: 10.1016/j.isci.2024.109185] [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: 09/02/2023] [Revised: 12/23/2023] [Accepted: 02/06/2024] [Indexed: 03/02/2024] Open
Abstract
Moderate activation of IFN-I contributes to the body's immune response, but its abnormal expression, stimulated by oxidative stress or other factors causes pathological damage. Heme oxygenase-1 (HO-1), induced by stress stimuli in the body, exerts a central role in cellular protection. Here we showed that HO-1 could promote IFN-1 under Spring Viremia of Carp virus (SVCV) infection and concomitantly attenuate the replication of SVCV. Further characterization of truncated mutants of HO-1 confirmed that intact HO-1 was essential for its antiviral function via IFN-I. Importantly, HO-1 inhibited the IFN-I signal by degrading the IRF3/7 through the autophagy pathway when it was triggered by H2O2 treatment. The iron ion-binding site (His28) was critical for HO-1 to degrade IRF3/7. HO-1 degradation of IRF3/7 is conserved in fish and mammals. Collectively, HO-1 regulates IFN-I positively under viral infection and negatively under oxidative stress, elucidating a mechanism by which HO-1 regulates IFN-I signaling in bi-directions.
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Affiliation(s)
- Miaomiao Wu
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, People’s Republic of China
- Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan 430070, People’s Republic of China
| | - Yihui Fan
- Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan 430070, People’s Republic of China
- National Aquatic Animal Diseases Para-reference laboratory (HZAU), Wuhan 430070, People’s Republic of China
| | - Lijuan Li
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, People’s Republic of China
- Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan 430070, People’s Republic of China
- National Aquatic Animal Diseases Para-reference laboratory (HZAU), Wuhan 430070, People’s Republic of China
| | - Junfa Yuan
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan 430070, People’s Republic of China
- Hubei Engineering Research Center for Aquatic Animal Diseases Control and Prevention, Wuhan 430070, People’s Republic of China
- National Aquatic Animal Diseases Para-reference laboratory (HZAU), Wuhan 430070, People’s Republic of China
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Daskou M, Fotooh Abadi L, Gain C, Wong M, Sharma E, Kombe Kombe AJ, Nanduri R, Kelesidis T. The Role of the NRF2 Pathway in the Pathogenesis of Viral Respiratory Infections. Pathogens 2023; 13:39. [PMID: 38251346 PMCID: PMC10819673 DOI: 10.3390/pathogens13010039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/27/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
In humans, acute and chronic respiratory infections caused by viruses are associated with considerable morbidity and mortality. Respiratory viruses infect airway epithelial cells and induce oxidative stress, yet the exact pathogenesis remains unclear. Oxidative stress activates the transcription factor NRF2, which plays a key role in alleviating redox-induced cellular injury. The transcriptional activation of NRF2 has been reported to affect both viral replication and associated inflammation pathways. There is complex bidirectional crosstalk between virus replication and the NRF2 pathway because virus replication directly or indirectly regulates NRF2 expression, and NRF2 activation can reversely hamper viral replication and viral spread across cells and tissues. In this review, we discuss the complex role of the NRF2 pathway in the regulation of the pathogenesis of the main respiratory viruses, including coronaviruses, influenza viruses, respiratory syncytial virus (RSV), and rhinoviruses. We also summarize the scientific evidence regarding the effects of the known NRF2 agonists that can be utilized to alter the NRF2 pathway.
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Affiliation(s)
- Maria Daskou
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Leila Fotooh Abadi
- Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.F.A.); (R.N.)
| | - Chandrima Gain
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Michael Wong
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Eashan Sharma
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Arnaud John Kombe Kombe
- Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.F.A.); (R.N.)
| | - Ravikanth Nanduri
- Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.F.A.); (R.N.)
| | - Theodoros Kelesidis
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
- Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; (L.F.A.); (R.N.)
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10
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Wei J, Zang N, Zhang J, He Y, Huang H, Liu X, Xu X, Ren L, Deng Y, Wu J, Seto D, Zhong W, Zhang Q, Liu E. Genome and proteomic analysis of risk factors for fatal outcome in children with severe community-acquired pneumonia caused by human adenovirus 7. J Med Virol 2023; 95:e29182. [PMID: 37909805 DOI: 10.1002/jmv.29182] [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: 06/05/2023] [Revised: 08/28/2023] [Accepted: 10/09/2023] [Indexed: 11/03/2023]
Abstract
INTRODUCTION Human adenovirus 7 (HAdV-7) is an important viral pathogen of severe pneumonia in children and a serious threat to health. METHODS A cohort of 45 pediatric patients diagnosed with HAdV-7-associated severe pneumonia and admitted to the Pediatric Intensive Care Unit at the Children's Hospital of Chongqing Medical University from May 2018 to January 2020 were included. Risk factors of death were analyzed by the Cox proportional risk mode with Clinical data, serum, and nasopharyngeal aspirate adenovirus load, Genome analysis, Olink proteomics, and cytokine profile between dead and surviving patients were also analyzed. RESULTS A total of 45 children with a median age of 12.0 months (interquartile range [IQR]: 6.5, 22.0) were included (female 14), including 14 (31.1%) who died. High serum viral load was an independent risk factor for mortality (hazard ratio [HR] = 2.16, 95% confidence interval [CI], 1.04-4.49, p = 0.039). BTB and CNC homology 1 (BACH1), interleukin-5 (IL-5), and IL-9 levels were significantly correlated with serum viral load (p = 0.0400, 0.0499, and 0.0290; r = 0.4663, 0.3339, and -0.3700, respectively), with significant differences between the dead and survival groups (p = 0.021, 0.001, and 0.021). CONCLUSIONS Severe cytokine storm-associated high serum viral load after HAdV-7 infection may be the main mechanism responsible for poor prognosis in children.
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Affiliation(s)
- Jianhua Wei
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Na Zang
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Zhang
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Ministry of Education, Institute of Medical Microbiology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yu He
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Haixia Huang
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
- Department of Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xiangyu Liu
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ximing Xu
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Luo Ren
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Deng
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jianguo Wu
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Ministry of Education, Institute of Medical Microbiology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Donald Seto
- Bioinformatics and Computational Biology Program, School of Systems Biology, George Mason University, Manassas, Virginia, USA
| | - Wen Zhong
- Science for Life Laboratory, Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Qiwei Zhang
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Ministry of Education, Institute of Medical Microbiology, College of Life Science and Technology, Jinan University, Guangzhou, China
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Enmei Liu
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
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Frishberg A, Milman N, Alpert A, Spitzer H, Asani B, Schiefelbein JB, Bakin E, Regev-Berman K, Priglinger SG, Schultze JL, Theis FJ, Shen-Orr SS. Reconstructing disease dynamics for mechanistic insights and clinical benefit. Nat Commun 2023; 14:6840. [PMID: 37891175 PMCID: PMC10611752 DOI: 10.1038/s41467-023-42354-8] [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: 01/18/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
Diseases change over time, both phenotypically and in their underlying molecular processes. Though understanding disease progression dynamics is critical for diagnostics and treatment, capturing these dynamics is difficult due to their complexity and the high heterogeneity in disease development between individuals. We present TimeAx, an algorithm which builds a comparative framework for capturing disease dynamics using high-dimensional, short time-series data. We demonstrate the utility of TimeAx by studying disease progression dynamics for multiple diseases and data types. Notably, for urothelial bladder cancer tumorigenesis, we identify a stromal pro-invasion point on the disease progression axis, characterized by massive immune cell infiltration to the tumor microenvironment and increased mortality. Moreover, the continuous TimeAx model differentiates between early and late tumors within the same tumor subtype, uncovering molecular transitions and potential targetable pathways. Overall, we present a powerful approach for studying disease progression dynamics-providing improved molecular interpretability and clinical benefits for patient stratification and outcome prediction.
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Affiliation(s)
- Amit Frishberg
- Department of Immunology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Institute of Computational Biology, Helmholtz Center Munich, 85764, Neuherberg, Germany
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- CytoReason, Tel-Aviv, Israel
| | - Neta Milman
- Department of Immunology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Ayelet Alpert
- Department of Immunology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Hannah Spitzer
- Institute of Computational Biology, Helmholtz Center Munich, 85764, Neuherberg, Germany
- Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Munich, Germany
| | - Ben Asani
- Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
| | | | | | | | | | - Joachim L Schultze
- Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE). PRECISE Platform for Genomics and Epigenomics at DZNE and University of Bonn, Bonn, Germany
| | - Fabian J Theis
- Institute of Computational Biology, Helmholtz Center Munich, 85764, Neuherberg, Germany
- Department of Mathematics, Technical University of Munich, 85748, Garching, Germany
- Technical University of Munich, TUM School of Life Sciences Weihenstephan, 85354, Freising, Germany
| | - Shai S Shen-Orr
- Department of Immunology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
- CytoReason, Tel-Aviv, Israel.
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12
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Lin YJ, Wang LC, Tsai HP, Chi CY, Chang CP, Chen SH, Wang SM. Antiviral and immunoregulatory effects of curcumin on coxsackievirus B3-infected hepatitis. Virus Res 2023; 336:199203. [PMID: 37625648 PMCID: PMC10485155 DOI: 10.1016/j.virusres.2023.199203] [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: 05/19/2023] [Revised: 08/16/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023]
Abstract
Fulminant hepatitis is a life-threatening complication of coxsackievirus B (CVB) 3 infections. The condition may deteriorate to disseminated intravascular coagulopathy with markedly increased liver enzymes, inflammatory cytokines, and chemokines, which significantly induce local and systemic inflammation. Curcumin exhibits anti-inflammatory and antiviral characteristics in inflammatory and infectious diseases. Here we determined effects of curcumin on viral replications, cytokine and chemokine expressions, and liver damage in CVB3-infected Huh-7 cells. The mouse-adapted CVB3 strain was used to investigate the antiviral and anti-inflammatory effects of curcumin on CVB3-induced hepatitis in a mouse model. In vitro studies showed that curcumin reduced viral protein and titer levels and increased cell viability. Curcumin enhanced the heme oxygenase-1 (HO-1) protein level and decreased the levels of cleaved caspase-3 protein and mRNA of gene encoding C-X-C motif chemokine 10 in infected cells. In vivo studies showed that curcumin improved the survival rate and clinical scores in mice and reduced the viral titer in the liver during CVB3 infection. Moreover, the HO-1 levels were increased, and the cleaved caspase-3 levels were diminished in the CVB3-infected liver. Curcumin reduced the levels of interferon (IFN)-γ and monokine induced by IFN-γ in liver and levels of interleukin (IL)-8 in serum, but increased levels of regulated activation, normal T cell expression in liver and levels of IL-10 in serum of CVB3-infected mice. In summary, curcumin presents antiviral and anti-inflammation efficacies in CVB3 infection in vitro and in vivo; these results provide potential evidence on the feasibility of curcumin for clinical treatment.
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Affiliation(s)
- Yu-Jheng Lin
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Li-Chiu Wang
- School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
| | - Huey-Pin Tsai
- Department of Pathology,College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 70401, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan
| | - Chia-Yu Chi
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County 35053, Taiwan
| | - Chih-Peng Chang
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70401, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan
| | - Shun-Hua Chen
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70401, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan.
| | - Shih-Min Wang
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70401, Taiwan; Center for Infection Control, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan.
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13
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Tang X, Li Y, Zhao J, Liang L, Zhang K, Zhang X, Yu H, Du H. Heme oxygenase-1 increases intracellular iron storage and suppresses inflammatory response of macrophages by inhibiting M1 polarization. Metallomics 2023; 15:mfad062. [PMID: 37838477 DOI: 10.1093/mtomcs/mfad062] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 10/13/2023] [Indexed: 10/16/2023]
Abstract
Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting enzymatic step of heme degradation, producing carbon monoxide, biliverdin, and free iron. Most iron is derived from aged erythrocytes by the decomposition of heme, which happened mainly in macrophages. However, the role of HO-1 on iron metabolism and function of macrophage is unclear. The present study investigated the effect of HO-1 on iron metabolism in macrophages, and explored the role of HO-1 on inflammatory response, polarization, and migration of macrophages. HO-1 inducer Hemin or HO-1 inhibitor zinc protoporphyrin was intravenously injected to C57BL/6 J mice every 4 d for 28 d. We found that HO-1 was mainly located in the cytoplasm of splenic macrophages of mice. Activation of HO-1 by Hemin significantly increased iron deposition in the spleen, up-regulated the gene expression of ferritin and ferroportin, and down-regulated gene expression of divalent metal transporter 1 and hepcidin. Induced HO-1 by Hemin treatment increased intracellular iron levels of macrophages, slowed down the absorption of extracellular iron, and accelerated the excretion of intracellular iron. In addition, activation of HO-1 significantly decreased the expression of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, and inducible nitric oxide synthase, but increased the expression of anti-inflammatory cytokines such as IL-10. Furthermore, activation of HO-1 inhibited macrophages to M1-type polarization, and increased the migration rate of macrophages. This study demonstrated that HO-1 was able to regulate iron metabolism, exert anti-inflammatory effects, and inhibit macrophages polarization to M1 type.
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Affiliation(s)
- Xueyou Tang
- MoE Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yunqin Li
- Analysis Center of Agrobiology and Environmental Science, Zhejiang University, Hangzhou 310058, China
| | - Jing Zhao
- MoE Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Li Liang
- MoE Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Kang Zhang
- MoE Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiaofeng Zhang
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310004, China
| | - Hong Yu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Huahua Du
- MoE Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, China
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14
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Mancuso C. Biliverdin as a disease-modifying agent: An integrated viewpoint. Free Radic Biol Med 2023; 207:133-143. [PMID: 37459935 DOI: 10.1016/j.freeradbiomed.2023.07.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/27/2023] [Accepted: 07/14/2023] [Indexed: 07/24/2023]
Abstract
Biliverdin is one of the three by-products of heme oxygenase (HO) activity, the others being ferrous iron and carbon monoxide. Under physiological conditions, once formed in the cell, BV is reduced to bilirubin (BR) by the biliverdin reductase (BVR). However, if BVR is inhibited by either genetic variants, as occurs in the Inuit ethnicity, or dioxin intoxication, BV accumulates in cells giving rise to a clinical syndrome known as green jaundice. Preclinical studies have demonstrated that BV not only has a direct antioxidant effect by scavenging free radicals, but also targets many signal transduction pathways, such as BVR, soluble guanylyl cyclase, and the aryl hydrocarbon receptor. Through these direct and indirect mechanisms, BV has shown beneficial roles in ischemia/reperfusion-related diseases, inflammatory diseases, graft-versus-host disease, viral infections and cancer. Unfortunately, no clinical data are available to confirm these potential therapeutic effects and the kinetics of exogenous BV in humans is unknown. These limitations have so far excluded the possibility of transforming BV from a mere by-product of heme degradation into a disease-modifying agent. A closer collaboration between basic and clinical researchers would be advantageous to overcome these issues and promote translational research on BV in free radical-induced diseases.
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Affiliation(s)
- Cesare Mancuso
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica Del Sacro Cuore, Largo F. Vito, 1, 00168, Rome, Italy.
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15
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Skrzydlewska E, Łuczaj W, Biernacki M, Wójcik P, Jarocka-Karpowicz I, Orehovec B, Baršić B, Tarle M, Kmet M, Lukšić I, Marušić Z, Bauer G, Žarković N. Preliminary Comparison of Molecular Antioxidant and Inflammatory Mechanisms Determined in the Peripheral Blood Granulocytes of COVID-19 Patients. Int J Mol Sci 2023; 24:13574. [PMID: 37686388 PMCID: PMC10488240 DOI: 10.3390/ijms241713574] [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: 07/19/2023] [Revised: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
The aim of this study was to evaluate selected parameters of redox signaling and inflammation in the granulocytes of COVID-19 patients who recovered and those who died. Upon admission, the patients did not differ in terms of any relevant clinical parameter apart from the percentage of granulocytes, which was 6% higher on average in those patients who died. Granulocytes were isolated from the blood of 15 healthy people and survivors and 15 patients who died within a week, and who were selected post hoc for analysis according to their matching gender and age. They differed only in the lethal outcome, which could not be predicted upon arrival at the hospital. The proteins level (respective ELISA), antioxidant activity (spectrophotometry), and lipid mediators (UPUPLC-MS) were measured in the peripheral blood granulocytes obtained via gradient centrifugation. The levels of Nrf2, HO-1, NFκB, and IL-6 were higher in the granulocytes of COVID-19 patients who died within a week, while the activity of cytoplasmic Cu,Zn-SOD and mitochondrial Mn-SOD and IL-2/IL-10 were lower in comparison to the levels observed in survivors. Furthermore, in the granulocytes of those patients who died, an increase in pro-inflammatory eicosanoids (PGE2 and TXB2), together with elevated cannabinoid receptors 1 and 2 (associated with a decrease in the anti-inflammatory 15d-PGJ2), were found. Hence, this study suggests that by triggering transcription factors, granulocytes activate inflammatory and redox signaling, leading to the production of pro-inflammatory eicosanoids while reducing cellular antioxidant capacity through SOD, thus expressing an altered response to COVID-19, which may result in the onset of systemic oxidative stress, ARDS, and the death of the patient.
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Affiliation(s)
- Elżbieta Skrzydlewska
- Department of Analytical Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.Ł.); (M.B.); (P.W.); (I.J.-K.)
| | - Wojciech Łuczaj
- Department of Analytical Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.Ł.); (M.B.); (P.W.); (I.J.-K.)
| | - Michał Biernacki
- Department of Analytical Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.Ł.); (M.B.); (P.W.); (I.J.-K.)
| | - Piotr Wójcik
- Department of Analytical Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.Ł.); (M.B.); (P.W.); (I.J.-K.)
| | - Iwona Jarocka-Karpowicz
- Department of Analytical Chemistry, Medical University of Bialystok, 15-222 Bialystok, Poland; (W.Ł.); (M.B.); (P.W.); (I.J.-K.)
| | - Biserka Orehovec
- Clinical Hospital Dubrava, HR-10000 Zagreb, Croatia; (B.O.); (B.B.); (M.T.); (M.K.); (I.L.)
| | - Bruno Baršić
- Clinical Hospital Dubrava, HR-10000 Zagreb, Croatia; (B.O.); (B.B.); (M.T.); (M.K.); (I.L.)
| | - Marko Tarle
- Clinical Hospital Dubrava, HR-10000 Zagreb, Croatia; (B.O.); (B.B.); (M.T.); (M.K.); (I.L.)
| | - Marta Kmet
- Clinical Hospital Dubrava, HR-10000 Zagreb, Croatia; (B.O.); (B.B.); (M.T.); (M.K.); (I.L.)
| | - Ivica Lukšić
- Clinical Hospital Dubrava, HR-10000 Zagreb, Croatia; (B.O.); (B.B.); (M.T.); (M.K.); (I.L.)
- School of Medicine, University of Zagreb, HR-10000 Zagreb, Croatia
| | - Zlatko Marušić
- Division of Pathology, Clinical Hospital Centre Zagreb, HR-10000 Zagreb, Croatia;
| | - Georg Bauer
- Institute of Virology, Medical Center–University of Freiburg, 79104 Freiburg, Germany;
| | - Neven Žarković
- Laboratory for Oxidative Stress (LabOS), Ruđer Bošković Institute, HR-10000 Zagreb, Croatia
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16
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Mhlekude B, Postmus D, Stenzel S, Weiner J, Jansen J, Zapatero-Belinchón FJ, Olmer R, Richter A, Heinze J, Heinemann N, Mühlemann B, Schroeder S, Jones TC, Müller MA, Drosten C, Pich A, Thiel V, Martin U, Niemeyer D, Gerold G, Beule D, Goffinet C. Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection. PLoS Pathog 2023; 19:e1011657. [PMID: 37747932 PMCID: PMC10629670 DOI: 10.1371/journal.ppat.1011657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/07/2023] [Accepted: 09/04/2023] [Indexed: 09/27/2023] Open
Abstract
Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. The antiviral activity manifested itself by reduced reporter expression of recombinant viruses, and reduced viral RNA quantities and infectious titers in the culture supernatant. While we confirmed JQ-1-mediated downregulation of expression of angiotensin-converting enzyme 2 (ACE2) and interferon-stimulated genes (ISGs), multi-omics analysis addressing the chromatin accessibility, transcriptome and proteome uncovered induction of an antiviral nuclear factor erythroid 2-related factor 2 (NRF-2)-mediated cytoprotective response as an additional mechanism through which JQ-1 inhibits SARS-CoV-2 replication. Pharmacological inhibition of NRF-2, and knockdown of NRF-2 and its target genes reduced JQ-1-mediated inhibition of SARS-CoV-2 replication. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variant, which exhibited resistance to JQ-1 and increased sensitivity to exogenously administered type I interferon (IFN-I), suggesting a minimised need for SARS-CoV-2 ORF6-mediated repression of IFN signalling in the presence of JQ-1. Importantly, JQ-1 exhibited a transient antiviral activity when administered prophylactically in human airway bronchial epithelial cells (hBAECs), which was gradually subverted by SARS-CoV-2, and no antiviral activity when administered therapeutically following an established infection. We propose that JQ-1 exerts pleiotropic effects that collectively induce an antiviral state in the host, which is ultimately nullified by SARS-CoV-2 infection, raising questions about the clinical suitability of the iBETs in the context of COVID-19.
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Affiliation(s)
- Baxolele Mhlekude
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Virology and Innate Immunity Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany
| | - Dylan Postmus
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Saskia Stenzel
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - January Weiner
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Jenny Jansen
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Francisco J. Zapatero-Belinchón
- Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden
| | - Ruth Olmer
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH—Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
| | - Anja Richter
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Julian Heinze
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nicolas Heinemann
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Barbara Mühlemann
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Simon Schroeder
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Terry C. Jones
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Centre for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, United Kingdom
| | - Marcel A. Müller
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christian Drosten
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Andreas Pich
- Institute of Toxicology, Hannover Medical School, Core Facility Proteomics, Hannover, Germany
| | - Volker Thiel
- Institute of Virology and Immunology (IVI), University of Bern, Bern, Switzerland
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Ulrich Martin
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, REBIRTH—Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
| | - Daniela Niemeyer
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Gisa Gerold
- Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
- Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
- Department of Clinical Microbiology, Virology & Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden
| | - Dieter Beule
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Christine Goffinet
- Institute of Virology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool United Kingdom
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17
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Grigorov I, Pejić S, Todorović A, Drakulić D, Veljković F, Vukajlović JM, Bobić K, Soldatović I, Đurašević S, Jasnić N, Stanković S, Glumac S, Mihailović-Vučinić V, Milenković B. Serum High-Mobility Group Box 1 and Heme Oxygenase-1 as Biomarkers in COVID-19 Patients at Hospital Admission. Int J Mol Sci 2023; 24:13164. [PMID: 37685970 PMCID: PMC10488018 DOI: 10.3390/ijms241713164] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/06/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
The careful monitoring of patients with mild/moderate COVID-19 is of particular importance because of the rapid progression of complications associated with COVID-19. For prognostic reasons and for the economic management of health care resources, additional biomarkers need to be identified, and their monitoring can conceivably be performed in the early stages of the disease. In this retrospective cross-sectional study, we found that serum concentrations of high-mobility group box 1 (HMGB1) and heme oxygenase-1 (HO-1), at the time of hospital admission, could be useful biomarkers for COVID-19 management. The study included 160 randomly selected recovered patients with mild to moderate COVID-19 on admission. Compared with healthy controls, serum HMGB1 and HO-1 levels increased by 487.6 pg/mL versus 43.1 pg/mL and 1497.7 pg/mL versus 756.1 pg/mL, respectively. Serum HO-1 correlated significantly with serum HMGB1, oxidative stress parameters (malondialdehyde (MDA), the phosphatidylcholine/lysophosphatidylcholine ratio (PC/LPC), the ratio of reduced and oxidative glutathione (GSH/GSSG)), and anti-inflammatory acute phase proteins (ferritin, haptoglobin). Increased heme catabolism/hemolysis were not detected. We hypothesize that the increase in HO-1 in the early phase of COVID-19 disease is likely to have a survival benefit by providing protection against oxidative stress and inflammation, whereas the level of HMGB1 increase reflects the activity of the innate immune system and represents levels within which the disease can be kept under control.
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Affiliation(s)
- Ilijana Grigorov
- Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Snežana Pejić
- Vinča Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (S.P.); (A.T.); (D.D.); (F.V.); (J.M.V.); (K.B.)
| | - Ana Todorović
- Vinča Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (S.P.); (A.T.); (D.D.); (F.V.); (J.M.V.); (K.B.)
| | - Dunja Drakulić
- Vinča Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (S.P.); (A.T.); (D.D.); (F.V.); (J.M.V.); (K.B.)
| | - Filip Veljković
- Vinča Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (S.P.); (A.T.); (D.D.); (F.V.); (J.M.V.); (K.B.)
| | - Jadranka Miletić Vukajlović
- Vinča Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (S.P.); (A.T.); (D.D.); (F.V.); (J.M.V.); (K.B.)
| | - Katarina Bobić
- Vinča Institute of Nuclear Sciences—National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (S.P.); (A.T.); (D.D.); (F.V.); (J.M.V.); (K.B.)
| | - Ivan Soldatović
- Institute of Medical Statistics and Informatic, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Siniša Đurašević
- Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (S.Đ.); (N.J.)
| | - Nebojša Jasnić
- Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (S.Đ.); (N.J.)
| | - Sanja Stanković
- Center for Medical Biochemistry, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
| | - Sofija Glumac
- Institute of Pathology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (S.G.); (V.M.-V.); (B.M.)
| | - Violeta Mihailović-Vučinić
- Institute of Pathology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (S.G.); (V.M.-V.); (B.M.)
- Clinic for Pulmonary Diseases, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Branislava Milenković
- Institute of Pathology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (S.G.); (V.M.-V.); (B.M.)
- Clinic for Pulmonary Diseases, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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18
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Nielsen A, Handel M, Stone J, Lee M. Misreport of burns as a result of 'coining', Gua sha; inherent harms from publication and ongoing citation of false facts. Integr Med Res 2023; 12:100953. [PMID: 37201160 PMCID: PMC10186471 DOI: 10.1016/j.imr.2023.100953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/02/2023] [Indexed: 05/20/2023] Open
Affiliation(s)
- Arya Nielsen
- Icahn School of Medicine at Mount Sinai, Department of Family Medicine & Community Health, New York, USA
- Corresponding author at: Icahn School of Medicine at Mount Sinai, Department of Family Medicine & Community Health, New York, USA
| | - Marsha Handel
- Icahn School of Medicine at Mount Sinai, Department of Family Medicine & Community Health, New York, USA
| | | | - Myeong Soo Lee
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
- Korean Convergence Medical Science, University of Science and Technology, Daejeon, Republic of Korea
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19
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Tognarelli EI, Duarte LF, Farías MA, Cancino FA, Corrales N, Ibáñez FJ, Riedel CA, Bueno SM, Kalergis AM, González PA. Heme Oxygenase-1 Expression in Dendritic Cells Contributes to Protective Immunity against Herpes Simplex Virus Skin Infection. Antioxidants (Basel) 2023; 12:1170. [PMID: 37371900 DOI: 10.3390/antiox12061170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/14/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023] Open
Abstract
Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are highly prevalent in the human population and produce mild to life-threatening diseases. These viruses interfere with the function and viability of dendritic cells (DCs), which are professional antigen-presenting cells that initiate and regulate the host's antiviral immune responses. Heme oxygenase-1 (HO-1) is an inducible host enzyme with reported antiviral activity against HSVs in epithelial cells and neurons. Here, we sought to assess whether HO-1 modulates the function and viability of DCs upon infection with HSV-1 or HSV-2. We found that the stimulation of HO-1 expression in HSV-inoculated DCs significantly recovered the viability of these cells and hampered viral egress. Furthermore, HSV-infected DCs stimulated to express HO-1 promoted the expression of anti-inflammatory molecules, such as PDL-1 and IL-10, and the activation of virus-specific CD4+ T cells with regulatory (Treg), Th17 and Treg/Th17 phenotypes. Moreover, HSV-infected DCs stimulated to express HO-1 and then transferred into mice, promoted the activation of virus-specific T cells and improved the outcome of HSV-1 skin infection. These findings suggest that stimulation of HO-1 expression in DCs limits the deleterious effects of HSVs over these cells and induces a favorable virus-specific immune response in the skin against HSV-1.
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Affiliation(s)
- Eduardo I Tognarelli
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Luisa F Duarte
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
- Millennium Institute on Immunology and Immunotherapy, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370133, Chile
| | - Mónica A Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Felipe A Cancino
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Nicolás Corrales
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Francisco J Ibáñez
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Claudia A Riedel
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
- Millennium Institute on Immunology and Immunotherapy, Departamento de Ciencias Biológicas, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370133, Chile
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile
| | - Pablo A González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
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20
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Durante W. Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19. Int J Mol Sci 2023; 24:7593. [PMID: 37108759 PMCID: PMC10144995 DOI: 10.3390/ijms24087593] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 04/29/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. Accumulating clinical data have discovered a deficiency of circulating glutamine in patients with COVID-19 that associates with disease severity. Glutamine is a semi-essential amino acid that is metabolized to a plethora of metabolites that serve as central modulators of immune and endothelial cell function. A majority of glutamine is metabolized to glutamate and ammonia by the mitochondrial enzyme glutaminase (GLS). Notably, GLS activity is upregulated in COVID-19, favoring the catabolism of glutamine. This disturbance in glutamine metabolism may provoke immune and endothelial cell dysfunction that contributes to the development of severe infection, inflammation, oxidative stress, vasospasm, and coagulopathy, which leads to vascular occlusion, multi-organ failure, and death. Strategies that restore the plasma concentration of glutamine, its metabolites, and/or its downstream effectors, in conjunction with antiviral drugs, represent a promising therapeutic approach that may restore immune and endothelial cell function and prevent the development of occlusive vascular disease in patients stricken with COVID-19.
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Affiliation(s)
- William Durante
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
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21
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Che S, Zhou N, Liu Y, Xie J, Liu E. Andrographolide exerts anti-respiratory syncytial virus activity by up-regulating heme oxygenase-1 independent of interferon responses in human airway epithelial cells. Mol Biol Rep 2023; 50:4261-4272. [PMID: 36918433 PMCID: PMC10013987 DOI: 10.1007/s11033-023-08346-z] [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: 08/11/2022] [Accepted: 02/17/2023] [Indexed: 03/15/2023]
Abstract
BACKGROUND Respiratory syncytial virus (RSV) is the leading cause of mortality and morbidity in children under the age of five. Despite this, there is still a lack of safe and effective vaccines and antiviral agents for clinical use. Andrographolide exerts antiviral functions against a variety of viruses, but whether (and how) it exerts antiviral effects on RSV remains unclear. METHODS AND RESULTS In vitro RSV infection models using A549 and 16HBE cell lines were established, and the effects of andrographolide on RSV were analyzed via RSV N gene load and proinflammatory cytokine levels. The RNA transcriptome was sequenced, and data were analyzed by R software. Andrographolide-related target genes were extracted via network pharmacology using online databases. Lentiviral transfection was applied to knockdown the heme oxygenase-1 gene (Hmox1, HO-1). Results showed that andrographolide suppressed RSV replication and attenuated subsequent inflammation. Network pharmacology and RNA sequencing analysis indicated that the hub gene HO-1 may play a pivotal role in the anti-RSV effects of andrographolide. Furthermore, andrographolide exerted antiviral effects against RSV partially by inducing HO-1 but did not activate the antiviral interferon response. CONCLUSION Our findings demonstrated that andrographolide exerted anti-RSV activity by up-regulating HO-1 expression in human airway epithelial cells, providing novel insights into potential therapeutic targets and drug repurposing in RSV infection.
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Affiliation(s)
- Siyi Che
- Department of Respiratory Medicine, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Na Zhou
- Department of Respiratory Medicine, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Ying Liu
- State Key Laboratory of Innovative Natural Medicine and TCM Injections, Jiangxi Qingfeng Pharmaceutical Co. Ltd, Ganzhou, 341000, China
| | - Jun Xie
- Department of Respiratory Medicine, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.
| | - Enmei Liu
- Department of Respiratory Medicine, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.
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22
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de Lima F, Moraes CRP, Barbosa MS, Bombassaro B, Palma AC, Dertkigil SSJ, Moretti ML, Orsi FA, Annichino-Bizzacchi JM, Mansour E, Velloso LA, De Paula EV. Association of heme-oxygenase 1, hemopexin, and heme levels with markers of disease severity in COVID-19. Exp Biol Med (Maywood) 2023; 248:309-316. [PMID: 36740756 PMCID: PMC9902789 DOI: 10.1177/15353702221139185] [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] [Indexed: 02/07/2023] Open
Abstract
Heme-oxygenase 1 (HO-1) is an enzyme with well-known anti-inflammatory and antioxidant properties, whose levels have been previously associated with disease severity in the context of sterile and infectious diseases. Moreover, the heme/HO-1 pathway has been associated with prothrombotic changes in other diseases. Accordingly, the potential of modulating HO-1 levels for the treatment of COVID-19 was extensively speculated during the COVID-19 pandemic, but very few actual data were generated. The aim of our study was to explore the association of HO-1, heme, and hemopexin (HPX) levels with COVID-19 severity and with markers of inflammation and coagulation activation. The study was conducted in 30 consecutive patients with COVID-19 admitted due to hypoxemia, and 30 healthy volunteers matched by sex, age, and geographic region. HO-1 and HPX levels were measured by enzyme immunoassay (ELISA) and heme levels were measured by a colorimetric method. A comprehensive panel of coagulation and fibrinolysis activation was also used. Patients with COVID-19 presented increased levels of HO-1 when compared to controls (5741 ± 2696 vs 1953 ± 612 pg/mL, respectively, P < 0.0001), as well as a trend toward increased levels of HPX (3.724 ± 0.880 vs 3.254 ± 1.022 mg/mL, respectively; P = 0.06). In addition, HO-1 and HPX levels reduced from admission to day + 4. HO-1 levels were associated with duration of intensive care unit stay and with several markers of coagulation activation. In conclusion, modulation of HO-1 could be associated with the prothrombotic state observed in COVID-19, and HO-1 could also represent a relevant biomarker for COVID-19. New independent studies are warranted to explore and expand these findings.
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Affiliation(s)
- Franciele de Lima
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil,Franciele de Lima.
| | | | - Mayck Silva Barbosa
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil
| | - Bruna Bombassaro
- Obesity and Comorbidities Research Center, University of Campinas, Campinas 13083-864, Brazil
| | - André C Palma
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil
| | | | - Maria Luiza Moretti
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil
| | | | - Joyce M Annichino-Bizzacchi
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil,Hematology and Hemotherapy Center, University of Campinas, Campinas 13083-878, Brazil
| | - Eli Mansour
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil
| | - Licio A Velloso
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil,Obesity and Comorbidities Research Center, University of Campinas, Campinas 13083-864, Brazil
| | - Erich Vinicius De Paula
- School of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil,Hematology and Hemotherapy Center, University of Campinas, Campinas 13083-878, Brazil
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23
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Gain C, Song S, Angtuaco T, Satta S, Kelesidis T. The role of oxidative stress in the pathogenesis of infections with coronaviruses. Front Microbiol 2023; 13:1111930. [PMID: 36713204 PMCID: PMC9880066 DOI: 10.3389/fmicb.2022.1111930] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/23/2022] [Indexed: 01/15/2023] Open
Abstract
Coronaviruses can cause serious respiratory tract infections and may also impact other end organs such as the central nervous system, the lung and the heart. The coronavirus disease 2019 (COVID-19) has had a devastating impact on humanity. Understanding the mechanisms that contribute to the pathogenesis of coronavirus infections, will set the foundation for development of new treatments to attenuate the impact of infections with coronaviruses on host cells and tissues. During infection of host cells, coronaviruses trigger an imbalance between increased production of reactive oxygen species (ROS) and reduced antioxidant host responses that leads to increased redox stress. Subsequently, increased redox stress contributes to reduced antiviral host responses and increased virus-induced inflammation and apoptosis that ultimately drive cell and tissue damage and end organ disease. However, there is limited understanding how different coronaviruses including SARS-CoV-2, manipulate cellular machinery that drives redox responses. This review aims to elucidate the redox mechanisms involved in the replication of coronaviruses and associated inflammation, apoptotic pathways, autoimmunity, vascular dysfunction and tissue damage that collectively contribute to multiorgan damage.
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Affiliation(s)
| | | | | | | | - Theodoros Kelesidis
- Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA, United States
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24
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Wang Y, Ma J, Jiang Y. Transcription factor Nrf2 as a potential therapeutic target for COVID-19. Cell Stress Chaperones 2023; 28:11-20. [PMID: 36417098 PMCID: PMC9685020 DOI: 10.1007/s12192-022-01296-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 08/08/2022] [Accepted: 09/09/2022] [Indexed: 11/24/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2). Critically ill patients with SARS-COV-2 infection frequently exhibit signs of high oxidative stress and systemic inflammation, which accounts for most of the mortality. Antiviral strategies to inhibit the pathogenic consequences of COVID-19 are urgently required. The nuclear factor erythroid 2-related transcription factor (Nrf2) is a transcription factor that is involved in antioxidant and anti-inflammatory defense in several tissues and cells. This review tries to present an overview of the role of Nrf2 in the treatment of COVID-19.
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Affiliation(s)
- Yifan Wang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Jing Ma
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yongfang Jiang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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25
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Naidu SAG, Clemens RA, Naidu AS. SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control. J Diet Suppl 2023; 20:312-371. [PMID: 35603834 DOI: 10.1080/19390211.2022.2075072] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Severe imbalance in iron metabolism among SARS-CoV-2 infected patients is prominent in every symptomatic (mild, moderate to severe) clinical phase of COVID-19. Phase-I - Hypoxia correlates with reduced O2 transport by erythrocytes, overexpression of HIF-1α, altered mitochondrial bioenergetics with host metabolic reprogramming (HMR). Phase-II - Hyperferritinemia results from an increased iron overload, which triggers a fulminant proinflammatory response - the acute cytokine release syndrome (CRS). Elevated cytokine levels (i.e. IL6, TNFα and CRP) strongly correlates with altered ferritin/TF ratios in COVID-19 patients. Phase-III - Thromboembolism is consequential to erythrocyte dysfunction with heme release, increased prothrombin time and elevated D-dimers, cumulatively linked to severe coagulopathies with life-threatening outcomes such as ARDS, and multi-organ failure. Taken together, Fe-R-H dysregulation is implicated in every symptomatic phase of COVID-19. Fe-R-H regulators such as lactoferrin (LF), hemoxygenase-1 (HO-1), erythropoietin (EPO) and hepcidin modulators are innate bio-replenishments that sequester iron, neutralize iron-mediated free radicals, reduce oxidative stress, and improve host defense by optimizing iron metabolism. Due to its pivotal role in 'cytokine storm', ferroptosis is a potential intervention target. Ferroptosis inhibitors such as ferrostatin-1, liproxstatin-1, quercetin, and melatonin could prevent mitochondrial lipid peroxidation, up-regulate antioxidant/GSH levels and abrogate iron overload-induced apoptosis through activation of Nrf2 and HO-1 signaling pathways. Iron chelators such as heparin, deferoxamine, caffeic acid, curcumin, α-lipoic acid, and phytic acid could protect against ferroptosis and restore mitochondrial function, iron-redox potential, and rebalance Fe-R-H status. Therefore, Fe-R-H restoration is a host biomarker-driven potential combat strategy for an effective clinical and post-recovery management of COVID-19.
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Affiliation(s)
| | - Roger A Clemens
- Department of International Regulatory Science, University of Southern California School of Pharmacy, Los Angeles, CA, USA
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Wang T, Cao Y, Zhang H, Wang Z, Man CH, Yang Y, Chen L, Xu S, Yan X, Zheng Q, Wang Y. COVID-19 metabolism: Mechanisms and therapeutic targets. MedComm (Beijing) 2022; 3:e157. [PMID: 35958432 PMCID: PMC9363584 DOI: 10.1002/mco2.157] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/26/2022] [Accepted: 06/29/2022] [Indexed: 01/18/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS-CoV-2-induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID-19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS-CoV-2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID-19 metabolism. SARS-CoV-2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS-CoV-2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID-19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS-CoV-2-induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID-19 pandemic.
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Affiliation(s)
- Tianshi Wang
- Shanghai Key Laboratory for Tumor Microenvironment and InflammationDepartment of Biochemistry and Molecular Cell BiologyShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ying Cao
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haiyan Zhang
- Bai Jia Obstetrics and Gynecology HospitalShanghaiChina
| | - Zihao Wang
- Fudan University Shanghai Cancer CenterKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyCancer Instituteand The Shanghai Key Laboratory of Medical EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- The International Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyShanghaiChina
| | - Cheuk Him Man
- Division of HematologyDepartment of MedicineUniversity of Hong KongPokfulamHong Kong, China
| | - Yunfan Yang
- Department of Cell BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinanChina
| | - Lingchao Chen
- Department of NeurosurgeryHuashan HospitalShanghai Medical CollegeFudan UniversityNational Center for Neurological DisordersShanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationNeurosurgical Institute of Fudan UniversityShanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Shuangnian Xu
- Department of HematologySouthwest HospitalArmy Medical UniversityChongqingChina
| | - Xiaojing Yan
- Department of HematologyThe First Affiliated Hospital of China Medical UniversityShenyangChina
| | - Quan Zheng
- Center for Single‐Cell OmicsSchool of Public HealthShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yi‐Ping Wang
- Fudan University Shanghai Cancer CenterKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyCancer Instituteand The Shanghai Key Laboratory of Medical EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- The International Co‐laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyShanghaiChina
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Silva RCMC, Vasconcelos LR, Travassos LH. The different facets of heme-oxygenase 1 in innate and adaptive immunity. Cell Biochem Biophys 2022; 80:609-631. [PMID: 36018440 DOI: 10.1007/s12013-022-01087-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 07/20/2022] [Indexed: 11/26/2022]
Abstract
Heme oxygenase (HO) enzymes are responsible for the main oxidative step in heme degradation, generating equimolar amounts of free iron, biliverdin and carbon monoxide. HO-1 is induced as a crucial stress response protein, playing protective roles in physiologic and pathological conditions, due to its antioxidant, anti-apoptotic and anti-inflammatory effects. The mechanisms behind HO-1-mediated protection are being explored by different studies, affecting cell fate through multiple ways, such as reduction in intracellular levels of heme and ROS, transcriptional regulation, and through its byproducts generation. In this review we focus on the interplay between HO-1 and immune-related signaling pathways, which culminate in the activation of transcription factors important in immune responses and inflammation. We also discuss the dual interaction of HO-1 and inflammatory mediators that govern resolution and tissue damage. We highlight the dichotomy of HO-1 in innate and adaptive immune cells development and activation in different disease contexts. Finally, we address different known anti-inflammatory pharmaceuticals that are now being described to modulate HO-1, and the possible contribution of HO-1 in their anti-inflammatory effects.
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Affiliation(s)
- Rafael Cardoso Maciel Costa Silva
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Luiz Ricardo Vasconcelos
- Cellular Signaling and Cytoskeletal Function Laboratory, The Francis Crick Institute, London, UK
| | - Leonardo Holanda Travassos
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Chen WC, Huang CH, Liu W, Lee JC. Sulforaphane suppresses dengue virus replication by inhibition of dengue protease and enhancement of antiviral interferon response through Nrf2-mediated heme oxygenase-1 induction. Antiviral Res 2022; 207:105400. [DOI: 10.1016/j.antiviral.2022.105400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/02/2022]
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Increased Heme Oxygenase 1 Expression upon a Primary Exposure to the Respiratory Syncytial Virus and a Secondary Mycobacterium bovis Infection. Antioxidants (Basel) 2022; 11:antiox11081453. [PMID: 35892656 PMCID: PMC9332618 DOI: 10.3390/antiox11081453] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/21/2022] [Accepted: 07/23/2022] [Indexed: 12/05/2022] Open
Abstract
The human respiratory syncytial virus (hRSV) is the leading cause of severe lower respiratory tract infections in infants. Because recurrent epidemics based on reinfection occur in children and adults, hRSV has gained interest as a potential primary pathogen favoring secondary opportunistic infections. Several infection models have shown different mechanisms by which hRSV promotes immunopathology to prevent the development of adaptive protective immunity. However, little is known about the long-lasting effects of viral infection on pulmonary immune surveillance mechanisms. As a first approach, here we evaluated whether a primary infection by hRSV, once resolved, dampens the host immune response to a secondary infection with an attenuated strain of Mycobacterium bovis (M. Bovis) strain referred as to Bacillus Calmette-Guerin (BCG). We analyzed leukocyte dynamics and immunomodulatory molecules in the lungs after eleven- and twenty-one-days post-infection with Mycobacterium, using previous hRSV infected mice, by flow cytometry and the expression of critical genes involved in the immune response by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Among the latter, we analyzed the expression of Heme Oxygenase (HO)-1 in an immunization scheme in mice. Our data suggest that a pre-infection with hRSV has a conditioning effect promoting lung pathology during a subsequent mycobacterial challenge, characterized by increased infiltration of innate immune cells, including interstitial and alveolar macrophages. Our data also suggest that hRSV impairs pulmonary immune responses, promoting secondary mycobacterial colonization and lung survival, which could be associated with an increase in the expression of HO-1. Additionally, BCG is a commonly used vaccine that can be used as a platform for the generation of new recombinant vaccines, such as a recombinant BCG strain expressing the nucleoprotein of hRSV (rBCG-N-hRSV). Therefore, we evaluated if the immunization with rBCG-N-hRSV could modulate the expression of HO-1. We found a differential expression pattern for HO-1, where a higher induction of HO-1 was detected on epithelial cells compared to dendritic cells during late infection times. This is the first study to demonstrate that infection with hRSV produces damage in the lung epithelium, promoting subsequent mycobacterial colonization, characterized by an increase in the neutrophils and alveolar macrophages recruitment. Moreover, we determined that immunization with rBCG-N-hRSV modulates differentially the expression of HO-1 on immune and epithelial cells, which could be involved in the repair of pulmonary tissue.
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Xu MM, Wu B, Huang GG, Feng CL, Wang XH, Wang HY, Wu YW, Tang W. Hemin protects against Zika virus infection by disrupting virus-endosome fusion. Antiviral Res 2022; 203:105347. [DOI: 10.1016/j.antiviral.2022.105347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 05/18/2022] [Accepted: 05/23/2022] [Indexed: 11/24/2022]
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Detsika MG, Nikitopoulou I, Veroutis D, Vassiliou AG, Jahaj E, Tsipilis S, Athanassiou N, Gakiopoulou H, Gorgoulis VG, Dimopoulou I, Orfanos SE, Kotanidou A. Increase of HO-1 Expression in Critically Ill COVID-19 Patients Is Associated with Poor Prognosis and Outcome. Antioxidants (Basel) 2022; 11:antiox11071300. [PMID: 35883791 PMCID: PMC9311906 DOI: 10.3390/antiox11071300] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/24/2022] [Accepted: 06/26/2022] [Indexed: 02/01/2023] Open
Abstract
Heme-oxygenase (HO)-1 is a cytoprotective enzyme with strong antioxidant and anti-apoptotic properties and previous reports have also emphasized the antiviral properties of HO-1, either directly or via induction of interferons. To investigate the potential role of HO-1 in patients with coronavirus disease 2019 (COVID-19), the present study assessed changes in HO-1 expression in whole blood and tissue samples. Upregulation of HO-1 protein was observed in lung, liver, and skin tissue independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presence. A significant increase of blood HO-1 mRNA levels was observed in critically ill COVID-19 patients compared to those in severe COVID-19 patients and healthy controls. This increase was accompanied by significantly elevated levels of serum ferritin and bilirubin in critically ill compared to patients with severe disease. Further grouping of patients in survivors and non-survivors revealed a significant increase of blood HO-1 mRNA levels in the later. Receiver operating characteristic (ROC) analysis for prediction of ICU admission and mortality yielded an AUC of 0.705 (p = 0.016) and 0.789 (p = 0.007) respectively indicating that HO-1 increase is associated with poor COVID-19 progression and outcome. The increase in HO-1 expression observed in critically ill COVID-19 patients could serve as a mechanism to counteract increased heme levels driving coagulation and thrombosis or as an induced protective mechanism.
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Affiliation(s)
- Maria G. Detsika
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Ioanna Nikitopoulou
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Dimitris Veroutis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, 10675 Athens, Greece; (D.V.); (V.G.G.)
| | - Alice G. Vassiliou
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Edison Jahaj
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Stamatis Tsipilis
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Nikolaos Athanassiou
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Hariklia Gakiopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vassilis G. Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, 10675 Athens, Greece; (D.V.); (V.G.G.)
- Biomedical Research Foundation, Academy of Athens, 10675 Athens, Greece
- Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M20 4GJ, UK
- Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 10675 Athens, Greece
- Faculty of Health and Medical Sciences, University of Surrey, Surrey GU2 7YH, UK
| | - Ioanna Dimopoulou
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Stylianos E. Orfanos
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
| | - Anastasia Kotanidou
- 1st Department of Critical Care Medicine & Pulmonary Services, GP Livanos and M Simou Laboratories, Evangelismos Hospital, National and Kapodistrian University of Athens, 10675 Athens, Greece; (M.G.D.); (I.N.); (A.G.V.); (E.J.); (S.T.); (N.A.); (I.D.); (S.E.O.)
- Correspondence:
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de Oliveira J, Denadai MB, Costa DL. Crosstalk between Heme Oxygenase-1 and Iron Metabolism in Macrophages: Implications for the Modulation of Inflammation and Immunity. Antioxidants (Basel) 2022; 11:861. [PMID: 35624725 PMCID: PMC9137896 DOI: 10.3390/antiox11050861] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 12/16/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is an enzyme that catalyzes the degradation of heme, releasing equimolar amounts of carbon monoxide (CO), biliverdin (BV), and iron. The anti-inflammatory and antioxidant properties of HO-1 activity are conferred in part by the release of CO and BV and are extensively characterized. However, iron constitutes an important product of HO-1 activity involved in the regulation of several cellular biological processes. The macrophage-mediated recycling of heme molecules, in particular those contained in hemoglobin, constitutes the major mechanism through which living organisms acquire iron. This process is finely regulated by the activities of HO-1 and of the iron exporter protein ferroportin. The expression of both proteins can be induced or suppressed in response to pro- and anti-inflammatory stimuli in macrophages from different tissues, which alters the intracellular iron concentrations of these cells. As we discuss in this review article, changes in intracellular iron levels play important roles in the regulation of cellular oxidation reactions as well as in the transcriptional and translational regulation of the expression of proteins related to inflammation and immune responses, and therefore, iron metabolism represents a potential target for the development of novel therapeutic strategies focused on the modulation of immunity and inflammation.
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Affiliation(s)
- Joseana de Oliveira
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil; (J.d.O.); (M.B.D.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil
| | - Marina B. Denadai
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil; (J.d.O.); (M.B.D.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil
| | - Diego L. Costa
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil; (J.d.O.); (M.B.D.)
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirao Preto 14049-900, Brazil
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Ulasov AV, Rosenkranz AA, Georgiev GP, Sobolev AS. Nrf2/Keap1/ARE signaling: Towards specific regulation. Life Sci 2022; 291:120111. [PMID: 34732330 PMCID: PMC8557391 DOI: 10.1016/j.lfs.2021.120111] [Citation(s) in RCA: 285] [Impact Index Per Article: 95.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/22/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023]
Abstract
The Nrf2 transcription factor governs the expression of hundreds genes involved in cell defense against oxidative stress, the hallmark of numerous diseases such as neurodegenerative, cardiovascular, some viral pathologies, diabetes and others. The main route for Nrf2 activity regulation is via interactions with the Keap1 protein. Under the normoxia the Keap1 binds the Nrf2 and targets it to the proteasomal degradation, while the Keap1 is regenerated. Upon oxidative stress the interactions between Nrf2 and Keap1 are interrupted and the Nrf2 activates the transcription of the protective genes. Currently, the Nrf2 system activation is considered as a powerful cytoprotective strategy for treatment of different pathologies, which pathogenesis relies on oxidative stress including viral diseases of pivotal importance such as COVID-19. The implementation of this strategy is accomplished mainly through the inactivation of the Keap1 "guardian" function. Two approaches are now developing: the Keap1 modification via electrophilic agents, which leads to the Nrf2 release, and direct interruption of the Nrf2:Keap1 protein-protein interactions (PPI). Because of theirs chemical structure, the Nrf2 electrophilic inducers could non-specifically interact with others cellular proteins leading to undesired effects. Whereas the non-electrophilic inhibitors of the Nrf2:Keap1 PPI could be more specific, thereby widening the therapeutic window.
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Affiliation(s)
- Alexey V Ulasov
- Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia.
| | - Andrey A Rosenkranz
- Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia; Faculty of Biology, Moscow State University, 1-12 Leninskiye Gory St., 119234 Moscow, Russia
| | - Georgii P Georgiev
- Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia
| | - Alexander S Sobolev
- Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., 119334 Moscow, Russia; Faculty of Biology, Moscow State University, 1-12 Leninskiye Gory St., 119234 Moscow, Russia
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Xiang Q, Cheng L, Zhang R, Liu Y, Wu Z, Zhang X. Tea Polyphenols Prevent and Intervene in COVID-19 through Intestinal Microbiota. Foods 2022; 11:506. [PMID: 35205982 PMCID: PMC8871045 DOI: 10.3390/foods11040506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/22/2022] [Accepted: 02/05/2022] [Indexed: 12/13/2022] Open
Abstract
Although all countries have taken corresponding measures, the coronavirus disease 2019 (COVID-19) is still ravaging the world. To consolidate the existing anti-epidemic results and further strengthen the prevention and control measures against the new coronavirus, we are now actively pioneering a novel research idea of regulating the intestinal microbiota through tea polyphenols for reference. Although studies have long revealed the regulatory effect of tea polyphenols on the intestinal microbiota to various gastrointestinal inflammations, little is known about the prevention and intervention of COVID-19. This review summarizes the possible mechanism of the influence of tea polyphenols on COVID-19 mediated by the intestinal microbiota. In this review, the latest studies of tea polyphenols exhibiting their own antibacterial and anti-inflammatory activities and protective effects on the intestinal mucosal barrier are combed through and summarized. Among them, (-)-epigallocatechin-3-gallate (EGCG), one of the main monomers of catechins, may be activated as nuclear factor erythroid 2 p45-related factor 2 (Nrf2). The agent inhibits the expression of ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2 to inhibit SARS-CoV-2 infection, inhibiting the life cycle of SARS-CoV-2. Thus, preliminary reasoning and judgments have been made about the possible mechanism of the effect of tea polyphenols on the COVID-19 control and prevention mediated by the microbiota. These results may be of great significance to the future exploration of specialized research in this field.
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Affiliation(s)
- Qiao Xiang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China; (Q.X.); (Y.L.); (Z.W.)
| | - Lu Cheng
- Department of Food Science, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA;
| | - Ruilin Zhang
- Key Laboratory of Animal Protein Deep Processing Technology of Zhejiang Province, Ningbo University, Ningbo 315211, China
| | - Yanan Liu
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China; (Q.X.); (Y.L.); (Z.W.)
| | - Zufang Wu
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China; (Q.X.); (Y.L.); (Z.W.)
| | - Xin Zhang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, China; (Q.X.); (Y.L.); (Z.W.)
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A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene? Antioxidants (Basel) 2022; 11:antiox11020276. [PMID: 35204159 PMCID: PMC8868141 DOI: 10.3390/antiox11020276] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 01/27/2023] Open
Abstract
Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe2+), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.
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Cicco G, Sablone S, Cazzato G, Cicco S, Ingravallo G, Introna F, Cossarizza A. Heme Oxygenase-1/High Mobility Group Box 1 Pathway May Have a Possible Role in COVID-19 ARDS (Acute Respiratory Distress Syndrome): A Pilot Histological Study. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1395:111-116. [PMID: 36527623 DOI: 10.1007/978-3-031-14190-4_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
COVID-19 is a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The persistent and excessive inflammatory response can build up a clinical picture that is difficult to manage and potentially fatal. Potent activators of inflammatory phenomena are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). HMGB1 is an intranuclear protein that is either passively released during hypoxia-related necrosis or actively released by macrophages. Heme oxygenase (HO-1) has an anti-inflammatory effect by inhibiting HMGB1, which could be a therapeutic target to reduce COVID-19 inflammation. In our study, we evaluated CD3, CD4, CD8, HMGB1 and HO-1 in the COVID-19 lung and correlated it to clinical data.
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Khan H, Patel S, Majumdar A. Role of NRF2 and Sirtuin activators in COVID-19. Clin Immunol 2021; 233:108879. [PMID: 34798239 PMCID: PMC8592856 DOI: 10.1016/j.clim.2021.108879] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 02/07/2023]
Abstract
COVID-19 is a pandemic requiring immediate solution for treatment because of its complex pathophysiology. Exploration of novel targets and thus treatment will be life savers which is the need of the hour. 2 host factors- TMPRSS2 and ACE2 are responsible for the way the virus will enter and replicate in the host. Also NRF2 is an important protein responsible for its anti-inflammatory role by multiple mechanisms of action like inhibition of NF-kB, suppression of pro-inflammatory genes, etc. NRF2 is deacetylated by Sirtuins and therefore both have a direct association. Absence of SIRT indicates inhibition of NRF2 expression and thus no anti-oxidative and anti-inflammatory protection for the cell. Therefore, we propose that NRF2 activators and/or SIRT activators can be evaluated to check their efficacy in ameliorating the symptoms of COVID-19.
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Affiliation(s)
- Hasnat Khan
- Department of Pharmacology, Bombay College of Pharmacy, Mumbai 400098, India
| | - Shivangi Patel
- Department of Pharmacology, Bombay College of Pharmacy, Mumbai 400098, India
| | - Anuradha Majumdar
- Department of Pharmacology, Bombay College of Pharmacy, Mumbai 400098, India.
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Induction of HOXA3 by PRRSV inhibits IFN-I response through negatively regulation of HO-1 transcription. J Virol 2021; 96:e0186321. [PMID: 34851144 DOI: 10.1128/jvi.01863-21] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Type I interferons (IFN-I) play a key role in the host defense against virus infection, but porcine reproductive and respiratory syndrome virus (PRRSV) infection does not effectively activate IFN-I response, and the underlying molecular mechanisms are poorly characterized. In this study, a novel transcription factor of the heme oxygenase-1 (HO-1) gene, homeobox A3 (HOXA3), was screened and identified. Here, we found that HOXA3 was significantly increased during PRRSV infection. We demonstrated that HOXA3 promotes PRRSV replication by negatively regulating the HO-1 gene transcription, which is achieved by regulating type I interferons (IFN-I) production. A detailed analysis showed that PRRSV exploits HOXA3 to suppress beta interferon (IFN-β) and IFN-stimulated gene (ISG) expression in host cells. We also provide direct evidence that the activation of IFN-I by HO-1 depends on its interaction with IRF3. Then we further proved that deficiency of HOXA3 promoted the HO-1-IRF3 interaction, and subsequently enhanced IRF3 phosphorylation and nuclear translocation in PRRSV-infected cells. These data suggest that PRRSV uses HOXA3 to negatively regulate the transcription of the HO-1 gene to suppress the IFN-I response for immune evasion. IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, leads the pork industry worldwide to significant economic losses. HOXA3 is generally considered to be an important molecule in the process of body development and cell differentiation. Here, we found a novel transcription factor of the HO-1 gene, HOXA3, can negatively regulate the transcription of the HO-1 gene and play an important role in the suppression of IFN-I response by PRRSV. PRRSV induces the upregulation of HOXA3, which can negatively regulate HO-1 gene transcription, thereby weakening the interaction between HO-1 and IRF3 for inhibiting the type I IFN response. This study extends the function of HOXA3 to the virus field for the first time and provides new insights into PRRSV immune evasion mechanism.
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Ma LL, Sun L, Wang YX, Sun BH, Li YF, Jin YL. Association between HO‑1 gene promoter polymorphisms and diseases (Review). Mol Med Rep 2021; 25:29. [PMID: 34841438 PMCID: PMC8669660 DOI: 10.3892/mmr.2021.12545] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 11/11/2021] [Indexed: 12/21/2022] Open
Abstract
Heme oxygenase‑1 (HO‑1) is an inducible cytoprotective enzyme that degrades heme into free iron, carbon monoxide and biliverdin, which is then rapidly converted into bilirubin. These degradation products serve an important role in the regulation of inflammation, oxidative stress and apoptosis. While the expression level of HO‑1 is typically low in most cells, it may be highly expressed when induced by a variety of stimulating factors, a process that contributes to the regulation of cell homeostasis. In the 5'‑non‑coding region of the HO‑1 gene, there are two polymorphic sites, namely the (GT)n dinucleotide and T(‑413)A single nucleotide polymorphism sites, which regulate the transcriptional activity of HO‑1. These polymorphisms have been shown to be closely associated with the occurrence and progression of numerous diseases, including cardiovascular, pulmonary, liver and kidney, various types of cancer and viral diseases. The present article reviews the progress that has been made in research on the association between the two types of polymorphisms and these diseases, which is expected to provide novel strategies for the diagnosis, treatment and prognosis of various diseases.
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Affiliation(s)
- Lin-Lin Ma
- School of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai 201318, P.R. China
| | - Lei Sun
- School of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai 201318, P.R. China
| | - Yu-Xi Wang
- School of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai 201318, P.R. China
| | - Bai-He Sun
- School of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai 201318, P.R. China
| | - Yan-Fei Li
- School of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai 201318, P.R. China
| | - Yue-Ling Jin
- Management Department of Scientific Research, Shanghai Science and Technology Museum, Shanghai 200127, P.R. China
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Khokhar M, Tomo S, Purohit P. MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19. Meta Gene 2021; 31:100990. [PMID: 34722158 PMCID: PMC8547816 DOI: 10.1016/j.mgene.2021.100990] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 01/08/2023] Open
Abstract
Background Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. Methods The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. Results Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. Conclusion An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.
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Key Words
- AHR, Aryl hydrocarbon receptor
- ARDS, acute respiratory distress syndrome
- BAL, Bronchoalveolar Lavage
- CC, Cellular components
- CCL, Chemokine (C-C motif) ligands
- CCL2, C-C motif chemokine 2
- CCL3, C-C motif chemokine 3
- CCL4, C-C motif chemokine 4
- CCR, CC chemokine receptor
- CEBPA, CCAAT/enhancer-binding protein alpha
- COVID-19
- COVID-19, Coronavirus Disease 2019
- CREM, cAMP responsive element modulator
- CRIEGs, Cytokine regulating immune expressed genes
- CSF2, Granulocyte-macrophage colony-stimulating factor
- CSF3, Granulocyte colony-stimulating factor
- CXCL10, C-X-C motif chemokine 10
- CXCL2, Chemokine (C-X-C motif) ligand 2
- CXCL8, Interleukin-8
- CXCR, C-X-C chemokine receptor
- Cytokine storm
- Cytokines
- DDIT3, DNA damage-inducible transcript 3 protein
- DEGs, Differentially expressed genes
- E2F1, Transcription factor E2F1
- EGR1, Early growth response protein 1
- EP300, Histone acetyltransferase p300
- ESR1, Estrogen receptor, Nuclear hormone receptor
- ETS2, Protein C-ets-2
- FOXP3, Forkhead box protein P3
- GO, Gene Ontology
- GSEs, Gene Series Expressions
- HDAC1, Histone deacetylase 1
- HDAC2, Histone deacetylase 2
- HSF1, Heat shock factor protein 1
- IL-6, interleukin-6
- IL10, Interleukin-10
- IL17A, Interleukin-17A
- IL1B, Interleukin-1
- IL2, Interleukin-2
- IL6, Interleukin-6
- IL7, Interleukin-7
- IL9, Interleukin-9
- IP-10, Interferon-Inducible Protein 10
- IRF1, Interferon regulatory factor 1
- Immuno-interactomics
- JAK-STAT, Janus kinase (JAK)-signal transducer and activator
- JAK2, Tyrosine-protein kinase JAK2
- JUN, Transcription factor AP-1
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- KLF4, Krueppel-like factor 4
- MicroRNA, SARS-CoV-2
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NFAT5, Nuclear factor of activated T-cells 5
- NFKB1, Nuclear factor NF-kappa-B p105 subunit
- NFKBIA, NF-kappa-B inhibitor alpha
- NR1I2, Nuclear receptor subfamily 1 group I member 2
- PDM, peripheral blood mononuclear cell
- REL, Proto-oncogene c-Rel
- RELA, Transcription factor p65
- RUNX1, Runt-related transcription factor 1
- SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2
- SIRT1, NAD-dependent protein deacetylase sirtuin-1
- SP1, Transcription factor Sp1
- SPI1, Transcription factor PU.1
- STAT1, Signal transducer and activator of transcription 1-alpha/beta
- STAT3, Signal transducer and activator of transcription 3
- TLR3, Toll-like receptor 3 (TLR3)
- TNF, Tumor necrosis factor
- TNF-α, Tumor Necrosis Factor-Alpha
- VDR, Vitamin D3 receptor
- XBP1, X-box-binding protein 1
- ZFP36, mRNA decay activator protein ZFP36
- ZNF300, Zinc finger protein 300, heme oxygenase-1 (HO-1)
- miEAA, miRNA Enrichment Analysis and Annotation t
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Affiliation(s)
- Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur 342005, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur 342005, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur 342005, India
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Kim DH, Ahn HS, Go HJ, Kim DY, Kim JH, Lee JB, Park SY, Song CS, Lee SW, Ha SD, Choi C, Choi IS. Hemin as a novel candidate for treating COVID-19 via heme oxygenase-1 induction. Sci Rep 2021; 11:21462. [PMID: 34728736 PMCID: PMC8563742 DOI: 10.1038/s41598-021-01054-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 10/22/2021] [Indexed: 11/24/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease-19 (COVID-19). More than 143 million cases of COVID-19 have been reported to date, with the global death rate at 2.13%. Currently, there are no licensed therapeutics for controlling SARS-CoV-2 infection. The antiviral effects of heme oxygenase-1 (HO-1), a cytoprotective enzyme that inhibits the inflammatory response and reduces oxidative stress, have been investigated in several viral infections. To confirm whether HO-1 suppresses SARS-CoV-2 infection, we assessed the antiviral activity of hemin, an effective and safe HO-1 inducer, in SARS-CoV-2 infection. We found that treatment with hemin efficiently suppressed SARS-CoV-2 replication (selectivity index: 249.7012). Besides, the transient expression of HO-1 using an expression vector also suppressed the growth of the virus in cells. Free iron and biliverdin, which are metabolic byproducts of heme catalysis by HO-1, also suppressed the viral infection. Additionally, hemin indirectly increased the expression of interferon-stimulated proteins known to restrict SARS-CoV-2 replication. Overall, the findings suggested that HO-1, induced by hemin, effectively suppressed SARS-CoV-2 in vitro. Therefore, HO-1 could be potential therapeutic candidate for COVID-19.
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Affiliation(s)
- Dong-Hwi Kim
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Hee-Seop Ahn
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Hyeon-Jeong Go
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Da-Yoon Kim
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Jae-Hyeong Kim
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Joong-Bok Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Seung-Yong Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Chang-Seon Song
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Sang-Won Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Sang-Do Ha
- Advanced Food Safety Research Group, BrainKorea21 Plus, Chung-Ang University, Anseong, Gyeonggi, 17546, Republic of Korea
| | - Changsun Choi
- Department of Food and Nutrition, School of Food Science and Technology, Chung-Ang University, Anseong, Gyeonggi, 17546, Republic of Korea
| | - In-Soo Choi
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
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Kaundal RK, Kalvala AK, Kumar A. Neurological Implications of COVID-19: Role of Redox Imbalance and Mitochondrial Dysfunction. Mol Neurobiol 2021; 58:4575-4587. [PMID: 34110602 PMCID: PMC8190166 DOI: 10.1007/s12035-021-02412-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/29/2021] [Indexed: 12/20/2022]
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 or COVID-19 has been declared as a pandemic disease by the World Health Organization (WHO). Globally, this disease affected 159 million of the population and reported ~ 3.3 million deaths to the current date (May 2021). There is no definitive treatment strategy that has been identified, although this disease has prevailed in its current form for the past 18 months. The main challenges in the (SARS-CoV)-2 infections are in identifying the heterogeneity in viral strains and the plausible mechanisms of viral infection to human tissues. In parallel to the investigations into the patho-mechanism of SARS-CoV-2 infection, understanding the fundamental processes underlying the clinical manifestations of COVID-19 is very crucial for designing effective therapies. Since neurological symptoms are very apparent in COVID-19 infected patients, here, we tried to emphasize the involvement of redox imbalance and subsequent mitochondrial dysfunction in the progression of the COVID-19 infection. It has been articulated that mitochondrial dysfunction is very apparent and also interlinked to neurological symptoms in COVID-19 infection. Overall, this article provides an in-depth overview of redox imbalance and mitochondrial dysfunction involvement in aggravating COVID-19 infection and its probable contribution to the neurological manifestation of the disease.
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Affiliation(s)
- Ravinder K Kaundal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Raebareli, Lucknow, India
- Icahn School of Medicine At Mount Sinai, 1470 Madison Ave, New York, NY, USA
| | - Anil K Kalvala
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, North America, USA
| | - Ashutosh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Kolkata, Kolkata, India.
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Rapozzi V, Juarranz A, Habib A, Ihan A, Strgar R. Is haem the real target of COVID-19? Photodiagnosis Photodyn Ther 2021; 35:102381. [PMID: 34119708 PMCID: PMC8192263 DOI: 10.1016/j.pdpdt.2021.102381] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 06/01/2021] [Indexed: 02/08/2023]
Abstract
Although a vaccination campaign has been launched in many countries, the COVID-19 pandemic is not under control. The main concern is the emergence of new variants of SARS-CoV-2; therefore, it is important to find approaches to prevent or reduce the virulence and pathogenicity of the virus. Currently, the mechanism of action of SARS-CoV-2 is not fully understood. Considering the clinical effects that occur during the disease, attacking the human respiratory and hematopoietic systems, and the changes in biochemical parameters (including decreases in haemoglobin [Hb] levels and increases in serum ferritin), it is clear that iron metabolism is involved. SARS-CoV-2 induces haemolysis and interacts with Hb molecules via ACE2, CD147, CD26, and other receptors located on erythrocytes and/or blood cell precursors that produce dysfunctional Hb. A molecular docking study has reported a potential link between the virus and the beta chain of haemoglobin and attack on haem. Considering that haem is involved in miRNA processing by binding to the DGCR8-DROSHA complex, we hypothesised that the virus may check this mechanism and thwart the antiviral response.
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Affiliation(s)
| | - Angeles Juarranz
- Department of Biology, University Autonoma of Madrid, Madrid 28049, Spain
| | - Ahsan Habib
- Department of Chemistry, University of Dhaka, Dhaka 1000, Bangladesh
| | - Alojz Ihan
- Institute for Microbiology and Immunology, Medical Faculty of Ljubljana, Slovenia
| | - Rebeka Strgar
- Institution of Applicative Biophotonics, Technological Park Ljubljana, Slovenia
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Gorini F, Del Turco S, Sabatino L, Gaggini M, Vassalle C. H 2S as a Bridge Linking Inflammation, Oxidative Stress and Endothelial Biology: A Possible Defense in the Fight against SARS-CoV-2 Infection? Biomedicines 2021; 9:biomedicines9091107. [PMID: 34572292 PMCID: PMC8472626 DOI: 10.3390/biomedicines9091107] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/12/2021] [Accepted: 08/26/2021] [Indexed: 12/17/2022] Open
Abstract
The endothelium controls vascular homeostasis through a delicate balance between secretion of vasodilators and vasoconstrictors. The loss of physiological homeostasis leads to endothelial dysfunction, for which inflammatory events represent critical determinants. In this context, therapeutic approaches targeting inflammation-related vascular injury may help for the treatment of cardiovascular disease and a multitude of other conditions related to endothelium dysfunction, including COVID-19. In recent years, within the complexity of the inflammatory scenario related to loss of vessel integrity, hydrogen sulfide (H2S) has aroused great interest due to its importance in different signaling pathways at the endothelial level. In this review, we discuss the effects of H2S, a molecule which has been reported to demonstrate anti-inflammatory activity, in addition to many other biological functions related to endothelium and sulfur-drugs as new possible therapeutic options in diseases involving vascular pathobiology, such as in SARS-CoV-2 infection.
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Affiliation(s)
- Francesca Gorini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (L.S.); (M.G.)
- Correspondence: (F.G.); (S.D.T.); (C.V.)
| | - Serena Del Turco
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (L.S.); (M.G.)
- Correspondence: (F.G.); (S.D.T.); (C.V.)
| | - Laura Sabatino
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (L.S.); (M.G.)
| | - Melania Gaggini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (L.S.); (M.G.)
| | - Cristina Vassalle
- Fondazione CNR-Regione Toscana G. Monasterio, 56124 Pisa, Italy
- Correspondence: (F.G.); (S.D.T.); (C.V.)
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Saheb Sharif-Askari N, Saheb Sharif-Askari F, Mdkhana B, Hussain Alsayed HA, Alsafar H, Alrais ZF, Hamid Q, Halwani R. Upregulation of oxidative stress gene markers during SARS-COV-2 viral infection. Free Radic Biol Med 2021; 172:688-698. [PMID: 34186206 PMCID: PMC8233550 DOI: 10.1016/j.freeradbiomed.2021.06.018] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/03/2021] [Accepted: 06/21/2021] [Indexed: 02/07/2023]
Abstract
Severe viral infections, including SARS-COV-2, could trigger disruption of the balance between pro-oxidant and antioxidant mediators; the magnitude of which could reflect the severity of infection and lung injury. Using publicly available COVID-19 transcriptomic datasets, we conducted an in-silico analyses to evaluate the expression levels of 125 oxidative stress genes, including 37 pro-oxidant genes, 32 oxidative-responsive genes, and 56 antioxidant genes. Seven oxidative stress genes were found to be upregulated in whole blood and lung autopsies (MPO, S100A8, S100A9, SRXN1, GCLM, SESN2, and TXN); these genes were higher in severe versus non-severe COVID-19 leucocytes. Oxidative genes were upregulated in inflammatory cells comprising macrophages and CD8+ T cells isolated from bronchioalveolar fluid (BALF), and neutrophils isolated from peripheral blood. MPO, S100A8, and S100A9 were top most upregulated oxidative markers within COVID-19's lung autopsies, whole blood, leucocytes, BALF derived macrophages and circulating neutrophils. The calprotectin's, S100A8 and S100A9 were upregulated in SARS-COV-2 infected human lung epithelium. To validate our in-silico analysis, we conducted qRT-PCR to measure MPO and calprotectin's levels in blood and saliva samples. Relative to uninfected donor controls, MPO, S100A8 and S100A9 were significantly higher in blood and saliva of severe versus asymptomatic COVID-19 patients. Compared to other different viral respiratory infections, coronavirus infection showed a prominent upregulation in oxidative stress genes with MPO and calprotectin at the top of the list. In conclusion, SARS-COV-2 induce the expression of oxidative stress genes via both immune as well as lung structural cells. The observed correlation between oxidative stress genes dysregulation and COVID-19 disease severity deserve more attention. Mechanistical studies are required to confirm the correlation between oxidative stress gene dysregulation, COVID-19 severity, and the net oxidative stress balance.
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Affiliation(s)
| | | | - Bushra Mdkhana
- Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | | | - Habiba Alsafar
- Department of Biomedical Engineering, College of Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; Department of Biomedical Engineering, College of Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates; Department of Genetics and Molecular Biology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Zeyad Faoor Alrais
- Anaesthesia and Intensive Care Unit, Dubai Health Authority, Dubai, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Meakins-Christie Laboratories, Research Institute of the McGill University Healthy Center, McGill University, Montreal, QC, Canada
| | - Rabih Halwani
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Prince Abdullah Ben Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Saudi Arabia.
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Narożna M, Rubiś B. Anti-SARS-CoV-2 Strategies and the Potential Role of miRNA in the Assessment of COVID-19 Morbidity, Recurrence, and Therapy. Int J Mol Sci 2021; 22:8663. [PMID: 34445368 PMCID: PMC8395427 DOI: 10.3390/ijms22168663] [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: 07/06/2021] [Revised: 08/07/2021] [Accepted: 08/08/2021] [Indexed: 02/06/2023] Open
Abstract
Recently, we have experienced a serious pandemic. Despite significant technological advances in molecular technologies, it is very challenging to slow down the infection spread. It appeared that due to globalization, SARS-CoV-2 spread easily and adapted to new environments or geographical or weather zones. Additionally, new variants are emerging that show different infection potential and clinical outcomes. On the other hand, we have some experience with other pandemics and some solutions in virus elimination that could be adapted. This is of high importance since, as the latest reports demonstrate, vaccine technology might not follow the new, mutated virus outbreaks. Thus, identification of novel strategies and markers or diagnostic methods is highly necessary. For this reason, we present some of the latest views on SARS-CoV-2/COVID-19 therapeutic strategies and raise a solution based on miRNA. We believe that in the face of the rapidly increasing global situation and based on analogical studies of other viruses, the possibility of using the biological potential of miRNA technology is very promising. It could be used as a promising diagnostic and prognostic factor, as well as a therapeutic target and tool.
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Affiliation(s)
- Maria Narożna
- Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4 Święcickiego St., 60-781 Poznan, Poland;
| | - Błażej Rubiś
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 49 Przybyszewskiego St., 60-355 Poznan, Poland
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Kim DH, Ahn HS, Go HJ, Kim DY, Kim JH, Lee JB, Park SY, Song CS, Lee SW, Choi IS. Heme Oxygenase-1 Exerts Antiviral Activity against Hepatitis A Virus In Vitro. Pharmaceutics 2021; 13:1229. [PMID: 34452191 PMCID: PMC8401830 DOI: 10.3390/pharmaceutics13081229] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/04/2021] [Accepted: 08/07/2021] [Indexed: 01/01/2023] Open
Abstract
Hepatitis A virus (HAV), the causative pathogen of hepatitis A, induces severe acute liver injuries in humans and is a serious public health concern worldwide. However, appropriate therapeutics have not yet been developed. The enzyme heme oxygenase-1 (HO-1) exerts antiviral activities in cells infected with several viruses including hepatitis B and C viruses. In this study, we demonstrated for the first time the suppression of virus replication by HO-1 in cells infected with HAV. Hemin (HO-1 inducer) induced HO-1 mRNA and protein expression, as expected, and below 50 mM, dose-dependently reduced the viral RNA and proteins in the HAV-infected cells without cytotoxicity. Additionally, HO-1 protein overexpression using a protein expression vector suppressed HAV replication. Although ZnPP-9, an HO-1 inhibitor, did not affect HAV replication, it significantly inhibited hemin-induced antiviral activity in HAV-infected cells. Additionally, FeCl3, CORM-3, biliverdin, and the HO-1 inducers andrographolide and CoPP inhibited HAV replication in the HAV-infected cells; andrographolide and CoPP exhibited a dose-dependent effect. In conclusion, these results suggest that HO-1 effectively suppresses HAV infection in vitro, and its enzymatic products appear to exert antiviral activity. We expect that these results could contribute to the development of a new antiviral drug for HAV.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - In-Soo Choi
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (D.-H.K.); (H.-S.A.); (H.-J.G.); (D.-Y.K.); (J.-H.K.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
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48
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Impact of Hypoxia over Human Viral Infections and Key Cellular Processes. Int J Mol Sci 2021; 22:ijms22157954. [PMID: 34360716 PMCID: PMC8347150 DOI: 10.3390/ijms22157954] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 01/01/2023] Open
Abstract
Oxygen is essential for aerobic cells, and thus its sensing is critical for the optimal maintenance of vital cellular and tissue processes such as metabolism, pH homeostasis, and angiogenesis, among others. Hypoxia-inducible factors (HIFs) play central roles in oxygen sensing. Under hypoxic conditions, the α subunit of HIFs is stabilized and forms active heterodimers that translocate to the nucleus and regulate the expression of important sets of genes. This process, in turn, will induce several physiological changes intended to adapt to these new and adverse conditions. Over the last decades, numerous studies have reported a close relationship between viral infections and hypoxia. Interestingly, this relation is somewhat bidirectional, with some viruses inducing a hypoxic response to promote their replication, while others inhibit hypoxic cellular responses. Here, we review and discuss the cellular responses to hypoxia and discuss how HIFs can promote a wide range of physiological and transcriptional changes in the cell that modulate numerous human viral infections.
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49
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Zhu DD, Tan XM, Lu LQ, Yu SJ, Jian RL, Liang XF, Liao YX, Fan W, Barbier-Torres L, Yang A, Yang HP, Liu T. Interplay between nuclear factor erythroid 2-related factor 2 and inflammatory mediators in COVID-19-related liver injury. World J Gastroenterol 2021; 27:2944-2962. [PMID: 34168400 PMCID: PMC8192291 DOI: 10.3748/wjg.v27.i22.2944] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/06/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide. In addition to respiratory symptoms, COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the expression of antioxidant proteins, participating in COVID-19-mediated inflammation and liver injury. Here, we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury. Additionally, we describe some mechanisms and treatment strategies.
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Affiliation(s)
- Dan-Dan Zhu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Xue-Mei Tan
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Li-Qing Lu
- Key Laboratory of Cancer proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Si-Jia Yu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Ru-Li Jian
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Xin-Fang Liang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Yi-Xuan Liao
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Wei Fan
- Department of Medicine, Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Lucíia Barbier-Torres
- Department of Medicine, Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Austin Yang
- Department of Biology, East Los Angeles College, Los Angeles, CA 91008, United States
| | - He-Ping Yang
- Department of Medicine, Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Ting Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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50
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Cheema PS, Nandi D, Nag A. Exploring the therapeutic potential of forkhead box O for outfoxing COVID-19. Open Biol 2021; 11:210069. [PMID: 34102081 PMCID: PMC8187014 DOI: 10.1098/rsob.210069] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/27/2021] [Indexed: 01/08/2023] Open
Abstract
The COVID-19 pandemic has wreaked unprecedented societal havoc worldwide. The infected individuals may present mild to severe symptoms, with nearly 20% of the confirmed patients impaired with significant complications, including multi-organ failure. Acute respiratory distress imposed by SARS-CoV-2 largely results from an aggravated cytokine storm and deregulated immune response. The forkhead box O (FoxO) transcription factors are reported to play a significant role in maintaining normal cell physiology by regulating survival, apoptosis, oxidative stress, development and maturation of T and B lymphocytes, secretion of inflammatory cytokines, etc. We propose a potent anti-inflammatory approach based on activation of the FoxO as an attractive strategy against the novel coronavirus. This regime will be focused on restoring redox and inflammatory homeostasis along with repair of the damaged tissue, activation of lymphocyte effector and memory cells. Repurposing FoxO activators as a means to alleviate the inflammatory burst following SARS-CoV-2 infection can prove immensely valuable in the ongoing pandemic and provide a reliable groundwork for enriching our repertoire of antiviral modalities for any such complication in the future. Altogether, our review highlights the possible efficacy of FoxO activation as a novel arsenal for clinical management of COVID-19.
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Affiliation(s)
- Pradeep Singh Cheema
- Department of Biochemistry, University of Delhi, South Campus, Biotech Building, 2nd Floor, Benito Juarez Road, Dhaula Kuan, New Delhi 110021, India
| | - Deeptashree Nandi
- Department of Biochemistry, University of Delhi, South Campus, Biotech Building, 2nd Floor, Benito Juarez Road, Dhaula Kuan, New Delhi 110021, India
| | - Alo Nag
- Department of Biochemistry, University of Delhi, South Campus, Biotech Building, 2nd Floor, Benito Juarez Road, Dhaula Kuan, New Delhi 110021, India
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