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Castorina A, Scheller J, Keay KA, Marzagalli R, Rose-John S, Campbell IL. Increased Expression of the Neuropeptides PACAP/VIP in the Brain of Mice with CNS Targeted Production of IL-6 Is Mediated in Part by Trans-Signalling. Int J Mol Sci 2024; 25:9453. [PMID: 39273398 PMCID: PMC11395455 DOI: 10.3390/ijms25179453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Inflammation with expression of interleukin 6 (IL-6) in the central nervous system (CNS) occurs in several neurodegenerative/neuroinflammatory conditions and may cause neurochemical changes to endogenous neuroprotective systems. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are two neuropeptides with well-established protective and anti-inflammatory properties. Yet, whether PACAP and VIP levels are altered in mice with CNS-restricted, astrocyte-targeted production of IL-6 (GFAP-IL6) remains unknown. In this study, PACAP/VIP levels were assessed in the brain of GFAP-IL6 mice. In addition, we utilised bi-genic GFAP-IL6 mice carrying the human sgp130-Fc transgene (termed GFAP-IL6/sgp130Fc mice) to determine whether trans-signalling inhibition rescued PACAP/VIP changes in the CNS. Transcripts and protein levels of PACAP and VIP, as well as their receptors PAC1, VPAC1 and VPAC2, were significantly increased in the cerebrum and cerebellum of GFAP-IL6 mice vs. wild type (WT) littermates. These results were paralleled by a robust activation of the JAK/STAT3, NF-κB and ERK1/2MAPK pathways in GFAP-IL6 mice. In contrast, co-expression of sgp130Fc in GFAP-IL6/sgp130Fc mice reduced VIP expression and activation of STAT3 and NF-κB pathways, but it failed to rescue PACAP, PACAP/VIP receptors and Erk1/2MAPK phosphorylation. We conclude that forced expression of IL-6 in astrocytes induces the activation of the PACAP/VIP neuropeptide system in the brain, which is only partly modulated upon IL-6 trans-signalling inhibition. Increased expression of PACAP/VIP neuropeptides and receptors may represent a homeostatic response of the CNS to an uncontrolled IL-6 synthesis and its neuroinflammatory consequences.
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Affiliation(s)
- Alessandro Castorina
- Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Jurgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany;
| | - Kevin A. Keay
- Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia;
| | - Rubina Marzagalli
- Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Stefan Rose-John
- Institute of Biochemistry, Medical Faculty, Christian Albrechts University, 24098 Kiel, Germany;
| | - Iain L. Campbell
- School of Molecular Bioscience, University of Sydney, Sydney, NSW 2006, Australia;
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Li R, Ye JJ, Gan L, Zhang M, Sun D, Li Y, Wang T, Chang P. Traumatic inflammatory response: pathophysiological role and clinical value of cytokines. Eur J Trauma Emerg Surg 2024; 50:1313-1330. [PMID: 38151578 PMCID: PMC11458723 DOI: 10.1007/s00068-023-02388-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 10/23/2023] [Indexed: 12/29/2023]
Abstract
Severe trauma is an intractable problem in healthcare. Patients have a widespread immune system response that is complex and vital to survival. Excessive inflammatory response is the main cause of poor prognosis and poor therapeutic effect of medications in trauma patients. Cytokines are signaling proteins that play critical roles in the body's response to injuries, which could amplify or suppress immune responses. Studies have demonstrated that cytokines are closely related to the severity of injuries and prognosis of trauma patients and help present cytokine-based diagnosis and treatment plans for trauma patients. In this review, we introduce the pathophysiological mechanisms of a traumatic inflammatory response and the role of cytokines in trauma patients. Furthermore, we discuss the potential of cytokine-based diagnosis and therapy for post-traumatic inflammatory response, although further clarification to elucidate the underlying mechanisms of cytokines following trauma is warranted.
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Affiliation(s)
- Rui Li
- Trauma Medicine Center, Peking University People's Hospital, Beijing, 100044, People's Republic of China
- Key Laboratory of Trauma and Neural Regeneration (Peking University) Ministry of Education, Beijing, 100044, People's Republic of China
- National Center for Trauma Medicine of China, Beijing, 100044, People's Republic of China
| | - Jing Jing Ye
- Trauma Medicine Center, Peking University People's Hospital, Beijing, 100044, People's Republic of China
- Key Laboratory of Trauma and Neural Regeneration (Peking University) Ministry of Education, Beijing, 100044, People's Republic of China
- National Center for Trauma Medicine of China, Beijing, 100044, People's Republic of China
| | - Lebin Gan
- Trauma Medicine Center, Peking University People's Hospital, Beijing, 100044, People's Republic of China
- Key Laboratory of Trauma and Neural Regeneration (Peking University) Ministry of Education, Beijing, 100044, People's Republic of China
- National Center for Trauma Medicine of China, Beijing, 100044, People's Republic of China
| | - Mengwei Zhang
- Trauma Medicine Center, Peking University People's Hospital, Beijing, 100044, People's Republic of China
- Key Laboratory of Trauma and Neural Regeneration (Peking University) Ministry of Education, Beijing, 100044, People's Republic of China
- National Center for Trauma Medicine of China, Beijing, 100044, People's Republic of China
| | - Diya Sun
- Trauma Medicine Center, Peking University People's Hospital, Beijing, 100044, People's Republic of China
- Key Laboratory of Trauma and Neural Regeneration (Peking University) Ministry of Education, Beijing, 100044, People's Republic of China
- National Center for Trauma Medicine of China, Beijing, 100044, People's Republic of China
| | - Yongzheng Li
- Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, People's Republic of China.
| | - Tianbing Wang
- Trauma Medicine Center, Peking University People's Hospital, Beijing, 100044, People's Republic of China.
- Key Laboratory of Trauma and Neural Regeneration (Peking University) Ministry of Education, Beijing, 100044, People's Republic of China.
- National Center for Trauma Medicine of China, Beijing, 100044, People's Republic of China.
| | - Panpan Chang
- Trauma Medicine Center, Peking University People's Hospital, Beijing, 100044, People's Republic of China.
- Key Laboratory of Trauma and Neural Regeneration (Peking University) Ministry of Education, Beijing, 100044, People's Republic of China.
- National Center for Trauma Medicine of China, Beijing, 100044, People's Republic of China.
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Goksu AY, Kocanci FG, Akinci E, Demir-Dora D, Erendor F, Sanlioglu S, Uysal H. Microglia cells treated with synthetic vasoactive intestinal peptide or transduced with LentiVIP protect neuronal cells against degeneration. Eur J Neurosci 2024; 59:1993-2015. [PMID: 38382910 DOI: 10.1111/ejn.16273] [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: 10/06/2023] [Revised: 01/11/2024] [Accepted: 01/18/2024] [Indexed: 02/23/2024]
Abstract
A common pathological hallmark of neurodegenerative disorders is neuronal cell death, accompanied by neuroinflammation and oxidative stress. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. The gene therapy field shows long-term promise for treating a wide range of neurodegenerative diseases (ND). In this study, we aimed to investigate the in vitro efficacy of transduction of microglia using lentiviral gene therapy vectors encoding VIP (LentiVIP). Additionally, we tested the protective effects of the secretome derived from LentiVIP-infected "immortalized human" microglia HMC3 cells, and cells treated with Synthetic VIP (SynVIP), against toxin-induced neurodegeneration. First, LentiVIP, which stably expresses VIP, was generated and purified. VIP secretion in microglial conditioned media (MG CM) for LentiVIP-infected HMC3 microglia cells was confirmed. Microglia cells were activated with lipopolysaccharide, and groups were formed as follows: 1) Control, 2) SynVIP-treated, or 3) LentiVIP-transduced. These MG CM were applied on an in vitro neurodegenerative model formed by differentiated (d)-SH-SY5Y cells. Then, cell survival analysis and apoptotic nuclear staining, besides measurement of oxidative/inflammatory parameters in CM of cells were performed. Activated MG CM reduced survival rates of both control and toxin-applied (d)-SH-SY5Y cells, whereas LentiVIP-infected MG CM and SynVIP-treated ones exhibited better survival rates. These findings were supported by apoptotic nuclear evaluations of (d)-SH-SY5Y cells, alongside oxidative/inflammatory parameters in their CM. LentiVIP seems worthy of further studies for the treatment of ND because of the potential of gene therapy to treat diseases effectively with a single injection.
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Affiliation(s)
- Azize Yasemin Goksu
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Fatma Gonca Kocanci
- Department of Medical Laboratory Techniques, Vocational High School of Health Services, Alanya Alaaddin Keykubat University, Alanya/Antalya, Turkey
| | - Ersin Akinci
- Brigham and Women's Hospital, Division of Genetics, Harvard Medical School, Boston, MA, USA
- Department of Biotechnology, Faculty of Agriculture, Akdeniz University, Antalya, Turkey
| | - Devrim Demir-Dora
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya, Turkey
- Department of Medical Pharmacology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Fulya Erendor
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya, Turkey
- Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Salih Sanlioglu
- Department of Gene and Cell Therapy, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Hilmi Uysal
- Department of Neurology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
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Jansen MI, Thomas Broome S, Castorina A. Exploring the Pro-Phagocytic and Anti-Inflammatory Functions of PACAP and VIP in Microglia: Implications for Multiple Sclerosis. Int J Mol Sci 2022; 23:ijms23094788. [PMID: 35563181 PMCID: PMC9104531 DOI: 10.3390/ijms23094788] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 02/04/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic neuroinflammatory and demyelinating disease of the central nervous system (CNS), characterised by the infiltration of peripheral immune cells, multifocal white-matter lesions, and neurodegeneration. In recent years, microglia have emerged as key contributors to MS pathology, acting as scavengers of toxic myelin/cell debris and modulating the inflammatory microenvironment to promote myelin repair. In this review, we explore the role of two neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), as important regulators of microglial functioning during demyelination, myelin phagocytosis, and remyelination, emphasising the potential of these neuropeptides as therapeutic targets for the treatment of MS.
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Sunkaria A, Bhardwaj S. Sleep Disturbance and Alzheimer's Disease: The Glial Connection. Neurochem Res 2022; 47:1799-1815. [PMID: 35303225 DOI: 10.1007/s11064-022-03578-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/27/2022] [Accepted: 03/09/2022] [Indexed: 12/28/2022]
Abstract
Poor quality and quantity of sleep are very common in elderly people throughout the world. Growing evidence has suggested that sleep disturbances could accelerate the process of neurodegeneration. Recent reports have shown a positive correlation between sleep deprivation and amyloid-β (Aβ)/tau aggregation in the brain of Alzheimer's patients. Glial cells have long been implicated in the progression of Alzheimer's disease (AD) and recent findings have also suggested their role in regulating sleep homeostasis. However, how glial cells control the sleep-wake balance and exactly how disturbed sleep may act as a trigger for Alzheimer's or other neurological disorders have recently gotten attention. In an attempt to connect the dots, the present review has highlighted the role of glia-derived sleep regulatory molecules in AD pathogenesis. Role of glia in sleep disturbance and Alzheimer's progression.
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Affiliation(s)
- Aditya Sunkaria
- Department of Biotechnology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
| | - Supriya Bhardwaj
- Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
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6
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VIP alleviates sepsis-induced cognitive dysfunction as the TLR-4/NF-κB signaling pathway is inhibited in the hippocampus of rats. J Mol Histol 2022; 53:369-377. [PMID: 35239068 DOI: 10.1007/s10735-022-10068-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/29/2021] [Indexed: 01/17/2023]
Abstract
Cognitive dysfunction caused by sepsis-associated encephalopathy (SAE) is still poorly understood. It is reported that vasoactive intestinal peptide (VIP) exerts its anti-inflammatory effects in multiple diseases, while its biological function in SAE remains unclear. We aimed to figure out whether VIP has influence on sepsis-induced neuroinflammation and cognitive dysfunction. To induce sepsis, rats were subjected to cecal ligation and puncture (CLP) operation. Morris water maze test and fear conditioning test were conducted to reveal cognitive dysfunctions. TUNEL assay was performed to evaluate apoptosis. We found out that the expression of VIP was downregulated in the hippocampus of septic rats. VIP was verified to attenuate sepsis-induced memory impairment following CLP. Additionally, we examined apoptosis and inflammation in rats' hippocampus. It is worth noting that VIP inhibited the apoptosis in the hippocampus and reduced the productions of proinflammatory cytokines TNF-α, IL-6 and IL-1β. Furthermore, our data confirmed that VIP was involved in regulating the TLR-4/NF-κB signaling. In conclusion, VIP inhibited neuroinflammation and cognitive impairment in hippocampus of septic rats through the TLR-4/NF-κB signaling pathway.
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7
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Karunia J, Niaz A, Mandwie M, Thomas Broome S, Keay KA, Waschek JA, Al-Badri G, Castorina A. PACAP and VIP Modulate LPS-Induced Microglial Activation and Trigger Distinct Phenotypic Changes in Murine BV2 Microglial Cells. Int J Mol Sci 2021; 22:ijms222010947. [PMID: 34681607 PMCID: PMC8535941 DOI: 10.3390/ijms222010947] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 01/01/2023] Open
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related immunosuppressive peptides. However, the underlying mechanisms through which these peptides regulate microglial activity are not fully understood. Using lipopolysaccharide (LPS) to induce an inflammatory challenge, we tested whether PACAP or VIP differentially affected microglial activation, morphology and cell migration. We found that both peptides attenuated LPS-induced expression of the microglial activation markers Iba1 and iNOS (### p < 0.001), as well as the pro-inflammatory mediators IL-1β, IL-6, Itgam and CD68 (### p < 0.001). In contrast, treatment with PACAP or VIP exerted distinct effects on microglial morphology and migration. PACAP reversed LPS-induced soma enlargement and increased the percentage of small-sized, rounded cells (54.09% vs. 12.05% in LPS-treated cells), whereas VIP promoted a phenotypic shift towards cell subpopulations with mid-sized, spindle-shaped somata (48.41% vs. 31.36% in LPS-treated cells). Additionally, PACAP was more efficient than VIP in restoring LPS-induced impairment of cell migration and the expression of urokinase plasminogen activator (uPA) in BV2 cells compared with VIP. These results suggest that whilst both PACAP and VIP exert similar immunosuppressive effects in activated BV2 microglia, each peptide triggers distinctive shifts towards phenotypes of differing morphologies and with differing migration capacities.
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Affiliation(s)
- Jocelyn Karunia
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (J.K.); (A.N.); (M.M.); (S.T.B.); (G.A.-B.)
| | - Aram Niaz
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (J.K.); (A.N.); (M.M.); (S.T.B.); (G.A.-B.)
| | - Mawj Mandwie
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (J.K.); (A.N.); (M.M.); (S.T.B.); (G.A.-B.)
| | - Sarah Thomas Broome
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (J.K.); (A.N.); (M.M.); (S.T.B.); (G.A.-B.)
| | - Kevin A. Keay
- School of Medical Science, [Neuroscience] and Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia;
| | - James A. Waschek
- Intellectual Development and Disabilities Research Centre, Semel Institute for Neuroscience and Human Behaviour/Neuropsychiatric Institute, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA;
| | - Ghaith Al-Badri
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (J.K.); (A.N.); (M.M.); (S.T.B.); (G.A.-B.)
| | - Alessandro Castorina
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (J.K.); (A.N.); (M.M.); (S.T.B.); (G.A.-B.)
- School of Medical Science, [Neuroscience] and Brain and Mind Centre, The University of Sydney, Sydney, NSW 2006, Australia;
- Correspondence:
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de Souza FRO, Ribeiro FM, Lima PMD. Implications of VIP and PACAP in Parkinson's Disease: What do we Know So Far? Curr Med Chem 2021; 28:1703-1715. [PMID: 32196442 DOI: 10.2174/0929867327666200320162436] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/30/2020] [Accepted: 02/03/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Parkinson's disease is one of the most common neurodegenerative disorders and although its aetiology is not yet fully understood, neuroinflammation has been identified as a key factor in the progression of the disease. Vasoactive intestinal peptide and pituitary adenylate-cyclase activating polypeptide are two neuropeptides that exhibit anti-inflammatory and neuroprotective properties, modulating the production of cytokines and chemokines and the behaviour of immune cells. However, the role of chemokines and cytokines modulated by the endogenous receptors of the peptides varies according to the stage of the disease. METHODS We present an overview of the relationship between some cytokines and chemokines with vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide and their endogenous receptors in the context of Parkinson's disease neuroinflammation and oxidative stress, as well as the modulation of microglial cells by the peptides in this context. RESULTS The two peptides exhibit neuroprotective and anti-inflammatory properties in models of Parkinson's disease, as they ameliorate cognitive functions, decrease the level of neuroinflammation and promote dopaminergic neuronal survival. The peptides have been tested in a variety of in vivo and in vitro models of Parkinson's disease, demonstrating the potential for therapeutic application. CONCLUSION More studies are needed to establish the clinical use of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide as safe candidates for treating Parkinson's disease, as the use of the peptides in different stages of the disease could produce different results concerning effectiveness.
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Affiliation(s)
- Filipe Resende Oliveira de Souza
- Laboratory of Immunology and Microbiology, Department of Natural Sciences, Federal University of Sao Joao Del Rei, Praca Dom Helvecio, n. 74, Fabricas, 36301160, Sao Joao Del Rei, MG, Brazil
| | - Fabiola Mara Ribeiro
- Laboratory of Neurobiochemistry, Department of Biochemistry and Immunology, Federal University of Minas Gerais, MG, Brazil
| | - Patrícia Maria d'Almeida Lima
- Laboratory of Immunology and Microbiology, Department of Natural Sciences, Federal University of Sao Joao Del Rei, Praca Dom Helvecio, n. 74, Fabricas, 36301160, Sao Joao Del Rei, MG, Brazil
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Kumar A, Doan VM, Kunkli B, Csősz É. Construction of Unified Human Antimicrobial and Immunomodulatory Peptide Database and Examination of Antimicrobial and Immunomodulatory Peptides in Alzheimer's Disease Using Network Analysis of Proteomics Datasets. Front Genet 2021; 12:633050. [PMID: 33995478 PMCID: PMC8113759 DOI: 10.3389/fgene.2021.633050] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/17/2021] [Indexed: 12/26/2022] Open
Abstract
The reanalysis of genomics and proteomics datasets by bioinformatics approaches is an appealing way to examine large amounts of reliable data. This can be especially true in cases such as Alzheimer's disease, where the access to biological samples, along with well-defined patient information can be challenging. Considering the inflammatory part of Alzheimer's disease, our aim was to examine the presence of antimicrobial and immunomodulatory peptides in human proteomic datasets deposited in the publicly available proteomics database ProteomeXchange (http://www.proteomexchange.org/). First, a unified, comprehensive human antimicrobial and immunomodulatory peptide database, containing all known human antimicrobial and immunomodulatory peptides was constructed and used along with the datasets containing high-quality proteomics data originating from the examination of Alzheimer's disease and control groups. A throughout network analysis was carried out, and the enriched GO functions were examined. Less than 1% of all identified proteins in the brain were antimicrobial and immunomodulatory peptides, but the alterations characteristic of Alzheimer's disease could be recapitulated with their analysis. Our data emphasize the key role of the innate immune system and blood clotting in the development of Alzheimer's disease. The central role of antimicrobial and immunomodulatory peptides suggests their utilization as potential targets for mechanistic studies and future therapies.
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Affiliation(s)
- Ajneesh Kumar
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Biomarker Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Vo Minh Doan
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Biomarker Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Balázs Kunkli
- Biomarker Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Éva Csősz
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Biomarker Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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VIP modulates human macrophages phenotype via FPRL1 via activation of RhoA-GTPase and PLC pathways. Inflamm Res 2021; 70:309-321. [PMID: 33502586 DOI: 10.1007/s00011-021-01436-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/26/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE AND DESIGN This study is aimed at uncovering the signaling pathways activated by vasoactive intestinal peptide in human macrophages MATERIALS: Human peripheral blood mononuclear cell-derived macrophages were used for the in vitro investigation of the VIP-activated signaling pathways. METHODS AND TREATMENT Time-course and dose-response experiments and siRNA were used in human macrophages co-challenged with various concentrations of VIP and different MAPK pharmacologic inhibitors to investigate signaling pathways activated by VIP. Flow analysis was performed to assess the levels of CD11b, CD35 and CD66. Luminescence spectrometry was used to measure the levels of the released hydrogen peroxide and the intracellular calcium levels in the media. RESULTS Macrophages incubated with VIP showed increased phospho-AKT and phospho-ERK1/2 levels in a GTP-RhoA-GTPase-dependent manner. Similarly, VIP increased intracellular release of H2O2 and calcium via PLC and GTP-RhoA-GTPase, in addition to inducing the expression of CD11b, CD35, CD66 and MMP9. Furthermore, VIP activated P38 MAPK through the cAMP/PKA pathway but was independent of both PLC and RhoA signaling. The above-mentioned VIP effects were mediated via activation of the FPRL1 receptor. CONCLUSION VIP/FPRL1/VPAC/GTP-RhoA-GTPase signaling modulated macrophages phenotype through activation of multiple signaling pathways including ERK1/2, AKT, P38, ROS, cAMP and calcium.
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TLR4 inhibition ameliorates mesencephalic substantia nigra injury in neonatal rats exposed to lipopolysaccharide via regulation of neuro-immunity. Brain Res Bull 2020; 165:90-96. [DOI: 10.1016/j.brainresbull.2020.09.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/09/2020] [Accepted: 09/11/2020] [Indexed: 02/02/2023]
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12
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Zhong X, Xie L, Yang X, Liang F, Yang Y, Tong J, Zhong Y, Zhao K, Tang Y, Yuan C. Ethyl pyruvate protects against sepsis-associated encephalopathy through inhibiting the NLRP3 inflammasome. Mol Med 2020; 26:55. [PMID: 32517686 PMCID: PMC7285451 DOI: 10.1186/s10020-020-00181-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 05/18/2020] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND With the advance of antibiotics and life support therapy, the mortality of sepsis has been decreasing in recent years. However, the incidence of sepsis-associated encephalopathy (SAE), a common complication of sepsis, is still high. There are few effective therapies to treat clinical SAE. We previously found that ethyl pyruvate (EP), a metabolite derivative, is able to effectively inhibit the NLRP3 inflammasome activation. Administration of ethyl pyruvate protects mice against polymicrobial sepsis in cecal ligation and puncture (CLP) model. The aim of present study is to investigate if ethyl pyruvate is able to attenuate SAE. METHODS After CLP, C57BL/6 mice were intraperitoneally or intrathecally injected with saline or ethyl pyruvate using the sham-operated mice as control. New Object Recognition (NOR) and Morris Water Maze (MWM) were conducted to determine the cognitive function. Brain pathology was assessed via immunohistochemistry. To investigate the mechanisms by which ethyl pyruvate prevent SAE, the activation of NLRP3 in the hippocampus and the microglia were determined using western blotting, and cognitive function, microglia activation, and neurogenesis were assessed using WT, Nlrp3-/- and Asc-/- mice in the sublethal CLP model. In addition, Nlrp3-/- and Asc-/- mice treated with saline or ethyl pyruvate were subjected to CLP. RESULTS Ethyl pyruvate treatment significantly attenuated CLP-induced cognitive decline, microglia activation, and impaired neurogenesis. In addition, EP significantly decreased the NLRP3 level in the hippocampus of the CLP mice, and inhibited the cleavage of IL-1β induced by NLRP3 inflammsome in microglia. NLRP3 and ASC deficiency demonstrated similar protective effects against SAE. Nlrp3-/- and Asc-/- mice significantly improved cognitive function and brain pathology when compared with WT mice in the CLP models. Moreover, ethyl pyruvate did not have additional effects against SAE in Nlrp3-/- and Asc-/- mice. CONCLUSION The results demonstrated that ethyl pyruvate confers protection against SAE through inhibiting the NLRP3 inflammasome.
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Affiliation(s)
- Xiaoli Zhong
- Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, P. R. China
- Department of Pathophysiology, School of Basic Medical Science, Central South University, 138 Tong-zi-po Road, Changsha, Hunan Province, 410000, P. R. China
| | - Lingli Xie
- Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, P. R. China
- Department of Pathophysiology, School of Basic Medical Science, Central South University, 138 Tong-zi-po Road, Changsha, Hunan Province, 410000, P. R. China
| | - Xiaolong Yang
- Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, P. R. China
- Department of Pathophysiology, School of Basic Medical Science, Central South University, 138 Tong-zi-po Road, Changsha, Hunan Province, 410000, P. R. China
| | - Fang Liang
- Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, P. R. China
| | - Yanliang Yang
- Department of Pathophysiology, School of Basic Medical Science, Central South University, 138 Tong-zi-po Road, Changsha, Hunan Province, 410000, P. R. China
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, 410000, P. R. China
| | - Jianbin Tong
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yanjun Zhong
- Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, P. R. China
- Department of Pathophysiology, School of Basic Medical Science, Central South University, 138 Tong-zi-po Road, Changsha, Hunan Province, 410000, P. R. China
- ICU Center, The Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Furong, Changsha, 410011, Hunan, China
| | - Kai Zhao
- Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, P. R. China
| | - Yiting Tang
- Department of Pathophysiology, School of Basic Medical Science, Central South University, 138 Tong-zi-po Road, Changsha, Hunan Province, 410000, P. R. China.
- Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, 410000, P. R. China.
| | - Chuang Yuan
- Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, 410000, P. R. China.
- Department of Pathophysiology, School of Basic Medical Science, Central South University, 138 Tong-zi-po Road, Changsha, Hunan Province, 410000, P. R. China.
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Abstract
Perinatal hypoxia is still one of the greatest threats to the newborn child, even in developed countries. However, there is a lack of works which summarize up-to-date information about that huge topic. Our review covers a broader spectrum of recent results from studies on mechanisms leading to hypoxia-induced injury. It also resumes possible primary causes and observed behavioral outcomes of perinatal hypoxia. In this review, we recognize two types of hypoxia, according to the localization of its primary cause: environmental and placental. Later we analyze possible pathways of prenatal hypoxia-induced injury including gene expression changes, glutaminergic excitatory damage (and a role of NMDA receptors in it), oxidative stress with ROS and RNS production, inflammation and apoptosis. Moreover, we focus on the impact of these pathophysiological changes on the structure and development of the brain, especially on its regions: corpus striatum and hippocampus. These brain changes of the offspring lead to impairments in their postnatal growth and sensorimotor development, and in their motor functions, activity, emotionality and learning ability in adulthood. Later we compare various animal models used to investigate the impact of prenatal and postnatal injury (hypoxic, ischemic or combinatory) on living organisms, and show their advantages and limitations.
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Affiliation(s)
- M Piešová
- Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovak Republic.
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Korkmaz OT, Tunçel N. Advantages of Vasoactive Intestinal Peptide for the Future Treatment of Parkinson's Disease. Curr Pharm Des 2019; 24:4693-4701. [PMID: 30636594 DOI: 10.2174/1381612825666190111150953] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 01/01/2019] [Accepted: 01/02/2019] [Indexed: 01/04/2023]
Abstract
Parkinson's disease is the second most common neurodegenerative disorder in adults over the age of 65. The characteristic symptoms of Parkinson's disease, such as resting tremor, muscular rigidity, bradykinesia, postural instability and gait imbalance, are thought to be a result of the progressive degeneration of the dopaminergic neurons of the substantia nigra compacta, resulting in insufficient dopamine integrated signalling on GABAergic medium spiny neurons in the striatum. Despite tremendous research, the molecular mechanisms underlying the pathogenesis of neurodegeneration in Parkinson's disease have remained largely unknown. Although a variety of possible pathogenic mechanisms have been proposed over the years, including excessive release of oxygen free radicals, impairment of mitochondrial function, loss of trophic support, abnormal kinase activity, disruption of calcium homeostasis, dysfunction of protein degradation and neuroinflammation, the pathogenesis is still largely uncertain, and there is currently no effective cure for Parkinson's disease. To develop potential therapies for Parkinson's disease, inflammatory processes, mitochondrial dynamics, oxidative stress, production of reactive aldehydes, excitotoxicity and synucleinopathies are to be targeted. In this respect, vasoactive intestinal peptide has beneficial effects that provide an advantage for the treatment of Parkinson's disease. Vasoactive intestinal peptide is a major neuropeptide-neurotransmitter having antioxidant, anti-inflammatory, neurotropic, neuromodulator, and anti-apoptotic properties. In addition to its direct neuroprotective actions regulating the activity of astrocytes, microglia and brain mast cells, it also plays important roles for neuronal adaptation, maintenance and survival.
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Affiliation(s)
- Orhan Tansel Korkmaz
- Eskisehir Osmangazi University, Medical Faculty, Department of Physiology and Neurophysiology Eskisehir 26480, Turkey
| | - Neşe Tunçel
- Eskisehir Osmangazi University, Medical Faculty, Department of Physiology and Neurophysiology Eskisehir 26480, Turkey
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15
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Li B, Zou Y, Li L, Deng H, Mi W, Wang X, Yin X. Therapeutic effect of vasoactive intestinal peptide on form-deprived amblyopic kittens. BMC Ophthalmol 2019; 19:190. [PMID: 31429729 PMCID: PMC6701149 DOI: 10.1186/s12886-019-1203-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 08/15/2019] [Indexed: 11/25/2022] Open
Abstract
Background Exploring the role of vasoactive intestinal peptide (VIP) in the lateral geniculate body (LGBd) in visual development and studying the therapeutic effect of VIP on amblyopic kittens. Methods Three-week-old domestic cats were divided into a control group (n = 10) and a monocular deprivation group (n = 20), with an eye mask covering the right eye of those in the deprived group. After pattern visual evoked potential (PVEP) recording confirmed the formation of monocular amblyopia, the left LGBd was isolated from 5 kittens in each group. The remaining control kittens continued to be raised, and the remaining deprivation group was divided into a VIP intervention group (n = 5), Sefsol (caprylic acid monoglyceride, VIP solution) intervention group (n = 5) and amblyopia non-intervention group (n = 5) after removal of the eye mask. Three weeks later, PVEPs, VIP immunohistochemistry and VIP mRNA expression in the left LGBd were compared across groups. Results At 6 weeks of age, there were significant differences in P100 wave latency and amplitude and VIP immunohistochemistry and in situ hybridization between the control group and the deprivation group (P < 0.05). After 3 weeks of the corresponding interventions, the latency and amplitude in the VIP intervention group were better than that in the Sefsol intervention group and amblyopia non-intervention group (P < 0.05). Furthermore, VIP treatment increased the number of immunohistochemical VIP-positive cells (P < 0.05) and the average optical density of positive cells (P > 0.05), as well as the number (P < 0.05) and average optical density of VIP mRNA-positive cells (P < 0.05). Conclusions VIP plays an important role in visual development. Nasal administration of VIP can improve the function of neurons in the LGBd of kittens and has a certain therapeutic effect on amblyopia.
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Affiliation(s)
- Bo Li
- Department of Optometry, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China
| | - Yunchun Zou
- Department of Optometry, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China.
| | - Liwen Li
- Department of Ophthalmology, Suining Central Hospital, Suining, 629000, Sichuan, People's Republic of China
| | - Hongwei Deng
- Department of Ophthalmology, Suining Central Hospital, Suining, 629000, Sichuan, People's Republic of China
| | - Wei Mi
- Department of Ophthalmology, Suining Central Hospital, Suining, 629000, Sichuan, People's Republic of China
| | - Xing Wang
- Department of Optometry, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China
| | - Ximin Yin
- Department of Optometry, North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China
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16
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Hohberger B, Jessberger C, Hermann F, Zenkel M, Kaser-Eichberger A, Bergua A, Jünemann AG, Schrödl F, Neuhuber W. VIP changes during daytime in chicken intrinsic choroidal neurons. Exp Eye Res 2018; 170:8-12. [DOI: 10.1016/j.exer.2018.01.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 12/06/2017] [Accepted: 01/29/2018] [Indexed: 12/01/2022]
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Borges SC, Ferreira PEB, da Silva LM, de Paula Werner MF, Irache JM, Cavalcanti OA, Buttow NC. Evaluation of the treatment with resveratrol-loaded nanoparticles in intestinal injury model caused by ischemia and reperfusion. Toxicology 2018; 396-397:13-22. [PMID: 29427784 DOI: 10.1016/j.tox.2018.02.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/31/2018] [Accepted: 02/05/2018] [Indexed: 01/07/2023]
Abstract
The gastrointestinal tract is extremely sensitive to ischemia and reperfusion (I/R). Studies have reported that resveratrol (RSV) is able to combat damage caused by intestinal I/R. Because of its effectiveness in increasing the permanence and bioavailability of resveratrol in the intestinal epithelium, we investigated whether the effect of resveratrol-loaded in poly(anhydride) nanoparticles reduce oxidative stress and promote myenteric neuroprotection in the ileum of rats subjected to I/R. Physicochemical evaluations were performed on nanoparticles. The animals were divided into nine groups (n = 6/group) and treated every 48 h. Treatments with resveratrol (7 mg/kg of body weight) were applied 5 days before surgery and continued for 7 days after surgery (reperfusion period). The superior mesenteric artery was occluded to cause I/R injury. Oxidative stress, myeloperoxidase, nitrite, aspartate aminotransferase, alanine aminotransferase, immunolabeling of myenteric neurons and glial cells, and gastrointestinal transit was evaluated. Both nanoparticle formulations presented negative charge with homogeneous distribution, and the payload, showed an encapsulation efficiency of 60%. Resveratrol administered in free form prevented alterations that were caused by I/R. The results of the groups treated with RSV-loaded nanoparticles presented similar results to the group treated with free resveratrol. Treatment with empty nanoparticles showed that poly(anhydride) is not an ideal nanocarrier for application in in vivo models of intestinal I/R injury, because of hepatotoxicity that may be caused by epithelial barrier dysfunction that triggers the translocation of nanoparticles.
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Affiliation(s)
- Stephanie Carvalho Borges
- Department of Morphological Sciences, State University of Maringá, Colombo Avenue, 5790, CEP: 87020-900, Maringá, Paraná, Brazil
| | - Paulo Emílio Botura Ferreira
- Campus Uruguaiana, Federal University of Pampa, BR 472 - Km 592, CEP: 97508-000, Uruguaiana, Rio Grande do Sul, Brazil
| | - Luisa Mota da Silva
- Postgraduate Program in Pharmaceutical Sciences, University Vale of Itajaí, Uruguai Street, 458, CEP: 88302-901, Itajaí, Santa Catarina, Brazil
| | - Maria Fernanda de Paula Werner
- Department of Pharmacology, Federal University of Paraná, XV de Novembro Street, 1299, CEP 80.060-000, Curitiba, Paraná, Brazil
| | - Juan Manuel Irache
- Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/Irunlarrea 1, E-31008, Pamplona, Spain
| | - Osvaldo Albuquerque Cavalcanti
- Department of Pharmacology and Therapeutics, State University of Maringá, Colombo Avenue, 5790, CEP: 87020-900, Maringá, Paraná, Brazil
| | - Nilza Cristina Buttow
- Department of Morphological Sciences, State University of Maringá, Colombo Avenue, 5790, CEP: 87020-900, Maringá, Paraná, Brazil.
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Clayton KA, Van Enoo AA, Ikezu T. Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy. Front Neurosci 2017; 11:680. [PMID: 29311768 PMCID: PMC5733046 DOI: 10.3389/fnins.2017.00680] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 11/21/2017] [Indexed: 01/15/2023] Open
Abstract
Brain aging is central to late-onset Alzheimer's disease (LOAD), although the mechanisms by which it occurs at protein or cellular levels are not fully understood. Alzheimer's disease is the most common proteopathy and is characterized by two unique pathologies: senile plaques and neurofibrillary tangles, the former accumulating earlier than the latter. Aging alters the proteostasis of amyloid-β peptides and microtubule-associated protein tau, which are regulated in both autonomous and non-autonomous manners. Microglia, the resident phagocytes of the central nervous system, play a major role in the non-autonomous clearance of protein aggregates. Their function is significantly altered by aging and neurodegeneration. This is genetically supported by the association of microglia-specific genes, TREM2 and CD33, and late onset Alzheimer's disease. Here, we propose that the functional characterization of microglia, and their contribution to proteopathy, will lead to a new therapeutic direction in Alzheimer's disease research.
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Affiliation(s)
- Kevin A Clayton
- Department of Pharmacology and Experimental Therapeutics, Medical School, Boston University, Boston, MA, United States
| | - Alicia A Van Enoo
- Department of Pharmacology and Experimental Therapeutics, Medical School, Boston University, Boston, MA, United States
| | - Tsuneya Ikezu
- Department of Pharmacology and Experimental Therapeutics, Medical School, Boston University, Boston, MA, United States.,Department of Neurology, Medical School, Boston University, Boston, MA, United States
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19
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Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases. Mediators Inflamm 2017; 2017:5048616. [PMID: 28154473 PMCID: PMC5244030 DOI: 10.1155/2017/5048616] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/26/2016] [Accepted: 12/05/2016] [Indexed: 12/15/2022] Open
Abstract
Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
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Abstract
Neurodegenerative disorders (NDDs) are characterized by neuronal death in the brain. The mechanism of the neuronal death is too complicated to be fully understood, although in many NDDs, aging and neurotoxins are known risk factors. In the central and peripheral nervous system, vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide, is released to support neuronal survival in both physiological and pathological condition. VIP can inhibit the neurodegeneration induced by the loss of neurons. The indirect protection effect is mainly mediated by glial cells through the production of neurotrophic factor(s) and inhibition of proinflammatory mediators. By remolding the structure and improving the transfer efficiency of VIP, its nerve protective function could be further improved. Its neuroprotective action and efficacy in inhibiting a broad range of inflammatory responses make VIP or related peptides becoming a novel therapeutic method to NDDs. In this review, we aim to summarize the relationship between VIP and NDDs.
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Affiliation(s)
- Guangxiu Deng
- a National Glycoengineering Research Center , Shandong University , Jinan , China
| | - Lan Jin
- a National Glycoengineering Research Center , Shandong University , Jinan , China
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21
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Resveratrol promotes myenteric neuroprotection in the ileum of rats after ischemia-reperfusion injury. Life Sci 2016; 166:54-59. [PMID: 27671039 DOI: 10.1016/j.lfs.2016.09.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 09/21/2016] [Accepted: 09/22/2016] [Indexed: 01/31/2023]
Abstract
AIMS The present study evaluated the effects of resveratrol in the myenteric plexus after intestinal ischemia-reperfusion (I/R) injury caused by occluding the superior mesenteric artery for 45min, followed by 7days of reperfusion. MAIN METHODS Forty-two male Wistar rats were divided into seven groups: control (C group), untreated sham surgery control (SC group), sham surgery control treated with resveratrol before surgery (STA group), sham surgery control treated with resveratrol before and after surgery (STAD group), ischemic control (IRC group), ischemic treated before I/R (IRTA group), and ischemic treated before and after I/R (IRTAD group). Resveratrol (10mg/kg) was administered for 4days and 2h prior to surgery and/or 7days later. Morphometric analyses were performed, and the density of the general neuronal population (HuC/D-immunoreactive [IR]), nitrergic subpopulation (neuronal nitric oxide synthase [nNOS]-IR), vasoactive intestinal peptide (VIP)ergic varicosities (VIP-IR), and glial cells (S100-IR) was determined. KEY FINDINGS Injury that was caused by I/R significantly reduced (p<0.01) the HuC/D-IR general neuronal population. Treatment with resveratrol before and after ischemia had a neuroprotective effect. Morphometric changes caused by I/R in nitrergic neurons and varicosities were also attenuated by resveratrol. Ischemia/reperfusion promoted the proliferation of enteric glial cells, and resveratrol treatment before and after I/R reversed this effect. SIGNIFICANCE Resveratrol had neuroprotective effects, showing promise for application in intestinal surgery and transplants.
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22
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Ballerini P, Di Iorio P, Ciccarelli R, Caciagli F, Poli A, Beraudi A, Buccella S, D'Alimonte I, D'Auro M, Nargi E, Patricelli P, Visini D, Traversa U. P2Y1 and Cysteinyl Leukotriene Receptors Mediate Purine and Cysteinyl Leukotriene Co-Release in Primary Cultures of Rat Microglia. Int J Immunopathol Pharmacol 2016; 18:255-68. [PMID: 15888248 DOI: 10.1177/039463200501800208] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Inflammation is widely recognized as contributing to the pathology of acute and chronic neurodegenerative conditions. Microglial cells are pathologic sensors in the brain and activated microglia have been viewed as detrimental. Leukotriene, including cysteinyl leukotrienes (CysLTs) are suggested to be involved in brain inflammation and neurological diseases and ATP, by its receptors is a candidate for microglia activation. A23187 (10μM) stimulated microglia to co-release CysLTs and [3H]adenine based purines ([3H]ABPs), mainly ATP. The biosynthetic production of CysLTs was abolished by 10μM MK-886, an inhibitor of 5-lipoxygenase-activating protein activity. RT-PCR analysis showed that microglia expressed both CysLT1 / CysLT2 receptors, P2Y1 ATP-receptors and several members of the ATP binding cassette (ABC) transporters including MRP1, MRP4 and Pgp. The increase in [Ca2+]i elicited by LTD4 (0.1 μM) and 2MeSATP (100μM), agonists for CysLT- and P2Y1-receptors, was abolished by the respective antagonists, BAYu9773 (0.5 μM) and suramin (50 μM). The stimulation of both receptor subtypes, induced a concomitant increase in the release of both [3H]ABPs and CysLTs that was blocked by the antagonists and significantly reduced by a cocktail of ABC transporter inhibitors, BAPTA/AM (intracellular Ca2+ chelator) and staurosporine (0.1 μM, PKC blocker). P2Y antagonist was unable to antagonise the effects of LTD4 and BAYu9773 did not reduce the effects of 2MeSATP. These data suggest that: i) the efflux of purines and cysteinyl-leukotrienes is specifically and independently controlled by the two receptor types, ii) calcium, PKC and the ABC transporter system can reasonably be considered common mechanisms underlying the release of ABPs and CysLTs from microglia. The blockade of P2Y1 or CysLT1/CysLT2 receptors by specific antagonists that abolished the raise in [Ca2+]i and drastically reduced the concomitant efflux of both compounds, as well as the effects of BAPTA and staurosporine support this hypothesis. In conclusion, the data of the present study suggest a cross talk between the purine and leukotriene systems in a possible autocrine/paracrine control of the microglia-mediated initiation and progression of an inflammatory response.
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Affiliation(s)
- P Ballerini
- Department of Biomedical Sciences, G. D'Annunzio University of Chieti, Italy.
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Yelkenli İH, Ulupinar E, Korkmaz OT, Şener E, Kuş G, Filiz Z, Tunçel N. Modulation of Corpus Striatal Neurochemistry by Astrocytes and Vasoactive Intestinal Peptide (VIP) in Parkinsonian Rats. J Mol Neurosci 2016; 59:280-9. [DOI: 10.1007/s12031-016-0757-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 04/11/2016] [Indexed: 12/29/2022]
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Delgado M. Immunobiology of the Pituitary Adenylate Cyclase-Activating Peptide. CURRENT TOPICS IN NEUROTOXICITY 2016:691-708. [DOI: 10.1007/978-3-319-35135-3_40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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25
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GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease. Neurobiol Dis 2015; 82:99-113. [DOI: 10.1016/j.nbd.2015.05.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 05/09/2015] [Accepted: 05/27/2015] [Indexed: 01/27/2023] Open
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CHEN LU, YUAN WEIJIE, CHEN ZHIKANG, WU SHAOBIN, GE JIE, CHEN JINXIANG, CHEN ZIHUA. Vasoactive intestinal peptide represses activation of tumor-associated macrophages in gastric cancer via regulation of TNFα, IL-6, IL-12 and iNOS. Int J Oncol 2015; 47:1361-70. [DOI: 10.3892/ijo.2015.3126] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 07/20/2015] [Indexed: 11/06/2022] Open
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Morara S, Colangelo AM, Provini L. Microglia-Induced Maladaptive Plasticity Can Be Modulated by Neuropeptides In Vivo. Neural Plast 2015; 2015:135342. [PMID: 26273481 PMCID: PMC4529944 DOI: 10.1155/2015/135342] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 06/25/2015] [Indexed: 02/06/2023] Open
Abstract
Microglia-induced maladaptive plasticity is being recognized as a major cause of deleterious self-sustaining pathological processes that occur in neurodegenerative and neuroinflammatory diseases. Microglia, the primary homeostatic guardian of the central nervous system, exert critical functions both during development, in neural circuit reshaping, and during adult life, in the brain physiological and pathological surveillance. This delicate critical role can be disrupted by neural, but also peripheral, noxious stimuli that can prime microglia to become overreactive to a second noxious stimulus or worsen underlying pathological processes. Among regulators of microglia, neuropeptides can play a major role. Their receptors are widely expressed in microglial cells and neuropeptide challenge can potently influence microglial activity in vitro. More relevantly, this regulator activity has been assessed also in vivo, in experimental models of brain diseases. Neuropeptide action in the central nervous system has been associated with beneficial effects in neurodegenerative and neuroinflammatory pathological experimental models. This review describes some of the mechanisms of the microglia maladaptive plasticity in vivo and how neuropeptide activity can represent a useful therapeutical target in a variety of human brain pathologies.
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Affiliation(s)
- Stefano Morara
- Neuroscience Institute (CNR), Via Vanvitelli 32, 20129 Milano, Italy
- Department of BIOMETRA, University of Milano, Via Vanvitelli 32, 20129 Milano, Italy
| | - Anna Maria Colangelo
- Laboratory of Neuroscience “R. Levi-Montalcini”, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
- SYSBIO Centre of Systems Biology, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
- NeuroMI Milan Center for Neuroscience, University of Milano-Bicocca, 20126 Milano, Italy
| | - Luciano Provini
- Department of BIOMETRA, University of Milano, Via Vanvitelli 32, 20129 Milano, Italy
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Lipopolysaccharides upregulate hepcidin in neuron via microglia and the IL-6/STAT3 signaling pathway. Mol Neurobiol 2015; 50:811-20. [PMID: 24659348 DOI: 10.1007/s12035-014-8671-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 02/28/2014] [Indexed: 12/13/2022]
Abstract
Neuroinflammation is closely related to brain iron homeostasis. Our previous study demonstrated that lipopolysaccharides (LPS) can regulate expression of iron-regulatory peptide hepcidin; however, the mechanism is undefined. Here, we demonstrated that intracerebroventricular injection of LPS in rat brain upregulated hepcidin and downregulated ferroportin 1 in the cortex and substantia nigra. LPS increased hepcidin expression in neurons only when they were co-cultured with BV-2 microglia, and the upregulation was suppressed by IL-6 neutralizing antibody in vitro. In addition, IL-6 but not IL-1α, IL-1β, or tumor necrosis factor-alpha increased hepcidin expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation in cortical neurons and MES23.5 dopaminergic neurons. These effects were blocked by the STAT3 inhibitor, stattic. Our results show that neurons are the major source of increased hepcidin expression in response to LPS challenge but microglia play a key mediator role by releasing IL-6 and recruiting the STAT3 pathway. We conclude that LPS upregulates hepcidin expression in neurons via microglia and the IL-6/STAT3 signaling pathway.
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Lee EH, Seo SR. Neuroprotective roles of pituitary adenylate cyclase-activating polypeptide in neurodegenerative diseases. BMB Rep 2015; 47:369-75. [PMID: 24856828 PMCID: PMC4163857 DOI: 10.5483/bmbrep.2014.47.7.086] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Indexed: 12/04/2022] Open
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic bioactive peptide that was first isolated from an ovine hypothalamus in 1989. PACAP belongs to the secretin/glucagon/vasoactive intestinal polypeptide (VIP) superfamily. PACAP is widely distributed in the central and peripheral nervous systems and acts as a neurotransmitter, neuromodulator, and neurotrophic factor via three major receptors (PAC1, VPAC1, and VPAC2). Recent studies have shown a neuroprotective role of PACAP using in vitro and in vivo models. In this review, we briefly summarize the current findings on the neurotrophic and neuroprotective effects of PACAP in different brain injury models, such as cerebral ischemia, Parkinson’s disease (PD), and Alzheimer’s disease (AD). This review will provide information for the future development of therapeutic strategies in treatment of these neurodegenerative diseases. [BMB Reports 2014; 47(7): 369-375]
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Affiliation(s)
- Eun Hye Lee
- Department of Molecular Bioscience, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 200-701, Korea
| | - Su Ryeon Seo
- Department of Molecular Bioscience, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 200-701, Korea
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Ganea D, Hooper KM, Kong W. The neuropeptide vasoactive intestinal peptide: direct effects on immune cells and involvement in inflammatory and autoimmune diseases. Acta Physiol (Oxf) 2015; 213:442-52. [PMID: 25422088 DOI: 10.1111/apha.12427] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 10/13/2014] [Accepted: 11/21/2014] [Indexed: 12/13/2022]
Abstract
Neuropeptides represent an important category of endogenous contributors to the establishment and maintenance of immune deviation in the immune-privileged organs such as the CNS and in the control of acute inflammation in the peripheral immune organs. Vasoactive intestinal peptide (VIP) is a major immunoregulatory neuropeptide widely distributed in the central and peripheral nervous system. In addition to neurones, VIP is synthesized by immune cells which also express VIP receptors. Here, we review the current information on VIP production and VIP-receptor-mediated effects in the immune system, the role of endogenous and exogenous VIP in inflammatory and autoimmune disorders and the present and future VIP therapeutic approaches.
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Affiliation(s)
- D. Ganea
- Department of Microbiology and Immunology; Temple University School of Medicine; Philadelphia PA USA
| | - K. M. Hooper
- Department of Microbiology and Immunology; Temple University School of Medicine; Philadelphia PA USA
| | - W. Kong
- Department of Microbiology and Immunology; Temple University School of Medicine; Philadelphia PA USA
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Vasoactive Intestinal Peptide (VIP) Nanoparticles for Diagnostics and for Controlled and Targeted Drug Delivery. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015; 98:145-68. [DOI: 10.1016/bs.apcsb.2014.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2563-2582. [PMID: 24892271 DOI: 10.1016/j.bbamcr.2014.05.014] [Citation(s) in RCA: 1437] [Impact Index Per Article: 130.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 05/22/2014] [Accepted: 05/23/2014] [Indexed: 12/14/2022]
Abstract
Inflammation occurs as a result of exposure of tissues and organs to harmful stimuli such as microbial pathogens, irritants, or toxic cellular components. The primary physical manifestations of inflammation are redness, swelling, heat, pain, and loss of function to the affected area. These processes involve the major cells of the immune system, including monocytes, macrophages, neutrophils, basophils, dendritic cells, mast cells, T-cells, and B-cells. However, examination of a range of inflammatory lesions demonstrates the presence of specific leukocytes in any given lesion. That is, the inflammatory process is regulated in such a way as to ensure that the appropriate leukocytes are recruited. These events are in turn controlled by a host of extracellular molecular regulators, including members of the cytokine and chemokine families that mediate both immune cell recruitment and complex intracellular signalling control mechanisms that characterise inflammation. This review will focus on the role of the main cytokines, chemokines, and their receptors in the pathophysiology of auto-inflammatory disorders, pro-inflammatory disorders, and neurological disorders involving inflammation.
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Affiliation(s)
- Mark D Turner
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom.
| | - Belinda Nedjai
- Leukocyte Biology Section, National Heart and Lung Institute, Imperial College, South Kensington, London SW7 2AZ, United Kingdom
| | - Tara Hurst
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, United Kingdom
| | - Daniel J Pennington
- Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, Whitechapel, London E1 2AT, United Kingdom
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Campos-Salinas J, Cavazzuti A, O'Valle F, Forte-Lago I, Caro M, Beverley SM, Delgado M, Gonzalez-Rey E. Therapeutic efficacy of stable analogues of vasoactive intestinal peptide against pathogens. J Biol Chem 2014; 289:14583-99. [PMID: 24706753 DOI: 10.1074/jbc.m114.560573] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide recently identified as a potential antimicrobial peptide. To overcome the metabolic limitations of VIP, we modified the native peptide sequence and generated two stable synthetic analogues (VIP51 and VIP51(6-30)) with better antimicrobial profiles. Herein we investigate the effects of both VIP analogues on cell viability, membrane integrity, and ultrastructure of various bacterial strains and Leishmania species. We found that the two VIP derivatives kill various non-pathogenic and pathogenic Gram-positive and Gram-negative bacteria as well as the parasite Leishmania major through a mechanism that depends on the interaction with certain components of the microbial surface, the formation of pores, and the disruption of the surface membrane. The cytotoxicity of the VIP derivatives is specific for pathogens, because they do not affect the viability of mammalian cells. Docking simulations indicate that the chemical changes made in the analogues are critical to increase their antimicrobial activities. Consequently, we found that the native VIP is less potent as an antibacterial and fails as a leishmanicidal. Noteworthy from a therapeutic point of view is that treatment with both derivatives increases the survival and reduces bacterial load and inflammation in mice with polymicrobial sepsis. Moreover, treatment with VIP51(6-30) is very effective at reducing lesion size and parasite burden in a model of cutaneous leishmaniasis. These results indicate that the VIP analogues emerge as attractive alternatives for treating drug-resistant infectious diseases and provide key insights into a rational design of novel agents against these pathogens.
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Affiliation(s)
| | - Antonio Cavazzuti
- From the Institute of Parasitology and Biomedicine, CSIC, Granada 18016, Spain
| | - Francisco O'Valle
- the Department of Pathological Anatomy, Medical School of Granada, Granada 18012, Spain
| | - Irene Forte-Lago
- From the Institute of Parasitology and Biomedicine, CSIC, Granada 18016, Spain
| | - Marta Caro
- From the Institute of Parasitology and Biomedicine, CSIC, Granada 18016, Spain
| | - Stephen M Beverley
- the Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, and
| | - Mario Delgado
- From the Institute of Parasitology and Biomedicine, CSIC, Granada 18016, Spain
| | - Elena Gonzalez-Rey
- From the Institute of Parasitology and Biomedicine, CSIC, Granada 18016, Spain, the Department of Biochemistry and Molecular Biology, Medical School of Seville, Seville 41009, Spain
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Deng Y, Xie D, Fang M, Zhu G, Chen C, Zeng H, Lu J, Charanjit K. Astrocyte-derived proinflammatory cytokines induce hypomyelination in the periventricular white matter in the hypoxic neonatal brain. PLoS One 2014; 9:e87420. [PMID: 24498101 PMCID: PMC3909103 DOI: 10.1371/journal.pone.0087420] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 12/21/2013] [Indexed: 02/04/2023] Open
Abstract
Hypoxic exposure in the perinatal period causes periventricular white matter damage (PWMD), a condition associated with myelination abnormalities. Under hypoxic conditions, glial cells were activated and released a large number of inflammatory mediators in the PWM in neonatal brain, which may result in oligodendrocyte (OL) loss and axonal injury. This study aims to determine if astrocytes are activated and generate proinflammatory cytokines that may be coupled with the oligodendroglial loss and hypomyelination observed in hypoxic PWMD. Twenty-four 1-day-old Wistar rats were exposed to hypoxia for 2 h. The rats were then allowed to recover under normoxic conditions for 7 or 28 days before being killed. Another group of 24 rats kept outside the chamber was used as age-matched controls. Upregulated expression of TNF-α and IL-1β was observed in astrocytes in the PWM of P7 hypoxic rats by double immunofluorescence, western blotting and real time RT-PCR. This was linked to apoptosis and enhanced expression of TNF-R1 and IL-1R1 in APC+ OLs. PLP expression was decreased significantly in the PWM of P28d hypoxic rats. The proportion of myelinated axons was markedly reduced by electron microscopy (EM) and the average g-ratios were higher in P28d hypoxic rats. Upregulated expression of TNF-α and IL-1β in primary cultured astrocytes as well as their corresponding receptors in primary culture APC+ oligodendrocytes were detected under hypoxic conditions. Our results suggest that following a hypoxic insult, astrocytes in the PWM of neonatal rats produce inflammatory cytokines such as TNF-α and IL-1β, which induce apoptosis of OLs via their corresponding receptors associated with them. This results in hypomyelination in the PWM of hypoxic rats.
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Affiliation(s)
- Yiyu Deng
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China
- * E-mail:
| | - Di Xie
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China
- Graduate School, Southern Medical University, Guangzhou, PR China
| | - Ming Fang
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China
| | - Gaofeng Zhu
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China
| | - Chunbo Chen
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China
| | - Hongke Zeng
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China
| | - Jia Lu
- Defense Medical and Environmental Research Institute, DSO National Laboratories, Singapore
| | - Kaur Charanjit
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Khan MM, Kempuraj D, Zaheer S, Zaheer A. Glia maturation factor deficiency suppresses 1-methyl-4-phenylpyridinium-induced oxidative stress in astrocytes. J Mol Neurosci 2014; 53:590-9. [PMID: 24430624 DOI: 10.1007/s12031-013-0225-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 12/26/2013] [Indexed: 12/11/2022]
Abstract
Inflammation is closely intertwined with pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that inhibition of glia-mediated inflammation might represent a promising therapeutic target for PD. Glia maturation factor (GMF), an inflammatory protein, predominantly localized in astrocytes is previously isolated, sequenced and cloned in our laboratory. In the present investigation, we demonstrate that GMF-deficiency in astrocytes upregulates the antioxidant status and limit the extent of lipid peroxidation and production of reactive oxygen species (ROS) along with diminished nuclear factor-κB-mediated inflammatory responses in 1-methyl-4-phenylpyridinium (MPP(+))-induced toxicity. Primary astrocytes obtained from wild-type (Wt) and GMF-deficient (GMF-KO) mice were treated with 5, 10, and 20 μM MPP(+) for 24, 48, and 72 h in vitro. Our results show decreased release of ROS and increased level of glutathione in astrocytes obtained from GMF-KO mice when compared to astrocytes derived from Wt mice following MPP(+) treatment. Additionally, we found decreased activity of NF-κB, and reduced levels of proinflammatory tumor necrosis factor- α, interleukin-1β (IL-1β), IL-17, IL-33, and chemokine (C-C motif) ligand 2 (CCL2) in GMF-KO astrocytes when compared to Wt astrocytes. Our overall results suggest that GMF-KO astrocytes are significantly resistant to MPP(+) toxicity when compared to Wt astrocytes.
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36
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Aguilar E, Cobo Pulido M, Martin F. Gene-modified mesenchymal stromal cells: A VIP experience. Inflamm Regen 2014. [DOI: 10.2492/inflammregen.34.176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Ferreira PEB, Lopes CRP, Alves AMP, Alves &EPB, Linden DR, Zanoni JN, Buttow NC. Diabetic neuropathy: an evaluation of the use of quercetin in the cecum of rats. World J Gastroenterol 2013; 19:6416-26. [PMID: 24151360 PMCID: PMC3801312 DOI: 10.3748/wjg.v19.i38.6416] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 05/20/2013] [Accepted: 06/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of quercetin supplementation on the myenteric neurons and glia in the cecum of diabetic rats. METHODS Total preparations of the muscular tunic were prepared from the ceca of twenty-four rats divided into the following groups: control (C), control supplemented with quercetin (200 mg/kg quercetin body weight) (CQ), diabetic (D) and diabetic supplemented with quercetin (DQ). Immunohistochemical double staining technique was performed with HuC/D (general population)/nitric oxide synthase (nNOS), HuC-D/S-100 and VIP. Density analysis of the general neuronal population HuC/D-IR, the nNOS-IR (nitrergic subpopulation) and the enteric glial cells (S-100) was performed, and the morphometry and the reduction in varicosity population (VIP-IR) in these populations were analyzed. RESULTS Diabetes promoted a significant reduction (25%) in the neuronal density of the HuC/D-IR (general population) and the nNOS-IR (nitrergic subpopulation) compared with the C group. Diabetes also significantly increased the areas of neurons, glial cells and VIP-IR varicosities. Supplementation with quercetin in the DQ group prevented neuronal loss in the general population and increased its area (P < 0.001) and the area of nitrergic subpopulation (P < 0.001), when compared to C group. Quercetin induced a VIP-IR and glial cells areas (P < 0.001) in DQ group when compared to C, CQ and D groups. CONCLUSION In diabetes, quercetin exhibited a neuroprotective effect by maintaining the density of the general neuronal population but did not affect the density of the nNOS subpopulation.
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38
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Christov A, Ottman JT, Grammas P. Vascular inflammatory, oxidative and protease-based processes: implications for neuronal cell death in Alzheimer's disease. Neurol Res 2013; 26:540-6. [PMID: 15265271 DOI: 10.1179/016164104225016218] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
A substantial literature demonstrates activation of inflammatory processes in the Alzheimer's disease (AD) brain and an association between inflammation and oxidative stress. We have shown that brain microvessels from AD patients express high levels of inflammatory proteins and that these proteins evoke release of the neurotoxic protease thrombin from brain endothelial cells. The objective of this study was to determine the effects of inflammatory proteins on brain endothelial cell reactive oxygen species generation, protease release and cell apoptosis. Also, the effects of inflammatory proteins on neuronal reactive oxygen species generation, injury and apoptosis were assessed. Treatment of cultured brain endothelial cells with inflammatory proteins (LPS, IL-1beta, IL-6, IFN-gamma, TNF-alpha) resulted in a significant increase (p < 0.01) in intracellular levels of reactive oxygen species by 1 h. Inflammatory proteins also caused release of tissue plasminogen activator and increased apoptosis by 24 h in these cells. In cultured neurons, inflammatory proteins caused an increase in reactive oxygen species, membrane fluidity, and apoptosis by 24 h, as detected by fluorescent microscopy. Taken together, these data support the hypothesis that vascular inflammatory, oxidative and protease-based processes contribute to neuronal cell death, and suggest that therapies targeted at these mediators and processes could be effective in AD.
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Affiliation(s)
- Alexander Christov
- Department of Pathology and the Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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Cobo M, Anderson P, Benabdellah K, Toscano MG, Muñoz P, García-Pérez A, Gutierrez I, Delgado M, Martin F. Mesenchymal Stem Cells Expressing Vasoactive Intestinal Peptide Ameliorate Symptoms in a Model of Chronic Multiple Sclerosis. Cell Transplant 2013; 22:839-54. [DOI: 10.3727/096368912x657404] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Multiple sclerosis (MS) is a severe debilitating disorder characterized by progressive demyelination and axonal damage of the central nervous system (CNS). Current therapies for MS inhibit the immune response and demonstrate reasonable benefits if applied during the early phase of relapsing–remitting MS (RRMS) while there are no treatments for patients that progress neither to the chronic phase nor for the primary progressive form of the disease. In this manuscript, we have studied the therapeutic efficacy of a cell and gene therapy strategy for the treatment of a mouse model of chronic MS [myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)]. We used allogenic mesenchymal stem cells (MSCs) as a therapeutic tool and also as vehicle to deliver fully processed 3.3-kDa vasoactive intestinal peptide (VIP) to the peripheral immune organs and to the inflamed CNS. Intraperitoneal administrations of MSCs expressing VIP stopped progression and reduced symptoms when administered at peak of disease. The improvement in clinical score correlated with diminished peripheral T-cell responses against MOG as well as lower inflammation, lower demyelination, and higher neuronal integrity in the CNS. Interestingly, neither lentiviral vectors expressing VIP nor unmodified MSCs were therapeutic when administer at the peak of disease. The increased therapeutic effect of MSCs expressing VIP over unmodified MSCs requires the immunoregulatory and neuroprotective roles of both VIP and MSCs and the ability of the MSCs to migrate to peripheral lymph organs and the inflamed CNS.
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Affiliation(s)
- Marién Cobo
- GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
| | - Per Anderson
- GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
| | - Karim Benabdellah
- GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
| | - Miguel G. Toscano
- GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
| | - Pilar Muñoz
- GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
| | - Angélica García-Pérez
- GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
| | - Iván Gutierrez
- Biobanco, Parque Tecnológico Salud (PTS), Armilla, Universidad de Granada, Granada, Spain
| | - Mario Delgado
- IPB Lopez Neyra, CSIC, Parque Tecnológico Salud (PTS), Armilla, Granada, Spain
| | - Francisco Martin
- GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
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Abstract
Neurogenesis must be properly regulated to ensure that cell production does not exceed the requirements of the growing cerebral cortex, yet our understanding of mechanisms that restrain neuron production remains incomplete. We investigated the function of microglial cells in the developing cerebral cortex of prenatal and postnatal macaques and rats and show that microglia limit the production of cortical neurons by phagocytosing neural precursor cells. We show that microglia selectively colonize the cortical proliferative zones and phagocytose neural precursor cells as neurogenesis nears completion. We found that deactivating microglia in utero with tetracyclines or eliminating microglia from the fetal cerebral cortex with liposomal clodronate significantly increased the number of neural precursor cells, while activating microglia in utero through maternal immune activation significantly decreased the number of neural precursor cells. These data demonstrate that microglia play a fundamental role in regulating the size of the precursor cell pool in the developing cerebral cortex, expanding our understanding of the mechanisms that regulate cortical development. Furthermore, our data suggest that any factor that alters the number or activation state of microglia in utero can profoundly affect neural development and affect behavioral outcomes.
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Nascimento RD, Martins PR, de Souza Lisboa A, Adad SJ, Morais da Silveira AB, Reis DD. An imbalance between substance P and vasoactive intestinal polypeptide might contribute to the immunopathology of megaesophagus after Trypanosoma cruzi infection. Hum Pathol 2013; 44:269-76. [DOI: 10.1016/j.humpath.2012.05.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Revised: 05/22/2012] [Accepted: 05/23/2012] [Indexed: 01/09/2023]
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Korkmaz O, Ay H, Ulupinar E, Tunçel N. Vasoactive intestinal peptide enhances striatal plasticity and prevents dopaminergic cell loss in Parkinsonian rats. J Mol Neurosci 2012; 48:565-73. [PMID: 22544516 DOI: 10.1007/s12031-012-9781-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 04/12/2012] [Indexed: 01/18/2023]
Abstract
Destruction of the nigrostriatal dopaminergic pathway by the administration of 6-OHDA generates an animal model of Parkinson's disease. The main characteristic of this progressive neurological disorder is the loss of the dopaminergic neurons located in the substantia nigra pars compacta (SNc). Dopaminergic inputs from the SNc innervate the medium spiny neurons of the striatum and modulate the spontaneous activity of the primary output nuclei of the basal ganglia, globus pallidus interna, and substantia nigra pars reticulata. In our previous studies, we showed that systematically administered vasoactive intestinal peptide (VIP) is effective at reversing motor deficits, decreasing neuronal cell death, and repairing the myelin sheet in parkinsonian rats. In the current study, the effects of VIP on the dendritic morphology of the striatal neurons and the number of dopaminergic neurons in the SNc were examined in 6-OHDA-lesioned rats using Golgi-Cox staining and design-based stereological methods, respectively. Adult Sprague-Dawley rats were separated into sham-operated, bilaterally 6-OHDA lesioned and lesioned + i.p. VIP-injected (25 ng/kg) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection (every 2 days for 15 days). The 6-OHDA significantly decreased the total number of dopaminergic neurons, branching, and spine density of the medium spiny neurons in the striatum. VIP significantly increased the number of neurons immunostained with tyrosine hydroxylase and the density of spines without altering the branching and the total length of dendrites. In conclusion, VIP might display synaptogenetic activity by enhancing the spine density in the striatum of the parkinsonian rats.
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Affiliation(s)
- OrhanTansel Korkmaz
- Department of Physiology and Neurophysiology, Eskişehir Osmangazi University, 26040 Eskisehir, Turkey
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Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids 2011; 45:25-39. [PMID: 22139413 DOI: 10.1007/s00726-011-1184-8] [Citation(s) in RCA: 134] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Accepted: 11/22/2011] [Indexed: 01/07/2023]
Abstract
Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide/neurotransmitter, is widely distributed in both the central and peripheral nervous system. VIP is released by both neurons and immune cells. Various cell types, including immune cells, express VIP receptors. VIP has pleiotropic effects as a neurotransmitter, immune regulator, vasodilator and secretagogue. This review is focused on VIP production and effects on immune cells, VIP receptor signaling as related to immune functions, and the involvement of VIP in inflammatory and autoimmune disorders. The review addresses present clinical use of VIP and future therapeutic directions.
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Affiliation(s)
- Mario Delgado
- Instituto de Parasitologia y Biomedicina, IPBLN-CSIC, Granada, Spain
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Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis. ASN Neuro 2011; 3:AN20110024. [PMID: 21895607 PMCID: PMC3189630 DOI: 10.1042/an20110024] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structure–activity relationship data and biophysical interaction studies of these peptides with their cognate receptors.
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45
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Malavolta L, Cabral FR. Peptides: important tools for the treatment of central nervous system disorders. Neuropeptides 2011; 45:309-16. [PMID: 21477861 DOI: 10.1016/j.npep.2011.03.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Revised: 02/11/2011] [Accepted: 03/14/2011] [Indexed: 01/08/2023]
Abstract
This review shows some classical applications of peptides and suggests there is great promise for the treatment of various central nervous system diseases. Actually, peptides are considered the new generation of biologically active tools because they are key regulators in cellular and intercellular physiological responses, which possess enormous potential for the treatment of various diseases. In spite of their clinical potential, native peptides have seen limited use due to their poor bioavailability and low stability in physiological conditions. Moreover, most peptide or protein pharmaceuticals currently in use are delivered by invasive routes such as via subcutaneous injection. Considerable efforts have been made to design new drugs based on peptides and recent developments in technology and science have provided the means and opportunity to produce a stable as well as controlled-release form of peptide and protein drugs to combat poorly controlled diseases and to increase patients' quality of life. A major challenge in this regard, however, is the delivery of peptides over the blood-brain barrier. This review gives an overview of some strategies used to improve both bioavailability and uptake of peptide drugs for delivery into the brain. Indeed, recent findings suggest that the use of peptides by conjugation to a polymer such as nanoparticles can offer tremendous hope in the treatment of brain disorders. The polymer conjugation improves pharmacokinetics by increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes. These new strategies will create new opportunities for the future development of neurotherapeutic drugs. In the present review we have focused our attention on the peptide controlled delivery, summarizing literature reports on the use of peptides and nanotechnology for the treatment and diagnosis of brain disorders.
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Affiliation(s)
- Luciana Malavolta
- Brain Institute-Instituto Israelita de Ensino e Pesquisa Albert Einstein, Morumbi-São Paulo, SP, Brazil.
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Tunçel N, Korkmaz OT, Tekin N, Şener E, Akyüz F, İnal M. Antioxidant and Anti-Apoptotic Activity of Vasoactive Intestinal Peptide (VIP) Against 6-Hydroxy Dopamine Toxicity in the Rat Corpus Striatum. J Mol Neurosci 2011; 46:51-7. [DOI: 10.1007/s12031-011-9618-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 08/04/2011] [Indexed: 01/17/2023]
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Abstract
Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.
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Aid S, Parikh N, Palumbo S, Bosetti F. Neuronal overexpression of cyclooxygenase-2 does not alter the neuroinflammatory response during brain innate immune activation. Neurosci Lett 2010; 478:113-8. [PMID: 20451580 PMCID: PMC2891071 DOI: 10.1016/j.neulet.2010.04.076] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 04/05/2010] [Accepted: 04/30/2010] [Indexed: 11/29/2022]
Abstract
Neuroinflammation is a critical component in the progression of several neurological and neurodegenerative diseases and cyclooxygenases (COX)-1 and -2 are key regulators of innate immune responses. We recently demonstrated that COX-1 deletion attenuates, whereas COX-2 deletion enhances, the neuroinflammatory response, blood-brain barrier permeability and leukocyte recruitment during lipopolysaccharide (LPS)-induced innate immune activation. Here, we used transgenic mice, which overexpressed human COX-2 via neuron-specific Thy-1 promoter (TgCOX-2), causing elevated prostaglandins (PGs) levels. We tested whether neuronal COX-2 overexpression affects the glial response to a single intracerebroventricular injection of LPS, which produces a robust neuroinflammatory reaction. Relative to non-transgenic controls (NTg), 7 month-old TgCOX-2 did not show any basal neuroinflammation, as assessed by gene expression of markers of inflammation and oxidative stress, neuronal damage, as assessed by Fluoro-JadeB staining, or systemic inflammation, as assessed by plasma levels of IL-1beta and corticosterone. Twenty-four hours after LPS injection, all mice showed increased microglial activation, as indicated by Iba1 immunostaining, neuronal damage, mRNA expression of cytokines (TNF-alpha, IL-6), reactive oxygen expressing enzymes (iNOS and NADPH oxidase subunits), endogenous COX-2, cPLA(2) and mPGES-1, and hippocampal and cortical IL-1beta levels. However, the increases were similar in TgCOX-2 and NTg. In NTg, LPS increased brain PGE(2) to the levels observed in TgCOX-2. These results suggest that PGs derived from neuronal COX-2 do not play a role in the neuroinflammatory response to acute activation of brain innate immunity. This is likely due to the direct effect of LPS on glial rather than neuronal cells.
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Affiliation(s)
- Saba Aid
- Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, NIH, Bethesda, MD 20892
| | - Nishant Parikh
- Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, NIH, Bethesda, MD 20892
| | - Sara Palumbo
- Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, NIH, Bethesda, MD 20892
| | - Francesca Bosetti
- Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, NIH, Bethesda, MD 20892
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Maguire-Zeiss KA, Federoff HJ. Future directions for immune modulation in neurodegenerative disorders: focus on Parkinson's disease. J Neural Transm (Vienna) 2010; 117:1019-25. [PMID: 20549523 DOI: 10.1007/s00702-010-0431-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Accepted: 05/22/2010] [Indexed: 02/06/2023]
Abstract
One common feature of neurodegenerative diseases is neuroinflammation. In the case of Parkinson's disease (PD), neuroinflammation appears early and persists throughout the disease course. The principal cellular mediator of brain inflammation is the resident microglia which share many features with related hematopoietically derived macrophages. Microglia can become activated by misfolded proteins including the PD relevant example, alpha-synuclein, a presynaptic protein. When activated, microglia release pro-inflammatory diffusible mediators that promote dysfunction and contribute to the death of the PD vulnerable dopaminergic neurons in the midbrain. Recently, the orphan nuclear receptor Nurr1, well known as a critical determinant in dopaminergic neuron maturation, has been ascribed two new properties. First, it promotes the production and release of the neuropeptide vasoactive intestinal peptide that functions both to stimulate dopaminergic neuron survival and inhibit neuroinflammation. Second, Nurr1 suppresses the expression and release of pro-inflammatory cytokines in glial cells. Herein, we discuss these new findings in context of strategies to attenuate neuroinflammation in PD.
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Alves EPB, Alves AMP, Pereira RVF, de Miranda Neto MH, Zanoni JN. Immunohistochemical study of vasoactive intestinal peptide (VIP) enteric neurons in diabetic rats supplemented with L-glutamine. Nutr Neurosci 2010; 13:43-51. [PMID: 20132654 DOI: 10.1179/147683010x12611460763841] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The purpose of this work was to study the area of the varicosities of nerve fibers of myenteric neurons immunoreactive to vasoactive intestinal peptide (VIP-IR) and of the cell bodies of VIP-IR submucosal neurons of the jejunum of diabetic rats supplemented with 2% L-glutamine. Twenty male rats were divided into the following groups: normoglycemic (N), normoglycemic supplemented with L-glutamine (NG), diabetic (D) and diabetic supplemented with L-glutamine (DG). Whole-mounts of the muscle tunica and the submucosal layer were subjected to the immunohistochemical technique for neurotransmitter VIP identification. Morphometric analyses were carried out in 500 VIP-IR cell bodies of submucosal neurons and 2000 VIP-IR varicosities from each group. L-Glutamine supplementation to the normoglycemic animals caused an increase in the areas of the cell bodies (8.49%) and varicosities (21.3%) relative to the controls (P < 0.05). On the other hand, there was a decrease in the areas of the cell bodies (4.55%) and varicosities (28.9%) of group DG compared to those of group D (P < 0.05). It is concluded that L-glutamine supplementation was positive both to normoglycemic and diabetic animals.
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Affiliation(s)
- Eder Paulo Belato Alves
- Department of Morphophysiological Sciences, Laboratory of Enteric Neurons, State University of Maringa, Avenida Colombo, 5790 Bloco H-79, CEP 87020-900 Maringá, PR, Brazil.
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