1
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Wang Y, Song D, Li Y, Qin L, Wan Q, Hu H, Wu M, Feng Y, Schang L, Weiss R, He ML. Erp57 facilitates ZIKV-induced DNA damage via NS2B/NS3 complex formation. Emerg Microbes Infect 2024; 13:2417864. [PMID: 39404735 PMCID: PMC11520102 DOI: 10.1080/22221751.2024.2417864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/20/2024] [Revised: 09/13/2024] [Accepted: 10/13/2024] [Indexed: 10/29/2024]
Abstract
It is believed that DNA double-strand breaks induced by Zika virus (ZIKV) infection in pregnant women is a main reason of brain damage (e.g. microcephaly, severe brain malformation, and neuropathy) in newborn babies [1,2], but its underlying mechanism is poorly understood. In this study, we report that the depletion of ERp57, a member of the protein disulphide isomerase (PDI) family, leads to the limited production of ZIKV in nerve cells. ERp57 knockout not only suppresses viral induced reactive oxygen species (ROS) mediated host DNA damage, but also decreases apoptosis. Strikingly, DNA damage depends on ERp57-bridged complex formation of viral protein NS2B/NS3. LOC14, an ERp57 inhibitor, restricts ZIKV infection and virus-induced DNA damage. Our work reveals an important role of ERp57 in both ZIKV propagation and virus-induced DNA damage, suggesting a potential target against ZIKV infection.
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Affiliation(s)
- Yiran Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Dan Song
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Yichen Li
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Leiying Qin
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Qianya Wan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Huan Hu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Mandi Wu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Yaxiu Feng
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Luis Schang
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Robert Weiss
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Ming-Liang He
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, People’s Republic of China
- CityU Shenzhen Research Institute, Shenzhen, People’s Republic of China
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2
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He R, Zhang X, Pang C, Lin L, Li S, Jin L, Ding L, Wang W. Inhibition of NADPH oxidase 2 improves cognitive abilities by modulating aquaporin-4 after traumatic brain injury in mice. Heliyon 2023; 9:e22035. [PMID: 38053850 PMCID: PMC10694165 DOI: 10.1016/j.heliyon.2023.e22035] [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] [Academic Contribution Register] [Received: 09/19/2022] [Revised: 09/02/2023] [Accepted: 11/02/2023] [Indexed: 12/07/2023] Open
Abstract
Traumatic brain injury (TBI) is caused by acquired damage that includes cerebral edema after a mechanical injury and may cause cognitive impairment. We explored the role of nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2; NOX2) and aquaporin-4 (AQP4) in the process of edema and cognitive abilities after TBI in NOX2-/- and AQP4-/- mice by using the Morris water maze test (MWM), step-down test (STD), novel object recognition test (NOR) and western blotting. Knockout of NOX2 in mice decreased the AQP4 and reduce edema in the hippocampus and cortex after TBI in mice. Moreover, inhibiting AQP4 by 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) or genetic deletion of AQP4 could attenuate neurological deficits without changing reactive oxygen species (ROS) levels after TBI in mice. Taken together, we suspected that inhibiting NOX2 could improve cognitive abilities by modulating ROS levels, then affecting AQP4 levels and brain edema after in TBI mice. Our study demonstrated that NOX2 play a key role in decreasing edema in brain and improving cognitive abilities by modulating AQP4 after TBI.
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Affiliation(s)
- Ruixing He
- Department of Neurosurgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China
| | - Xiaotian Zhang
- Department of Neurosurgery, Hongze District People's Hospital of Huai'an City, Huai'an, Jiangsu, 223300, China
| | - Cong Pang
- Department of Neurosurgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China
| | - Lihui Lin
- Department of Pharmacy, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, China
| | - Shaoxun Li
- Department of Neurosurgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China
| | - Luhao Jin
- Department of Neurosurgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China
| | - Lianshu Ding
- Department of Neurosurgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China
| | - Weijie Wang
- Department of Neurosurgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, 223300, China
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3
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Fesharaki-Zadeh A. Oxidative Stress in Traumatic Brain Injury. Int J Mol Sci 2022; 23:ijms232113000. [PMID: 36361792 PMCID: PMC9657447 DOI: 10.3390/ijms232113000] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/07/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 11/17/2022] Open
Abstract
Traumatic Brain Injury (TBI) remains a major cause of disability worldwide. It involves a complex neurometabolic cascade, including oxidative stress. The products of this manuscript is examining the underlying pathophysiological mechanism, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). This process in turn leads to secondary injury cascade, which includes lipid peroxidation products. These reactions ultimately play a key role in chronic inflammation and synaptic dysfunction in a synergistic fashion. Although there are no FDA approved antioxidant therapy for TBI, there is a number of antioxidant therapies that have been tested and include free radical scavengers, activators of antioxidant systems, inhibitors of free radical generating enzymes, and antioxidant enzymes. Antioxidant therapies have led to cognitive and functional recovery post TBI, and they offer a promising treatment option for patients recovering from TBI. Current major challenges in treatment of TBI symptoms include heterogenous nature of injury, as well as access to timely treatment post injury. The inherent benefits of antioxidant therapies include minimally reported side effects, and relative ease of use in the clinical setting. The current review also provides a highlight of the more studied anti-oxidant regimen with applicability for TBI treatment with potential use in the real clinical setting.
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Affiliation(s)
- Arman Fesharaki-Zadeh
- Yale School of Medicine, Department of Neurology, Yale University, New Haven, CT 06510, USA
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4
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Damle VG, Wu K, Arouri DJ, Schirhagl R. Detecting free radicals post viral infections. Free Radic Biol Med 2022; 191:8-23. [PMID: 36002131 DOI: 10.1016/j.freeradbiomed.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/03/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022]
Abstract
Free radical generation plays a key role in viral infections. While free radicals have an antimicrobial effect on bacteria or fungi, their interplay with viruses is complicated and varies greatly for different types of viruses as well as different radical species. In some cases, radical generation contributes to the defense against the viruses and thus reduces the viral load. In other cases, radical generation induces mutations or damages the host tissue and can increase the viral load. This has led to antioxidants being used to treat viral infections. Here we discuss the roles that radicals play in virus pathology. Furthermore, we critically review methods that facilitate the detection of free radicals in vivo or in vitro in viral infections.
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Affiliation(s)
- V G Damle
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - K Wu
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - D J Arouri
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - R Schirhagl
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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5
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Caillet C, Stofberg ML, Muleya V, Shonhai A, Zininga T. Host cell stress response as a predictor of COVID-19 infectivity and disease progression. Front Mol Biosci 2022; 9:938099. [PMID: 36032680 PMCID: PMC9411049 DOI: 10.3389/fmolb.2022.938099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/06/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
The coronavirus disease (COVID-19) caused by a coronavirus identified in December 2019 has caused a global pandemic. COVID-19 was declared a pandemic in March 2020 and has led to more than 6.3 million deaths. The pandemic has disrupted world travel, economies, and lifestyles worldwide. Although vaccination has been an effective tool to reduce the severity and spread of the disease there is a need for more concerted approaches to fighting the disease. COVID-19 is characterised as a severe acute respiratory syndrome . The severity of the disease is associated with a battery of comorbidities such as cardiovascular diseases, cancer, chronic lung disease, and renal disease. These underlying diseases are associated with general cellular stress. Thus, COVID-19 exacerbates outcomes of the underlying conditions. Consequently, coronavirus infection and the various underlying conditions converge to present a combined strain on the cellular response. While the host response to the stress is primarily intended to be of benefit, the outcomes are occasionally unpredictable because the cellular stress response is a function of complex factors. This review discusses the role of the host stress response as a convergent point for COVID-19 and several non-communicable diseases. We further discuss the merits of targeting the host stress response to manage the clinical outcomes of COVID-19.
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Affiliation(s)
- Celine Caillet
- Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa
| | | | - Victor Muleya
- Department of Biochemistry, Midlands State University, Gweru, Zimbabwe
| | - Addmore Shonhai
- Department of Biochemistry and Microbiology, University of Venda, Thohoyandou, South Africa
| | - Tawanda Zininga
- Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa
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6
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Wang W, Zhang X, Lin L, Ren J, He R, Sun K. Inhibition of NADPH oxidase 2 (NOX2) reverses cognitive deficits by modulating excitability and excitatory transmission in the hippocampus after traumatic brain injury. Biochem Biophys Res Commun 2022; 617:1-7. [DOI: 10.1016/j.bbrc.2022.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/23/2022] [Revised: 04/30/2022] [Accepted: 05/01/2022] [Indexed: 11/16/2022]
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7
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Shao F, Wang X, Wu H, Wu Q, Zhang J. Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration. Front Aging Neurosci 2022; 14:825086. [PMID: 35401152 PMCID: PMC8990307 DOI: 10.3389/fnagi.2022.825086] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/30/2021] [Accepted: 02/21/2022] [Indexed: 12/11/2022] Open
Abstract
Traumatic brain injury (TBI) is one of the most common diseases in the central nervous system (CNS) with high mortality and morbidity. Patients with TBI usually suffer many sequelae in the life time post injury, including neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the pathological mechanisms connecting these two processes have not yet been fully elucidated. It is important to further investigate the pathophysiological mechanisms underlying TBI and TBI-induced neurodegeneration, which will promote the development of precise treatment target for these notorious neurodegenerative consequences after TBI. A growing body of evidence shows that neuroinflammation is a pivotal pathological process underlying chronic neurodegeneration following TBI. Microglia, as the immune cells in the CNS, play crucial roles in neuroinflammation and many other CNS diseases. Of interest, microglial activation and functional alteration has been proposed as key mediators in the evolution of chronic neurodegenerative pathology following TBI. Here, we review the updated studies involving phenotypical and functional alterations of microglia in neurodegeneration after injury, survey key molecules regulating the activities and functional responses of microglia in TBI pathology, and explore their potential implications to chronic neurodegeneration after injury. The work will give us a comprehensive understanding of mechanisms driving TBI-related neurodegeneration and offer novel ideas of developing corresponding prevention and treatment strategies for this disease.
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Affiliation(s)
- Fangjie Shao
- Department of Plastic and Aesthetic Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haijian Wu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qun Wu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Qun Wu,
| | - Jianmin Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Brain Research Institute, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, China
- Jianmin Zhang,
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8
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Hosoi R, Fujii Y, Hiroyuki O, Shukuri M, Nishiyama S, Kanazawa M, Todoroki K, Arano Y, Sakai T, Tsukada H, Inoue O. Evaluation of intracellular processes in quinolinic acid-induced brain damage by imaging reactive oxygen species generation and mitochondrial complex I activity. EJNMMI Res 2021; 11:99. [PMID: 34628558 PMCID: PMC8502189 DOI: 10.1186/s13550-021-00841-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/27/2021] [Accepted: 09/17/2021] [Indexed: 11/10/2022] Open
Abstract
PURPOSE Our study aimed to elucidate the intracellular processes associated with quinolinic acid (QA)-induced brain injury by acquiring semiquantitative fluorescent images of reactive oxygen species (ROS) generation and positron emission tomography (PET) images of mitochondrial complex I (MC-I) activity. METHODS Ex vivo fluorescent imaging with dihydroethidium (DHE) and PET scans with 18F-BCPP-EF were conducted at 3 h and 24 h after QA injection into the rat striatum. Immunohistochemical studies were performed 24 h after QA injection into the rat brain using monoclonal antibodies against neuronal nuclei (NeuN) and CD11b. RESULTS A strong DHE-derived fluorescent signal was detected in a focal area within the QA-injected striatum 3 h after QA injection, and increased fluorescent signal spread throughout the striatum and parts of the cerebral cortex after 24 h. By contrast, 18F-BCPP-EF uptake in the QA-injected rat brain was unchanged after 3 h and markedly decreased after 24 h, not only in the striatum but also in the cerebral hemisphere. The fluorescent signal in the striatum 24 h after QA injection colocalised with microglial marker expression. CONCLUSIONS We successfully obtained functional images of focal ROS generation during the early period of excitotoxic injury, and microglial ROS generation and mitochondrial dysfunction were observed during the progression of the inflammatory response. Both ex vivo DHE imaging and in vivo 18F-BCPP-EF-PET were sufficiently sensitive to detect the respective processes of QA-induced brain damage. Our study contributes to the functional imaging of multiple events during the pathological process.
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Affiliation(s)
- Rie Hosoi
- Division of Health Sciences, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Yuka Fujii
- Division of Health Sciences, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ohba Hiroyuki
- Central Research Laboratory, Hamamatsu Photonics K. K, 5000 Hirakuchi, Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan
| | - Miho Shukuri
- Laboratory of Physical Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo, 194-8543, Japan
| | - Shingo Nishiyama
- Central Research Laboratory, Hamamatsu Photonics K. K, 5000 Hirakuchi, Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan
| | - Masakatsu Kanazawa
- Central Research Laboratory, Hamamatsu Photonics K. K, 5000 Hirakuchi, Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan
| | - Kenichiro Todoroki
- Department of Analytical and Bio-Analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka, 422-8526, Japan
| | - Yasushi Arano
- Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba, 260-8675, Japan
| | - Toshihiro Sakai
- Hanwa Intelligent Medical Center, Hanwa Daini Senboku Hospital, 3176 Fukaikitamachi, Naka-ku, Sakai, Osaka, 599-8271, Japan
| | - Hideo Tsukada
- Central Research Laboratory, Hamamatsu Photonics K. K, 5000 Hirakuchi, Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan
| | - Osamu Inoue
- Hanwa Intelligent Medical Center, Hanwa Daini Senboku Hospital, 3176 Fukaikitamachi, Naka-ku, Sakai, Osaka, 599-8271, Japan
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9
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Sander WJ, Fourie C, Sabiu S, O'Neill FH, Pohl CH, O'Neill HG. Reactive oxygen species as potential antiviral targets. Rev Med Virol 2021; 32:e2240. [PMID: 33949029 DOI: 10.1002/rmv.2240] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/02/2021] [Indexed: 12/14/2022]
Abstract
Reactive oxygen species (ROS) are by-products of cellular metabolism and can be either beneficial, at low levels, or deleterious, at high levels, to the cell. It is known that several viral infections can increase oxidative stress, which is mainly facilitated by viral-induced imbalances in the antioxidant defence mechanisms of the cell. While the exact role of ROS in certain viral infections (adenovirus and dengue virus) remains unknown, other viruses can use ROS for enhancement of pathogenesis (SARS coronavirus and rabies virus) or replication (rhinovirus, West Nile virus and vesicular stomatitis virus) or both (hepatitis C virus, human immunodeficiency virus and influenza virus). While several viral proteins (mainly for hepatitis C and human immunodeficiency virus) have been identified to play a role in ROS formation, most mediators of viral ROS modulation are yet to be elucidated. Treatment of viral infections, including hepatitis C virus, human immunodeficiency virus and influenza virus, with ROS inhibitors has shown a decrease in both pathogenesis and viral replication both in vitro and in animal models. Clinical studies indicating the potential for targeting ROS-producing pathways as possible broad-spectrum antiviral targets should be evaluated in randomized controlled trials.
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Affiliation(s)
- Willem J Sander
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, South Africa
| | - Corinne Fourie
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, South Africa
| | - Saheed Sabiu
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, South Africa.,Department of Biotechnology and Food Science, Durban University of Technology, Durban, South Africa
| | - Frans H O'Neill
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, South Africa
| | - Carolina H Pohl
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, South Africa
| | - Hester G O'Neill
- Department of Microbiology and Biochemistry, University of the Free State, Bloemfontein, South Africa
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10
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Wan Q, Song D, Li H, He ML. Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development. Signal Transduct Target Ther 2020; 5:125. [PMID: 32661235 PMCID: PMC7356129 DOI: 10.1038/s41392-020-00233-4] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/10/2020] [Revised: 05/26/2020] [Accepted: 06/13/2020] [Indexed: 02/06/2023] Open
Abstract
Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson’s diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.
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Affiliation(s)
- Qianya Wan
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Dan Song
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Huangcan Li
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Ming-Liang He
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China. .,CityU Shenzhen Research Institute, Shenzhen, China.
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11
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Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7289120. [PMID: 32322337 PMCID: PMC7165344 DOI: 10.1155/2020/7289120] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 10/16/2019] [Revised: 01/31/2020] [Accepted: 02/10/2020] [Indexed: 12/13/2022]
Abstract
Eukaryotic cells adopt highly tuned stress response physiology under threats of exogenous stressors including viruses to maintain cellular homeostasis. Not surprisingly, avoidance of cellular stress response pathways is an essential facet of virus-induced obligatory host reprogramming to invoke a cellular environment conducive to viral perpetuation. Adaptive cellular responses to oxidative and electrophilic stress are usually taken care of by an antioxidant defense system, core to which lies the redox-responsive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-driven transcriptional cascade. Deregulation of host redox balance and redox stress-sensitive Nrf2 antioxidant defense have been reported for many viruses. In the current study, we aimed to study the modulation of the Nrf2-based host cellular redox defense system in response to Rotavirus (RV) infection in vitro. Interestingly, we found that Nrf2 protein levels decline sharply with progression of RV infection beyond an initial upsurge. Moreover, Nrf2 decrease as a whole was found to be accompanied by active nuclear vacuity of Nrf2, resulting in lowered expression of stress-responsive Nrf2 target genes heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 1 both in the presence and absence of Nrf2-driven transcriptional inducers. Initial induction of Nrf2 concurred with RV-induced early burst of oxidative stress and therefore was sensitive to treatments with antioxidants. Reduction of Nrf2 levels beyond initial hours, however, was found to be independent of the cellular redox status. Furthermore, increasing the half-life of Nrf2 through inhibition of the Kelch-like erythroid cell-derived protein with CNC homology- (ECH-) associated protein 1/Cullin3-RING Box1-based canonical Nrf2 turnover pathway could not restore Nrf2 levels post RV-SA11 infection. Depletion of the Nrf2/HO-1 axis was subsequently found to be sensitive to proteasome inhibition with concurrent observation of increased K48-linked ubiquitination associated with Nrf2. Together, the present study describes robust downregulation of Nrf2-dependent cellular redox defense beyond initial hours of RV infection, justifying our previous observation of potent antirotaviral implications of Nrf2 agonists.
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12
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Wang M, Luo L. An Effective NADPH Oxidase 2 Inhibitor Provides Neuroprotection and Improves Functional Outcomes in Animal Model of Traumatic Brain Injury. Neurochem Res 2020; 45:1097-1106. [PMID: 32072445 DOI: 10.1007/s11064-020-02987-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2019] [Revised: 02/07/2020] [Accepted: 02/11/2020] [Indexed: 12/23/2022]
Abstract
Traumatic brain injury (TBI) has become a leading cause of death and disability all over the world. Pharmacological suppression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) can inhibit oxidative stress which is implicated in the pathology of TBI. GSK2795039 was reported to target NOX2 to inhibit [Formula: see text] and ROS production. The present study aimed to investigate the effect of GSK2795039 on NOX2 activity and neurological deficits in a TBI mouse model. TBI mouse model was established by a weight-drop to mouse skull. GSK2795039 at a dose of 100 mg/kg was administrated to mice 30 min before TBI. NOX2 expression and activity were detected by Western blot and biochemical method. Neurological damage and apoptosis were detected by behavioral test and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. GSK2795039 significantly inhibited NOX2 expression and activity in the TBI mouse model. It also attenuated TBI-induced neurological deficits, apoptosis, and neurological recovery. The results indicate that GSK2795039 can be used as a potential drug for TBI treatment.
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Affiliation(s)
- Mengwei Wang
- Department of Emergency, The Fourth Affiliated Hospital of China Medical University, No. 4 Chongshan East Road, Huanggu District, Shenyang, 110032, Liaoning, China.
| | - Le Luo
- Shanghai Zhuole Biotechnology Center, No. 2066 Wangyuan Road, Shanghai, 201499, China
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13
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Funk KE, Klein RS. CSF1R antagonism limits local restimulation of antiviral CD8 + T cells during viral encephalitis. J Neuroinflammation 2019; 16:22. [PMID: 30704498 PMCID: PMC6354430 DOI: 10.1186/s12974-019-1397-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/24/2018] [Accepted: 01/02/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. We hypothesize that CSF1R plays a critical role in myeloid cell responses that restrict viral replication and locally restimulate recruited antiviral T cells within the CNS. METHODS The impact of CSF1R signaling during West Nile virus infection was assessed in vivo using a mouse model of neurotropic infection. Pharmacological inactivation of CSF1R was achieved using PLX5622 prior to infection with virulent or attenuated strains of West Nile virus (WNV), an emerging neuropathogen. The subsequent effect of CSF1R antagonism on virologic control was assessed by measuring mortality and viral titers in the CNS and peripheral organs. Immune responses were assessed by flow cytometric-based phenotypic analyses of both peripheral and CNS immune cells. RESULTS Mice treated with CSF1R antagonist prior to infection exhibited higher susceptibility to lethal WNV infection and lack of virologic control in both the CNS and periphery. CSFR1 antagonism reduced B7 co-stimulatory signals on peripheral and CNS antigen-presenting cells (APCs) by depleting CNS cellular sources, which limited local reactivation of CNS-infiltrating virus-specific T cells and reduced viral clearance. CONCLUSIONS Our results demonstrate the impact of CSF1R antagonism on APC activation in the CNS and periphery and the importance of microglia in orchestrating the CNS immune response following neurotropic viral infection. These data will be an important consideration when assessing the benefit of CSF1R antagonism, which has been investigated as a therapeutic for neurodegenerative conditions, in which neuroinflammation is a contributing factor.
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Affiliation(s)
- Kristen E. Funk
- Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO 63110 USA
| | - Robyn S. Klein
- Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO 63110 USA
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110 USA
- Department of Neurosciences, Washington University School of Medicine, Saint Louis, MO 63110 USA
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14
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Gallelli CA, Calcagnini S, Romano A, Koczwara JB, de Ceglia M, Dante D, Villani R, Giudetti AM, Cassano T, Gaetani S. Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues. Antioxidants (Basel) 2018; 7:E93. [PMID: 30021985 PMCID: PMC6070960 DOI: 10.3390/antiox7070093] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2018] [Revised: 07/10/2018] [Accepted: 07/13/2018] [Indexed: 02/06/2023] Open
Abstract
Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts.
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Affiliation(s)
- Cristina Anna Gallelli
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Silvio Calcagnini
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Adele Romano
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Justyna Barbara Koczwara
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Marialuisa de Ceglia
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Donatella Dante
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Rosanna Villani
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Anna Maria Giudetti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni, 73100 Lecce, Italy.
| | - Tommaso Cassano
- Department of Clinical and Experimental Medicine, University of Foggia, Via Luigi Pinto, c/o Ospedali Riuniti, 71122 Foggia, Italy.
| | - Silvana Gaetani
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
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15
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Chen D, Tian X, Zou X, Xu S, Wang H, Zheng N, Wu Z. Harmine, a small molecule derived from natural sources, inhibits enterovirus 71 replication by targeting NF-κB pathway. Int Immunopharmacol 2018; 60:111-120. [DOI: 10.1016/j.intimp.2018.04.050] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/13/2018] [Revised: 04/17/2018] [Accepted: 04/30/2018] [Indexed: 01/24/2023]
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16
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Vitamin D Receptor Activation Influences NADPH Oxidase (NOX 2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:9245702. [PMID: 29410737 PMCID: PMC5749321 DOI: 10.1155/2017/9245702] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 04/05/2017] [Revised: 07/18/2017] [Accepted: 07/30/2017] [Indexed: 12/29/2022]
Abstract
Traumatic brain injury (TBI) is a worldwide phenomenon which results in significant neurological and cognitive deficits in humans. Vitamin D (VD) is implicated as a therapeutic strategy for various neurological diseases now. Recently, inhibition of the NADPH oxidase (NOX2) was reported to protect against oxidative stress (ROS) production. However, whether alterations in NOX2 expression and NOX activity are associated with calcitriol (active metabolite of VD) treatment following TBI remains unclear. In the present study, rats were randomly assigned to the sham, TBI, and calcitriol-treated groups. Calcitriol was administered intraperitoneally (2 μg/kg) at 30 min, 24 h, and 48 h after TBI insult. We observed that calcitriol treatment alleviated neurobehavioral deficits and brain edema following TBI. At the molecular levels, administration of calcitriol activated the expression of VDR and downregulated NOX2 as well as suppressed apoptosis cell rate in the hippocampus CA1 region of TBI rats. In conclusion, our findings indicate that the protective effects of calcitriol may be related to the modulation of NADPH oxidase and thereby ultimately inhibited the progression of apoptosis. Calcitriol may be promising as a protective intervention following TBI, and more study is warranted for its clinical testing in the future.
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17
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Holze C, Michaudel C, Mackowiak C, Haas DA, Benda C, Hubel P, Pennemann FL, Schnepf D, Wettmarshausen J, Braun M, Leung DW, Amarasinghe GK, Perocchi F, Staeheli P, Ryffel B, Pichlmair A. Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. Nat Immunol 2017; 19:130-140. [PMID: 29255269 PMCID: PMC5786482 DOI: 10.1038/s41590-017-0013-y] [Citation(s) in RCA: 270] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/10/2017] [Accepted: 11/17/2017] [Indexed: 12/13/2022]
Abstract
Reactive oxygen species (ROS) are generated by virally-infected cells however the physiological significance of ROS generated under these conditions is unclear. Here we show that inflammation and cell death induced by exposure of mice or cells to sources of ROS is not altered in the absence of canonical ROS-sensing pathways or known cell death pathways. ROS-induced cell death signaling involves interaction between the cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5−/− mice show exacerbated lung inflammation and proinflammatory cytokines in an ozone exposure model. Similarly, challenge with influenza A virus leads to increased virus infiltration, lymphocytic bronchiolitis and reduced survival of Pgam5−/− mice. This pathway, which we term ‘oxeiptosis’, is a ROS-sensitive, caspase independent, non-inflammatory cell death pathway and is important to protect against inflammation induced by ROS or ROS-generating agents such as viral pathogens.
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Affiliation(s)
- Cathleen Holze
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany
| | - Chloé Michaudel
- INEM, Experimental Molecular Immunology, UMR7355 CNRS and University, Orleans, France
| | - Claire Mackowiak
- INEM, Experimental Molecular Immunology, UMR7355 CNRS and University, Orleans, France
| | - Darya A Haas
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany
| | - Christian Benda
- Department of Structural Cell Biology, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany
| | - Philipp Hubel
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany
| | - Friederike L Pennemann
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany
| | - Daniel Schnepf
- Institute of Virology, University of Freiburg, Freiburg, Germany.,Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany
| | - Jennifer Wettmarshausen
- Department of Biochemistry, Gene Center Munich, Munich, Germany.,Institute for Diabetes and Obesity, Helmholtz Zentrum Munchen, Neuherberg, Germany
| | - Marianne Braun
- EM-Histo Lab, Max-Planck Institute of Neurobiology, Martinsried, Munich, Germany
| | - Daisy W Leung
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Gaya K Amarasinghe
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Fabiana Perocchi
- Department of Biochemistry, Gene Center Munich, Munich, Germany.,Institute for Diabetes and Obesity, Helmholtz Zentrum Munchen, Neuherberg, Germany
| | - Peter Staeheli
- Institute of Virology, University of Freiburg, Freiburg, Germany.,Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bernhard Ryffel
- INEM, Experimental Molecular Immunology, UMR7355 CNRS and University, Orleans, France.,Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Andreas Pichlmair
- Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Martinsried, Munich, Germany. .,School of Medicine, Institute of Virology, Technical University of Munich, Munich, Germany. .,German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.
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18
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Protective Role of Apocynin via Suppression of Neuronal Autophagy and TLR4/NF-κB Signaling Pathway in a Rat Model of Traumatic Brain Injury. Neurochem Res 2017; 42:3296-3309. [DOI: 10.1007/s11064-017-2372-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/02/2016] [Revised: 06/14/2017] [Accepted: 08/01/2017] [Indexed: 10/19/2022]
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19
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Dominiak A, Wilkaniec A, Wroczyński P, Adamczyk A. Selenium in the Therapy of Neurological Diseases. Where is it Going? Curr Neuropharmacol 2016; 14:282-99. [PMID: 26549649 PMCID: PMC4857624 DOI: 10.2174/1570159x14666151223100011] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/16/2015] [Revised: 08/20/2015] [Accepted: 09/16/2015] [Indexed: 12/19/2022] Open
Abstract
Selenium (34Se), an antioxidant trace element, is an important regulator of brain function. These beneficial properties that Se possesses are attributed to its ability to be incorporated into selenoproteins as an amino acid. Several selenoproteins are expressed in the brain, in which some of them, e.g. glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) or selenoprotein P (SelP), are strongly involved in antioxidant defence and in maintaining intercellular reducing conditions. Since increased oxidative stress has been implicated in neurological disorders, including Parkinson’s disease, Alzheimer’s disease, stroke, epilepsy and others, a growing body of evidence suggests that Se depletion followed by decreased activity of Se-dependent enzymes may be important factors connected with those pathologies. Undoubtedly, the remarkable progress that has been made in understanding the biological function of Se in the brain has opened up new potential possibilities for the treatment of neurological diseases by using Se as a potential drug. However, further research in the search for optimal Se donors is necessary in order to achieve an effective and safe therapeutic income.
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Affiliation(s)
| | - Anna Wilkaniec
- Department of Cellular Signaling, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5 St., 02-106 Warsaw, Poland.
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20
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Popkov VA, Zorova LD, Korvigo IO, Silachev DN, Jankauskas SS, Babenko VA, Pevzner IB, Danilina TI, Zorov SD, Plotnikov EY, Zorov DB. Do Mitochondria Have an Immune System? BIOCHEMISTRY (MOSCOW) 2016; 81:1229-1236. [PMID: 27908248 DOI: 10.1134/s0006297916100217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022]
Abstract
The question if mitochondria have some kind of immune system is not trivial. The basis for raising this question is the fact that bacteria, which are progenitors of mitochondria, do have an immune system. The CRISPR system in bacteria based on the principle of RNA interference serves as an organized mechanism for destroying alien nucleic acids, primarily those of viral origin. We have shown that mitochondria are also a target for viral attacks, probably due to a related organization of genomes in these organelles and bacteria. Bioinformatic analysis performed in this study has not given a clear answer if there is a CRISPR-like immune system in mitochondria. However, this does not preclude the possibility of mitochondrial immunity that can be difficult to decipher or that is based on some principles other than those of CRISPR.
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Affiliation(s)
- V A Popkov
- Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow, 119991, Russia.
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21
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Su ZJ, Yang J, Luo WJ, Wei YY, Shuai XH, Hu TJ. Inhibitory effect of Sophora subprosrate polysaccharide on mitochondria oxidative stress induced by PCV-2 infection in RAW264.7 cells. Int J Biol Macromol 2016; 95:608-617. [PMID: 27908718 DOI: 10.1016/j.ijbiomac.2016.11.101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/21/2016] [Revised: 11/19/2016] [Accepted: 11/26/2016] [Indexed: 01/29/2023]
Abstract
In the present study, the inhibitory effect of Sophora subprosrate polysaccharide (SSP) on PCV-2-induced mitochondrial respiratory burst in RAW264.7 cells was first investigated. The findings suggested that SOD activity and the anti-superoxide anion radical activity of the RAW264.7 cells were significantly decreased after PCV-2 infection, and MnSOD mRNA levels were significantly decreased, while NOX2 mRNA levels and protein expression were increased. Meanwhile, the O2•- levels and mitochondrial membrane potentials were significantly increased. After treatment with SSP, significant increases in the activities of SOD, anti-superoxide anion radical activities, and MnSOD mRNA levels in the PCV-2 infected cells were observed. Meanwhile, significant increases in NOX2 mRNA levels and protein expression, O2•- levels and mitochondrial membrane potentials were also observed. The results showed that PCV2 infection resulted in the mitochondria oxidative stress of RAW264.7 cells as indicated by an increasing mitochondrial membrane potential, which was then inhibited by SSP. It was concluded that RAW264.7 cells treated with SSP could suffer from mitochondrial damage, which may be mediated by the inhibition of the mitochondrial membrane potential.
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Affiliation(s)
- Zi-Jie Su
- College of Animal Science and Technology, Guangxi University, Nanning 530005, PR China
| | - Jian Yang
- College of Animal Science and Technology, Guangxi University, Nanning 530005, PR China
| | - Wen-Juan Luo
- College of Animal Science and Technology, Guangxi University, Nanning 530005, PR China
| | - Ying-Yi Wei
- College of Animal Science and Technology, Guangxi University, Nanning 530005, PR China
| | - Xue-Hong Shuai
- Veterinary Department of Rongchang Campuses, Southwest University, Rongchang, Chongqing 402460, PR China
| | - Ting-Jun Hu
- College of Animal Science and Technology, Guangxi University, Nanning 530005, PR China.
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22
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Guerrero CA, Acosta O. Inflammatory and oxidative stress in rotavirus infection. World J Virol 2016; 5:38-62. [PMID: 27175349 PMCID: PMC4861870 DOI: 10.5501/wjv.v5.i2.38] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/12/2015] [Revised: 10/23/2015] [Accepted: 01/29/2016] [Indexed: 02/05/2023] Open
Abstract
Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum (ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species (ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virus-associated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.
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23
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Amatore D, Sgarbanti R, Aquilano K, Baldelli S, Limongi D, Civitelli L, Nencioni L, Garaci E, Ciriolo MR, Palamara AT. Influenza virus replication in lung epithelial cells depends on redox-sensitive pathways activated by NOX4-derived ROS. Cell Microbiol 2014; 17:131-45. [PMID: 25154738 PMCID: PMC4311438 DOI: 10.1111/cmi.12343] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2013] [Revised: 07/16/2014] [Accepted: 08/19/2014] [Indexed: 01/25/2023]
Abstract
An overproduction of reactive oxygen species (ROS) mediated by NADPH oxidase 2 (NOX2) has been related to airway inflammation typical of influenza infection. Virus-induced oxidative stress may also control viral replication, but the mechanisms underlying ROS production, as well as their role in activating intracellular pathways and specific steps of viral life cycle under redox control have to be fully elucidated. In this study, we demonstrate that influenza A virus infection of lung epithelial cells causes a significant ROS increase that depends mainly on NOX4, which is upregulated at both mRNA and protein levels, while the expression of NOX2, the primary source of ROS in inflammatory cells, is downregulated. Inhibition of NOX4 activity through chemical inhibitors or RNA silencing blocks the ROS increase, prevents MAPK phosphorylation, and inhibits viral ribonucleoprotein (vRNP) nuclear export and viral release. Overall these data, obtained in cell lines and primary culture, describe a so far unrecognized role for NOX4-derived ROS in activating redox-regulated intracellular pathways during influenza virus infection and highlight their relevance in controlling specific steps of viral replication in epithelial cells. Pharmacological modulation of NOX4-mediated ROS production may open the way for new therapeutic approaches to fighting influenza by targeting cell and not the virus.
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Affiliation(s)
- Donatella Amatore
- Department of Public Health and Infectious Diseases, Pasteur Institute-Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, 00185, Italy; CEINGE Advanced Biotechnology, Naples, 80145, Italy
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24
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Jin Y, Dong L, Wu C, Qin J, Li S, Wang C, Shao X, Huang D. Buyang Huanwu Decoction fraction protects against cerebral ischemia/reperfusion injury by attenuating the inflammatory response and cellular apoptosis. Neural Regen Res 2014; 8:197-207. [PMID: 25206589 PMCID: PMC4107522 DOI: 10.3969/j.issn.1673-5374.2013.03.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/10/2012] [Accepted: 11/20/2012] [Indexed: 01/08/2023] Open
Abstract
Buyang Huanwu Decoction fraction extracted from Buyang Huanwu Decoction contains saponins of Astragalus, total paeony glycoside and safflower flavones. The aim of this study was to demonstrate the neuroprotective effect and mechanism of Buyang Huanwu Decoction fraction on ischemic injury both in vivo and in vitro. In vivo experiments showed that 50-200 mg/kg Buyang Huanwu Decoction fraction reduced infarct volume and pathological injury in ischemia/reperfusion rats, markedly inhibited expression of nuclear factor-κB and tumor necrosis factor-α and promoted nestin protein expression in brain tissue. Buyang Huanwu Decoction fraction (200 mg/kg) exhibited significant effects, which were similar to those of 100 mg/kg Ginkgo biloba extract. In vitro experimental results demonstrated that 10-100 mg/L Buyang Huanwu Decoction fraction significantly improved cell viability, decreased the release of lactate dehydrogenase and malondialdehyde levels, and inhibited the rate of apoptosis in HT22 cells following oxygen-glucose deprivation. Buyang Huanwu Decoction fraction (100 mg/L) exhibited significant effects, which were similar to those of 100 mg/L Ginkgo biloba extract. These findings suggest that Buyang Huanwu Decoction fraction may represent a novel, protective strategy against cerebral ischemia/reperfusion injury in rats and oxygen-glucose deprivation-induced damage in HT22 cells in vitro by attenuating the inflammatory response and cellular apoptosis.
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Affiliation(s)
- Yulian Jin
- Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education; Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China ; Anhui Provincial Children's Hospital, Hefei 230051, Anhui Province, China
| | - Liuyi Dong
- Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education; Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Changqing Wu
- Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education; Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Jiang Qin
- Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education; Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Sheng Li
- Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education; Key Laboratory of Chinese Medicine Research and Development, State Administration of Traditional Chinese Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Chunyan Wang
- Anhui Institute of Materia Medica, Hefei 230022, Anhui Province, China
| | - Xu Shao
- Hefei Qi-xing Medicine and Technology Co., Ltd., Hefei 230088, Anhui Province, China
| | - Dake Huang
- Synthetic Laboratory of Basic Medicine College, Anhui Medical University, Hefei 230032, Anhui Province, China
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25
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Activation of intrinsic immune responses and microglial phagocytosis in an ex vivo spinal cord slice culture model of West Nile virus infection. J Virol 2014; 88:13005-14. [PMID: 25165111 DOI: 10.1128/jvi.01994-14] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/28/2022] Open
Abstract
UNLABELLED West Nile virus (WNV) is a neurotropic flavivirus that causes significant neuroinvasive disease involving the brain and/or spinal cord. Experimental mouse models of WNV infection have established the importance of innate and adaptive immune responses in controlling the extent and severity of central nervous system (CNS) disease. However, differentiating between immune responses that are intrinsic to the CNS and those that are dependent on infiltrating inflammatory cells has proven difficult. We used a murine ex vivo spinal cord slice culture (SCSC) model to determine the innate immune processes specific to the CNS during WNV infections. By 7 days after ex vivo infection of SCSCs, the majority of neurons and a substantial percentage of astrocytes were infected with WNV, resulting in apoptotic cell death and astrogliosis. Microglia, the resident immune cells of the CNS, were activated by WNV infection, as exemplified by their amoeboid morphology, the development of filopodia and lamellipodia, and phagocytosis of WNV-infected cells and debris. Microglial cell activation was concomitant with increased expression of proinflammatory cytokines and chemokines, including CXCL10, CXCL1, CCL5, CCL3, CCL2, tumor necrosis factor alpha (TNF-α), TNF-related apoptosis-inducing ligand (TRAIL), and interleukin-6 (IL-6). The application of minocycline, an inhibitor of neuroinflammation, altered the WNV-induced proinflammatory cytokine/chemokine expression profile, with inhibited production of CCL5, CCL2, and IL-6. Our findings establish that CNS-resident cells have the capacity to initiate a robust innate immune response against WNV infection in the absence of infiltrating inflammatory cells and systemic immune responses. IMPORTANCE There are no specific treatments of proven efficacy available for WNV neuroinvasive disease. A better understanding of the pathogenesis of WNV CNS infection is crucial for the rational development of novel therapies. Development of a spinal cord slice culture (SCSC) model facilitates the study of WNV pathogenesis and allows investigation of the intrinsic immune responses of the CNS. Our studies demonstrate that robust CNS innate immune responses, including microglial activation and proinflammatory cytokine/chemokine production, develop independently of contributions from the peripheral immune system and CNS-infiltrating inflammatory cells.
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26
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Anandamide protects HT22 cells exposed to hydrogen peroxide by inhibiting CB1 receptor-mediated type 2 NADPH oxidase. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:893516. [PMID: 25136404 PMCID: PMC4127243 DOI: 10.1155/2014/893516] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 12/11/2013] [Revised: 06/23/2014] [Accepted: 06/25/2014] [Indexed: 11/25/2022]
Abstract
Background. Endogenous cannabinoid anandamide (AEA) protects neurons from oxidative injury in rodent models; however the mechanism of AEA-induced neuroprotection remains to be determined. Activation of neuronal NADPH oxidase 2 (Nox2) contributes to oxidative damage of the brain, and inhibition of Nox2 can attenuate cerebral oxidative stress. We aimed to determine whether the neuronal Nox2 was involved in protection mediated by AEA. Methods. The mouse hippocampal neuron cell line HT22 was exposed to hydrogen peroxide (H2O2) to mimic oxidative injury of neurons. The protective effect of AEA was assessed by measuring cell metabolic activity, apoptosis, lactate dehydrogenase (LDH) release, cellular morphology, intracellular reactive oxygen species (ROS), and antioxidant and oxidant levels and Nox2 expression. Results. HT22 cells exposed to H2O2 demonstrated morphological changes, decreased LDH release, reduced metabolic activity, increased levels of intracellular ROS and oxidized glutathione (GSSG), reduced levels of superoxide dismutase (SOD), and reduced glutathione (GSH) and increased expression of Nox2. AEA prevented these effects, a property abolished by simultaneous administration of CB1 antagonist AM251 or CB1-siRNA. Conclusion. Nox2 inhibition is involved in AEA-induced cytoprotection against oxidative stress through CB1 activation in HT22 cells.
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Taguchi A, Niwa M, Hoshi M, Saito K, Masutani T, Hisamatsu K, Kobayashi K, Hatano Y, Tomita H, Hara A. Indoleamine 2,3-dioxygenase 1 is upregulated in activated microglia in mice cerebellum during acute viral encephalitis. Neurosci Lett 2014; 564:120-5. [DOI: 10.1016/j.neulet.2014.01.051] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/29/2013] [Revised: 01/16/2014] [Accepted: 01/24/2014] [Indexed: 11/25/2022]
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NADPH oxidase inhibition improves neurological outcome in experimental traumatic brain injury. Neurochem Int 2014; 69:14-9. [DOI: 10.1016/j.neuint.2014.02.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/03/2013] [Revised: 01/13/2014] [Accepted: 02/25/2014] [Indexed: 11/21/2022]
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Binias C, Gonzalez P, Provost M, Lambert C, de Montaudouin X. Brown muscle disease: impact on Manila clam Venerupis (=Ruditapes) philippinarum biology. FISH & SHELLFISH IMMUNOLOGY 2014; 36:510-518. [PMID: 24378680 DOI: 10.1016/j.fsi.2013.12.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 06/27/2013] [Revised: 12/04/2013] [Accepted: 12/18/2013] [Indexed: 06/03/2023]
Abstract
This study assessed the effect of Brown Muscle Disease (BMD) on Manila clam Venerupis philippinarum fitness. BMD was discovered in 2005. It affects the posterior adductor muscle and leads to clam gaping and eventually death. Three statuses of clams were compared: buried individuals with no signs of BMD (BUR); clams at the surface of the sediment with no signs of BMD (SURF) and clams at the surface of the sediment exhibiting signs of brown muscle disease (BMD). Physiological (condition index), immune (hemocyte parameters) and molecular (gene expressions) parameters collected seasonally were analyzed and compared. Results demonstrated a seasonal pattern in condition index (CI) with peaks in spring/summer and decreases in autumn/winter. At each season, the highest CI was observed in BUR and the lowest CI was observed in BMD. In terms of immune response, phagocytosis rate and capacity were higher in clams with BMD whereas the health status of the clams did not influence the total hemocyte count. Genes involved in the immune system (comp, tnf, inter) were upregulated in clams with BMD. The molecular analysis of gill and posterior muscle showed higher mitochondrial metabolism (cox-1, 16S) in cells of infected clams, suggesting a stronger energetic demand by these cells. Finally, genes involved in oxidative stress response (cat, sod), detoxification (mt) and DNA repair (gadd45) were also overexpressed due to reactive oxygen species production. Most of the studied parameters underlined a cause-effect correlation between Manila clam health status (BUR, SUR, BMD) and physiological parameters. An important stress response was observed in BMD-infected clams at different scales, i.e. condition index, immune parameters and stress-related gene expression.
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Affiliation(s)
- Cindy Binias
- Université Bordeaux, EPOC, UMR 5805, 33120 Arcachon, France.
| | | | - Margot Provost
- Université Bordeaux, EPOC, UMR 5805, 33120 Arcachon, France
| | - Christophe Lambert
- LEMAR CNRS (UMR 6539), IUEM, Université de Bretagne occidentale, 29280 Plouzané, France
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Anand SK, Tikoo SK. Viruses as modulators of mitochondrial functions. Adv Virol 2013; 2013:738794. [PMID: 24260034 PMCID: PMC3821892 DOI: 10.1155/2013/738794] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/26/2013] [Accepted: 08/30/2013] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are multifunctional organelles with diverse roles including energy production and distribution, apoptosis, eliciting host immune response, and causing diseases and aging. Mitochondria-mediated immune responses might be an evolutionary adaptation by which mitochondria might have prevented the entry of invading microorganisms thus establishing them as an integral part of the cell. This makes them a target for all the invading pathogens including viruses. Viruses either induce or inhibit various mitochondrial processes in a highly specific manner so that they can replicate and produce progeny. Some viruses encode the Bcl2 homologues to counter the proapoptotic functions of the cellular and mitochondrial proteins. Others modulate the permeability transition pore and either prevent or induce the release of the apoptotic proteins from the mitochondria. Viruses like Herpes simplex virus 1 deplete the host mitochondrial DNA and some, like human immunodeficiency virus, hijack the host mitochondrial proteins to function fully inside the host cell. All these processes involve the participation of cellular proteins, mitochondrial proteins, and virus specific proteins. This review will summarize the strategies employed by viruses to utilize cellular mitochondria for successful multiplication and production of progeny virus.
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Affiliation(s)
- Sanjeev K. Anand
- Vaccine & Infection Disease Organization-International Vaccine Center (VIDO-InterVac), University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
- Veterinary Microbiology, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
| | - Suresh K. Tikoo
- Vaccine & Infection Disease Organization-International Vaccine Center (VIDO-InterVac), University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
- Veterinary Microbiology, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
- School of Public Health, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
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Abstract
It has been established that oxidative stress, defined as the condition in which the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson disease. Glutathione is a ubiquitous thiol tripeptide that acts alone or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals, and peroxynitrites. In this review, we examine the synthesis, metabolism, and functional interactions of glutathione and discuss how these relate to the protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson disease.
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Affiliation(s)
- Michelle Smeyne
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, 901-595-3066
| | - Richard Jay Smeyne
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, 901-595-2830
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Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol 2013; 87:5005-18. [PMID: 23427152 DOI: 10.1128/jvi.00082-13] [Citation(s) in RCA: 206] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/20/2022] Open
Abstract
Inflammasomes are multiprotein complexes that recognize pathogens and pathogen- or danger-associated molecular patterns. They induce the maturation and secretion of powerful proinflammatory interleukin-1B (IL-1β), IL-18, and IL-33 cytokines, which in turn activate expression of other immune genes and lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Inflammasomes are comprised of cytoplasmic sensor molecules, such as NLRP3 and AIM2 or nuclear sensor IFI16, the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD), and the effector protein procaspase-1. Herpes simplex virus 1 (HSV-1), a ubiquitous virus that infects humans and establishes life-long latency, has evolved numerous mechanisms to evade host detection and immune responses. Here, we show that early during in vitro infection of human foreskin fibroblasts (2 to 4 h), HSV-1 induced the activation of the IFI16 and NLRP3 inflammasomes and maturation of IL-1β. Independent of viral gene expression, IFI16 recognized the HSV-1 genome in infected cell nuclei, relocalized, and colocalized with ASC in the cytoplasm. However, HSV-1 specifically targeted IFI16 for rapid proteasomic degradation at later times postinfection, which was dependent on the expression of ICP0, an immediate early protein of HSV-1. In contrast, NLRP3, AIM2, and ASC levels were not decreased. Also, caspase-1 was "trapped" in actin clusters at later time points that likely blocked the NLRP3/IFI16 inflammasome activity. In addition, the secretion of mature IL-1β was inhibited. These results suggest that though the host cell responds to HSV-1 infection by IFI16 and NLRP3 inflammasomes early during infection, HSV-1 has evolved mechanisms to shut down these responses to evade the proinflammatory consequences.
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Abstract
The encephalomyocarditis virus (EMCV) is a small non-enveloped single-strand RNA virus, the causative agent of not only myocarditis and encephalitis, but also neurological diseases, reproductive disorders and diabetes in many mammalian species. EMCV pathogenesis appears to be viral strain- and host-specific, and a better understanding of EMCV virulence factors is increasingly required. Indeed, EMCV is often used as a model for diabetes and viral myocarditis, and is also widely used in immunology as a double-stranded RNA stimulus in the study of Toll-like as well as cytosolic receptors. However, EMCV virulence and properties have often been neglected. Moreover, EMCV is able to infect humans albeit with a low morbidity. Progress on xenografts, such as pig heart transplantation in humans, has raised safety concerns that need to be explored. In this review we will highlight the biology of EMCV and all known and potential virulence factors.
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Affiliation(s)
- Margot Carocci
- Microbiology Immunology Department, Harvard Medical School, Boston, MA, USA.
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Ano Y, Sakudo A, Onodera T. Role of microglia in oxidative toxicity associated with encephalomycarditis virus infection in the central nervous system. Int J Mol Sci 2012; 13:7365-7374. [PMID: 22837699 PMCID: PMC3397531 DOI: 10.3390/ijms13067365] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/02/2012] [Revised: 05/28/2012] [Accepted: 06/05/2012] [Indexed: 12/13/2022] Open
Abstract
The single-stranded RNA encephalomyocarditis virus (EMCV) can replicate in the central nervous system (CNS) and lead to prominent brain lesions in the stratum pyramidale hippocampus and the stratum granulosum cerebelli. Activated microglia cells infected by EMCV produce a massive burst of reactive oxygen species (ROS) via NADPH oxidase 2 (NOX2) activation, leading to neuronal death. Balancing this effect is mechanisms by which ROS are eliminated from the CNS. Cellular prion protein (PrPC) plays an important antioxidant role and contributes to cellular defense against EMCV infection. This review introduces recent knowledge on brain injury induced by EMCV infection via ROS generation as well as the involvement of various mediators and regulators in the pathogenesis.
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Affiliation(s)
- Yasuhisa Ano
- Central Laboratories for Frontier Technology, Kirin Holdings Co, Ltd, 1–13-5 Fukuura Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan; E-Mail:
| | - Akikazu Sakudo
- Laboratory of Biometabolic Chemistry, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan; E-Mail:
| | - Takashi Onodera
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +81-03-5841-5389; Fax: +81-03-5841-5389
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Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors. Cell Mol Life Sci 2012; 69:2409-27. [PMID: 22581365 DOI: 10.1007/s00018-012-1015-4] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/18/2012] [Revised: 04/18/2012] [Accepted: 04/20/2012] [Indexed: 12/24/2022]
Abstract
Microglia are key sentinels of central nervous system health, and their dysfunction has been widely implicated in the progressive nature of neurodegenerative diseases. While microglia can produce a host of factors that are toxic to neighboring neurons, NOX2 has been implicated as a common and essential mechanism of microglia-mediated neurotoxicity. Accumulating evidence indicates that activation of the NOX2 enzyme complex in microglia is neurotoxic, both through the production of extracellular reactive oxygen species that damage neighboring neurons as well as the initiation of redox signaling in microglia that amplifies the pro-inflammatory response. More specifically, evidence supports that NOX2 redox signaling enhances microglial sensitivity to pro-inflammatory stimuli, and amplifies the production of neurotoxic cytokines, to promote chronic and neurotoxic microglial activation. Here, we describe the evidence denoting the role of NOX2 in microglia-mediated neurotoxicity with an emphasis on Alzheimer's and Parkinson's disease, describe available inhibitors that have been tested, and detail evidence of the neuroprotective and therapeutic potential of targeting this enzyme complex to regulate microglia.
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Oxidative and Nitrosative Stress on Phagocytes’ Function: from Effective Defense to Immunity Evasion Mechanisms. Arch Immunol Ther Exp (Warsz) 2011; 59:441-8. [DOI: 10.1007/s00005-011-0144-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/24/2011] [Accepted: 06/27/2011] [Indexed: 12/12/2022]
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Encephalomyocarditis virus 2A protein is required for viral pathogenesis and inhibition of apoptosis. J Virol 2011; 85:10741-54. [PMID: 21849462 DOI: 10.1128/jvi.00394-11] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/16/2022] Open
Abstract
The encephalomyocarditis virus (EMCV), a Picornaviridae virus, has a wide host spectrum and can cause various diseases. EMCV virulence factors, however, are as yet ill defined. Here, we demonstrate that the EMCV 2A protein is essential for the pathogenesis of EMCV. Infection of mice with the B279/95 strain of EMCV resulted in acute fatal disease, while the clone C9, derived by serial in vitro passage of the B279/95 strain, was avirulent. C9 harbored a large deletion in the gene encoding the 2A protein. This deletion was incorporated into the cDNA of a pathogenic EMCV1.26 strain. The new virus, EMCV1.26Δ2A, was capable of replicating in vitro, albeit more slowly than EMCV1.26. Only mice inoculated with EMCV1.26 triggered death within a few days. Mice infected with EMCV1.26Δ2A did not exhibit clinical signs, and histopathological analyses showed no damage in the central nervous system, unlike EMCV1.26-infected mice. In vitro, EMCV1.26Δ2A presented a defect in viral particle release correlating with prolonged cell viability. Unlike EMCV1.26, which induced cytopathic cell death, EMCV1.26Δ2A induced apoptosis via caspase 3 activation. This strongly suggests that the 2A protein is required for inhibition of apoptosis during EMCV infection. All together, our data indicate that the EMCV 2A protein is important for the virus in counteracting host defenses, since Δ2A viruses were no longer pathogenic and were unable to inhibit apoptosis in vitro.
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