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Koru I, Atasever-Arslan B. Protective effects of sesamol against cigarette smoke toxicity on the blood-brain barrier. BMC Complement Med Ther 2025; 25:68. [PMID: 39987119 PMCID: PMC11846467 DOI: 10.1186/s12906-025-04796-z] [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: 10/04/2024] [Accepted: 01/29/2025] [Indexed: 02/24/2025] Open
Abstract
Cigarette smoke comprises nicotine, reactive oxygen species (ROS), and carcinogens, which can induce oxidative stress and inflammation, leading to disruption of the blood-brain barrier. This study utilized cigarette smoke extract (CSE) in an in vitro model of the blood-brain barrier (BBB).Sesamol is a phenolic compound derived from Sesamum indicum L. Its potential to reduce inflammation and provide protection was also examined. As a result of the study, it was found that CSE significantly increases permeability by degrading the BBB, whereas a protective effect was observed in the sesamol-incubated group within the BBB model. While the Sesamol + CSE group does not entirely prevent the damage induced by CSE in the barrier, it does exhibit a mitigating effect on the damage.In HUVEC cells, a significant decrease in IL-8 levels was observed in sesamol and sesamol + CSE groups. In T98G cells, IL-8 levels were elevated in the CSE group, while a reduction was observed in the sesamol and sesamol + CSE groups. TNF-α levels went up in the CSE group but down in the sesamol and sesamol + CSE groups in T98G cells. Furthermore, the IL-6 levels were significantly increased in both the sesamol and sesamol + CSE groups in HUVEC cells, while a decrease was noted in T98G cells in sesamol treatment. The increase in IL-8 and TNF-α levels in T98G cells due to CSE indicates an inflammatory response. It can contribute to the enhanced BBB permeability. As a result, sesamol reduced inflammation caused by CSE by controlling IL-8, IL-6, and TNF-α. This molecule may serve a therapeutic role by diminishing inflammation and protecting the blood-brain barrier from damage.
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Affiliation(s)
- Ildem Koru
- Department of Biotechnology, Graduate School of Science, Uskudar University, Istanbul, Turkey
| | - Belkıs Atasever-Arslan
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul, Turkey.
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Ho J, Sukati S, Taylor T, Carter S, Fuller B, Marmo A, Sorge C, D'Orazio J, Butterfield DA, Bondada S, Weiss H, St Clair DK, Chaiswing L. Extracellular vesicles released by ALL patients contain HNE-adducted proteins: Implications of collateral damage. Free Radic Biol Med 2025; 227:312-321. [PMID: 39643137 PMCID: PMC11786608 DOI: 10.1016/j.freeradbiomed.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/19/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024]
Abstract
Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off-target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage by isolating EVs from pediatric ALL patients throughout their first 2 months of treatment. EVs were measured throughout the collection points for: 1) number of EV particles generated using nanoparticle tracking analysis (NTA); 2) markers of neurons (NeuN), astrocyte activation (GFAP), neuronal stability (BDNF), 3) markers of pre-B cell ALL (CD19 and CD22); and) 4-hydroxy-2-nonenal (HNE) adducted proteins. HNE protein adductions were measured in the patient sera and CSF. Pro-inflammatory cytokine levels were also measured in patient sera because of their contribution to oxidative stress and neuronal injury. Our results: 1) demonstrate EVs are a sensitive indicator of oxidative damage; 2) suggest EVs as a marker of a decline in neuronal stability; and 3) show the presence of leukemia has a greater contribution to pro-inflammatory cytokine production in the patient's serum than the cancer treatment. Specifically, we observed a significant decrease in cytokine levels (e.g., TNF-α, IL-1β, IL-6, and IL-8) following the initiation of treatment, highlighting the influence of leukemia burden on systemic inflammation. The results support the utilization of EVs as a sensitive marker of oxidative stress and off-target tissue damage.
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Affiliation(s)
- Jenni Ho
- Department of Toxicology and Cancer Biology, University of Kentucky, USA; Markey Cancer Center, University of Kentucky, USA
| | - Suriyan Sukati
- Department of Medical Technology, Walailak University, Thailand
| | - Tamara Taylor
- Department of Pediatrics, University of Kentucky, USA
| | - Sherry Carter
- Department of Pediatrics, University of Kentucky, USA
| | | | - Amy Marmo
- Department of Pediatrics, University of Kentucky, USA
| | - Caryn Sorge
- Department of Pediatrics, University of Kentucky, USA
| | - John D'Orazio
- Markey Cancer Center, University of Kentucky, USA; Department of Pediatrics, University of Kentucky, USA
| | - D Allan Butterfield
- Markey Cancer Center, University of Kentucky, USA; Department of Chemistry, University of Kentucky, USA
| | - Subbarao Bondada
- Markey Cancer Center, University of Kentucky, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, USA
| | - Heidi Weiss
- Markey Cancer Center, University of Kentucky, USA; Department of Surgery and Biostatistics, University of Kentucky, USA
| | - Daret K St Clair
- Department of Toxicology and Cancer Biology, University of Kentucky, USA; Markey Cancer Center, University of Kentucky, USA
| | - Luksana Chaiswing
- Department of Toxicology and Cancer Biology, University of Kentucky, USA; Markey Cancer Center, University of Kentucky, USA.
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Digiovanni S, Lorenzati M, Bianciotto OT, Godel M, Fontana S, Akman M, Costamagna C, Couraud PO, Buffo A, Kopecka J, Riganti C, Salaroglio IC. Blood-brain barrier permeability increases with the differentiation of glioblastoma cells in vitro. Fluids Barriers CNS 2024; 21:89. [PMID: 39487455 PMCID: PMC11529439 DOI: 10.1186/s12987-024-00590-0] [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: 12/31/2023] [Accepted: 10/24/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is an aggressive tumor, difficult to treat pharmacologically because of the blood-brain barrier (BBB), which is rich in ATP-binding cassette (ABC) transporters and tight junction (TJ) proteins. The BBB is disrupted within GBM bulk, but it is competent in brain-adjacent-to-tumor areas, where eventual GBM foci can trigger tumor relapse. How GBM cells influence the permeability of BBB is poorly investigated. METHODS To clarify this point, we co-cultured human BBB models with 3 patient-derived GBM cells, after separating from each tumor the stem cell/neurosphere (SC/NS) and the differentiated/adherent cell (AC) components. Also, we set up cultures of BBB cells with the conditioned medium of NS or AC, enriched or depleted of IL-6. Extracellular cytokines were measured by protein arrays and ELISA. The intracellular signaling in BBB cells was measured by immunoblotting, in the presence of STAT3 pharmacological inhibitor or specific PROTAC. The competence of BBB was evaluated by permeability assays and TEER measurement. RESULTS The presence of GBM cells or their conditioned medium increased the permeability to doxorubicin, mitoxantrone and dextran-70, decreased TEER, down-regulated ABC transporters and TJ proteins at the transcriptional level. These effects were higher with AC or their medium than with NS. The secretome analysis identified IL-6 as significantly more produced by AC than by NS. Notably, AC-conditioned medium treated with an IL-6 neutralizing antibody reduced the BBB permeability to NS levels, while NS-conditioned medium enriched with IL-6 increased BBB permeability to AC levels. Mechanistically, IL-6 released by AC GBM cells activated STAT3 in BBB cells. In turn, STAT3 down-regulated ABC transporter and TJ expression, increased permeability and decreased TEER. The same effects were obtained in BBB cells treated with STA-21, a pharmacological inhibitor of STAT3, or with a PROTAC targeting STAT3. CONCLUSIONS Our work demonstrates for the first time that the degree of GBM differentiation influences BBB permeability. The crosstalk between GBM cells that release IL-6 and BBB cells that respond by activating STAT3, controls the expression of ABC transporters and TJ proteins on BBB. These results may pave the way for novel therapeutic tools to tune BBB permeability and improve drug delivery to GBM.
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Affiliation(s)
- Sabrina Digiovanni
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy
- Molecular Biotechnology Center "Guido Tarone", University of Torino, piazza Nizza 44, Torino, 10126, Italy
| | - Martina Lorenzati
- Department of Neuroscience Rita Levi Montalcini, Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano, 10043, Italy
| | - Olga Teresa Bianciotto
- Department of Neuroscience Rita Levi Montalcini, Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano, 10043, Italy
| | - Martina Godel
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy
| | - Simona Fontana
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy
- Molecular Biotechnology Center "Guido Tarone", University of Torino, piazza Nizza 44, Torino, 10126, Italy
| | - Muhlis Akman
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy
| | - Costanzo Costamagna
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy
- Molecular Biotechnology Center "Guido Tarone", University of Torino, piazza Nizza 44, Torino, 10126, Italy
| | | | - Annalisa Buffo
- Department of Neuroscience Rita Levi Montalcini, Institute Cavalieri Ottolenghi, Regione Gonzole 10, Orbassano, 10043, Italy
| | - Joanna Kopecka
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy
- Molecular Biotechnology Center "Guido Tarone", University of Torino, piazza Nizza 44, Torino, 10126, Italy
| | - Chiara Riganti
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy.
- Molecular Biotechnology Center "Guido Tarone", University of Torino, piazza Nizza 44, Torino, 10126, Italy.
| | - Iris Chiara Salaroglio
- Department of Oncology, University of Torino, piazza Nizza 44, Torino, 10126, Italy
- Molecular Biotechnology Center "Guido Tarone", University of Torino, piazza Nizza 44, Torino, 10126, Italy
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Tastan B, Heneka MT. The impact of neuroinflammation on neuronal integrity. Immunol Rev 2024; 327:8-32. [PMID: 39470038 DOI: 10.1111/imr.13419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
Neuroinflammation, characterized by a complex interplay among innate and adaptive immune responses within the central nervous system (CNS), is crucial in responding to infections, injuries, and disease pathologies. However, the dysregulation of the neuroinflammatory response could significantly affect neurons in terms of function and structure, leading to profound health implications. Although tremendous progress has been made in understanding the relationship between neuroinflammatory processes and alterations in neuronal integrity, the specific implications concerning both structure and function have not been extensively covered, with the exception of perspectives on glial activation and neurodegeneration. Thus, this review aims to provide a comprehensive overview of the multifaceted interactions among neurons and key inflammatory players, exploring mechanisms through which inflammation influences neuronal functionality and structural integrity in the CNS. Further, it will discuss how these inflammatory mechanisms lead to impairment in neuronal functions and architecture and highlight the consequences caused by dysregulated neuronal functions, such as cognitive dysfunction and mood disorders. By integrating insights from recent research findings, this review will enhance our understanding of the neuroinflammatory landscape and set the stage for future interventions that could transform current approaches to preserve neuronal integrity and function in CNS-related inflammatory conditions.
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Affiliation(s)
- Bora Tastan
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Michael T Heneka
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, North Worcester, Massachusetts, USA
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Wu JJ, Zhang SY, Mu L, Dong ZG, Zhang YJ. Heyingwuzi formulation alleviates diabetic retinopathy by promoting mitophagy via the HIF-1α/BNIP3/NIX axis. World J Diabetes 2024; 15:1317-1339. [PMID: 38983802 PMCID: PMC11229969 DOI: 10.4239/wjd.v15.i6.1317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/22/2024] [Accepted: 04/01/2024] [Indexed: 06/11/2024] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is the primary cause of visual problems in patients with diabetes. The Heyingwuzi formulation (HYWZF) is effective against DR. AIM To determine the HYWZF prevention mechanisms, especially those underlying mitophagy. METHODS Human retinal capillary endothelial cells (HRCECs) were treated with high glucose (hg), HYWZF serum, PX-478, or Mdivi-1 in vitro. Then, cell counting kit-8, transwell, and tube formation assays were used to evaluate HRCEC proliferation, invasion, and tube formation, respectively. Transmission electron microscopy was used to assess mitochondrial morphology, and Western blotting was used to determine the protein levels. Flow cytometry was used to assess cell apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Moreover, C57BL/6 mice were established in vivo using streptozotocin and treated with HYWZF for four weeks. Blood glucose levels and body weight were monitored continuously. Changes in retinal characteristics were evaluated using hematoxylin and eosin, tar violet, and periodic acid-Schiff staining. Protein levels in retinal tissues were determined via Western blotting, immunohistochemistry, and immunostaining. RESULTS HYWZF inhibited excessive ROS production, apoptosis, tube formation, and invasion in hg-induced HRCECs via mitochondrial autophagy in vitro. It increased the mRNA expression levels of BCL2-interacting protein 3 (BNIP3), FUN14 domain-containing 1, BNIP3-like (BNIP3L, also known as NIX), PARKIN, PTEN-induced kinase 1, and hypoxia-inducible factor (HIF)-1α. Moreover, it downregulated the protein levels of vascular endothelial cell growth factor and increased the light chain 3-II/I ratio. However, PX-478 and Mdivi-1 reversed these effects. Additionally, PX-478 and Mdivi-1 rescued the effects of HYWZF by decreasing oxidative stress and apoptosis and increasing mitophagy. HYWZF intervention improved the symptoms of diabetes, tissue damage, number of acellular capillaries, and oxidative stress in vivo. Furthermore, in vivo experiments confirmed the results of in vitro experiments. CONCLUSION HYWZF alleviated DR and associated damage by promoting mitophagy via the HIF-1α/BNIP3/NIX axis.
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Affiliation(s)
- Jia-Jun Wu
- Department of Ophthalmology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Shu-Yan Zhang
- Department of Ophthalmology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Lin Mu
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China
| | - Zhi-Guo Dong
- Department of Ophthalmology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yin-Jian Zhang
- Department of Ophthalmology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Auriti C, Mondì V, Piersigilli F, Timelli L, Del Pinto T, Prencipe G, Lucignani G, Longo D, Bersani I. Plasmatic profiles of cytokines/chemokines, glial fibrillary acidic protein (GFAP) and MRI brain damage in neonates with hypoxic ischemic encephalopathy (HIE). Cytokine 2024; 177:156565. [PMID: 38442443 DOI: 10.1016/j.cyto.2024.156565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/21/2024] [Accepted: 02/29/2024] [Indexed: 03/07/2024]
Abstract
BACKGROUND Perinatal hypoxia triggers the release of cytokines and chemokines by neurons, astrocytes and microglia. In response to hypoxia-ischemia resting/ramified microglia proliferate and undergo activation, producing proinflammatory molecules. The brain damage extension seems to be related to both the severity of hypoxia and the balance between pro and anti-inflammatory response and can be explored with neuroimaging. AIMS The aim of this preliminary study was to explore possible relationships between plasma levels of inflammatory cytokines/chemokines and the severe brain damage detectable by Magnetic Resonance Imaging (MRI), performed during the hospitalization. METHODS In 10 full terms neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH), divided into cases and controls, according to MRI results, we measured and compared the plasma levels of CCL2/MCP-1, CXCL8, GFAP, IFN y, IL-10, IL-18, IL-6, CCL3, ENOLASE2, GM-CSF, IL-1b, IL-12p70, IL-33, TNFα, collected at four different time points during TH (24, 25-48, 49-72 h of life, and 7-10 days from birth). Five of enrolled babies had pathological brain MRI (cases) and 5 had a normal MRI examination (controls). Cytokines were measured by Magnetic Luminex Assay. MRI images were classified according to Barkovich's score. RESULTS Mean levels of all cytokines and molecules at time T1 were not significantly different in the two groups. Comparing samples paired by day of collection, the greatest differences between cases and controls were found at times T2 and T3, during TH. At T4, levels tended to get closer again (except for IL-6, IL10 and IL18). Infants with worse MRI showed higher plasmatic GFAP levels than those with normal MRI, while their IL-18 was lower. The mean levels of CCL3MIP1alpha, GMCSF, IL1BETA overlapped throughout the observation period in both groups. CONCLUSION In a small number of infants with worse brain MRI, we found higher levels of GFAP and of IL-10 at T4 and a trend toward low IL-18 levels than in infants with normal MRI, considered early biomarker of brain damage and a predictor of adverse outcome, respectively. The greatest, although not significant, difference between the levels of molecules was found in cases and controls at time points T2 and T3, during TH.
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Affiliation(s)
- Cinzia Auriti
- Unicamillus-Saint Camillus International University of Health Sciences, Rome, Italy; Villa Margherita Private Clinic, Rome, Italy.
| | - Vito Mondì
- Neonatology and Neonatal Intensive Care Unit, Policlinico Casilino, Via Casilina 1049, Rome, Italy
| | - Fiammetta Piersigilli
- Section of Neonatology, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Avenue Hippocrate 10, Bruxelles, Belgium
| | - Laura Timelli
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy
| | - Tamara Del Pinto
- Unicamillus-Saint Camillus International University of Health Sciences, Rome, Italy
| | - Giusi Prencipe
- Laboratory of Immuno-Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy
| | - Giulia Lucignani
- Department of Imaging, "Bambino Gesù" Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy
| | - Daniela Longo
- Department of Imaging, "Bambino Gesù" Children's Hospital IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy
| | - Iliana Bersani
- Neonatal Intensive Care Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy
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7
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Carregari VC, Reis-de-Oliveira G, Crunfli F, Smith BJ, de Souza GF, Muraro SP, Saia-Cereda VM, Vendramini PH, Baldasso PA, Silva-Costa LC, Zuccoli GS, Brandão-Teles C, Antunes A, Valença AF, Davanzo GG, Virgillio-da-Silva JV, Dos Reis Araújo T, Guimarães RC, Chaim FDM, Chaim EA, Kawagosi Onodera CM, Ludwig RG, Saccon TD, Damásio ARL, Leiria LOS, Vinolo MAR, Farias AS, Moraes-Vieira PM, Mori MA, Módena JLP, Martins-de-Souza D. Diving into the proteomic atlas of SARS-CoV-2 infected cells. Sci Rep 2024; 14:7375. [PMID: 38548777 PMCID: PMC10978884 DOI: 10.1038/s41598-024-56328-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/05/2024] [Indexed: 04/01/2024] Open
Abstract
The COVID-19 pandemic was initiated by the rapid spread of a SARS-CoV-2 strain. Though mainly classified as a respiratory disease, SARS-CoV-2 infects multiple tissues throughout the human body, leading to a wide range of symptoms in patients. To better understand how SARS-CoV-2 affects the proteome from cells with different ontologies, this work generated an infectome atlas of 9 cell models, including cells from brain, blood, digestive system, and adipocyte tissue. Our data shows that SARS-CoV-2 infection mainly trigger dysregulations on proteins related to cellular structure and energy metabolism. Despite these pivotal processes, heterogeneity of infection was also observed, highlighting many proteins and pathways uniquely dysregulated in one cell type or ontological group. These data have been made searchable online via a tool that will permit future submissions of proteomic data ( https://reisdeoliveira.shinyapps.io/Infectome_App/ ) to enrich and expand this knowledgebase.
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Affiliation(s)
- Victor C Carregari
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
| | - Guilherme Reis-de-Oliveira
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Fernanda Crunfli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Bradley J Smith
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Gabriela Fabiano de Souza
- Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Stéfanie Primon Muraro
- Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Veronica M Saia-Cereda
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Pedro H Vendramini
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Paulo A Baldasso
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Lícia C Silva-Costa
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Giuliana S Zuccoli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Caroline Brandão-Teles
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - André Antunes
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Aline F Valença
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Gustavo G Davanzo
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - João Victor Virgillio-da-Silva
- Department of Pharmacology, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
- Center for Research in Inflammatory Diseases, Ribeirão Preto, SP, Brazil
| | | | - Raphael Campos Guimarães
- Center for Research in Inflammatory Diseases, Ribeirão Preto, SP, Brazil
- Obesity and Comorbidities Research Center (OCRC), Campinas, São Paulo, Brazil
| | | | - Elinton Adami Chaim
- Department of Surgery, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil
| | | | - Raissa Guimarães Ludwig
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Tatiana Dandolini Saccon
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - André R L Damásio
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Luiz Osório S Leiria
- Department of Pharmacology, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
- Center for Research in Inflammatory Diseases, Ribeirão Preto, SP, Brazil
| | - Marco Aurélio R Vinolo
- Obesity and Comorbidities Research Center (OCRC), Campinas, São Paulo, Brazil
- Hematology-Hemotherapy Center, University of Campinas, Campinas, SP, Brazil
- Laboratory of Immunoinflammation, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Alessandro S Farias
- Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, 05403-000, Brazil
- D'Or Institute for Research and Education (IDOR), São Paulo, 04501-000, Brazil
- Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Pedro M Moraes-Vieira
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
- Obesity and Comorbidities Research Center (OCRC), Campinas, São Paulo, Brazil
- Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Marcelo A Mori
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Pharmacology, Ribeirão Preto Medical School (FMRP), University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
- Laboratory of Immunoinflammation, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - José Luiz P Módena
- Laboratory of Emerging Viruses, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
- D'Or Institute for Research and Education (IDOR), São Paulo, 04501-000, Brazil.
- Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
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Lee YE, Lee SH, Kim WU. Cytokines, Vascular Endothelial Growth Factors, and PlGF in Autoimmunity: Insights From Rheumatoid Arthritis to Multiple Sclerosis. Immune Netw 2024; 24:e10. [PMID: 38455464 PMCID: PMC10917575 DOI: 10.4110/in.2024.24.e10] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
In this review, we will explore the intricate roles of cytokines and vascular endothelial growth factors in autoimmune diseases (ADs), with a particular focus on rheumatoid arthritis (RA) and multiple sclerosis (MS). AD is characterized by self-destructive immune responses due to auto-reactive T lymphocytes and Abs. Among various types of ADs, RA and MS possess inflammation as a central role but in different sites of the patients. Other common aspects among these two ADs are their chronicity and relapsing-remitting symptoms requiring continuous management. First factor inducing these ADs are cytokines, such as IL-6, TNF-α, and IL-17, which play significant roles in the pathogenesis by contributing to inflammation, immune cell activation, and tissue damage. Secondly, vascular endothelial growth factors, including VEGF and angiopoietins, are crucial in promoting angiogenesis and inflammation in these two ADs. Finally, placental growth factor (PlGF), an emerging factor with bi-directional roles in angiogenesis and T cell differentiation, as we introduce as an "angio-lymphokine" is another key factor in ADs. Thus, while angiogenesis recruits more inflammatory cells into the peripheral sites, cytokines secreted by effector cells play critical roles in the pathogenesis of ADs. Various therapeutic interventions targeting these soluble molecules have shown promise in managing autoimmune pathogenic conditions. However, delicate interplay between cytokines, angiogenic factors, and PlGF has more to be studied when considering their complementary role in actual pathogenic conditions. Understanding the complex interactions among these factors provides valuable insights for the development of innovative therapies for RA and MS, offering hope for improved patient outcomes.
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Affiliation(s)
- Young eun Lee
- Graduate School of Medical Science and Engineering (GSMSE), Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Seung-Hyo Lee
- Graduate School of Medical Science and Engineering (GSMSE), Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Wan-Uk Kim
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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9
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Logsdon AF, Erickson MA, Herbert MJ, Noonan C, Foresi BD, Qiu J, Lim YP, Banks WA, Stonestreet BS. Inter-alpha inhibitor proteins attenuate lipopolysaccharide-induced blood-brain barrier disruption in neonatal mice. Exp Neurol 2023; 370:114563. [PMID: 37806514 DOI: 10.1016/j.expneurol.2023.114563] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/21/2023] [Accepted: 10/05/2023] [Indexed: 10/10/2023]
Abstract
There is a paucity of information regarding efficacious pharmacological neuroprotective strategies to attenuate or reduce brain injury in neonates. Lipopolysaccharide (LPS) disrupts blood-brain barrier (BBB) function in adult rodents and increases inflammation in adults and neonates. Human blood-derived Inter-alpha Inhibitor Proteins (IAIPs) are neuroprotective, improve neonatal survival after LPS, and attenuate LPS-induced disruption of the BBB in adult male mice. We hypothesized that LPS also disrupts the function of the BBB in neonatal mice and that IAIPs attenuate the LPS-induced BBB disruption in male and female neonatal mice. IAIPs were administered to neonatal mice after LPS and BBB permeability quantified with intravenous 14C-sucrose and 99mTc-albumin. Although repeated high doses (3 mg/kg) of LPS in neonates resulted in high mortality rates and a robust increase in BBB permeability, repeated lower doses (1 mg/kg) of LPS resulted in lower mortality rates and disruption of the BBB in both male and female neonates. IAIP treatment attenuated disruption of the BBB similarly to sucrose and albumin after exposure to low-dose LPS in neonatal mice. Exposure to low-dose LPS elevated IAIP concentrations in blood, but it did not appear to increase the systemic levels of Pre-alpha inhibitor (PaI), one of the family members of the IAIPs that contains heavy chain 3. We conclude that IAIPs attenuate LPS-related disruption of the BBB in both male and female neonatal mice.
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Affiliation(s)
- Aric F Logsdon
- Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
| | - Michelle A Erickson
- Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Melanie J Herbert
- Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Cassidy Noonan
- Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Brian D Foresi
- College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA
| | - Joseph Qiu
- ProThera Biologics, Inc., Providence, RI 02903, USA
| | - Yow-Pin Lim
- ProThera Biologics, Inc., Providence, RI 02903, USA; Department of Pathology and Laboratory Medicine, The Alpert Medical School of Brown University, Providence, RI, 02905, USA
| | - William A Banks
- Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Barbara S Stonestreet
- The Alpert Medical School of Brown University, Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA
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10
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Ciryam P, Gerzanich V, Simard JM. Interleukin-6 in Traumatic Brain Injury: A Janus-Faced Player in Damage and Repair. J Neurotrauma 2023; 40:2249-2269. [PMID: 37166354 PMCID: PMC10649197 DOI: 10.1089/neu.2023.0135] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
Traumatic brain injury (TBI) is a common and often devastating illness, with wide-ranging public health implications. In addition to the primary injury, victims of TBI are at risk for secondary neurological injury by numerous mechanisms. Current treatments are limited and do not target the profound immune response associated with injury. This immune response reflects a convergence of peripheral and central nervous system-resident immune cells whose interaction is mediated in part by a disruption in the blood-brain barrier (BBB). The diverse family of cytokines helps to govern this communication and among these, Interleukin (IL)-6 is a notable player in the immune response to acute neurological injury. It is also a well-established pharmacological target in a variety of other disease contexts. In TBI, elevated IL-6 levels are associated with worse outcomes, but the role of IL-6 in response to injury is double-edged. IL-6 promotes neurogenesis and wound healing in animal models of TBI, but it may also contribute to disruptions in the BBB and the progression of cerebral edema. Here, we review IL-6 biology in the context of TBI, with an eye to clarifying its controversial role and understanding its potential as a target for modulating the immune response in this disease.
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Affiliation(s)
- Prajwal Ciryam
- Shock Trauma Neurocritical Care, Program in Trauma, R Adams Cowley Shock Trauma Center, University of Maryland Medical System, Baltimore, Maryland, USA
- Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Volodymyr Gerzanich
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - J. Marc Simard
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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11
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Jamil Al-Obaidi MM, Desa MNM. A review of the mechanisms of blood-brain barrier disruption during COVID-19 infection. J Neurosci Res 2023; 101:1687-1698. [PMID: 37462109 DOI: 10.1002/jnr.25232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 06/20/2023] [Accepted: 07/06/2023] [Indexed: 09/10/2023]
Abstract
Coronaviruses are prevalent in mammals and birds, including humans and bats, and they often spread through airborne droplets. In humans, these droplets then interact with angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which are the main receptors for the SARS-CoV-2 virus. It can infect several organs, including the brain. The blood-brain barrier (BBB) is designed to maintain the homeostatic neural microenvironment of the brain, which is necessary for healthy neuronal activity, function, and stability. It prevents viruses from entering the brain parenchyma and does not easily allow chemicals to pass into the brain while assisting numerous compounds in exiting the brain. The purpose of this review was to examine how COVID-19 influences the BBB along with the mechanisms that indicate the BBB's deterioration. In addition, the cellular mechanism through which SARS-CoV-2 causes BBB destruction by binding to ACE2 was evaluated and addressed. The mechanisms of the immunological reaction that occurs during COVID-19 infection that may contribute to the breakdown of the BBB were also reviewed. It was discovered that the integrity of the tight junction (TJs), basement membrane, and adhesion molecules was damaged during COVID-19 infection, which led to the breakdown of the BBB. Therefore, understanding how the BBB is disrupted by COVID-19 infection will provide an indication of how the SARS-CoV-2 virus is able to reach the central nervous system (CNS). The findings of this research may help in the identification of treatment options for COVID-19 that can control and manage the infection.
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Affiliation(s)
- Mazen M Jamil Al-Obaidi
- Biology Unit, Science Department, Rustaq College of Education, University of Technology and Applied Sciences, Al-Rustaq, Oman
| | - Mohd Nasir Mohd Desa
- Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
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12
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Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease. Front Immunol 2023; 14:1255533. [PMID: 37841263 PMCID: PMC10569068 DOI: 10.3389/fimmu.2023.1255533] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 09/11/2023] [Indexed: 10/17/2023] Open
Abstract
Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes, blood brain barrier permeability, synovial inflammation, hematopoiesis, and embryonic development. This cytokine empowers the transition between innate and adaptive immune responses and helps recruit macrophages and lymphocytes to the sites of injury or infection. Given that IL-6 is involved both in the immune homeostasis and pathogenesis of several autoimmune diseases, research into therapeutic modulation of IL-6 axis resulted in the approval of a number of effective treatments for several autoimmune disorders like neuromyelitis optica spectrum disorder (NMOSD), rheumatoid arthritis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis (GCA), and cytokine release syndrome, associated with SARS-CoV2 pneumonia. This review discusses downstream inflammatory pathways of IL-6 expression and therapeutic applications of IL-6 blockade, currently investigated for the treatment of several other autoimmune conditions such as autoimmune encephalitis, autoimmune epilepsy, as well as myelin oligodendrocyte glycoprotein associated demyelination (MOGAD). This review further highlights the need for clinical trials to evaluate IL-6 blockade in disorders such neuropsychiatric lupus erythematosus (SLE), sarcoidosis and Behcet's.
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Affiliation(s)
- Elena Grebenciucova
- Feinberg School of Medicine, Department of Neurology, Northwestern University, Chicago, IL, United States
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13
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Yang J, Li Y, Bhalla A, Maienschein-Cline M, Fukuchi KI. A novel co-culture model for investigation of the effects of LPS-induced macrophage-derived cytokines on brain endothelial cells. PLoS One 2023; 18:e0288497. [PMID: 37440496 PMCID: PMC10343049 DOI: 10.1371/journal.pone.0288497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
In order to study effects of macrophage-derived inflammatory mediators associated with systemic inflammation on brain endothelial cells, we have established a co-culture system consisting of bEnd.3 cells and LPS-activated Raw 264.7 cells and performed its cytokine profiling. The cytokine profile of the co-culture model was compared to that of mice treated with intraperitoneal LPS injection. We found that, among cytokines profiled, eight cytokines/chemokines were similarly upregulated in both in vivo mouse and in vitro co-culture model. In contrast to the co-culture model, the cytokine profile of a common mono-culture system consisting of only LPS-activated bEnd.3 cells had little similarity to that of the in vivo mouse model. These results indicate that the co-culture of bEnd.3 cells with LPS-activated Raw 264.7 cells is a better model than the common mono-culture of LPS-activated bEnd.3 cells to investigate the molecular mechanism in endothelial cells, by which systemic inflammation induces neuroinflammation. Moreover, fibrinogen adherence both to bEnd.3 cells in the co-culture and to brain blood vessels in a LPS-treated animal model of Alzheimer's disease increased. To the best of our knowledge, this is the first to utilize bEnd.3 cells co-cultured with LPS-activated Raw 264.7 cells as an in vitro model to investigate the consequence of macrophage-derived inflammatory mediators on brain endothelial cells.
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Affiliation(s)
- Junling Yang
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United states of America
| | - Yinchuan Li
- Institute of Reproductive Medicine, Medical School of Nantong University, Nantong, Jiangsu, People’s Republic of China
| | - Ambuj Bhalla
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United states of America
| | - Mark Maienschein-Cline
- Research Informatics Core, Research Resources Center, University of Illinois Chicago, Chicago, Illinois, United States of America
| | - Ken-ichiro Fukuchi
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United states of America
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14
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de Rus Jacquet A, Alpaugh M, Denis HL, Tancredi JL, Boutin M, Decaestecker J, Beauparlant C, Herrmann L, Saint-Pierre M, Parent M, Droit A, Breton S, Cicchetti F. The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson's disease. Nat Commun 2023; 14:3651. [PMID: 37339976 DOI: 10.1038/s41467-023-39038-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 05/26/2023] [Indexed: 06/22/2023] Open
Abstract
Astrocyte dysfunction has previously been linked to multiple neurodegenerative disorders including Parkinson's disease (PD). Among their many roles, astrocytes are mediators of the brain immune response, and astrocyte reactivity is a pathological feature of PD. They are also involved in the formation and maintenance of the blood-brain barrier (BBB), but barrier integrity is compromised in people with PD. This study focuses on an unexplored area of PD pathogenesis by characterizing the interplay between astrocytes, inflammation and BBB integrity, and by combining patient-derived induced pluripotent stem cells with microfluidic technologies to generate a 3D human BBB chip. Here we report that astrocytes derived from female donors harboring the PD-related LRRK2 G2019S mutation are pro-inflammatory and fail to support the formation of a functional capillary in vitro. We show that inhibition of MEK1/2 signaling attenuates the inflammatory profile of mutant astrocytes and rescues BBB formation, providing insights into mechanisms regulating barrier integrity in PD. Lastly, we confirm that vascular changes are also observed in the human postmortem substantia nigra of both males and females with PD.
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Affiliation(s)
- A de Rus Jacquet
- Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC, G1V 4G2, Canada.
- Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, 20147, USA.
| | - M Alpaugh
- Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC, G1V 4G2, Canada
- Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - H L Denis
- Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC, G1V 4G2, Canada
- Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada
| | - J L Tancredi
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, 20147, USA
- Cell Biology R&D, Thermo Fisher Scientific, Frederick, MD, 21704, USA
| | - M Boutin
- Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC, G1V 4G2, Canada
| | - J Decaestecker
- Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie, Québec, QC, G1V 4G2, Canada
| | - C Beauparlant
- Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie, Québec, QC, G1V 4G2, Canada
| | - L Herrmann
- Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie, Québec, QC, G1V 4G2, Canada
| | - M Saint-Pierre
- Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC, G1V 4G2, Canada
| | - M Parent
- Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada
- CERVO Brain Research Center, Québec, QC, G1E 1T2, Canada
| | - A Droit
- Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie, Québec, QC, G1V 4G2, Canada
| | - S Breton
- Centre de Recherche du CHU de Québec - Université Laval, Axe Reproduction, santé de la mère et de l'enfant, Québec, QC, G1V 4G2, Canada
- Centre de recherche en reproduction, développement et santé intergénérationnelle, Université Laval, Québec, QC, G1V 4G2, Canada
| | - F Cicchetti
- Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC, G1V 4G2, Canada.
- Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada.
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15
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Girolamo F, Lim YP, Virgintino D, Stonestreet BS, Chen XF. Inter-Alpha Inhibitor Proteins Modify the Microvasculature after Exposure to Hypoxia-Ischemia and Hypoxia in Neonatal Rats. Int J Mol Sci 2023; 24:6743. [PMID: 37047713 PMCID: PMC10094872 DOI: 10.3390/ijms24076743] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/21/2023] [Accepted: 03/29/2023] [Indexed: 04/08/2023] Open
Abstract
Microvasculature develops during early brain development. Hypoxia-ischemia (HI) and hypoxia (H) predispose to brain injury in neonates. Inter-alpha inhibitor proteins (IAIPs) attenuate injury to the neonatal brain after exposure to HI. However, the effects of IAIPs on the brain microvasculature after exposure to HI have not been examined in neonates. Postnatal day-7 rats were exposed to sham treatment or right carotid artery ligation and 8% oxygen for 90 min. HI comprises hypoxia (H) and ischemia to the right hemisphere (HI-right) and hypoxia to the whole body, including the left hemisphere (H-left). Human IAIPs (hIAIPs, 30 mg/kg) or placebo were injected immediately, 24 and 48 h after HI/H. The brains were analyzed 72 h after HI/H to determine the effects of hIAIPs on the microvasculature by laminin immunohistochemistry and calculation of (1) the percentage area stained by laminin, (2) cumulative microvessel length, and (3) density of tunneling nanotubes (TNTs), which are sensitive indicators of the earliest phases of neo-vascularization/collateralization. hIAIPs mainly affected the percent of the laminin-stained area after HI/H, cumulative vessel length after H but not HI, and TNT density in females but not males. hIAIPs modify the effects of HI/H on the microvasculature after brain injury in neonatal rats and exhibit sex-related differential effects. Our findings suggest that treatment with hIAIPs after exposure to H and HI in neonatal rats affects the laminin content of the vessel basal lamina and angiogenic responses in a sex-related fashion.
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Affiliation(s)
- Francesco Girolamo
- Department of Translational Biomedicines and Neuroscience (DiBraiN), University of Bari School of Medicine, 70124 Bari, Italy
| | - Yow-Pin Lim
- ProThera Biologics, Inc., Providence, RI 02905, USA
- Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Providence, RI 02905, USA
| | - Daniela Virgintino
- Department of Translational Biomedicines and Neuroscience (DiBraiN), University of Bari School of Medicine, 70124 Bari, Italy
| | - Barbara S. Stonestreet
- Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, Providence, RI 02905, USA
| | - Xiaodi F. Chen
- Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, Providence, RI 02905, USA
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16
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Devi VJ, Radhika A, Biju PG. Adenosine receptor activation promotes macrophage class switching from LPS-induced acute inflammatory M1 to anti-inflammatory M2 phenotype. Immunobiology 2023. [PMID: 36863089 DOI: 10.1016/j.imbio.2023.152362] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Lipopolysaccharide induced monocytes/macrophages exhibit a pro-inflammatory M1 phenotype. Elevated levels of the purine nucleoside adenosine play a major role in this response. The role of adenosine receptor modulation in directing the macrophage phenotype switch from proinflammatory classically activated M1 phenotype to an anti-inflammatory alternatively activated M2 phenotype is investigated in this study. The mouse macrophage cell line RAW 264.7 was used as the experimental model and stimulated with Lipopolysaccharide (LPS) at a dose of 1 μg/ml. Adenosine receptors were activated by treating cells with the receptor agonist NECA (1 μM). Adenosine receptor stimulation in macrophages is found to suppress LPS-induced production of proinflammatory mediators (pro-inflammatory cytokines, Reactive Oxygen Species and nitrite levels). M1 marker CD38 (Cluster of Differentiation 38) and CD83 (Cluster of Differentiation 83) were significantly decreased while M2 markers Th2 cytokines, Arginase, TIMP (Tissue Inhibitor of Metalloproteinases) and CD206 (Cluster of Differentiation 206) exhibited an increase. Hence from our study we observed that activation of adenosine receptors can program the macrophages from a pro-inflammatory classically activated M1 phenotype to an anti-inflammatory alternatively activated M2 phenotype. We report the significance and a time course profile of phenotype switching by receptor activation. Adenosine receptor targeting may be explored as a therapeutic intervention strategy in addressing acute inflammation.
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Affiliation(s)
- Velayudhan Jayasree Devi
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala 695581, India
| | - Achuthan Radhika
- Department of Biochemistry, Government College, Kariavattom, Thiruvananthapuram, Kerala 695581, India
| | - Prabath Gopalakrishnan Biju
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala 695581, India.
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17
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Li Y, Song J, Huq AM, Timilsina S, Gershwin ME. Posterior reversible encephalopathy syndrome and autoimmunity. Autoimmun Rev 2023; 22:103239. [PMID: 36464226 DOI: 10.1016/j.autrev.2022.103239] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022]
Abstract
Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by acute or subacute onset of neurological symptoms (e.g., headache, seizure, confusion, vomiting, and diminished eyesight) and impaired endothelial barrier function of the cerebral circulation that leads to bilateral subcortical vasogenic edema, while exhibiting a "reversible" feature in most cases. Clinically, various predisposing or precipitating conditions have been identified, such as hypertension, autoimmune diseases, renal dysfunction/failure, preeclampsia/eclampsia, post-transplantation conditions, and certain therapeutic agents. Among several putative mechanisms, the immune activation hypothesis prevails, as up to 50% of patients with PRES harbor abnormalities related to autoimmunity, such as concurrent systemic lupus erythematosus. In this Review, we summarize the clinical and laboratory evidence that places PRES in the context of autoimmunity.
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Affiliation(s)
- Yang Li
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, PR China
| | - Junmin Song
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, PR China.
| | - Ahm M Huq
- Department of Pediatrics, Central Michigan University, Detroit, MI 48201, USA
| | - Suraj Timilsina
- Division of Rheumatology/Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA 95616, USA
| | - M Eric Gershwin
- Division of Rheumatology/Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA 95616, USA
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18
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Pawar B, Vasdev N, Gupta T, Mhatre M, More A, Anup N, Tekade RK. Current Update on Transcellular Brain Drug Delivery. Pharmaceutics 2022; 14:pharmaceutics14122719. [PMID: 36559214 PMCID: PMC9786068 DOI: 10.3390/pharmaceutics14122719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/24/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
It is well known that the presence of a blood-brain barrier (BBB) makes drug delivery to the brain more challenging. There are various mechanistic routes through which therapeutic molecules travel and deliver the drug across the BBB. Among all the routes, the transcellular route is widely explored to deliver therapeutics. Advances in nanotechnology have encouraged scientists to develop novel formulations for brain drug delivery. In this article, we have broadly discussed the BBB as a limitation for brain drug delivery and ways to solve it using novel techniques such as nanomedicine, nose-to-brain drug delivery, and peptide as a drug delivery carrier. In addition, the article will help to understand the different factors governing the permeability of the BBB, as well as various formulation-related factors and the body clearance of the drug delivered into the brain.
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Affiliation(s)
| | | | | | | | | | | | - Rakesh Kumar Tekade
- Correspondence: ; Tel.: +91-796674550 or +91-7966745555; Fax: +91-7966745560
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19
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Yuan M, Jin X, Qin F, Zhang X, Wang X, Yuan E, Shi Y, Xu F. The association of γδT lymphocytes with cystic leukomalacia in premature infants. Front Neurol 2022; 13:1043142. [PMID: 36530609 PMCID: PMC9755680 DOI: 10.3389/fneur.2022.1043142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/09/2022] [Indexed: 09/19/2023] Open
Abstract
Background Periventricular leukomalacia (PVL) is an essential cause of cerebral palsy in preterm infants, and cystic PVL (cPVL) is the most severe form of the disease. The pathogenesis of cPVL is complex, and immune imbalances and inflammatory responses may play an essential role in it. Objective This study aimed to investigate the correlation between peripheral blood lymphocyte subsets, especially γδT cells with the pathogenesis of cPVL in preterm infants. Methods Peripheral blood from preterm infants with GA < 32 weeks and BW < 1,500 g was used in this study and was collected at 34 weeks corrected gestational age and within 24 h after the diagnosis with cranial MRI or cranial ultrasound. The infants were divided into cPVL groups and control groups. Flow cytometry was used to detect peripheral blood γδT, CD3+, CD4+, CD8+, and the proportion of total lymphocytes. Multiplex cell assays were used to detect the concentration of extracellular serum cytokines IL-6, IL-2, IL-8, IL-17A, IL-10, IL-1RA, eotaxin (CCL11), MCP-1 (CCL2), CXCL1, G-CSF, and IFNγ. A follow-up visit was carried out when the patient was 3 years old. Results After correcting for confounding factors, the proportion of peripheral blood γδT in the cPVL group was significantly lower than that in the control group (β: 0.216; 95% CI: 0.058-0.800, P < 0.022). Peripheral blood γδT (AUC: 0.722, P=0.006) and multivariate binary regression model (AUC: 0.865, P < 0.000) have good diagnostic values for cPVL. Peripheral blood γδT has some predictive power for neurodevelopmental outcomes in preterm infants (AUC: 0.743, P = 0.002). Conclusion It seems that peripheral blood γδT cells are inversely correlated with cPVL, which is not only a risk factor for cPVL disease but also neurodevelopmental outcomes in preterm infants. However, the causality of cPVL and various lymphocytes is unclear and needs further study.
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Affiliation(s)
- Mengjie Yuan
- Department of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
| | - Xinyun Jin
- Department of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
| | - Fanyue Qin
- Department of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
| | - Xiaoli Zhang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Xiaoyang Wang
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
| | - Enwu Yuan
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying Shi
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Falin Xu
- Department of Neonatology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China
- Advanced Medical Research Center of Zhengzhou University, Zhengzhou, Henan, China
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Chen P, Li Y, Liu R, Xie Y, Jin Y, Wang M, Yu Z, Wang W, Luo X. Non-small cell lung cancer-derived exosomes promote proliferation, phagocytosis, and secretion of microglia via exosomal microRNA in the metastatic microenvironment. Transl Oncol 2022; 27:101594. [PMID: 36463825 PMCID: PMC9719005 DOI: 10.1016/j.tranon.2022.101594] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/29/2022] [Accepted: 11/23/2022] [Indexed: 12/04/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common tumor that metastasizes to the brain. It is now accepted that the successful colonization and growth of tumor cells are determined by the interaction between tumor cells and the tumor microenvironment (TME). Microglia, brain innate immune cells, have been reported to play a vital role in the establishment of brain metastases. As essential mediators of intercellular communications, tumor-derived exosomes have an important role in the pathogenesis and progression of cancer by transferring their cargos to specific recipient cells. The crosstalk between microglia and tumor-derived exosomes has been extensively described. However, it is still unclear whether metastatic NSCLC cells secret exosomes to microglia and regulate the microglial functions. Here, our results showed that microglia aggregated in the brain metastatic sites. Meanwhile, microglia could take up the exosomes derived from NSCLC cells, leading to alterations of microglial morphology and increased proliferation, phagocytosis, and release of inflammatory cytokines including interleukin-6, interleukin-8, and CXCL1. Further investigation indicated that miR1246 was the most enriched microRNA in NSCLC-derived exosomes and mediated the partial effects of exosomes on microglia. Notably, miR1246 was also upregulated in the plasmatic exosomes of NSCLC patients. These results offer a new insight into the impact of NSCLC-derived exosomes on microglia and provide a new potential biomarker for diagnosing NSCLC.
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Affiliation(s)
- Peng Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ying Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Rui Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yi Xie
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yu Jin
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Minghuan Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhiyuan Yu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiang Luo
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China,Correspondence author.
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The Crosstalk between the Blood–Brain Barrier Dysfunction and Neuroinflammation after General Anaesthesia. Curr Issues Mol Biol 2022; 44:5700-5717. [PMID: 36421670 PMCID: PMC9689502 DOI: 10.3390/cimb44110386] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022] Open
Abstract
As we know, with continuous medical progress, the treatment of many diseases can be conducted via surgery, which often relies on general anaesthesia for its satisfactory performance. With the widespread use of general anaesthetics, people are beginning to question the safety of general anaesthesia and there is a growing interest in central nervous system (CNS) complications associated with anaesthetics. Recently, abundant evidence has suggested that both blood–brain barrier (BBB) dysfunction and neuroinflammation play roles in the development of CNS complications after anaesthesia. Whether there is a crosstalk between BBB dysfunction and neuroinflammation after general anaesthesia, and whether this possible crosstalk could be a therapeutic target for CNS complications after general anaesthesia needs to be clarified by further studies.
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22
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Jiao L, Guo S. Anti-IL-6 therapies in central nervous system inflammatory demyelinating diseases. Front Immunol 2022; 13:966766. [PMID: 36389702 PMCID: PMC9647084 DOI: 10.3389/fimmu.2022.966766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/20/2022] [Indexed: 08/11/2023] Open
Abstract
Current treatments for central nervous system (CNS) inflammatory demyelinating diseases (IDDs) include corticosteroids, plasma exchange, intravenous immunoglobulin, and immunosuppressant drugs. However, some patients do not respond well to traditional therapies. In recent years, novel drugs, such as monoclonal antibodies, targeting the complement component C5, CD19 on B cells, and the interleukin-6 (IL-6) receptor, have been used for the treatment of patients with refractory CNS IDDs. Among these, tocilizumab and satralizumab, humanized monoclonal antibodies against the IL-6 receptor, have shown beneficial effects in the treatment of this group of diseases. In this review, we summarize current research progress and prospects relating to anti-IL-6 therapies in CNS IDDs.
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Affiliation(s)
- Li Jiao
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shougang Guo
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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23
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Yang J, Ran M, Li H, Lin Y, Ma K, Yang Y, Fu X, Yang S. New insight into neurological degeneration: Inflammatory cytokines and blood–brain barrier. Front Mol Neurosci 2022; 15:1013933. [PMID: 36353359 PMCID: PMC9637688 DOI: 10.3389/fnmol.2022.1013933] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/20/2022] [Indexed: 11/30/2022] Open
Abstract
Neurological degeneration after neuroinflammation, such as that resulting from Alzheimer’s disease (AD), stroke, multiple sclerosis (MS), and post-traumatic brain injury (TBI), is typically associated with high mortality and morbidity and with permanent cognitive dysfunction, which places a heavy economic burden on families and society. Diagnosing and curing these diseases in their early stages remains a challenge for clinical investigation and treatment. Recent insight into the onset and progression of these diseases highlights the permeability of the blood–brain barrier (BBB). The primary factor that influences BBB structure and function is inflammation, especially the main cytokines including IL-1β, TNFα, and IL-6, the mechanism on the disruption of which are critical component of the aforementioned diseases. Surprisingly, the main cytokines from systematic inflammation can also induce as much worse as from neurological diseases or injuries do. In this review, we will therefore discuss the physiological structure of BBB, the main cytokines including IL-1β, TNFα, IL-6, and their mechanism on the disruption of BBB and recent research about the main cytokines from systematic inflammation inducing the disruption of BBB and cognitive impairment, and we will eventually discuss the need to prevent the disruption of BBB.
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Affiliation(s)
- Jie Yang
- Research Centre for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital, PLA Medical College, Beijing, China
- Department of Dermatology, 4th Medical Centre, PLA General Hospital, Beijing, China
| | - Mingzi Ran
- Research Centre for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital, PLA Medical College, Beijing, China
- Department of Anaesthesiology, 4th Medical Centre, PLA General Hospital, Beijing, China
| | - Hongyu Li
- Research Centre for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital, PLA Medical College, Beijing, China
- Department of Dermatology, 4th Medical Centre, PLA General Hospital, Beijing, China
| | - Ye Lin
- Department of Neurology, The First Medical Centre, PLA General Hospital, Beijing, China
| | - Kui Ma
- Research Centre for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital, PLA Medical College, Beijing, China
| | - Yuguang Yang
- Department of Dermatology, 4th Medical Centre, PLA General Hospital, Beijing, China
| | - Xiaobing Fu
- Research Centre for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital, PLA Medical College, Beijing, China
- Xiaobing Fu,
| | - Siming Yang
- Research Centre for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital, PLA Medical College, Beijing, China
- Department of Dermatology, 4th Medical Centre, PLA General Hospital, Beijing, China
- *Correspondence: Siming Yang,
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Adesse D, Gladulich L, Alvarez-Rosa L, Siqueira M, Marcos AC, Heider M, Motta CS, Torices S, Toborek M, Stipursky J. Role of aging in Blood-Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19. Fluids Barriers CNS 2022; 19:63. [PMID: 35982454 PMCID: PMC9386676 DOI: 10.1186/s12987-022-00357-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 07/18/2022] [Indexed: 12/21/2022] Open
Abstract
COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. The blood-brain barrier (BBB) was suggested to be the major route of SARS-CoV-2 infection of the brain. Functionally, the BBB is created by an interactome between endothelial cells, pericytes, astrocytes, microglia, and neurons, which form the neurovascular units (NVU). However, at present, the interactions of SARS-CoV-2 with the NVU and the outcomes of this process are largely unknown. Moreover, age was described as one of the most prominent risk factors for hospitalization and deaths, along with other comorbidities such as diabetes and co-infections. This review will discuss the impact of SARS-CoV-2 on the NVU, the expression profile of SARS-CoV-2 receptors in the different cell types of the CNS and the possible role of aging in the neurological outcomes of COVID-19. A special emphasis will be placed on mitochondrial functions because dysfunctional mitochondria are also a strong inducer of inflammatory reactions and the "cytokine storm" associated with SARS-CoV-2 infection. Finally, we will discuss possible drug therapies to treat neural endothelial function in aged patients, and, thus, alleviate the neurological symptoms associated with COVID-19.
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Affiliation(s)
- Daniel Adesse
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Pavilhão Carlos Chagas, sala 307b, Rio de Janeiro, RJ, 21040-360, Brazil.
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| | - Luis Gladulich
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Pavilhão Carlos Chagas, sala 307b, Rio de Janeiro, RJ, 21040-360, Brazil
| | - Liandra Alvarez-Rosa
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Pavilhão Carlos Chagas, sala 307b, Rio de Janeiro, RJ, 21040-360, Brazil
- Laboratório Compartilhado, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Michele Siqueira
- Laboratório Compartilhado, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Anne Caroline Marcos
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Pavilhão Carlos Chagas, sala 307b, Rio de Janeiro, RJ, 21040-360, Brazil
| | - Marialice Heider
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Pavilhão Carlos Chagas, sala 307b, Rio de Janeiro, RJ, 21040-360, Brazil
| | - Caroline Soares Motta
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Avenida Brasil, 4365, Pavilhão Carlos Chagas, sala 307b, Rio de Janeiro, RJ, 21040-360, Brazil
| | - Silvia Torices
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Michal Toborek
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
- Institute of Physiotherapy and Health Sciences, The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
| | - Joice Stipursky
- Laboratório Compartilhado, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Activation of NLRP3 Is Required for a Functional and Beneficial Microglia Response after Brain Trauma. Pharmaceutics 2022; 14:pharmaceutics14081550. [PMID: 35893807 PMCID: PMC9332196 DOI: 10.3390/pharmaceutics14081550] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 12/04/2022] Open
Abstract
Despite the numerous research studies on traumatic brain injury (TBI), many physiopathologic mechanisms remain unknown. TBI is a complex process, in which neuroinflammation and glial cells play an important role in exerting a functional immune and damage-repair response. The activation of the NLRP3 inflammasome is one of the first steps to initiate neuroinflammation and so its regulation is essential. Using a closed-head injury model and a pharmacological (MCC950; 3 mg/kg, pre- and post-injury) and genetical approach (NLRP3 knockout (KO) mice), we defined the transcriptional and behavioral profiles 24 h after TBI. Wild-type (WT) mice showed a strong pro-inflammatory response, with increased expression of inflammasome components, microglia and astrocytes markers, and cytokines. There was no difference in the IL1β production between WT and KO, nor compensatory mechanisms of other inflammasomes. However, some microglia and astrocyte markers were overexpressed in KO mice, resulting in an exacerbated cytokine expression. Pretreatment with MCC950 replicated the behavioral and blood-brain barrier results observed in KO mice and its administration 1 h after the lesion improved the damage. These findings highlight the importance of NLRP3 time-dependent activation and its role in the fine regulation of glial response.
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The role of IL-6 in TBI and PTSD, a potential therapeutic target? Clin Neurol Neurosurg 2022; 218:107280. [PMID: 35567833 DOI: 10.1016/j.clineuro.2022.107280] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/15/2022] [Accepted: 05/02/2022] [Indexed: 01/14/2023]
Abstract
This literature review focuses on the role of IL-6 in TBI or PTSD-induced neuroinflammation. While TBI and PTSD are widely prevalent, these diagnoses are particularly common amongst veterans. Given the role of IL-6 in neuroprotection acutely, compared to detrimental chronically, targeting this cytokine at specific time points may be beneficial in modulating neuroinflammation. Current treatments for TBI or PTSD are variably affective. By reviewing the role of IL-6 in these two diagnoses, future studies can focus on therapeutics to treat neuroinflammation and ultimately reduce the devastating impacts of neuroinflammation on cognition in PTSD and TBI.
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Mu X, Zhang X, Gao H, Gao L, Li Q, Zhao C. Crosstalk between peripheral and the brain-resident immune components in epilepsy. J Integr Neurosci 2022; 21:9. [PMID: 35164445 DOI: 10.31083/j.jin2101009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 03/30/2021] [Accepted: 05/31/2021] [Indexed: 01/05/2025] Open
Abstract
Epilepsy is one of the most common neurology diseases. It is characterized by recurrent, spontaneous seizures and accompanied by various comorbidities which can significantly affect a person's life. Accumulating evidence indicates an essential pathophysiological role for neuroinflammation in epilepsy, which involves activation of microglia and astrocytes, recruitment of peripheral leukocytes into the central nervous system, and release of some inflammatory mediators, including pro-inflammatory factors and anti-inflammatory cytokines. There is complex crosstalk between the central nervous system and peripheral immune responses associated with the progression of epilepsy. This review provides an update of current knowledge about the contribution of this crosstalk associated with epilepsy. Additionally, how gut microbiota is involved in epilepsy and its possible influence on crosstalk is also discussed. Such recent advances in understanding suggest innovative methods for targeting the molecules correlated with the crosstalk and may provide a better prognosis for patients diagnosed with epilepsy.
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Affiliation(s)
- Xiaopeng Mu
- Neurology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
- Neurology, The Fourth Hospital of China Medical University, 110032 Shenyang, Liaoning, China
| | - Xiuchun Zhang
- Neurology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
| | - Honghua Gao
- Neurology, The Fourth Hospital of China Medical University, 110032 Shenyang, Liaoning, China
| | - Lianbo Gao
- Neurology, The Fourth Hospital of China Medical University, 110032 Shenyang, Liaoning, China
| | - Qingchang Li
- Department of Pathology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
| | - Chuansheng Zhao
- Neurology, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
- Stroke Center, The First Hospital of China Medical University, 110001 Shenyang, Liaoning, China
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Targeting tight junctions to fight against viral neuroinvasion. Trends Mol Med 2021; 28:12-24. [PMID: 34810086 DOI: 10.1016/j.molmed.2021.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 11/23/2022]
Abstract
The clinical impact of viral neuroinvasion on the central nervous system (CNS) ranges from barely detectable to deadly, including acute and chronic outcomes. Developing innovative therapeutic strategies is important to mitigate virus-induced neurological and psychiatric disorders. A key gatekeeper to the CNS is the neurovascular unit (NVU), a major obstacle to viral neuroinvasion and antiviral therapies. The NVU isolates the brain from the blood through firm sealing operated by the tight junctions (TJs) of endothelial cells. Here, we make the thought-provoking assumption that TJs can be targets to prevent or treat viral neuroinvasion and resulting disorders. This review aims at defining the conceptual diverse mode of actions of such approaches, evaluates their feasibility, and discusses future challenges in the field.
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Dunton AD, Göpel T, Ho DH, Burggren W. Form and Function of the Vertebrate and Invertebrate Blood-Brain Barriers. Int J Mol Sci 2021; 22:ijms222212111. [PMID: 34829989 PMCID: PMC8618301 DOI: 10.3390/ijms222212111] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/23/2021] [Accepted: 10/28/2021] [Indexed: 12/25/2022] Open
Abstract
The need to protect neural tissue from toxins or other substances is as old as neural tissue itself. Early recognition of this need has led to more than a century of investigation of the blood-brain barrier (BBB). Many aspects of this important neuroprotective barrier have now been well established, including its cellular architecture and barrier and transport functions. Unsurprisingly, most research has had a human orientation, using mammalian and other animal models to develop translational research findings. However, cell layers forming a barrier between vascular spaces and neural tissues are found broadly throughout the invertebrates as well as in all vertebrates. Unfortunately, previous scenarios for the evolution of the BBB typically adopt a classic, now discredited 'scala naturae' approach, which inaccurately describes a putative evolutionary progression of the mammalian BBB from simple invertebrates to mammals. In fact, BBB-like structures have evolved independently numerous times, complicating simplistic views of the evolution of the BBB as a linear process. Here, we review BBBs in their various forms in both invertebrates and vertebrates, with an emphasis on the function, evolution, and conditional relevance of popular animal models such as the fruit fly and the zebrafish to mammalian BBB research.
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Affiliation(s)
- Alicia D. Dunton
- Developmental Integrative Biology Group, Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA; (T.G.); (W.B.)
- Correspondence:
| | - Torben Göpel
- Developmental Integrative Biology Group, Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA; (T.G.); (W.B.)
| | - Dao H. Ho
- Department of Clinical Investigation, Tripler Army Medical Center, Honolulu, HI 96859, USA;
| | - Warren Burggren
- Developmental Integrative Biology Group, Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA; (T.G.); (W.B.)
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Archie SR, Al Shoyaib A, Cucullo L. Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview. Pharmaceutics 2021; 13:pharmaceutics13111779. [PMID: 34834200 PMCID: PMC8622070 DOI: 10.3390/pharmaceutics13111779] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/15/2021] [Accepted: 10/20/2021] [Indexed: 01/22/2023] Open
Abstract
The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the trafficking of immune cells between the blood and the brain. The BBB is primarily composed of highly specialized microvascular endothelial cells. These cells’ special features and physiological properties are acquired and maintained through the concerted effort of hemodynamic and cellular cues from the surrounding environment. This complex multicellular system, comprising endothelial cells, astrocytes, pericytes, and neurons, is known as the neurovascular unit (NVU). The BBB strictly controls the transport of nutrients and metabolites into brain parenchyma through a tightly regulated transport system while limiting the access of potentially harmful substances via efflux transcytosis and metabolic mechanisms. Not surprisingly, a disruption of the BBB has been associated with the onset and/or progression of major neurological disorders. Although the association between disease and BBB disruption is clear, its nature is not always evident, specifically with regard to whether an impaired BBB function results from the pathological condition or whether the BBB damage is the primary pathogenic factor prodromal to the onset of the disease. In either case, repairing the barrier could be a viable option for treating and/or reducing the effects of CNS disorders. In this review, we describe the fundamental structure and function of the BBB in both healthy and altered/diseased conditions. Additionally, we provide an overview of the potential therapeutic targets that could be leveraged to restore the integrity of the BBB concomitant to the treatment of these brain disorders.
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Affiliation(s)
- Sabrina Rahman Archie
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (S.R.A.); (A.A.S.)
| | - Abdullah Al Shoyaib
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (S.R.A.); (A.A.S.)
| | - Luca Cucullo
- Department of Foundational Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, MI 48309, USA
- Correspondence: ; Tel.: +1-248-370-3884; Fax: +1-248-370-4060
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Lashkari A, Ranjbar R. A case-based systematic review on the SARS-COVID-2-associated cerebrovascular diseases and the possible virus routes of entry. J Neurovirol 2021; 27:691-701. [PMID: 34546547 PMCID: PMC8454012 DOI: 10.1007/s13365-021-01013-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/13/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sparked a global pandemic that continues to affect various facets of human existence. Many sources reported virus-induced acute cerebrovascular disorders. Systematically, this paper reviews the case studies of COVID-19-related acute cerebrovascular diseases such as ischaemic stroke, intracerebral hemorrhage, and cerebral sinus thrombosis. We also spoke about how SARS-CoV-2 can infect the brain and trigger the aforementioned disorders. We stated that SARS-CoV-2 neuroinvasion and BBB dysfunction could cause the observed disorders; however, further research is required to specify the mechanisms and pathogenesis of the virus.
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Affiliation(s)
- Ali Lashkari
- Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Reza Ranjbar
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Li J, Zheng M, Shimoni O, Banks WA, Bush AI, Gamble JR, Shi B. Development of Novel Therapeutics Targeting the Blood-Brain Barrier: From Barrier to Carrier. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2101090. [PMID: 34085418 PMCID: PMC8373165 DOI: 10.1002/advs.202101090] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/11/2021] [Indexed: 05/05/2023]
Abstract
The blood-brain barrier (BBB) is a highly specialized neurovascular unit, initially described as an intact barrier to prevent toxins, pathogens, and potentially harmful substances from entering the brain. An intact BBB is also critical for the maintenance of normal neuronal function. In cerebral vascular diseases and neurological disorders, the BBB can be disrupted, contributing to disease progression. While restoration of BBB integrity serves as a robust biomarker of better clinical outcomes, the restrictive nature of the intact BBB presents a major hurdle for delivery of therapeutics into the brain. Recent studies show that the BBB is actively engaged in crosstalk between neuronal and the circulatory systems, which defines another important role of the BBB: as an interfacing conduit that mediates communication between two sides of the BBB. This role has been subject to extensive investigation for brain-targeted drug delivery and shows promising results. The dual roles of the BBB make it a unique target for drug development. Here, recent developments and novel strategies to target the BBB for therapeutic purposes are reviewed, from both barrier and carrier perspectives.
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Affiliation(s)
- Jia Li
- School of PharmacyHenan UniversityKaifeng475001China
- Centre for Motor Neuron DiseaseDepartment of Biomedical SciencesFaculty of Medicine & Health SciencesMacquarie UniversitySydneyNew South Wales2109Australia
| | - Meng Zheng
- Henan‐Macquarie University Joint Center for Biomedical InnovationSchool of Life SciencesHenan UniversityKaifengHenan475004China
| | - Olga Shimoni
- Institute for Biomedical Materials and DevicesSchool of Mathematical and Physical SciencesFaculty of ScienceUniversity of Technology SydneySydneyNew South Wales2007Australia
| | - William A. Banks
- Geriatric Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care System and Division of Gerontology and Geriatric MedicineDepartment of MedicineUniversity of Washington School of MedicineSeattleWA98108USA
| | - Ashley I. Bush
- Melbourne Dementia Research CenterThe Florey Institute for Neuroscience and Mental HealthThe University of MelbourneParkvilleVictoria3052Australia
| | - Jennifer R. Gamble
- Center for the EndotheliumVascular Biology ProgramCentenary InstituteThe University of SydneySydneyNew South Wales2042Australia
| | - Bingyang Shi
- School of PharmacyHenan UniversityKaifeng475001China
- Centre for Motor Neuron DiseaseDepartment of Biomedical SciencesFaculty of Medicine & Health SciencesMacquarie UniversitySydneyNew South Wales2109Australia
- Henan‐Macquarie University Joint Center for Biomedical InnovationSchool of Life SciencesHenan UniversityKaifengHenan475004China
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Chatterjee S, Bose D, Seth R. Host gut microbiome and potential therapeutics in Gulf War Illness: A short review. Life Sci 2021; 280:119717. [PMID: 34139232 DOI: 10.1016/j.lfs.2021.119717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 05/22/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023]
Abstract
AIMS Since our troops had returned from the first Persian Gulf War in 1990-91, the veterans have reported chronic multisymptomatic illness widely referred to as Gulf War Illness (GWI). We aim to review the current directions of GWI pathology research in the context of chronic multisymptomatic illness and its possible gut microbiome targeted therapies. The veterans of Gulf War show symptoms of chronic fatigue, cognitive deficits, and a subsection report of gastrointestinal complications. METHOD Efforts of finding a suitable treatment regimen and clinical management remain a challenge. More recently, we have shown that the pathology is connected to alterations in the gut microbiome, and efforts of finding a suitable regimen for gut-directed therapeutics are underway. We discuss the various clinical interventions and summarize the possible effectiveness of gut-directed therapies such as the use of short-chain fatty acids (SCFA), phenolic compounds, and their metabolites, use of probiotics, and fecal microbiota transfer. SIGNIFICANCE The short review will be helpful to GWI researchers to expand their studies to the gut and find an effective treatment strategy for chronic multisymptomatic illness.
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Affiliation(s)
- Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA; Columbia VA Medical Center, Columbia, SC 29205, USA.
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA; Columbia VA Medical Center, Columbia, SC 29205, USA
| | - Ratanesh Seth
- Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA; Columbia VA Medical Center, Columbia, SC 29205, USA
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De Angulo A, Travis P, Galvan GC, Jolly C, deGraffenried L. Obesity-Modified CD4+ T-Cells Promote an Epithelial-Mesenchymal Transition Phenotype in Prostate Cancer Cells. Nutr Cancer 2021; 74:650-659. [PMID: 33715540 DOI: 10.1080/01635581.2021.1898649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Obesity is associated with low-grade chronic inflammation, and metabolic dysregulation. Evidence shows that chronic inflammation inhibits protective immunity mediated by CD4+ T cells. Additionally, obesity-induced inflammation affects prostate cancer progression. However, the effect of obesity on CD4+ T-cell- response to prostate cancer is not well understood. To investigate whether obesity induces changes in CD4+ T cell cytokine profile, cytokine expression was measured in splenic CD4+ T-cells from 10-week-old male C57Bl/6 mice exposed to conditioned media (CM) from macrophages grown in sera from obese subjects. Additionally, expression levels of key regulators of Epithelial-Mesenchymal Transition (EMT) were measure in prostate cancer epithelial cells exposed to conditioned media from obesity-modified T-cells. Cell migration and invasion was measured in prostate cancer epithelial cells exposed to CM from obesity-modified CD4+ T-cells. Obesity suppressed the expression of IFNγ and IL-2 in CD4+ T-cells but up-regulated the expression of IL-6. Prostate epithelial cancer cells exposed to conditioned media from obesity-modified T cell increased the expression of EMT markers and showed a higher invasive and migratory capacity.
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Affiliation(s)
- Alejandra De Angulo
- Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA
| | - Peyton Travis
- Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA
| | - Gloria Cecilia Galvan
- Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA
| | - Christopher Jolly
- Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA
| | - Linda deGraffenried
- Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, Austin, Texas, USA
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Koehn LM, Chen X, Logsdon AF, Lim YP, Stonestreet BS. Novel Neuroprotective Agents to Treat Neonatal Hypoxic-Ischemic Encephalopathy: Inter-Alpha Inhibitor Proteins. Int J Mol Sci 2020; 21:E9193. [PMID: 33276548 PMCID: PMC7731124 DOI: 10.3390/ijms21239193] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/27/2020] [Accepted: 11/30/2020] [Indexed: 02/02/2023] Open
Abstract
Perinatal hypoxia-ischemia (HI) is a major cause of brain injury and mortality in neonates. Hypoxic-ischemic encephalopathy (HIE) predisposes infants to long-term cognitive deficits that influence their quality of life and place a large burden on society. The only approved treatment to protect the brain after HI is therapeutic hypothermia, which has limited effectiveness, a narrow therapeutic time window, and is not considered safe for treatment of premature infants. Alternative or adjunctive therapies are needed to improve outcomes of full-term and premature infants after exposure to HI. Inter-alpha inhibitor proteins (IAIPs) are immunomodulatory molecules that are proposed to limit the progression of neonatal inflammatory conditions, such as sepsis. Inflammation exacerbates neonatal HIE and suggests that IAIPs could attenuate HI-related brain injury and improve cognitive outcomes associated with HIE. Recent studies have shown that intraperitoneal treatment with IAIPs can decrease neuronal and non-neuronal cell death, attenuate glial responses and leukocyte invasion, and provide long-term behavioral benefits in neonatal rat models of HI-related brain injury. The present review summarizes these findings and outlines the remaining experimental analyses necessary to determine the clinical applicability of this promising neuroprotective treatment for neonatal HI-related brain injury.
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Affiliation(s)
- Liam M. Koehn
- Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA; (L.M.K.); (X.C.)
| | - Xiaodi Chen
- Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA; (L.M.K.); (X.C.)
| | - Aric F. Logsdon
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA;
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Yow-Pin Lim
- ProThera Biologics, Inc., Providence, RI 02903, USA;
- Department of Pathology and Laboratory Medicine, The Alpert Medical School of Brown University, Providence, RI 02903, USA
| | - Barbara S. Stonestreet
- Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA; (L.M.K.); (X.C.)
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Boissady E, Kohlhauer M, Lidouren F, Hocini H, Lefebvre C, Chateau‐Jouber S, Mongardon N, Deye N, Cariou A, Micheau P, Ghaleh B, Tissier R. Ultrafast Hypothermia Selectively Mitigates the Early Humoral Response After Cardiac Arrest. J Am Heart Assoc 2020; 9:e017413. [PMID: 33198571 PMCID: PMC7763769 DOI: 10.1161/jaha.120.017413] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 09/18/2020] [Indexed: 12/17/2022]
Abstract
Background Total liquid ventilation (TLV) has been shown to prevent neurological damage though ultrafast cooling in animal models of cardiac arrest. We investigated whether its neuroprotective effect could be explained by mitigation of early inflammatory events. Methods and Results Rabbits were submitted to 10 minutes of ventricular fibrillation. After resuscitation, they underwent normothermic follow-up (control) or ultrafast cooling by TLV and hypothermia maintenance for 3 hours (TLV). Immune response, survival, and neurological dysfunction were assessed for 3 days. TLV improved neurological recovery and reduced cerebral lesions and leukocyte infiltration as compared with control (eg, neurological dysfunction score=34±6 versus 66±6% at day 1, respectively). TLV also significantly reduced interleukin-6 blood levels during the hypothermic episode (298±303 versus 991±471 pg/mL in TLV versus control at 3 hours after resuscitation, respectively), but not after rewarming (752±563 versus 741±219 pg/mL in TLV versus control at 6 hours after resuscitation, respectively). In vitro assays confirmed the high temperature sensitivity of interleukin-6 secretion. Conversely, TLV did not modify circulating high-mobility group box 1 levels or immune cell recruitment into the peripheral circulation. The link between interleukin-6 early transcripts (<8 hours) and neurological outcome in a subpopulation of the previously described Epo-ACR-02 (High Dose of Erythropoietin Analogue After Cardiac Arrest) trial confirmed the importance of this cytokine at the early stages as compared with delayed stages (>8 hours). Conclusions The neuroprotective effect of hypothermic TLV was associated with a mitigation of humoral interleukin-6 response. A temperature-dependent attenuation of immune cell reactivity during the early phase of the post-cardiac arrest syndrome could explain the potent effect of rapid hypothermia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00999583.
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Affiliation(s)
- Emilie Boissady
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
| | - Matthias Kohlhauer
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
| | - Fanny Lidouren
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
| | - Hakim Hocini
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
- Vaccine Research InstituteUniv Paris Est‐CreteilCreteilFrance
| | - Cécile Lefebvre
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
- Vaccine Research InstituteUniv Paris Est‐CreteilCreteilFrance
| | | | - Nicolas Mongardon
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
- Service d’anesthésie‐Réanimation ChirurgicaleDMU CAREAPHPHôpitaux Universitaires Henri MondorCréteilFrance
| | - Nicolas Deye
- Medical ICUInserm U942Lariboisiere HospitalAPHPParisFrance
| | - Alain Cariou
- Service de Réanimation MédicaleHôpitaux Universitaires Paris CentreHopital CochinParisFrance
| | | | - Bijan Ghaleh
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
| | - Renaud Tissier
- INSERMIMRBEcole Nationale Vétérinaire d’AlfortUniv Paris Est CreteilCreteilFrance
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Verhoog QP, Holtman L, Aronica E, van Vliet EA. Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis. Front Neurol 2020; 11:591690. [PMID: 33324329 PMCID: PMC7726323 DOI: 10.3389/fneur.2020.591690] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/26/2020] [Indexed: 12/11/2022] Open
Abstract
Astrocytes are key homeostatic regulators in the central nervous system and play important roles in physiology. After brain damage caused by e.g., status epilepticus, traumatic brain injury, or stroke, astrocytes may adopt a reactive phenotype. This process of reactive astrogliosis is important to restore brain homeostasis. However, persistent reactive astrogliosis can be detrimental for the brain and contributes to the development of epilepsy. In this review, we will focus on physiological functions of astrocytes in the normal brain as well as pathophysiological functions in the epileptogenic brain, with a focus on acquired epilepsy. We will discuss the role of astrocyte-related processes in epileptogenesis, including reactive astrogliosis, disturbances in energy supply and metabolism, gliotransmission, and extracellular ion concentrations, as well as blood-brain barrier dysfunction and dysregulation of blood flow. Since dysfunction of astrocytes can contribute to epilepsy, we will also discuss their role as potential targets for new therapeutic strategies.
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Affiliation(s)
- Quirijn P. Verhoog
- Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands
- Department of Neuropathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Linda Holtman
- Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands
| | - Eleonora Aronica
- Department of Neuropathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
| | - Erwin A. van Vliet
- Department of Neuropathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
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Achar A, Ghosh C. COVID-19-Associated Neurological Disorders: The Potential Route of CNS Invasion and Blood-Brain Relevance. Cells 2020; 9:cells9112360. [PMID: 33120941 PMCID: PMC7692725 DOI: 10.3390/cells9112360] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/16/2020] [Accepted: 10/26/2020] [Indexed: 12/22/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). The virus invades human cells through the angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway, primarily targeting the human respiratory tract. However, emerging reports of neurological manifestations demonstrate the neuroinvasive potential of SARS-CoV-2. This review highlights the possible routes by which SARS-CoV-2 may invade the central nervous system (CNS) and provides insight into recent case reports of COVID-19-associated neurological disorders, namely ischaemic stroke, encephalitis, encephalopathy, epilepsy, neurodegenerative diseases, and inflammatory-mediated neurological disorders. We hypothesize that SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may be implicated in the development of the observed disorders; however, further research is critical to understand the detailed mechanisms and pathway of infectivity behind CNS pathogenesis.
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Affiliation(s)
- Aneesha Achar
- Cerebrovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Chaitali Ghosh
- Cerebrovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
- Department of Biomedical Engineering and Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Correspondence: ; Tel.: +1-216-445-0559
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Aguiar de Sousa D, Pereira-Santos MC, Serra-Caetano A, Lucas Neto L, Sousa AL, Gabriel D, Correia M, Gil-Gouveia R, Oliveira R, Penas S, Carvalho Dias M, Correia MA, Carvalho M, Sousa AE, Canhão P, Ferro JM. Blood biomarkers associated with inflammation predict poor prognosis in cerebral venous thrombosis:: a multicenter prospective observational study. Eur J Neurol 2020; 28:202-208. [PMID: 32918842 DOI: 10.1111/ene.14526] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/31/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND PURPOSE Experimental studies suggest inflammation can contribute to blood barrier disruption and brain injury in cerebral venous thrombosis (CVT). We aimed to determine whether blood biomarkers of inflammation were associated with the evolution of brain lesions, persistent venous occlusion or functional outcome in patients with CVT. METHODS Pathophysiology of Venous Infarction-Prediction of Infarction and Recanalization in CVT (PRIORITy-CVT) was a multicenter prospective cohort study of patients with newly diagnosed CVT. Evaluation of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) concentrations in peripheral blood samples was performed at admission in 62 patients. Additional quantification of interleukin (IL)-6 was performed at day 1, 3 and 8 in 35 patients and 22 healthy controls. Standardized magnetic resonance imaging was performed at day 1, 8 and 90. Primary outcomes were early evolution of brain lesion, early recanalization and functional outcome at 90 days. RESULTS Interleukin-6 levels were increased in patients with CVT with a peak at baseline. IL-6, NLR and CRP levels were not related with brain lesion outcomes or early recanalization but had a significant association with unfavourable functional outcome at 90 days (IL-6: OR = 1.28, 95% CI: 1.05-1.56, P = 0.046; NLR: OR = 1.39, 95% CI: 1.4-1.87, P = 0.014; CRP: OR = 1.756, 95% CI: 1.010-3.051, P = 0.029). Baseline IL-6 had the best discriminative capacity, with an area under the receiver operating characteristic curve to predict unfavourable functional outcome of 0.74 (P = 0.031). CONCLUSIONS Increased baseline levels of NLR, CRP and IL-6 may serve as new predictive markers of worse functional prognosis at 90 days in patients with CVT. No association was found between inflammatory markers and early evolution of brain lesion or venous recanalization.
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Affiliation(s)
- D Aguiar de Sousa
- Department, of Neurosciences and Mental Health (Neurology), Hospital Santa Maria/Centro Hospitalar Universitário Lisboa Norte, Lisbon.,Institute of Anatomy, Faculdade de Medicina, Universidade de Lisboa, Lisbon.,Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal
| | | | - A Serra-Caetano
- Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal
| | - L Lucas Neto
- Institute of Anatomy, Faculdade de Medicina, Universidade de Lisboa, Lisbon.,Department of Neuroradiology, Hospital de Santa Maria/Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - A L Sousa
- Department of Neurology, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal
| | - D Gabriel
- Department of Neurology, Centro Hospitalar Universitário do Porto - Hospital Santo António, Porto, Portugal
| | - M Correia
- Department of Neurology, Centro Hospitalar Universitário do Porto - Hospital Santo António, Porto, Portugal
| | - R Gil-Gouveia
- Department of Neurology, Hospital da Luz, Lisbon, Portugal
| | - R Oliveira
- Department of Neurology, Hospital da Luz, Lisbon, Portugal
| | - S Penas
- Institute of Anatomy, Faculdade de Medicina, Universidade de Lisboa, Lisbon
| | - M Carvalho Dias
- Department, of Neurosciences and Mental Health (Neurology), Hospital Santa Maria/Centro Hospitalar Universitário Lisboa Norte, Lisbon
| | - M A Correia
- Department of Neuroradiology, Hospital de Santa Maria/Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - M Carvalho
- Department of Neurology, Centro Hospitalar Universitário de São João and Faculty of Medicine, University of Porto, Porto, Portugal
| | - A E Sousa
- Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal
| | - P Canhão
- Department, of Neurosciences and Mental Health (Neurology), Hospital Santa Maria/Centro Hospitalar Universitário Lisboa Norte, Lisbon.,Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal
| | - J M Ferro
- Department, of Neurosciences and Mental Health (Neurology), Hospital Santa Maria/Centro Hospitalar Universitário Lisboa Norte, Lisbon.,Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal
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Furutama D, Matsuda S, Yamawaki Y, Hatano S, Okanobu A, Memida T, Oue H, Fujita T, Ouhara K, Kajiya M, Mizuno N, Kanematsu T, Tsuga K, Kurihara H. IL-6 Induced by Periodontal Inflammation Causes Neuroinflammation and Disrupts the Blood-Brain Barrier. Brain Sci 2020; 10:brainsci10100679. [PMID: 32992470 PMCID: PMC7599694 DOI: 10.3390/brainsci10100679] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/10/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
Background: Periodontal disease (PD) is a risk factor for systemic diseases, including neurodegenerative diseases. The role of the local and systemic inflammation induced by PD in neuroinflammation currently remains unclear. The present study investigated the involvement of periodontal inflammation in neuroinflammation and blood–brain barrier (BBB) disruption. Methods: To induce PD in mice (c57/BL6), a ligature was placed around the second maxillary molar. Periodontal, systemic, and neuroinflammation were assessed based on the inflammatory cytokine mRNA or protein levels using qPCR and ELISA. The BBB permeability was evaluated by the mRNA levels and protein levels of tight junction-related proteins in the hippocampus using qPCR and immunofluorescence. Dextran tracing in the hippocampus was also conducted to examine the role of periodontal inflammation in BBB disruption. Results: The TNF-α, IL-1β, and IL-6 levels markedly increased in gingival tissue 1 week after ligation. The IL-6 serum levels were also increased by ligature-induced PD. In the hippocampus, the IL-1β mRNA expression levels were significantly increased by ligature-induced PD through serum IL-6. The ligature-induced PD decreased the claudin 5 expression levels in the hippocampus, and the neutralization of IL-6 restored its levels. The extravascular 3-kDa dextran levels were increased by ligature-induced PD. Conclusions: These results suggest that the periodontal inflammation-induced expression of IL-6 is related to neuroinflammation and BBB disruption in the hippocampus, ultimately leading to cognitive impairment. Periodontal therapy may protect against neurodegenerative diseases.
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Affiliation(s)
- Daisuke Furutama
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Shinji Matsuda
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
- Correspondence: ; Tel.: +81-082-257-5663
| | - Yosuke Yamawaki
- Department of Advanced Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-cho, Minami-ku Fukuoka 815-8511, Japan;
| | - Saki Hatano
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Ai Okanobu
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Takumi Memida
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Hiroshi Oue
- Department of Advanced Prosthodontics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (H.O.); (K.T.)
| | - Tsuyoshi Fujita
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Kazuhisa Ouhara
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Mikihito Kajiya
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Noriyoshi Mizuno
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
| | - Takashi Kanematsu
- Laboratory of Cell Biology and Pharmacology, Kyushu University Faculty of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;
| | - Kazuhiro Tsuga
- Department of Advanced Prosthodontics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (H.O.); (K.T.)
| | - Hidemi Kurihara
- Department of Periodontal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (D.F.); (S.H.); (A.O.); (T.M.); (T.F.); (K.O.); (M.K.); (N.M.); (H.K.)
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Fujihara K, Bennett JL, de Seze J, Haramura M, Kleiter I, Weinshenker BG, Kang D, Mughal T, Yamamura T. Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2020; 7:7/5/e841. [PMID: 32820020 PMCID: PMC7455314 DOI: 10.1212/nxi.0000000000000841] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/05/2020] [Indexed: 01/03/2023]
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.
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Affiliation(s)
- Kazuo Fujihara
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
| | - Jeffrey L Bennett
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Jerome de Seze
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Masayuki Haramura
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Ingo Kleiter
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Brian G Weinshenker
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Delene Kang
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Tabasum Mughal
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Takashi Yamamura
- From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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Ophelders DR, Gussenhoven R, Klein L, Jellema RK, Westerlaken RJ, Hütten MC, Vermeulen J, Wassink G, Gunn AJ, Wolfs TG. Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key. Cells 2020; 9:E1871. [PMID: 32785181 PMCID: PMC7464163 DOI: 10.3390/cells9081871] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/31/2020] [Accepted: 08/05/2020] [Indexed: 02/08/2023] Open
Abstract
With a worldwide incidence of 15 million cases, preterm birth is a major contributor to neonatal mortality and morbidity, and concomitant social and economic burden Preterm infants are predisposed to life-long neurological disorders due to the immaturity of the brain. The risks are inversely proportional to maturity at birth. In the majority of extremely preterm infants (<28 weeks' gestation), perinatal brain injury is associated with exposure to multiple inflammatory perinatal triggers that include antenatal infection (i.e., chorioamnionitis), hypoxia-ischemia, and various postnatal injurious triggers (i.e., oxidative stress, sepsis, mechanical ventilation, hemodynamic instability). These perinatal insults cause a self-perpetuating cascade of peripheral and cerebral inflammation that plays a critical role in the etiology of diffuse white and grey matter injuries that underlies a spectrum of connectivity deficits in survivors from extremely preterm birth. This review focuses on chorioamnionitis and hypoxia-ischemia, which are two important antenatal risk factors for preterm brain injury, and highlights the latest insights on its pathophysiology, potential treatment, and future perspectives to narrow the translational gap between preclinical research and clinical applications.
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Affiliation(s)
- Daan R.M.G. Ophelders
- Department of Pediatrics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; (D.R.M.G.O.); (R.G.); (L.K.); (R.K.J.); (R.J.J.W.); (M.C.H.)
- School for Oncology and Developmental Biology (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ruth Gussenhoven
- Department of Pediatrics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; (D.R.M.G.O.); (R.G.); (L.K.); (R.K.J.); (R.J.J.W.); (M.C.H.)
| | - Luise Klein
- Department of Pediatrics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; (D.R.M.G.O.); (R.G.); (L.K.); (R.K.J.); (R.J.J.W.); (M.C.H.)
- School for Mental Health and Neuroscience (MHeNS), Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Reint K. Jellema
- Department of Pediatrics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; (D.R.M.G.O.); (R.G.); (L.K.); (R.K.J.); (R.J.J.W.); (M.C.H.)
| | - Rob J.J. Westerlaken
- Department of Pediatrics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; (D.R.M.G.O.); (R.G.); (L.K.); (R.K.J.); (R.J.J.W.); (M.C.H.)
- School for Oncology and Developmental Biology (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Matthias C. Hütten
- Department of Pediatrics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; (D.R.M.G.O.); (R.G.); (L.K.); (R.K.J.); (R.J.J.W.); (M.C.H.)
- School for Oncology and Developmental Biology (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Jeroen Vermeulen
- Department of Pediatric Neurology, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands;
| | - Guido Wassink
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland 1023, New Zealand; (G.W.); (A.J.G.)
| | - Alistair J. Gunn
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland 1023, New Zealand; (G.W.); (A.J.G.)
| | - Tim G.A.M. Wolfs
- Department of Pediatrics, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands; (D.R.M.G.O.); (R.G.); (L.K.); (R.K.J.); (R.J.J.W.); (M.C.H.)
- School for Oncology and Developmental Biology (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands
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Suwannasual U, Lucero J, Davis G, McDonald JD, Lund AK. Mixed Vehicle Emissions Induces Angiotensin II and Cerebral Microvascular Angiotensin Receptor Expression in C57Bl/6 Mice and Promotes Alterations in Integrity in a Blood-Brain Barrier Coculture Model. Toxicol Sci 2020; 170:525-535. [PMID: 31132127 DOI: 10.1093/toxsci/kfz121] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Exposure to traffic-generated pollution is associated with alterations in blood-brain barrier (BBB) integrity and exacerbation of cerebrovascular disorders. Angiotensin (Ang) II signaling through the Ang II type 1 (AT1) receptor is known to promote BBB disruption. We have previously reported that exposure to a mixture of gasoline and diesel vehicle engine emissions (MVE) mediates alterations in cerebral microvasculature of C57Bl/6 mice, which is exacerbated through consumption of a high-fat (HF) diet. Thus, we investigated the hypothesis that inhalation exposure to MVE results in altered central nervous system microvascular integrity mediated by Ang II-AT1 signaling. Three-month-old male C57Bl/6 mice were placed on an HF or low-fat diet and exposed via inhalation to either filtered air (FA) or MVE (100 μg/m3 PM) 6 h/d for 30 days. Exposure to HF+MVE resulted in a significant increase in plasma Ang II and expression of AT1 in the cerebral microvasculature. Results from a BBB coculture study showed that transendothelial electrical resistance was decreased, associated with reduced expression of claudin-5 and occludin when treated with plasma from MVE+HF animals. These effects were attenuated through pretreatment with the AT1 antagonist, Losartan. Our BBB coculture showed increased levels of astrocyte AT1 and decreased expression of aryl hydrocarbon receptor and glutathione peroxidase-1, associated with increased interleukin-6 and transforming growth factor-β in the astrocyte media, when treated with plasma from MVE-exposed groups. Our results indicate that inhalation exposure to traffic-generated pollutants results in altered BBB integrity, mediated through Ang II-AT1 signaling and inflammation, which is exacerbated by an HF diet.
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Affiliation(s)
- Usa Suwannasual
- Department of Biological Sciences, Advanced Environmental Research Institute, University of North Texas, Denton, Texas 76201
| | - JoAnn Lucero
- Department of Biological Sciences, Advanced Environmental Research Institute, University of North Texas, Denton, Texas 76201
| | - Griffith Davis
- Department of Biological Sciences, Advanced Environmental Research Institute, University of North Texas, Denton, Texas 76201
| | - Jacob D McDonald
- Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico 87108
| | - Amie K Lund
- Department of Biological Sciences, Advanced Environmental Research Institute, University of North Texas, Denton, Texas 76201
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DISDIER C, STONESTREET BS. Hypoxic-ischemic-related cerebrovascular changes and potential therapeutic strategies in the neonatal brain. J Neurosci Res 2020; 98:1468-1484. [PMID: 32060970 PMCID: PMC7242133 DOI: 10.1002/jnr.24590] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/20/2020] [Accepted: 01/28/2020] [Indexed: 12/11/2022]
Abstract
Perinatal hypoxic-ischemic (HI)-related brain injury is an important cause of morbidity and long-standing disability in newborns. The only currently approved therapeutic strategy available to reduce brain injury in the newborn is hypothermia. Therapeutic hypothermia can only be used to treat HI encephalopathy in full-term infants and survivors remain at high risk for a wide spectrum of neurodevelopmental abnormalities as a result of residual brain injury. Therefore, there is an urgent need for adjunctive therapeutic strategies. Inflammation and neurovascular damage are important factors that contribute to the pathophysiology of HI-related brain injury and represent exciting potential targets for therapeutic intervention. In this review, we address the role of each component of the neurovascular unit (NVU) in the pathophysiology of HI-related injury in the neonatal brain. Disruption of the blood-brain barrier (BBB) observed in the early hours after an HI-related event is associated with a response at the basal lamina level, which comprises astrocytes, pericytes, and immune cells, all of which could affect BBB function to further exacerbate parenchymal injury. Future research is required to determine potential drugs that could prevent or attenuate neurovascular damage and/or augment repair. However, some studies have reported beneficial effects of hypothermia, erythropoietin, stem cell therapy, anti-cytokine therapy and metformin in ameliorating several different facets of damage to the NVU after HI-related brain injury in the perinatal period.
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Affiliation(s)
- Clémence DISDIER
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA
| | - Barbara S STONESTREET
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA
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Briguglio M, Bona A, Porta M, Dell'Osso B, Pregliasco FE, Banfi G. Disentangling the Hypothesis of Host Dysosmia and SARS-CoV-2: The Bait Symptom That Hides Neglected Neurophysiological Routes. Front Physiol 2020; 11:671. [PMID: 32581854 PMCID: PMC7292028 DOI: 10.3389/fphys.2020.00671] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/26/2020] [Indexed: 12/20/2022] Open
Abstract
The respiratory condition COVID-19 arises in a human host upon the infection with SARS-CoV-2, a coronavirus that was first acknowledged in Wuhan, China, at the end of December 2019 after its outbreak of viral pneumonia. The full-blown COVID-19 can lead, in susceptible individuals, to premature death because of the massive viral proliferation, hypoxia, misdirected host immunoresponse, microthrombosis, and drug toxicities. Alike other coronaviruses, SARS-CoV-2 has a neuroinvasive potential, which may be associated with early neurological symptoms. In the past, the nervous tissue of patients infected with other coronaviruses was shown to be heavily infiltrated. Patients with SARS-CoV-2 commonly report dysosmia, which has been related to the viral access in the olfactory bulb. However, this early symptom may reflect the nasal proliferation that should not be confused with the viral access in the central nervous system of the host, which can instead be allowed by means of other routes for spreading in most of the neuroanatomical districts. Axonal, trans-synaptic, perineural, blood, lymphatic, or Trojan routes can gain the virus multiples accesses from peripheral neuronal networks, thus ultimately invading the brain and brainstem. The death upon respiratory failure may be also associated with the local inflammation- and thrombi-derived damages to the respiratory reflexes in both the lung neuronal network and brainstem center. Beyond the infection-associated neurological symptoms, long-term neuropsychiatric consequences that could occur months after the host recovery are not to be excluded. While our article does not attempt to fully comprehend all accesses for host neuroinvasion, we aim at stimulating researchers and clinicians to fully consider the neuroinvasive potential of SARS-CoV-2, which is likely to affect the peripheral nervous system targets first, such as the enteric and pulmonary nervous networks. This acknowledgment may shed some light on the disease understanding further guiding public health preventive efforts and medical therapies to fight the pandemic that directly or indirectly affects healthy isolated individuals, quarantined subjects, sick hospitalized, and healthcare workers.
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Affiliation(s)
- Matteo Briguglio
- IRCCS Orthopedic Institute Galeazzi, Scientific Direction, Milan, Italy
| | - Alberto Bona
- Department of Neurosurgery, ICCS Istituto Clinico Città Studi, Milan, Italy
| | - Mauro Porta
- IRCCS Orthopedic Institute Galeazzi, Movement Disorder Center, Milan, Italy
| | - Bernardo Dell'Osso
- Department of Clinical and Biomedical Sciences Luigi Sacco, ASST Fatebenefratelli-Sacco, University of Milan, Ospedale Sacco Polo Universitario, Milan, Italy
- “Aldo Ravelli” Center for Neurotechnology and Brain Therapeutic, University of Milan, Milan, Italy
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
| | - Fabrizio Ernesto Pregliasco
- IRCCS Orthopedic Institute Galeazzi, Health Management, Milan, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Giuseppe Banfi
- IRCCS Orthopedic Institute Galeazzi, Scientific Direction, Milan, Italy
- Faculty of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
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Disdier C, Awa F, Chen X, Dhillon SK, Galinsky R, Davidson JO, Lear CA, Bennet L, Gunn AJ, Stonestreet BS. Lipopolysaccharide-induced changes in the neurovascular unit in the preterm fetal sheep brain. J Neuroinflammation 2020; 17:167. [PMID: 32466771 PMCID: PMC7257152 DOI: 10.1186/s12974-020-01852-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
Background Exposure to inflammation during pregnancy can predispose to brain injury in premature infants. In the present study, we investigated the effects of prolonged exposure to inflammation on the cerebrovasculature of preterm fetal sheep. Methods Chronically instrumented fetal sheep at 103–104 days of gestation (full term is ~ 147 days) received continuous low-dose lipopolysaccharide (LPS) infusions (100 ng/kg over 24 h, followed by 250 ng/kg/24 h for 96 h plus boluses of 1 μg LPS at 48, 72, and 96 h) or the same volume of normal saline (0.9%, w/v). Ten days after the start of LPS exposure at 113–114 days of gestation, the sheep were killed, and the fetal brain perfused with formalin in situ. Vessel density, pericyte and astrocyte coverage of the blood vessels, and astrogliosis in the cerebral cortex and white matter were determined using immunohistochemistry. Results LPS exposure reduced (P < 0.05) microvascular vessel density and pericyte vascular coverage in the cerebral cortex and white matter of preterm fetal sheep, and increased the activation of perivascular astrocytes, but decreased astrocytic vessel coverage in the white matter. Conclusions Prolonged exposure to LPS in preterm fetal sheep resulted in decreased vessel density and neurovascular remodeling, suggesting that chronic inflammation adversely affects the neurovascular unit and, therefore, could contribute to long-term impairment of brain development.
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Affiliation(s)
- Clémence Disdier
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA
| | - Fares Awa
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA
| | - Xiaodi Chen
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA
| | | | - Robert Galinsky
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Joanne O Davidson
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Christopher A Lear
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Laura Bennet
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Alistair J Gunn
- Department of Physiology, The University of Auckland, Auckland, New Zealand
| | - Barbara S Stonestreet
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02905, USA.
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Experimental evidence for alpha enolase as one potential autoantigen in the pathogenesis of both autoimmune thyroiditis and its related encephalopathy. Int Immunopharmacol 2020; 85:106563. [PMID: 32442899 DOI: 10.1016/j.intimp.2020.106563] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 04/26/2020] [Accepted: 05/03/2020] [Indexed: 11/24/2022]
Abstract
Alpha-enolase (ENO1) is a ubiquitous protein. Patients with autoimmune thyroiditis-associated encephalopathy have high serum ENO1Ab titers. We aimed to explore whether ENO1Ab was the pathogenic antibody in the thyroid and brain. The serum ENO1Ab titers were significantly increased in the mice immunized with Thyroglobulin (Tg). And in the mice immunized with ENO1, serum levels of both TgAb and thyroid-stimulating hormone (TSH) were significantly increased. Obvious CD16+ cell infiltration, IgG deposit and cleaved caspase-3 were observed in the thyroid of ENO1-immunized mice. Spatial learning and memory abilities and synaptic functions were impaired in ENO1-immunized mice. Furthermore, the expression levels of Iba-1, GFAP, interlukin-6, CDK5, and phosphorylated tau were increased, and endothelial tight junction proteins were decreased in the brain of ENO1-immunized mice. These results suggest that ENO1Ab can cause thyrocyte damage via ADCC effect and impair cerebral function by disrupting the blood-brain barrier.
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Logsdon AF, Erickson MA, Chen X, Qiu J, Lim YP, Stonestreet BS, Banks WA. Inter-alpha inhibitor proteins attenuate lipopolysaccharide-induced blood-brain barrier disruption and downregulate circulating interleukin 6 in mice. J Cereb Blood Flow Metab 2020; 40:1090-1102. [PMID: 31234704 PMCID: PMC7181088 DOI: 10.1177/0271678x19859465] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/07/2019] [Accepted: 06/04/2019] [Indexed: 02/06/2023]
Abstract
Circulating levels of inter-alpha inhibitor proteins change dramatically in acute inflammatory disorders, which suggest an important contribution to the immunomodulatory system. Human blood-derived inter-alpha inhibitor proteins are neuroprotective and improve survival of neonatal mice exposed to lipopolysaccharide. Lipopolysaccharide augments inflammatory conditions and disrupts the blood-brain barrier. There is a paucity of therapeutic strategies to treat blood-brain barrier dysfunction, and the neuroprotective effects of human blood-derived inter-alpha inhibitor proteins are not fully understood. To examine the therapeutic potential of inter-alpha inhibitor proteins, we administered human blood-derived inter-alpha inhibitor proteins to male and female CD-1 mice after lipopolysaccharide exposure and quantified blood-brain barrier permeability of intravenously injected 14C-sucrose and 99mTc-albumin. We hypothesized that human blood-derived inter-alpha inhibitor protein treatment would attenuate lipopolysaccharide-induced blood-brain barrier disruption and associated inflammation. Lipopolysaccharide increased blood-brain barrier permeability to both 14C-sucrose and 99mTc-albumin, but human blood-derived inter-alpha inhibitor protein treatment only attenuated increases in 14C-sucrose blood-brain barrier permeability in male mice. Lipopolysaccharide stimulated a more robust elevation of male serum inter-alpha inhibitor protein concentration compared to the elevation measured in female serum. Lipopolysaccharide administration also increased multiple inflammatory factors in serum and brain tissue, including interleukin 6. Human blood-derived inter-alpha inhibitor protein treatment downregulated serum interleukin 6 levels, which were inversely correlated with serum inter-alpha inhibitor protein concentration. We conclude that inter-alpha inhibitor proteins may be neuroprotective through mechanisms of blood-brain barrier disruption associated with systemic inflammation.
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Affiliation(s)
- Aric F Logsdon
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Michelle A Erickson
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Xiaodi Chen
- Department of Pediatrics, Women & Infants Hospital of RI, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Joseph Qiu
- ProThera Biologics, Inc., Providence, RI, USA
| | - Yow-Pin Lim
- ProThera Biologics, Inc., Providence, RI, USA
- Department of Pathology and Laboratory Medicine, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Barbara S Stonestreet
- Department of Pediatrics, Women & Infants Hospital of RI, The Alpert Medical School of Brown University, Providence, RI, USA
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
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Hadian Y, Fregoso D, Nguyen C, Bagood MD, Dahle SE, Gareau MG, Isseroff RR. Microbiome-skin-brain axis: A novel paradigm for cutaneous wounds. Wound Repair Regen 2020; 28:282-292. [PMID: 32034844 DOI: 10.1111/wrr.12800] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/12/2022]
Abstract
Chronic wounds cause a significant burden on society financially, medically, and psychologically. Unfortunately, patients with nonhealing wounds often suffer from comorbidities that further compound their disability. Given the high rate of depressive symptoms experienced by patients with chronic wounds, further studies are needed to investigate the potentially linked pathophysiological changes in wounds and depression in order to improve patient care. The English literature on wound healing, inflammatory and microbial changes in chronic wounds and depression, and antiinflammatory and probiotic therapy was reviewed on PubMed. Chronic wound conditions and depression were demonstrated to share common pathologic features of dysregulated inflammation and altered microbiome, indicating a possible relationship. Furthermore, alternative treatment strategies such as immune-targeted and probiotic therapy showed promising potential by addressing both pathophysiological pathways. However, many existing studies are limited to a small study population, a cross-sectional design that does not establish temporality, or a wide range of confounding variables in the context of a highly complex and multifactorial disease process. Therefore, additional preclinical studies in suitable wound models, as well as larger clinical cohort studies and trials are necessary to elucidate the relationship between wound microbiome, healing, and depression, and ultimately guide the most effective therapeutic and management plan for chronic wound patients.
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Affiliation(s)
- Yasmin Hadian
- Department of Dermatology, School of Medicine, University of California, Davis, California.,Dermatology Section, VA Northern California Health Care System, Mather, California
| | - Daniel Fregoso
- Department of Dermatology, School of Medicine, University of California, Davis, California
| | - Chuong Nguyen
- Department of Dermatology, School of Medicine, University of California, Davis, California
| | - Michelle D Bagood
- Department of Dermatology, School of Medicine, University of California, Davis, California
| | - Sara E Dahle
- Department of Dermatology, School of Medicine, University of California, Davis, California.,Podiatry Section, VA Northern California Health Care System, Mather, California
| | - Melanie G Gareau
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California
| | - Roslyn Rivkah Isseroff
- Department of Dermatology, School of Medicine, University of California, Davis, California.,Dermatology Section, VA Northern California Health Care System, Mather, California
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50
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Wu L, Xiong X, Wu X, Ye Y, Jian Z, Zhi Z, Gu L. Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury. Front Mol Neurosci 2020; 13:28. [PMID: 32194375 PMCID: PMC7066113 DOI: 10.3389/fnmol.2020.00028] [Citation(s) in RCA: 284] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 02/04/2020] [Indexed: 12/11/2022] Open
Abstract
The cerebral ischemia injury can result in neuronal death and/or functional impairment, which leads to further damage and dysfunction after recovery of blood supply. Cerebral ischemia/reperfusion injury (CIRI) often causes irreversible brain damage and neuronal injury and death, which involves many complex pathological processes including oxidative stress, amino acid toxicity, the release of endogenous substances, inflammation and apoptosis. Oxidative stress and inflammation are interactive and play critical roles in ischemia/reperfusion injury in the brain. Oxidative stress is important in the pathological process of ischemic stroke and is critical for the cascade development of ischemic injury. Oxidative stress is caused by reactive oxygen species (ROS) during cerebral ischemia and is more likely to lead to cell death and ultimately brain death after reperfusion. During reperfusion especially, superoxide anion free radicals, hydroxyl free radicals, and nitric oxide (NO) are produced, which can cause lipid peroxidation, inflammation and cell apoptosis. Inflammation alters the balance between pro-inflammatory and anti-inflammatory factors in cerebral ischemic injury. Inflammatory factors can therefore stimulate or exacerbate inflammation and aggravate ischemic injury. Neuroprotective therapies for various stages of the cerebral ischemia cascade response have received widespread attention. At present, neuroprotective drugs mainly include free radical scavengers, anti-inflammatory agents, and anti-apoptotic agents. However, the molecular mechanisms of the interaction between oxidative stress and inflammation, and their interplay with different types of programmed cell death in ischemia/reperfusion injury are unclear. The development of a suitable method for combination therapy has become a hot topic.
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Affiliation(s)
- Liquan Wu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaomin Wu
- Department of Anesthesiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Yingze Ye
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zeng Zhi
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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