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Stegnjaić G, Nikolovski N, Stanisavljević S, Lazarević M, Momčilović M, Foresti R, Motterlini R, Miljković Đ. Immunomodulatory effects of HYCO-3, a dual action CO-releaser/Nrf2 activator. Clin Exp Immunol 2025; 219:uxae100. [PMID: 39540912 PMCID: PMC11773809 DOI: 10.1093/cei/uxae100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/09/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
HYCOs are hybrid molecules consisting of activators of the transcription factor Nrf2 conjugated to carbon monoxide (CO)-releasing moieties. These 'dual action' compounds (HYCOs) have been designed to mimic the activity of heme oxygenase-1 (HO-1), a stress inducible cytoprotective enzyme that degrades heme to CO which expression is regulated by Nrf2. HYCOs have recently shown efficacy in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the mechanism(s) of action of HYCOs still remains to be fully investigated. Here, we assessed the effects of HYCO-3, a prototype of these hybrids, on myeloid-derived cells, microglial cells and T lymphocytes obtained from EAE-immunized mice. HYCO-3 exerted immunomodulatory effects on all the examined cell populations by inhibiting the generation of pro-inflammatory cytokines and nitric oxide, and downregulating antigen-presenting capacity of these cells. The observed effects support the view that HYCOs are promising candidates to be developed for the treatment of autoimmune and chronic inflammatory disorders.
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Affiliation(s)
- Goran Stegnjaić
- Department of Immunology, Institute for Biological Research ‘Siniša Stanković’ - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Neda Nikolovski
- Department of Immunology, Institute for Biological Research ‘Siniša Stanković’ - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Suzana Stanisavljević
- Department of Immunology, Institute for Biological Research ‘Siniša Stanković’ - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Milica Lazarević
- Department of Immunology, Institute for Biological Research ‘Siniša Stanković’ - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Miljana Momčilović
- Department of Immunology, Institute for Biological Research ‘Siniša Stanković’ - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Roberta Foresti
- Faculty of Health, University Paris Est-Créteil, INSERM, IMRB, Paris, France
| | - Roberto Motterlini
- Faculty of Health, University Paris Est-Créteil, INSERM, IMRB, Paris, France
| | - Đorđe Miljković
- Department of Immunology, Institute for Biological Research ‘Siniša Stanković’ - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Wu M, Yu S, Yan S, Wu M, Zhang L, Chen S, Shi D, Liu S, Fan Y, Lin X, Shen J. Peroxynitrite reduces Treg cell expansion and function by mediating IL-2R nitration and aggravates multiple sclerosis pathogenesis. Redox Biol 2024; 75:103240. [PMID: 38889621 PMCID: PMC11231601 DOI: 10.1016/j.redox.2024.103240] [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: 03/23/2024] [Revised: 05/08/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024] Open
Abstract
T-helper 17 cells and regulatory T cells (Treg) are critical regulators in the pathogenesis of multiple sclerosis (MS) but the factors affecting Treg/Th17 balance remains largely unknown. Redox balance is crucial to maintaining immune homeostasis and reducing the severity of MS but the underlying mechanisms are unclear yet. Herein, we tested the hypothesis that peroxynitrite, a representative molecule of reactive nitrogen species (RNS), could inhibit peripheral Treg cells, disrupt Treg/Th17 balance and aggravate MS pathology by inducing nitration of interleukin-2 receptor (IL-2R) and down-regulating RAS/JNK-AP-1 signalling pathway. Experimental autoimmune encephalomyelitis (EAE) mouse model and serum samples of MS patients were used in the study. We found that the increases of 3-nitrotyrosine and IL-2R nitration in Treg cells were coincided with disease severity in the active EAE mice. Mechanistically, peroxynitrite-induced IL-2R nitration down-regulated RAS/JNK signalling pathway, subsequently impairing peripheral Treg expansion and function, increasing Teff infiltration into the central nerve system (CNS), aggravating demyelination and neurological deficits in the EAE mice. Those changes were abolished by peroxynitrite decomposition catalyst (PDC) treatment. Furthermore, transplantation of the PDC-treated-autologous Treg cells from donor EAE mice significantly decreased Th17 cells in both axillary lymph nodes and lumbar spinal cord, and ameliorated the neuropathology of the recipient EAE mice. Those results suggest that peroxynitrite could disrupt peripheral Treg/Th17 balance, and aggravate neuroinflammation and neurological deficit in active EAE/MS pathogenesis. The underlying mechanisms are related to induce the nitration of IL-2R and inhibit the RAS/JNK-AP-1 signalling pathway in Treg cells. The study highlights that targeting peroxynitrite-mediated peripheral IL-2R nitration in Treg cells could be a novel therapeutic strategy to restore Treg/Th17 balance and ameliorate MS/EAE pathogenesis. The study provides valuable insights into potential role of peripheral redox balance in maintaining CNS immune homeostasis.
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MESH Headings
- Peroxynitrous Acid/metabolism
- Animals
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/immunology
- Mice
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Humans
- Receptors, Interleukin-2/metabolism
- Female
- Signal Transduction/drug effects
- Disease Models, Animal
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Male
- Tyrosine/analogs & derivatives
- Tyrosine/metabolism
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Affiliation(s)
- Meiling Wu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Sulan Yu
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Shenyu Yan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Minghui Wu
- Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
| | - Lu Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Shuang Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Dongyun Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200000, China
| | - Shanlin Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200000, China; Free Radical Regulation and Application Research Center of Fudan University, Shanghai, 200000, China
| | - Yongping Fan
- Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
| | - Xiang Lin
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China.
| | - Jiangang Shen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China.
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Darwish SF, Elbadry AMM, Elbokhomy AS, Salama GA, Salama RM. The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases. FRONTIERS IN AGING 2023; 4:1231706. [PMID: 37744008 PMCID: PMC10513083 DOI: 10.3389/fragi.2023.1231706] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023]
Abstract
The pathophysiology of different neurodegenerative illnesses is significantly influenced by the polarization regulation of microglia and macrophages. Traditional classifications of macrophage phenotypes include the pro-inflammatory M1 and the anti-inflammatory M2 phenotypes. Numerous studies demonstrated dynamic non-coding RNA modifications, which are catalyzed by microglia-induced neuroinflammation. Different nutraceuticals focus on the polarization of M1/M2 phenotypes of microglia and macrophages, offering a potent defense against neurodegeneration. Caeminaxin A, curcumin, aromatic-turmerone, myricetin, aurantiamide, 3,6'-disinapoylsucrose, and resveratrol reduced M1 microglial inflammatory markers while increased M2 indicators in Alzheimer's disease. Amyloid beta-induced microglial M1 activation was suppressed by andrographolide, sulforaphane, triptolide, xanthoceraside, piperlongumine, and novel plant extracts which also prevented microglia-mediated necroptosis and apoptosis. Asarone, galangin, baicalein, and a-mangostin reduced oxidative stress and pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in M1-activated microglia in Parkinson's disease. Additionally, myrcene, icariin, and tenuigenin prevented the nod-like receptor family pyrin domain-containing 3 inflammasome and microglial neurotoxicity, while a-cyperone, citronellol, nobiletin, and taurine prevented NADPH oxidase 2 and nuclear factor kappa B activation. Furthermore, other nutraceuticals like plantamajoside, swertiamarin, urolithin A, kurarinone, Daphne genkwa flower, and Boswellia serrata extracts showed promising neuroprotection in treating Parkinson's disease. In Huntington's disease, elderberry, curcumin, iresine celosia, Schisandra chinensis, gintonin, and pomiferin showed promising results against microglial activation and improved patient symptoms. Meanwhile, linolenic acid, resveratrol, Huperzia serrata, icariin, and baicalein protected against activated macrophages and microglia in experimental autoimmune encephalomyelitis and multiple sclerosis. Additionally, emodin, esters of gallic and rosmarinic acids, Agathisflavone, and sinomenine offered promising multiple sclerosis treatments. This review highlights the therapeutic potential of using nutraceuticals to treat neurodegenerative diseases involving microglial-related pathways.
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Affiliation(s)
- Samar F. Darwish
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Abdullah M. M. Elbadry
- Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
- Nanotechnology Research Center (NTRC), The British University in Egypt (BUE), El-Sherouk City, Egypt
| | | | - Ghidaa A. Salama
- Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Rania M. Salama
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University, Cairo, Egypt
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Phenethyl Ester of Gallic Acid Ameliorates Experimental Autoimmune Encephalomyelitis. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248770. [PMID: 36557903 PMCID: PMC9782083 DOI: 10.3390/molecules27248770] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/18/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
Gallic acid is a phenolic acid present in various plants, nuts, and fruits. It is well known for its anti-oxidative and anti-inflammatory properties. The phenethyl ester of gallic acid (PEGA) was synthesized with the aim of increasing the bioavailability of gallic acid, and thus its pharmacological potential. Here, the effects of PEGA on encephalitogenic cells were examined, and PEGA was found to modulate the inflammatory activities of T cells and macrophages/microglia. Specifically, PEGA reduced the release of interleukin (IL)-17 and interferon (IFN)-γ from T cells, as well as NO, and IL-6 from macrophages/microglia. Importantly, PEGA ameliorated experimental autoimmune encephalomyelitis, an animal model of chronic inflammatory disease of the central nervous system (CNS)-multiple sclerosis. Thus, PEGA is a potent anti-inflammatory compound with a perspective to be further explored in the context of CNS autoimmunity and other chronic inflammatory disorders.
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Stegnjaić G, Lazarević M, Diamantis D, Djedović N, Jevtić B, Stanisavljević S, Dimitrijević M, Momčilović M, Tzakos AG, Miljković Đ. Phenethyl ester of rosmarinic acid ameliorates experimental autoimmune encephalomyelitis. Immunol Lett 2022; 251-252:9-19. [DOI: 10.1016/j.imlet.2022.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/13/2022] [Accepted: 09/25/2022] [Indexed: 11/24/2022]
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Zha Z, Liu S, Liu Y, Li C, Wang L. Potential Utility of Natural Products against Oxidative Stress in Animal Models of Multiple Sclerosis. Antioxidants (Basel) 2022; 11:antiox11081495. [PMID: 36009214 PMCID: PMC9404913 DOI: 10.3390/antiox11081495] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/27/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022] Open
Abstract
Multiple sclerosis (MS) is an autoimmune-mediated degenerative disease of the central nervous system (CNS) characterized by immune cell infiltration, demyelination and axonal injury. Oxidative stress-induced inflammatory response, especially the destructive effect of immune cell-derived free radicals on neurons and oligodendrocytes, is crucial in the onset and progression of MS. Therefore, targeting oxidative stress-related processes may be a promising preventive and therapeutic strategy for MS. Animal models, especially rodent models, can be used to explore the in vivo molecular mechanisms of MS considering their similarity to the pathological processes and clinical signs of MS in humans and the significant oxidative damage observed within their CNS. Consequently, these models have been used widely in pre-clinical studies of oxidative stress in MS. To date, many natural products have been shown to exert antioxidant effects to attenuate the CNS damage in animal models of MS. This review summarized several common rodent models of MS and their association with oxidative stress. In addition, this review provides a comprehensive and concise overview of previously reported natural antioxidant products in inhibiting the progression of MS.
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das Neves SP, Sousa JC, Sousa N, Cerqueira JJ, Marques F. Altered astrocytic function in experimental neuroinflammation and multiple sclerosis. Glia 2020; 69:1341-1368. [PMID: 33247866 DOI: 10.1002/glia.23940] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/14/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects about 2.5 million people worldwide. In MS, the patients' immune system starts to attack the myelin sheath, leading to demyelination, neurodegeneration, and, ultimately, loss of vital neurological functions such as walking. There is currently no cure for MS and the available treatments only slow the initial phases of the disease. The later-disease mechanisms are poorly understood and do not directly correlate with the activity of immune system cells, the main target of the available treatments. Instead, evidence suggests that disease progression and disability are better correlated with the maintenance of a persistent low-grade inflammation inside the CNS, driven by local glial cells, like astrocytes and microglia. Depending on the context, astrocytes can (a) exacerbate inflammation or (b) promote immunosuppression and tissue repair. In this review, we will address the present knowledge that exists regarding the role of astrocytes in MS and experimental animal models of the disease.
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Affiliation(s)
- Sofia Pereira das Neves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
| | - João Carlos Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
| | - Nuno Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal.,Clinical Academic Center, Braga, Portugal
| | - João José Cerqueira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal.,Clinical Academic Center, Braga, Portugal
| | - Fernanda Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga, Portugal
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Mitochondrial Dysfunction in EAE Mice Brains and Impact of HIF1-α Induction to Compensate Energy Loss. ARCHIVES OF NEUROSCIENCE 2020. [DOI: 10.5812/ans.104209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Mitochondrial dysfunction may be involved in the process of degradation and death of gray matter cells of the central nervous system (CNS) in patients with multiple sclerosis (MS). MS is known as a chronic, progressive demyelinating disease of the CNS. Objectives: Experimental autoimmune encephalomyelitis (EAE) mouse model of MS is the best method for extracting data trend for diagnosing this disorder. The aim of this study was to evaluate the specific activity of the Cytochrome oxidase (COX), ATP, and hypoxia-inducible factor 1 alpha (HIF-1α) in brain tissues of the EAE mice model. Methods: Twenty-one female mice (C57BL/6) were used, 9 for inducing the EAE model and 6 for each of both negative and sham control groups. The specific activity of the COX, ATP, and HIF-1α levels were evaluated in the whole brain of all 3 mice groups. Results: According to the findings, specific COX activity and ATP levels were decreased significantly, which could be due to the mitochondrial dysfunction and neuronal loss in MS lesions, whereas HIF-1α levels increased significantly in the EAE mice group, compared to the sham and negative control groups. The significant increase of HIF-1α levels reinforces the hypothesis that the HIF-1α induction may provide prevention of neuronal death by compensating energy loss under hypoxia-like conditions in EAE mice brains. Conclusions: The results of this study suggest that HIF-1α induction may also be a potential target for controlling the progression of MS, or the development of HIF-1α inducing compounds could be a potential candidate for the management of this disease and provide a rationale to conduct further research in this area.
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Li W, Deng R, Jing X, Chen J, Yang D, Shen J. Acteoside ameliorates experimental autoimmune encephalomyelitis through inhibiting peroxynitrite-mediated mitophagy activation. Free Radic Biol Med 2020; 146:79-91. [PMID: 31634539 DOI: 10.1016/j.freeradbiomed.2019.10.408] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/24/2019] [Accepted: 10/17/2019] [Indexed: 02/06/2023]
Abstract
Multiple sclerosis (MS) is an inflammatory disease in central nervous system (CNS) with limited therapeutic drugs. In the present study, we explored the anti-inflammatory/neuroprotective properties of Acteoside (AC), an active compound from medicinal herb Radix Rehmanniae (RR), and neuroprotective effects of AC on MS pathology by using an experimental autoimmune encephalomyelitis (EAE) model. We tested the hypothesis that AC could alleviate EAE pathogenesis through inhibiting inflammation and ONOO--mediated mitophagy activation in vivo and in vitro. The results showed that AC treatment effectively ameliorated neurological deficit score and postponed disease onset in the EAE mice. AC treatment inhibited inflammation/demyelination, alleviated peripheral activation and CNS infiltration of encephalitogenic CD4+ T cells and CD11b+ activated microglia/macrophages in the spinal cord of EAE mice. Meanwhile, AC treatment reduced ONOO- production, down-regulated the expression of iNOS and NADPH oxidases, and inhibited neuronal apoptotic cell death and mitochondrial damage in the spinal cords of the EAE mice. Furthermore, AC treatment decreased the ratio of LC3-II to LC3-I in mitochondrial fraction, and inhibited the translocation of Drp1 to the mitochondria. In vitro studies further proved that AC possessed strong ONOO- scavenging capability and protected the neuronal cells from nitrative cytotoxicity via suppressing ONOO--mediated excessive mitophagy. Taken together, Acteoside could be a potential therapeutic agent for multiple sclerosis treatment. The suppression of ONOO--induced excessive mitophagy activation could be one of the critical mechanisms contributing to its anti-inflammatory and anti-demyelinating properties.
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Affiliation(s)
- Wenting Li
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Ruixia Deng
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Xiaoshu Jing
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Jianping Chen
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Dan Yang
- Department of Chemistry, The University of Hong Kong, Hong Kong SAR, China.
| | - Jiangang Shen
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
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Waslo C, Bourdette D, Gray N, Wright K, Spain R. Lipoic Acid and Other Antioxidants as Therapies for Multiple Sclerosis. Curr Treat Options Neurol 2019; 21:26. [PMID: 31056714 DOI: 10.1007/s11940-019-0566-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Oxidative stress (OS), when oxidative forces outweigh endogenous and nutritional antioxidant defenses, contributes to the pathophysiology of multiple sclerosis (MS). Evidence of OS is found during acute relapses, in active inflammatory lesions, and in chronic, longstanding plaques. OS results in both ongoing inflammation and neurodegeneration. Antioxidant therapies are a rational strategy for people with MS with all phenotypes and disease durations. PURPOSE OF REVIEW: To understand the function of OS in health and disease, to examine the contributions of OS to MS pathophysiology, and to review current evidence for the effects of selected antioxidant therapies in people with MS (PwMS) with a focus on lipoic acid (LA). RECENT FINDINGS: Studies of antioxidant interventions in both animal and in vivo models result in reductions in serum markers of OS and increases in levels and activity of antioxidant enzymes. Antioxidant trials in PwMS, while generally underpowered, detect short-term improvements in markers of OS and antioxidant defenses, and to a lesser extent, in clinical symptoms (fatigue, depression). The best evidence to date is a 2-year trial of LA in secondary progressive MS which demonstrated a significant reduction of whole-brain atrophy and trend toward improvement in walking speed. Antioxidant therapy is a promising approach to treat MS across the spectrum and duration of disease. Rigorous and well-powered trials are needed to determine their therapeutic benefits.
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Affiliation(s)
- Carin Waslo
- Veterans Affairs Portland Health Care System, Portland, OR, USA
| | - Dennis Bourdette
- Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road - L226, Portland, OR, 97239, USA
| | - Nora Gray
- Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road - L226, Portland, OR, 97239, USA
| | - Kirsten Wright
- Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road - L226, Portland, OR, 97239, USA
| | - Rebecca Spain
- Veterans Affairs Portland Health Care System, Portland, OR, USA.
- Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road - L226, Portland, OR, 97239, USA.
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Sonar SA, Lal G. The iNOS Activity During an Immune Response Controls the CNS Pathology in Experimental Autoimmune Encephalomyelitis. Front Immunol 2019; 10:710. [PMID: 31019516 PMCID: PMC6458273 DOI: 10.3389/fimmu.2019.00710] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/15/2019] [Indexed: 12/23/2022] Open
Abstract
Inducible nitric oxide synthase (iNOS) plays a critical role in the regulation of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Previous studies have shown that iNOS plays pathogenic as well as regulatory roles in MS and EAE. However, how does iNOS alters the pathophysiology of the central nervous system (CNS) in neuronal autoimmunity is not clearly understood. In the present work, we show that treatment of mice with L-NAME, an iNOS inhibitor, during the antigen-priming phase primarily alters brain pathology, while in the subsequent effector phase of the immune response, the spinal cord is involved. Inhibition of iNOS during the priming phase of the immune response promotes the infiltration of pathogenic CD11b+F4/80-Gr-1+ cells, but there is low recruitment of regulatory CD11b+F4/80+ cells in the brain. Inhibition of iNOS during the effector phase shows similar pathogenic alterations in the spinal cord, instead of in the brain. Treatment of wild-type mice with L-NAME or mice having genetic deficiency of iNOS show lower MHC-II expression on the dendritic cells, but not on macrophages. Our data suggest that iNOS has a critical regulatory role during antigen-priming as well as in the effector phase of EAE, and inhibition iNOS at different stages of the immune response can differentially alter either the brain or spinal cord pathology. Understanding the cellular and molecular mechanisms through which iNOS functions could help to design a better strategies for the clinical management of neuroinflammation and neuronal autoimmunity.
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Janssens R, Struyf S, Proost P. Pathological roles of the homeostatic chemokine CXCL12. Cytokine Growth Factor Rev 2018; 44:51-68. [PMID: 30396776 DOI: 10.1016/j.cytogfr.2018.10.004] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 10/19/2018] [Indexed: 12/12/2022]
Abstract
CXCL12 is a CXC chemokine that traditionally has been classified as a homeostatic chemokine. It contributes to physiological processes such as embryogenesis, hematopoiesis and angiogenesis. In contrast to these homeostatic functions, increased expression of CXCL12 in general, or of a specific CXCL12 splicing variant has been demonstrated in various pathologies. In addition to this increased or differential transcription of CXCL12, also upregulation of its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) contributes to the onset or progression of diseases. Moreover, posttranslational modification of CXCL12 during disease progression, through interaction with locally produced molecules or enzymes, also affects CXCL12 activity, adding further complexity. As CXCL12, CXCR4 and ACKR3 are broadly expressed, the number of pathologies wherein CXCL12 is involved is growing. In this review, the role of the CXCL12/CXCR4/ACKR3 axis will be discussed for the most prevalent pathologies. Administration of CXCL12-neutralizing antibodies or small-molecule antagonists of CXCR4 or ACKR3 delays disease onset or prevents disease progression in cancer, viral infections, inflammatory bowel diseases, rheumatoid arthritis and osteoarthritis, asthma and acute lung injury, amyotrophic lateral sclerosis and WHIM syndrome. On the other hand, CXCL12 has protective properties in Alzheimer's disease and multiple sclerosis, has a beneficial role in wound healing and has crucial homeostatic properties in general.
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Affiliation(s)
- Rik Janssens
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, B-3000 Leuven, Belgium
| | - Sofie Struyf
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, B-3000 Leuven, Belgium
| | - Paul Proost
- KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, B-3000 Leuven, Belgium.
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Xie X, Tang F, Liu G, Li Y, Su X, Jiao X, Wang X, Tang B. Mitochondrial Peroxynitrite Mediation of Anthracycline-Induced Cardiotoxicity as Visualized by a Two-Photon Near-Infrared Fluorescent Probe. Anal Chem 2018; 90:11629-11635. [DOI: 10.1021/acs.analchem.8b03207] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Xilei Xie
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
| | - Fuyan Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
| | - Guangzhao Liu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
| | - Yong Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
| | - Xingxing Su
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
| | - Xiaoyun Jiao
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
| | - Xu Wang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, PR China
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14
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Chen Z, Yan P, Zou L, Zhao M, Jiang J, Liu S, Zhang KY, Huang W, Zhao Q. Using Ultrafast Responsive Phosphorescent Nanoprobe to Visualize Elevated Peroxynitrite In Vitro and In Vivo via Ratiometric and Time-Resolved Photoluminescence Imaging. Adv Healthc Mater 2018; 7:e1800309. [PMID: 29968378 DOI: 10.1002/adhm.201800309] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 06/08/2018] [Indexed: 12/13/2022]
Abstract
Peroxynitrite (ONOO- ), a potent biological oxidant, which has a short half-life in physiological conditions, is related to many diseases. Accurate peroxynitrite determination with superior selectivity and sensitivity is important for understanding biological roles of peroxynitrite in different health and disease tissues. Autofluorescence is an inevitable interference in luminescence biodetection and bioimaging, which often reduces signal-to-noise ratio during detection. In this work, a phosphorescent peroxynitrite nanoprobe (MSN-ONOO) which displays two emission bands is prepared by immobilizing two long-lived phosphorescent iridium(III) complexes that are peroxynitrite-activable and -inert, respectively, into water-dispersible mesoporous silica nanoparticles. Owing to the fast response rate, excellent sensitivity and outstanding selectivity of the nanoprobe toward peroxynitrite, it is further used for peroxynitrite determination in vitro and in vivo via ratiometric photoluminescence imaging. More notably, taking advantage of the long-lived phosphorescence of MSN-ONOO, in vivo elevated peroxynitrite is imaged with diminished autofluorescence interference and improved signal-to-noise ratio via time-resolved photoluminescence imaging. As far as it is known, this is the first time for endogenous peroxynitrite detection in vivo via the time-resolved photoluminescence imaging. Furthermore, the production of peroxynitrite in inflamed tissues is visualized.
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Affiliation(s)
- Zejing Chen
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
| | - Peng Yan
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
| | - Liang Zou
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
| | - Menglong Zhao
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
| | - Jiayang Jiang
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
| | - Shujuan Liu
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
| | - Kenneth Yin Zhang
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
| | - Wei Huang
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
- Shaanxi Institute of Flexible Electronics (SIFE); Northwestern Polytechnical University (NPU); Xi'an 710072 Shaanxi China
| | - Qiang Zhao
- Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors; Institute of Advanced Materials (IAM); Nanjing University of Posts and Telecommunications (NUPT); Nanjing 210023 P. R. China
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15
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Li W, Wu H, Gao C, Yang D, Yang D, Shen J. Radix Rehmanniae Extract Ameliorates Experimental Autoimmune Encephalomyelitis by Suppressing Macrophage-Derived Nitrative Damage. Front Physiol 2018; 9:864. [PMID: 30079025 PMCID: PMC6062770 DOI: 10.3389/fphys.2018.00864] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 06/18/2018] [Indexed: 12/24/2022] Open
Abstract
Multiple sclerosis (MS) is a neuroinflammatory disease in central nervous system (CNS) without effective treatment or medication yet. With high prevalence of MS patients worldwide and poor therapeutic outcome, seeking novel therapeutic strategy for MS is timely important. Radix Rehmanniae (RR), a typical Chinese Medicinal herb, has been used for neuroinflammatory diseases in Traditional Chinese Medicine for centuries. However, scientific evidence and underlying mechanisms of RR for MS are unclear. In this study, we tested the hypothesis that RR could attenuate the progress and severity of MS via suppressing macrophage-derived nitrative damage and inflammation by using experimental autoimmune encephalomyelitis (EAE) model for mimicking MS pathology. The results showed the RR treatment effectively ameliorated clinical disease severity, inhibited inflammation/demyelination in spinal cord, and alleviated CNS infiltration of encephalitogenic T cells and activated macrophages. Meanwhile, RR possessed bioactivities of scavenging ONOO- and reducing the expression of iNOS and NADPH oxidases in the spinal cords of the EAE mice. Furthermore, RR treatment suppressed nuclear factor-κB (NF-κB) signaling pathway in the splenocytes of EAE mice. The in vitro experiments on macrophages and neuronal cells exerted consistent results with the in vivo animal experiments. Taken together, we conclude that Radix Rehmanniae extract has therapeutic values for ameliorating EAE/MS pathological process and disease severity and its underlying mechanisms are associated with anti-inflammation and inhibiting macrophage-derived nitrative damages. Further study could yield novel promising therapeutic agent for multiple sclerosis.
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Affiliation(s)
- Wenting Li
- LKS Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Hao Wu
- LKS Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Chong Gao
- LKS Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Dan Yang
- Department of Chemistry, The University of Hong Kong, Hong Kong, Hong Kong
| | - Depo Yang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiangang Shen
- LKS Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong
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16
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Fagone P, Mazzon E, Bramanti P, Bendtzen K, Nicoletti F. Gasotransmitters and the immune system: Mode of action and novel therapeutic targets. Eur J Pharmacol 2018; 834:92-102. [PMID: 30016662 DOI: 10.1016/j.ejphar.2018.07.026] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 06/29/2018] [Accepted: 07/13/2018] [Indexed: 12/12/2022]
Abstract
Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the immune system has grown significantly in the past years, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune responses. Moreover, encouraging results come from the efficacy of NO-, CO- and H2S -donors in preclinical animal models of autoimmune, acute and chronic inflammatory diseases. To date, data on the influence of gasotransmitters in immunity and immunopathology are often scattered and partial, and the scarcity of clinical trials using NO-, CO- and H2S -donors, reveals that more effort is warranted. This review focuses on the role of gasotransmitters in the immune system and covers the evidences on the possible use of gasotransmitters for the treatment of inflammatory conditions.
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Affiliation(s)
- Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Klaus Bendtzen
- Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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17
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Romero JM, Carrizo ME, Curtino JA. Characterization of human triosephosphate isomerase S-nitrosylation. Nitric Oxide 2018; 77:26-34. [PMID: 29678765 DOI: 10.1016/j.niox.2018.04.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 04/10/2018] [Accepted: 04/16/2018] [Indexed: 12/23/2022]
Abstract
Triosephosphate isomerase (TPI), the glycolytic enzyme that catalyzes the isomerization of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P), has been frequently identified as a target of S-nitrosylation by proteomic studies. However, the effect of S-nitrosylation on its activity has only been explored in plants and algae. Here, we describe the in vitro S-nitrosylation of human TPI (hTPI), and the effect of the modification on its enzymatic parameters. NO-incorporation into the enzyme cysteine residues occurred by a time-dependent S-transnitrosylation from both, S-nitrosocysteine (CySNO) and S-nitrosoglutathione (GSNO), with CySNO being the more efficient NO-donor. Both X-ray crystal structure and mass spectrometry analyses showed that only Cys217 was S-nitrosylated. hTPI S-nitrosylation produced a 30% inhibition of the Vmax of the DHAP conversion to G3P, without affecting the Km for DHAP. This is the first study describing features of human TPI S-nitrosylation.
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Affiliation(s)
- Jorge Miguel Romero
- Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, Universidad Nacional de Córdoba - Consejo Nacional de Investigaciones Científicas y Técnicas (UNC-CONICET)), Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina.
| | - María Elena Carrizo
- Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, Universidad Nacional de Córdoba - Consejo Nacional de Investigaciones Científicas y Técnicas (UNC-CONICET)), Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
| | - Juan Agustín Curtino
- Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, Universidad Nacional de Córdoba - Consejo Nacional de Investigaciones Científicas y Técnicas (UNC-CONICET)), Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA, Córdoba, Argentina
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18
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Monro JA, Puri BK. A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications. Mol Neurobiol 2018; 55:7377-7388. [PMID: 29411266 PMCID: PMC6096969 DOI: 10.1007/s12035-018-0928-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 01/24/2018] [Indexed: 12/11/2022]
Abstract
Currently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME)/systemic exertion intolerance disease (SEID). However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood–brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation. Evidence is also detailed for biologically based potential therapeutic options, including: nutritional supplementation, for example in order to downregulate the nitric oxide-peroxynitrite cycle to prevent its perpetuation; antiviral therapy; and monoclonal antibody treatment. It is concluded that there is strong evidence of a molecular neurobiological aetiology, and so it is suggested that biologically based therapeutic interventions should constitute a focus for future research into CFS/ME/SEID.
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Affiliation(s)
- Jean A Monro
- Breakspear Medical Group, Hemel Hempstead, England, UK
| | - Basant K Puri
- Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
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19
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Miao J, Huo Y, Shi H, Fang J, Wang J, Guo W. A Si-rhodamine-based near-infrared fluorescent probe for visualizing endogenous peroxynitrite in living cells, tissues, and animals. J Mater Chem B 2018; 6:4466-4473. [DOI: 10.1039/c8tb00987b] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
An aromatic tertiary amine-functionalized Si-rhodamine dye has been exploited as a near-infrared fluorescent probe for visualizing endogenous peroxynitrite in living cells, tissues, and mice.
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Affiliation(s)
- Junfeng Miao
- School of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
| | - Yingying Huo
- School of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
| | - Hu Shi
- School of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
- Institute of Molecular Science
| | - Junru Fang
- School of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
| | - Juanjuan Wang
- Scientific Instrument Center
- Shanxi University
- Taiyuan 030006
- China
| | - Wei Guo
- School of Chemistry and Chemical Engineering
- Shanxi University
- Taiyuan 030006
- China
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20
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Jevtić B, Djedović N, Stanisavljević S, Gašić U, Mišić D, Despotović J, Samardžić J, Miljković D, Timotijević G. Anti-encephalitogenic effects of cucumber leaf extract. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.07.060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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21
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Ding Z, Tan J, Feng G, Yuan Z, Wu C, Zhang X. Nanoscale metal-organic frameworks coated with poly(vinyl alcohol) for ratiometric peroxynitrite sensing through FRET. Chem Sci 2017; 8:5101-5106. [PMID: 28970896 PMCID: PMC5613240 DOI: 10.1039/c7sc01077j] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 05/08/2017] [Indexed: 12/27/2022] Open
Abstract
This work describes a facile yet powerful approach to energy-transfer NMOF (nanoscale metal–organic framework) fabrication for ratiometric peroxynitrite (ONOO–) sensing.
This work describes a facile yet powerful approach to energy-transfer NMOF (nanoscale metal–organic framework) fabrication for ratiometric peroxynitrite (ONOO–) sensing. Poly(vinyl alcohol) (PVA) is chosen to organize the energy donor (NMOF) and acceptor (molecular probes). PVA can conveniently graft onto the NMOF surface and bind to the molecular probes bearing the arylboronic acid group through multiple weak coordination interactions. Due to efficient Förster resonance energy transfer (FRET), the bright blue fluorescence of the NMOF is quenched while the green or red emission from the acceptor is enhanced. Upon reacting with ONOO–, the ONOO– sensors depart from the NMOF and the FRET is interrupted and the fluorescence of the NMOF recovered. Based on this strategy, we developed two ratiometric ONOO– nanosensors for the detection of ONOO– in solutions and living cells. This work is the first report of NMOF ONOO– sensors through FRET and could inspire the design of other NMOF based chemical sensors and biosensors.
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Affiliation(s)
- Zhaoyang Ding
- Faculty of Health Sciences , University of Macau , Macau SAR , China .
| | - Jinyun Tan
- Faculty of Health Sciences , University of Macau , Macau SAR , China .
| | - Gang Feng
- Faculty of Health Sciences , University of Macau , Macau SAR , China .
| | - Zhen Yuan
- Faculty of Health Sciences , University of Macau , Macau SAR , China .
| | - Changfeng Wu
- Department of Biomedical Engineering , Southern University of Science and Technology , Shenzhen , Guangdong 518055 , China
| | - Xuanjun Zhang
- Faculty of Health Sciences , University of Macau , Macau SAR , China .
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22
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Li Y, Xie X, Yang X, Li M, Jiao X, Sun Y, Wang X, Tang B. Two-photon fluorescent probe for revealing drug-induced hepatotoxicity via mapping fluctuation of peroxynitrite. Chem Sci 2017; 8:4006-4011. [PMID: 28580117 PMCID: PMC5434753 DOI: 10.1039/c7sc00303j] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 03/13/2017] [Indexed: 12/28/2022] Open
Abstract
Drug-induced injury has attracted increasing attention in public health issues. Among them, hepatotoxicity has been regarded as the leading clinical problem caused by drug toxicity. However, owing to the complexity of the involved pathophysiological mechanisms and the lack of noninvasive, straightforward, and real-time tools, drug-induced hepatotoxicity has rarely been predicted satisfactorily. In this paper, by utilizing the reactive species peroxynitrite (ONOO-) as a biomarker, we present a two-photon fluorescent probe, TP-KA, holding rapid response, high specificity and sensitivity towards ONOO-, to investigate drug (acetaminophen and tolcapone)-related liver injury and the remediate effect of N-acetyl cysteine (NAC). With the support of TP-KA, we obtained direct and visual evidence of the upregulation of ONOO- during drug challenge both in live cells and mice, which was accompanied by liver tissue injury and tyrosine nitration. These findings demonstrate that ONOO- is a good and appropriate biomarker of hepatotoxicity, and nitrosative stress may be necessary for acetaminophen and tolcapone to exert their toxicity. Moreover, TP-KA can be employed as a powerful tool to pre-detect drug-induced organism injury and study the effect of antidotes.
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Affiliation(s)
- Yong Li
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xilei Xie
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xiu'e Yang
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Mengmeng Li
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xiaoyun Jiao
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Yuhui Sun
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xu Wang
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Bo Tang
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
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23
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Rezapour-Firouzi S. Herbal Oil Supplement With Hot-Nature Diet for Multiple Sclerosis. NUTRITION AND LIFESTYLE IN NEUROLOGICAL AUTOIMMUNE DISEASES 2017:229-245. [DOI: 10.1016/b978-0-12-805298-3.00024-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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24
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A new class of fast-response and highly selective fluorescent probes for visualizing peroxynitrite in live cells, subcellular organelles, and kidney tissue of diabetic rats. Biomaterials 2016; 107:33-43. [DOI: 10.1016/j.biomaterials.2016.08.032] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 08/15/2016] [Accepted: 08/18/2016] [Indexed: 11/23/2022]
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25
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Chen M, Lai L, Li X, Zhang X, He X, Liu W, Li R, Ke X, Fu C, Huang Z, Duan C. Baicalein Attenuates Neurological Deficits and Preserves Blood-Brain Barrier Integrity in a Rat Model of Intracerebral Hemorrhage. Neurochem Res 2016; 41:3095-3102. [PMID: 27518088 DOI: 10.1007/s11064-016-2032-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 07/12/2016] [Accepted: 08/05/2016] [Indexed: 01/19/2023]
Abstract
Previous studies have demonstrated that baicalein has protective effects against several diseases, which including ischemic stroke. The effect of baicalein on the blood-brain barrier (BBB) in intracerebral hemorrhage (ICH) and its related mechanisms are not well understood. We aimed to investigate the mechanisms by which baicalein may influence the BBB in a rat model of ICH. The rat model of ICH was induced by intravenous injection of collagenase IV into the brain. Animals were randomly divided into three groups: sham operation, vehicle, and baicalein group. Each group was then divided into subgroups, in which the rats were sacrificed at 24 and 72 h after ICH. We assessed brain edema, behavioral changes, BBB leakage, apoptosis, inducible nitric oxide synthase (iNOS), zonula occludens (ZO)-1, Mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). Treatment with baicalein reduced brain water content, BBB leakage, apoptosis, and neurologic deficits, compared with vehicle. Baicalein also decreased ICH-induced changes in the levels of iNOS but increased the levels of ZO-1. The protective effect of baicalein on the BBB in ICH rats was possibly invoked by attenuated p-38 MAPK and JNK phosphorylation, and decreased activation of the NF-κB signaling pathway, which may have suppressed gene transcription, including iNOS, and eventually decreased formation of peroxynitrite (ONOO-). Our results suggest that baicalein exerts a protective effect on BBB disruption in the rat model of ICH. The likely mechanism is via inhibition of MAPKs and NF-κB signaling pathways, leading to decreased formation of iNOS and ONOO-, thereby improving neurological function.
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Affiliation(s)
- Min Chen
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Lingfeng Lai
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Xifeng Li
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Xin Zhang
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Xuying He
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Wenchao Liu
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Ran Li
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Xunchang Ke
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Chuanyi Fu
- Department of Neurosurgery, People's Hospital of Hainan Province, Haikou, Hainan, China
| | - Zhiwei Huang
- Department of Neurosurgery, Liuzhou Worker's Hospital, Guangxi, China
| | - Chuanzhi Duan
- The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
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Jevtić B, Djedović N, Stanisavljević S, Despotović J, Miljković D, Timotijević G. Cucurbitacin E Potently Modulates the Activity of Encephalitogenic Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:4900-7. [PMID: 27225664 DOI: 10.1021/acs.jafc.6b00951] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Cucurbitacin E (CucE) is a highly oxidized steroid consisting of a tetracyclic triterpene. It is a member of a Cucurbitacin family of biomolecules that are predominantly found in Cucurbitaceae plants. CucE has already been identified as a potent anti-inflammatory compound. Here, its effects on CD4(+) T helper (Th) cells and macrophages, as the major encephalitogenic cells in the autoimmunity of the central nervous system, were investigated. Production of major pathogenic Th cell cytokines: interferon-gamma and interleukin-17 were inhibited under the influence of CucE. The effects of CucE on CD4(+) T cells were mediated through the modulation of aryl hydrocarbon receptor, STAT3, NFκB, p38 MAPK, and miR-146 signaling. Further, production of nitric oxide and reactive oxygen species, as well as phagocytic ability, were inhibited in macrophages treated with CucE. These results imply that CucE possesses powerful antiencephalitogenic activity.
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Affiliation(s)
- Bojan Jevtić
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade , Belgrade, Serbia
| | - Neda Djedović
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade , Belgrade, Serbia
| | - Suzana Stanisavljević
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade , Belgrade, Serbia
| | - Jovana Despotović
- Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Belgrade, Serbia
| | - Djordje Miljković
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade , Belgrade, Serbia
| | - Gordana Timotijević
- Laboratory for Plant Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade , Belgrade, Serbia
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Giacoppo S, Galuppo M, Pollastro F, Grassi G, Bramanti P, Mazzon E. A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis. ACTA ACUST UNITED AC 2015; 23:48. [PMID: 26489494 PMCID: PMC4618347 DOI: 10.1186/s40199-015-0131-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/28/2015] [Indexed: 11/20/2022]
Abstract
Background The present study was designed to investigate the efficacy of a new formulation of alone, purified cannabidiol (CBD) (>98 %), the main non-psychotropic cannabinoid of Cannabis sativa, as a topical treatment in an experimental model of autoimmune encephalomyelitis (EAE), the most commonly used model for multiple sclerosis (MS). Particularly, we evaluated whether administration of a topical 1 % CBD-cream, given at the time of symptomatic disease onset, could affect the EAE progression and if this treatment could also recover paralysis of hind limbs, qualifying topical-CBD for the symptomatic treatment of MS. Methods In order to have a preparation of 1 % of CBD-cream, pure CBD have been solubilized in propylene glycoland basic dense cream O/A. EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG35–55) in C57BL/6 mice. After EAE onset, mice were allocated into several experimental groups (Naïve, EAE, EAE-1 % CBD-cream, EAE-vehicle cream, CTRL-1 % CBD-cream, CTRL-vehicle cream). Mice were observed daily for signs of EAE and weight loss. At the sacrifice of the animals, which occurred at the 28th day from EAE-induction, spinal cord and spleen tissues were collected in order to perform histological evaluation, immunohistochemistry and western blotting analysis. Results Achieved results surprisingly show that daily treatment with topical 1 % CBD-cream may exert neuroprotective effects against EAE, diminishing clinical disease score (mean of 5.0 in EAE mice vs 1.5 in EAE + CBD-cream), by recovering of paralysis of hind limbs and by ameliorating histological score typical of disease (lymphocytic infiltration and demyelination) in spinal cord tissues. Also, 1 % CBD-cream is able to counteract the EAE-induced damage reducing release of CD4 and CD8α T cells (spleen tissue localization was quantified about 10,69 % and 35,96 % of positive staining respectively in EAE mice) and expression of the main pro-inflammatory cytokines as well as several other direct or indirect markers of inflammation (p-selectin, IL-10, GFAP, Foxp3, TGF-β, IFN-γ), oxidative injury (Nitrotyrosine, iNOS, PARP) and apoptosis (Cleaved caspase 3). Conclusion All these data suggest an interesting new profile of CBD that could lead to its introduction in the clinical management of MS and its associated symptoms at least in association with current conventional therapy. Electronic supplementary material The online version of this article (doi:10.1186/s40199-015-0131-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sabrina Giacoppo
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Maria Galuppo
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Federica Pollastro
- Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy
| | - Gianpaolo Grassi
- Consiglio per le Ricerca e la sperimentazione in Agricoltura - Centro di Ricerca per le Colture Industriali (CRA-CIN), Viale G. Amendola 82, 45100, Rovigo, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy.
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Li X, Tao RR, Hong LJ, Cheng J, Jiang Q, Lu YM, Liao MH, Ye WF, Lu NN, Han F, Hu YZ, Hu YH. Visualizing peroxynitrite fluxes in endothelial cells reveals the dynamic progression of brain vascular injury. J Am Chem Soc 2015; 137:12296-303. [PMID: 26352914 DOI: 10.1021/jacs.5b06865] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Accumulating evidence suggests that formation of peroxynitrite (ONOO(-)) in the cerebral vasculature contributes to the progression of ischemic damage, while the underlying molecular mechanisms remain elusive. To fully understand ONOO(-) biology, efficient tools that can realize the real-time tracing of endogenous ONOO(-) fluxes are indispensable. While a few ONOO(-) fluorescent probes have been reported, direct visualization of ONOO(-) fluxes in the cerebral vasculature of live mice remains a challenge. Herein, we present a fluorescent switch-on probe (NP3) for ONOO(-) imaging. NP3 exhibits good specificity, fast response, and high sensitivity toward ONOO(-) both in vitro and in vivo. Moreover, NP3 is two-photon excitable and readily blood-brain barrier penetrable. These desired photophysical and pharmacokinetic properties endow NP3 with the capability to monitor brain vascular ONOO(-) generation after injury with excellent temporal and spatial resolution. As a proof of concept, NP3 has enabled the direct visualization of neurovascular ONOO(-) formation in ischemia progression in live mouse brain by use of two-photon laser scanning microscopy. Due to these favorable properties, NP3 holds great promise for visualizing endogenous peroxynitrite fluxes in a variety of pathophysiological progressions in vitro and in vivo.
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Affiliation(s)
- Xin Li
- ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Rong-Rong Tao
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Ling-Juan Hong
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Juan Cheng
- ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Quan Jiang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Ying-Mei Lu
- School of Medicine, Zhejiang University City College , Hangzhou 310015, China
| | - Mei-Hua Liao
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Wei-Feng Ye
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Nan-Nan Lu
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Feng Han
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - Yong-Zhou Hu
- ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
| | - You-Hong Hu
- ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058, China
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Predonzani A, Calì B, Agnellini AHR, Molon B. Spotlights on immunological effects of reactive nitrogen species: When inflammation says nitric oxide. World J Exp Med 2015; 5:64-76. [PMID: 25992321 PMCID: PMC4436941 DOI: 10.5493/wjem.v5.i2.64] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 01/09/2015] [Accepted: 02/04/2015] [Indexed: 02/06/2023] Open
Abstract
Over the last decades, nitric oxide (NO) has been definitively recognised as one of the key players involved in immunity and inflammation. NO generation was originally described in activated macrophages, which still represent the prototype of NO-producing cells. Notwithstanding, additional cell subsets belonging to both innate and adaptive immunity have been documented to sustain NO propagation by means of the enzymatic activity of different nitric oxide synthase isoforms. Furthermore, due to its chemical characteristics, NO could rapidly react with other free radicals to generate different reactive nitrogen species (RNS), which have been intriguingly associated with many pathological conditions. Nonetheless, the plethora of NO/RNS-mediated effects still remains extremely puzzling. The aim of this manuscript is to dig into the broad literature on the topic to provide intriguing insights on NO-mediated circuits within immune system. We analysed NO and RNS immunological clues arising from their biochemical properties, immunomodulatory activities and finally dealing with their impact on different pathological scenarios with far prompting intriguing perspectives for their pharmacological targeting.
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Giacoppo S, Galuppo M, Lombardo GE, Ulaszewska MM, Mattivi F, Bramanti P, Mazzon E, Navarra M. Neuroprotective effects of a polyphenolic white grape juice extract in a mouse model of experimental autoimmune encephalomyelitis. Fitoterapia 2015; 103:171-86. [PMID: 25863350 DOI: 10.1016/j.fitote.2015.04.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 03/31/2015] [Accepted: 04/02/2015] [Indexed: 10/23/2022]
Abstract
In the last 20 years, wine phenolic compounds have received increasing interest since several epidemiological studies have suggested associations between regular consumption of moderate amount of wine and prevention of certain chronic pathologies, such as neurodegenerative diseases. This study was aimed to investigate the possible neuroprotective role of a polyphenolic white grape juice extract (WGJe) in an experimental mice model of autoimmune encephalomyelitis (EAE), the most commonly used model for multiple sclerosis (MS) in vivo. EAE mimics the main features of MS, including paralysis, weight loss, demyelination, central nervous system (CNS) inflammation and blood-brain barrier (BBB) breakdown. Our study demonstrated that oral administration of WGJe (20 and 40 mg/kg/day) may exert neuroprotective effects against MS, diminishing both clinical signs and histological score typical of disease (lymphocytic infiltration and demyelination). In particular, by western blot, histological evaluations and immunolocalization of the main markers of inflammation, oxidative stress and apoptosis (TNF-α, iNOS, Nitrotyrosine, PARP, Foxp3, Bcl-2, Caspase 3 and DNA fragmentation), we documented that WGJe counteracts the alteration of all these inflammatory and oxidative pathway, without any apparent sign of toxicity. On these bases, we propose this natural product as putative novel helpful tools for the prevention of autoimmune and neurodegenerative diseases such as MS. WGJe could have considerable implication for future therapies of MS, and this study may represents the starting point for further investigation on the role of WGJe in neuroinflammation.
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Affiliation(s)
- Sabrina Giacoppo
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Maria Galuppo
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Giovanni Enrico Lombardo
- Università degli Studi di Messina, Dipartimento di Scienze del farmaco e dei Prodotti per la Salute, Viale Annunziata, 98168, Messina, Italy
| | - Maria Malgorzata Ulaszewska
- Fondazione Edmund Mach, Centro Ricerca e Innovazione, Dipartimento Qualità Alimentare e Nutrizione, Via E. Mach 1, 38010 - San Michele all'Adige, Trento, Italy
| | - Fulvio Mattivi
- Fondazione Edmund Mach, Centro Ricerca e Innovazione, Dipartimento Qualità Alimentare e Nutrizione, Via E. Mach 1, 38010 - San Michele all'Adige, Trento, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, contrada Casazza, 98124, Messina, Italy.
| | - Michele Navarra
- Università degli Studi di Messina, Dipartimento di Scienze del farmaco e dei Prodotti per la Salute, Viale Annunziata, 98168, Messina, Italy
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Oxidative tissue injury in multiple sclerosis is only partly reflected in experimental disease models. Acta Neuropathol 2014; 128:247-66. [PMID: 24622774 PMCID: PMC4102830 DOI: 10.1007/s00401-014-1263-5] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 01/22/2014] [Accepted: 02/17/2014] [Indexed: 12/22/2022]
Abstract
Recent data suggest that oxidative injury may play an important role in demyelination and neurodegeneration in multiple sclerosis (MS). We compared the extent of oxidative injury in MS lesions with that in experimental models driven by different inflammatory mechanisms. It was only in a model of coronavirus-induced demyelinating encephalomyelitis that we detected an accumulation of oxidised phospholipids, which was comparable in extent to that in MS. In both, MS and coronavirus-induced encephalomyelitis, this was associated with massive microglial and macrophage activation, accompanied by the expression of the NADPH oxidase subunit p22phox but only sparse expression of inducible nitric oxide synthase (iNOS). Acute and chronic CD4+ T cell-mediated experimental autoimmune encephalomyelitis lesions showed transient expression of p22phox and iNOS associated with inflammation. Macrophages in chronic lesions of antibody-mediated demyelinating encephalomyelitis showed lysosomal activity but very little p22phox or iNOS expressions. Active inflammatory demyelinating lesions induced by CD8+ T cells or by innate immunity showed macrophage and microglial activation together with the expression of p22phox, but low or absent iNOS reactivity. We corroborated the differences between acute CD4+ T cell-mediated experimental autoimmune encephalomyelitis and acute MS lesions via gene expression studies. Furthermore, age-dependent iron accumulation and lesion-associated iron liberation, as occurring in the human brain, were only minor in rodent brains. Our study shows that oxidative injury and its triggering mechanisms diverge in different models of rodent central nervous system inflammation. The amplification of oxidative injury, which has been suggested in MS, is only reflected to a limited degree in the studied rodent models.
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Petković F, Blaževski J, Momčilović M, Mostarica Stojkovic M, Miljković D. Nitric oxide inhibits CXCL12 expression in neuroinflammation. Immunol Cell Biol 2013; 91:427-34. [PMID: 23732617 DOI: 10.1038/icb.2013.23] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 05/07/2013] [Accepted: 05/08/2013] [Indexed: 02/07/2023]
Abstract
Chemokine CXCL12 (C-X-C motif chemokine ligand 12) restricts immune cell invasion of the central nervous system (CNS) and limits neuroinflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of inflammatory and demyelinating disease of the CNS, multiple sclerosis (MS). Nitric oxide (NO), by contrast, predominantly contributes to CNS tissue destruction in MS and EAE. Thus, the influence of NO on CXCL12 in the inflamed CNS was investigated. Excess expression of inducible NO synthase was inversely correlated to CXCL12 gene expression in spinal cord homogenates of rats immunized to develop EAE. NO inhibited gene expression of CXCL12 in astrocytes and endothelial cells in vitro. The inhibition was paralleled with reduction of p38 mitogen-activated protein kinase (MAPK) phosphorylation and it was mimicked with inhibitors of p38 MAPK activation in astrocytes. In vivo suppression of nitric generation recovered CXCL12 expression in the CNS and attenuated EAE in Dark Agouti rats. On the contrary, in vivo NO donation decreased CXCL12 expression in the CNS of EAE-resistant Albino Oxford (AO) rats. However, the effect was not paralleled with induction of EAE in AO rats. It is suggested that NO acting through suppression of p38 MAPK inhibits CXCL12 expression in neuroinflammation. These results imply that downregulation of NO release and protection of CXCL12 expression within the CNS might present the potential approaches in MS therapy.
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Affiliation(s)
- Filip Petković
- Department of Immunology, Institute for Biological Research, Siniša Stanković, University of Belgrade, Belgrade, Serbia
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Ashtari F, Bahar M, Aghaei M, Zahed A. Serum uric acid level in patients with relapsing-remitting multiple sclerosis. J Clin Neurosci 2013; 20:676-8. [PMID: 23528410 DOI: 10.1016/j.jocn.2012.05.054] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Revised: 05/09/2012] [Accepted: 05/16/2012] [Indexed: 10/27/2022]
Abstract
Uric acid (UA) is a hydrophilic antioxidant product associated with multiple sclerosis (MS). We conducted a randomized case-control study to evaluate the serum level of UA in different phases of MS in comparison with levels in a healthy control population. Serum UA was checked in 130 patients with relapsing-remitting MS (85 patients in remitting and 45 patients in relapsing phase) and 50 age-matched controls using a quantitative enzyme-linked immunosorbent assay (ELISA). The mean concentrations of UA in serum was 6.41(±3.18)mg/dL in patients with remitting MS, 4.76(±1.66)mg/dL in patients with relapsing MS and 6.33(±2.94)mg/dL in controls. There was a significant difference between mean UA concentration in relapsing MS and remitting MS (p<0.001), and between patients with relapsing MS and controls (p=0.002); however, the difference between levels for patients in the remitting phase of MS and the control group was not significant (p=0.87). It seems probable that UA has a role in the prevention of disease activity in MS.
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Affiliation(s)
- Fereshteh Ashtari
- Department of Neurology, Isfahan University of Medical Sciences, Isfahan Neuroscience Research Center, Isfahan, Iran
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Ljubisavljevic S, Stojanovic I, Vojinovic S, Stojanov D, Stojanovic S, Cvetkovic T, Savic D, Pavlovic D. The patients with clinically isolated syndrome and relapsing remitting multiple sclerosis show different levels of advanced protein oxidation products and total thiol content in plasma and CSF. Neurochem Int 2013; 62:988-97. [PMID: 23500606 DOI: 10.1016/j.neuint.2013.02.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 02/01/2013] [Accepted: 02/28/2013] [Indexed: 01/16/2023]
Abstract
Advanced oxidation protein products (AOPP) and total thiol (SH) groups levels in plasma and CSF were studied in a cohort of 50 clinically isolated syndrome (CIS) and 57 relapsing remittent multiple sclerosis (RRMS) patients related to 20 control group (CG) patients' values. The obtained results were compared regarding patients demographic, biochemical, clinical (EDSS) and MRI features (total T2 weighted lesions number and Gd enhancement lesion volume). Plasma and CSF AOPP levels in CIS and RRMS patients were higher than those in CG, while SH groups showed lower values compared to CG (p<0.05). Both parameters were higher in CIS than in RRMS patients (p<0.05). Related to EDSS median range, all patients were divided into those with slight or mild and those with severe clinical presentation. AOPP and SH group changes were more pronounced in both, CIS and RRMS patients with higher, compared to those with lower EDSS (p<0.05). AOPP, SH group levels and EDSS positive correlations were observed in both study groups (p<0.01). Both parameters showed the same approach regarding the median range of total T2 weighted lesions and Gd enhancement lesion volume mean values (p<0.05), but no correlation was found between AOPP and SH levels and these patients radiological characteristics (p>0.01). The data support the fact that oxidative stress is always involved in CIS and RRMS pathophysiology, but not always as a disease determinant dependent on its intensity, which might be important for new therapeutic strategies based on antioxidant approach in those patients.
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Affiliation(s)
- Srdjan Ljubisavljevic
- Clinic of Neurology, Clinical Center Nis, Bul. Dr Zorana Djindjica 48, 18000 Nis, Serbia.
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Betulinic acid regulates generation of neuroinflammatory mediators responsible for tissue destruction in multiple sclerosis in vitro. Acta Pharmacol Sin 2013; 34:424-31. [PMID: 23377550 DOI: 10.1038/aps.2012.181] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIM To investigate the influences of betulinic acid (BA), a triterpenoid isolated from birch bark, on neuroinflammatory mediators involved in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis in vitro. METHODS Encephalitogenic T cells were prepared from draining lymph nodes and spinal cords of Dark Agouti rats 8 to 10 d after immunization with myelin basic protein (MBP) and complete Freund's adjuvant. Macrophages were isolated from the peritoneal cavity of adult untreated rats. Astrocytes were isolated from neonatal rat brains. The cells were cultured and then treated with different agents. IFN-γ, IL-17, iNOS and CXCL12 mRNA levels in the cells were analyzed with RT-PCR. iNOS and CXCL12 protein levels were detected using immunoblot. NO and ROS generation was measured using Griess reaction and flow cytometry, respectively. RESULTS In encephalitogenic T cells stimulated with MBP (10 μg/mL), addition of BA inhibited IL-17 and IFN-γ production in a dose-dependent manner. The estimated IC(50) values for IL-17 and IFN γ were 11.2 and 63.8 μmol/L, respectively. When the macrophages were stimulated with LPS (10 ng/mL), addition of BA (50 μmol/L) significantly increased ROS generation, and suppressed NO generation. The astrocytes were stimulated with ConASn containing numerous inflammatory mediators, which mimicked the inflammatory milieu within CNS; addition of BA (50 μmol/L) significantly increased ROS generation, and blocked ConASn-induced increases in iNOS and CXCL12 mRNA levels, but did not affect iNOS and CXCL12 protein levels. Importantly, in both the macrophages and astrocytes, addition of BA (50 μmol/L) inhibited lipid peroxidation. CONCLUSION Besides inhibiting encephalitogenic T cell cytokines and reducing NO generation, BA induces tissue-damaging ROS generation within CNS.
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Brosnan CF, Raine CS. The astrocyte in multiple sclerosis revisited. Glia 2013; 61:453-65. [DOI: 10.1002/glia.22443] [Citation(s) in RCA: 172] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Accepted: 10/02/2012] [Indexed: 12/18/2022]
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Timotijević G, Mostarica Stojković M, Miljković D. CXCL12: Role in neuroinflammation. Int J Biochem Cell Biol 2012; 44:838-41. [DOI: 10.1016/j.biocel.2012.03.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Revised: 03/14/2012] [Accepted: 03/22/2012] [Indexed: 01/20/2023]
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Colombo E, Cordiglieri C, Melli G, Newcombe J, Krumbholz M, Parada LF, Medico E, Hohlfeld R, Meinl E, Farina C. Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. ACTA ACUST UNITED AC 2012; 209:521-35. [PMID: 22393127 PMCID: PMC3302220 DOI: 10.1084/jem.20110698] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Neurotrophin growth factors support neuronal survival and function. In this study, we show that the expression of the neurotrophin receptor TrkB is induced on astrocytes in white matter lesions in multiple sclerosis (MS) patients and mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice lacking TrkB specifically in astrocytes were protected from EAE-induced neurodegeneration. In an in vitro assay, astrocytes stimulated with the TrkB agonist brain-derived neurotrophic factor (BDNF) released nitric oxide (NO), and conditioned medium from activated astrocytes had detrimental effects on the morphology and survival of neurons. This neurodegenerative process was amplified by NO produced by neurons. NO synthesis in the central nervous system during EAE depended on astrocyte TrkB. Together, these findings suggest that TrkB expression on astrocytes may represent a new target for neuroprotective therapies in MS.
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Affiliation(s)
- Emanuela Colombo
- Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy
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Acs P, Kalman B. Pathogenesis of multiple sclerosis: what can we learn from the cuprizone model. Methods Mol Biol 2012; 900:403-431. [PMID: 22933081 DOI: 10.1007/978-1-60761-720-4_20] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Multiple sclerosis is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS). The primary cause of the disease remains unknown, but an altered immune regulation with features of autoimmunity has generally been considered to play a critical role in the pathogenesis. Historically, lesion development has been attributed to activation of CD4 and CD8 T lymphocytes, B lymphocytes, and monocytes in the peripheral circulation and the migration of these cells through the blood-brain barrier to exert direct or indirect cytotoxic effects on myelin, oligodendrocytes and neuronal processes in the CNS. This broadly accepted concept was significantly influenced by the experimental autoimmune encephalitis (EAE) model, in which either immunization with myelin antigens or injection of a myelin antigen-specific T cell line into a recipient results in inflammatory demyelination in the CNS. More recent studies reveal that the loss of oligodendrocytes and neurons begins in the earliest stages of the disease and may not always be associated with blood-derived inflammatory cells. The pathology affects both the white and the gray matters and the clinical disability best correlates with the overall neurodegenerative process. These newer observations prompted several revisions of the classical concept of MS and facilitated a shift from using EAE to using other model systems. This chapter summarizes the classical and more contemporary concepts of MS, and provides methodologies for employing the cuprizone model for further explorations of the pathogenesis and treatment of the disease.
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Affiliation(s)
- Peter Acs
- Department of Neurology, SUNY Upstate Medical University, VA Medical Center, Syracuse, NY, USA
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Loss of CD4 T-cell-dependent tolerance to proteins with modified amino acids. Proc Natl Acad Sci U S A 2011; 108:12821-6. [PMID: 21768354 DOI: 10.1073/pnas.1110042108] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The site-specific incorporation of the unnatural amino acid p-nitrophenylalanine (pNO(2)Phe) into autologous proteins overcomes self-tolerance and induces a long-lasting polyclonal IgG antibody response. To determine the molecular mechanism by which such simple modifications to amino acids are able to induce autoantibodies, we incorporated pNO(2)Phe, sulfotyrosine (SO(3)Tyr), and 3-nitrotyrosine (3NO(2)Tyr) at specific sites in murine TNF-α and EGF. A subset of TNF-α and EGF mutants with these nitrated or sulfated residues is highly immunogenic and induces antibodies against the unaltered native protein. Analysis of the immune response to the TNF-α mutants in different strains of mice that are congenic for the H-2 locus indicates that CD4 T-cell recognition is necessary for autoantibody production. IFN-γ ELISPOT analysis of CD4 T cells isolated from vaccinated mice demonstrates that peptides with mutated residues, but not the wild-type residues, are recognized. Immunization of these peptides revealed that a CD4 repertoire exists for the mutated peptides but is lacking for the wild-type peptides and that the mutated residues are processed, loaded, and presented on the I-A(b) molecule. Overall, our results illustrate that, although autoantibodies are generated against the endogenous protein, CD4 cells are activated through a neo-epitope recognition mechanism. Therefore, tolerance is maintained at a CD4 level but is broken at the level of antibody production. Finally, these results suggest that naturally occurring posttranslational modifications such as nitration may play a role in antibody-mediated autoimmune disorders.
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Miljković D, Momčilović M, Stanojević Ž, Rašić D, Mostarica-Stojković M. It is still not for the old iron: adjuvant effects of carbonyl iron in experimental autoimmune encephalomyelitis induction. J Neurochem 2011; 118:205-14. [DOI: 10.1111/j.1471-4159.2011.07303.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Li S, Vana AC, Ribeiro R, Zhang Y. Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis. Neuroscience 2011; 184:107-19. [PMID: 21511012 DOI: 10.1016/j.neuroscience.2011.04.007] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2010] [Revised: 03/19/2011] [Accepted: 04/05/2011] [Indexed: 01/24/2023]
Abstract
Nitric oxide has been implicated in the pathogenesis of multiple sclerosis. However, it is still unclear whether nitric oxide plays a protective role or is deleterious. We have previously shown that peroxynitrite, a reaction product of nitric oxide and superoxide, is toxic to mature oligodendrocytes (OLs). The toxicity is mediated by intracellular zinc release, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), activation of 12-lipoxygenase (12-LOX) and the formation of reactive oxygen species (ROS). In this study, we found that the donors of nitric oxide, dipropylenetriamine NONOate (DPT NONOate) and diethylenetriamine NONOate (DETA NONOate), protected OLs from peroxynitrite or zinc-induced toxicity. The protective mechanisms appear to be attributable to their inhibition of peroxynitrite- or zinc-induced ERK1/2 phosphorylation and 12-LOX activation. In cultures of mature OLs exposed to lipopolysaccharide (LPS), induction of inducible nitric oxide synthase (iNOS) generated nitric oxide and rendered OLs resistant to peroxynitrite-induced toxicity. The protection was eliminated when 1400W, a specific inhibitor of iNOS, was co-applied with LPS. Using MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we found that nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was increased in the spinal cord white matter, which correlated with the loss of mature OLs. Targeted gene deletion of the NADPH oxidase component gp91phox reduced clinical scores, the formation of nitrotyrosine and the loss of mature OLs. These results suggest that blocking the formation specifically of peroxynitrite, rather than nitric oxide, may be a protective strategy against oxidative stress induced toxicity to OLs.
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Affiliation(s)
- S Li
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Science, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
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Miljković D, Timotijević G, Stojković MM. Astrocytes in the tempest of multiple sclerosis. FEBS Lett 2011; 585:3781-8. [DOI: 10.1016/j.febslet.2011.03.047] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2011] [Revised: 03/21/2011] [Accepted: 03/23/2011] [Indexed: 12/11/2022]
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Inflammation induced neurological handicap processes in multiple sclerosis: new insights from preclinical studies. J Neural Transm (Vienna) 2010; 117:907-17. [PMID: 20571836 DOI: 10.1007/s00702-010-0432-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Accepted: 05/26/2010] [Indexed: 12/28/2022]
Abstract
Multiple sclerosis (MS) is described as originating from incompletely explained neuroinflammatory processes, dysfunction of neuronal repair mechanisms and chronicity of inflammation events. Blood-borne immune cell infiltration and microglia activation are causing both neuronal destruction and myelin loss, which are responsible for progressive motor deficiencies, organic and cognitive dysfunctions. MRI as a non-invasive imaging method offers various ways to visualise de- and remyelination, neuronal loss, leukocyte infiltration, blood-brain barrier modification and new sensors are emerging to detect inflammatory lesions at an early stage. We describe studies performed on experimental autoimmune encephalomyelitis (EAE) animal models of MS that shed new light on mechanisms of functional impairments to understand the neurological handicap in MS. We focus on examples of neuroinflammation-mediated inhibition of CNS repair involving adult neurogenesis in the sub-ventricular zone and hippocampus and such experimentally observed inhibitions could reflect deficient plasticity and activation of compensatory mechanisms in MS. In parallel with cognitive decline, organic deficits such as bladder dysfunction are described in most of MS patients. Neuropharmacological interventions, electrical stimulation of nerves, MRI and histopathology follow-up studies helped in understanding the operating events to remodel the neurological networks and to compensate the inflammatory lesions both in spinal cord and in cortical regions. At the molecular level, the local production of reactive products is a well-described phenomenon: oxidative species disturb cellular physiology and generate new molecular epitopes that could further promote immune reactions. The translational research from EAE animal models to MS patient cohorts helps in understanding the mechanisms of the neurological handicap and in development of new therapeutic concepts in MS.
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Trujillo M, Alvarez B, Souza JM, Romero N, Castro L, Thomson L, Radi R. Mechanisms and Biological Consequences of Peroxynitrite-Dependent Protein Oxidation and Nitration. Nitric Oxide 2010. [DOI: 10.1016/b978-0-12-373866-0.00003-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Wu M, Tsirka SE. Endothelial NOS-deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis. Glia 2009; 57:1204-15. [PMID: 19170181 DOI: 10.1002/glia.20842] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Multiple sclerosis (MS) is a demyelinating autoimmune disease characterized by infiltration of T cells into the central nervous system (CNS) after compromise of the blood-brain barrier. A model used to mimic the disease in mice is experimental autoimmune encephalomyelitis (EAE). In this report, we examine the clinical and histopathological course of EAE in eNOS-deficient (eNOS-/-) mice to determine the role of nitric oxide (NO) derived from this enzyme in the disease progression. We find that eNOS-/- mice exhibit a delayed onset of EAE that correlates with delayed BBB breakdown, thus suggesting that NO production by eNOS underlies the T cell infiltration into the CNS. However, the eNOS-/- mice also eventually exhibit more severe EAE and delayed recovery, indicating that NO undertakes dual roles in MS/EAE, one proinflammatory that triggers disease onset, and the other neuroprotective that promotes recovery from disease exacerbation events.
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Affiliation(s)
- Muzhou Wu
- Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794-8651, USA
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Kanabrocki EL, Ryan MD, Hermida RC, Ayala DE, Scott GS, Murray D, Bremner WF, Third JLHC, Johnson MC, Foley S, Van Cauteren J, Shah F, Shirazi P, Nemchausky BA, Hooper DC. Altered Circadian Relationship Between Serum Nitric Oxide, Carbon Dioxide, and Uric Acid in Multiple Sclerosis. Chronobiol Int 2009; 21:739-58. [PMID: 15470965 DOI: 10.1081/cbi-200025981] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The free radical nitric oxide (NO*) is involved in a variety of diverse biological processes from acting as a vasodilator in the cardiovascular system to being the rate-limiting component in the production of peroxynitrite (ONOO-), a contributor to neurodegenerative disorders such as multiple sclerosis (MS). Uric acid (UA), the end product of purine metabolism in humans and a selective inhibitor of toxic reactions attributed to radicals formed by the interaction of ONOO- and CO2, is generally low in MS patients. We investigated the relationship between serum ONOO-, CO2, and UA in MS patients and normal controls by comparing the circadian characteristics of the NO* metabolites nitrite/ nitrate (NO), CO2, and UA. In this preliminary study, we found the functional relationship ascribed to the circadian timing of the peak and trough levels of NO, CO2, and UA in healthy subjects to be clearly altered in MS patients. These findings suggest that alterations in the temporal relationship between the 24h pattern in serum ONOO- formation and UA may either contribute to or reflect the disease processes in MS.
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Affiliation(s)
- E L Kanabrocki
- VA Hospital, Nuclear Medicine Service 115, Hines, Illinois 60141, USA.
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Bolton C, Wood EG, Scott GS, Flower RJ. A comparative evaluation of the response to peroxynitrite by a brain endothelial cell line and control of the effects by drug targeting. Cell Mol Neurobiol 2009; 29:707-17. [PMID: 19330446 PMCID: PMC11506105 DOI: 10.1007/s10571-009-9391-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Accepted: 03/09/2009] [Indexed: 01/29/2023]
Abstract
The potent oxidant peroxynitrite (ONOO(-)) is formed after the combination of nitric oxide with superoxide and has been closely associated with the pathology of inflammatory disease. In particular, the generation of ONOO(-) has been linked to central nervous system disorders including Alzheimer's and Parkinson's disease, multiple sclerosis and bacterial and viral meningitis. Specifically, ONOO(-) has been implicated in the loss of blood-brain barrier (BBB) integrity during neuroinflammation, but the precise mechanisms through which the molecule acts to mediate neurovascular breakdown have not been established. The disruptive effects of ONOO(-) could be mediated by either direct or indirect actions on the endothelial cells that comprise the major component of the BBB. The current study has comparatively assessed the direct toxic effects of ONOO(-) on the brain endothelial cell line, b.End3 and C6 astrocytoma and NA neuroblastoma preparations. b.End3 cells were relatively resistant to ONOO(-)-induced cell death compared with C6 and NA cultures. The indirect involvement of ONOO(-) in neuroendothelial disruption was pharmacologically determined via adhesion molecule expression and immunocompetent cell attachment to b.End3 cells. ONOO(-)-targeted drugs, including the selective free radical scavenger, uric acid, the decomposition catalyst 5,10,15,20-tetrakis (4-sulphonatophenyl) porphyrinatoiron (III) (FeTPPS) and the poly(ADP-ribose) polymerase inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride (PJ34) revealed that ONOO(-) was only partly involved in E-selectin, ICAM-1 and VCAM-1 expression on b.End3 cells and also cytokine-induced T-lymphocyte attachment to the cell line. The results indicate that ONOO(-) contributes to b.End3 cell disruption but is not exclusively responsible for the breakdown of neuroendothelial function.
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Affiliation(s)
- Christopher Bolton
- Centre for Biochemical Pharmacology, The William Harvey Research Institute, St. Bartholomew's Hospital Medical College and the London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK.
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Mirshafiey A, Mohsenzadegan M. Antioxidant therapy in multiple sclerosis. Immunopharmacol Immunotoxicol 2009; 31:13-29. [PMID: 18763202 DOI: 10.1080/08923970802331943] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Reactive oxygen species (ROS) play an important role in various events underlying multiple sclerosis pathology. In the initial phase of lesion formation, ROS are known to mediate the transendothelial migration of monocytes and induce a dysfunction in the blood-brain barrier. Although the pathogenesis of MS is not completely understood, various studies suggest that reactive oxygen species contribute to the formation and persistence of multiple sclerosis lesions by acting on distinct pathological processes. The detrimental effects of ROS in the central nervous system are endowed with a protective mechanism consisting of enzymatic and non-enzymatic antioxidant. Antioxidant therapy may therefore represent an attractive treatment of MS. Several studies have shown that antioxidant therapy is beneficial in vitro and in vivo in animal models for MS. Since oxidative damage has been known to be involved in inflammatory and autoimmune-mediated tissue destruction in which, modulation of oxygen free radical production represents a new approach to the treatment of inflammatory and autoimmune diseases. Several experimental studies have been performed to see whether dietary intake of several antioxidants can prevent and or reduce the progression of EAE or not. Although a few antioxidants showed some efficacy in these studies, little information is available on the effect of treatments with such compounds in patients with MS. In this review, our aim is to clarify the therapeutic efficacy of antioxidants in MS disease.
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Affiliation(s)
- Abbas Mirshafiey
- Department of Immunology, Tehran University of Medical Sciences, Iran.
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