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Deng F, Yang D, Qing L, Chen Y, Zou J, Jia M, Wang Q, Jiang R, Huang L. Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway: a potential therapeutic approach for neurodegenerative diseases. Neural Regen Res 2025; 20:3095-3112. [PMID: 39589173 PMCID: PMC11881707 DOI: 10.4103/nrr.nrr-d-24-00607] [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: 06/01/2024] [Revised: 08/07/2024] [Accepted: 09/10/2024] [Indexed: 11/27/2024] Open
Abstract
The interaction between the gut microbiota and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut-brain axis. The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites, which activates the vagus nerve and modulates the immune and neuroendocrine systems. Conversely, alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota, creating a dynamic network of microbial-host interactions. This reciprocal regulation affects neurodevelopment, neurotransmitter control, and behavioral traits, thus playing a role in the modulation of neurological diseases. The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation, mitochondrial dysfunction, abnormal energy metabolism, microglial activation, oxidative stress, and neurotransmitter release, which collectively influence the onset and progression of neurological diseases. This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway, along with its implications for potential therapeutic interventions in neurological diseases. Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders. This can be achieved through various methods such as dietary modifications, probiotic supplements, Chinese herbal extracts, combinations of Chinese herbs, and innovative dosage forms. These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.
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Affiliation(s)
- Fengcheng Deng
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Dan Yang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Lingxi Qing
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Yifei Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Jilian Zou
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Meiling Jia
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Qian Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Runda Jiang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Lihua Huang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
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Singh AK, Ma SJ, Blakaj D, Zhu S, Almeida ND, Koempel A, Yuan G, Wang G, Wooten K, Gupta V, McSpadden R, Kuriakose MA, Markiewicz MR, Yao S, Hicks WL, Seshadri M, Repasky EA, Bouchard EG, Farrugia MK, Yu H. An integrated machine learning-based prognostic model in head and neck cancer using the systemic inflammatory response index and correlations with patient reported financial toxicity. RESEARCH SQUARE 2025:rs.3.rs-6529613. [PMID: 40386418 PMCID: PMC12083689 DOI: 10.21203/rs.3.rs-6529613/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/02/2025]
Abstract
Objective : To investigate the prognostic utility of systemic inflammatory response index (SIRI) as a biological readout of stress associated immune modulation in head and neck cancer patients who underwent radiation therapy. Methods : Random survival forest machine learning was used to model survival in 568 head and neck cancer patients. SIRI was calculated via pre-treatment bloodwork. Model validation was performed in an external cohort of 345 patients. Baseline financial toxicity (FT) and SIRI were studied in 638 patients. Results : Incorporation of SIRI (with performance status and smoking history) into a machine learning model identified three risk-groups that significantly stratified overall survival (p<0.0001,) and these findings were validated in the external validation cohort (p<0.001.) Increasing levels of FT were significantly associated with increasing SIRI levels. (p=0.001.) Conclusions and Relevance : An integrated machine learning model using clinical features was successfully developed and externally validated. SIRI was significantly associated with increasing FT. Our findings highlight the potential utility of SIRI as a biological marker of FT in head and neck cancer patients.
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Affiliation(s)
- Anurag K. Singh
- Department of Radiation Medicine Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Sung Jun Ma
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Dukagjin Blakaj
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Simeng Zhu
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Neil D. Almeida
- Department of Radiation Medicine Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Andrew Koempel
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Guangwei Yuan
- Department of Biostatistics and Bioinformatics Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Grace Wang
- Department of Biostatistics and Bioinformatics Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Kimberly Wooten
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Vishal Gupta
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Ryan McSpadden
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Moni A. Kuriakose
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Michael R. Markiewicz
- Department of Oral and Maxillofacial Surgery School of Dental Medicine University at Buffalo, The State University of New York 3435 Main Street Buffalo, NY 14214. USA
- Department of Neurosurgery Department of Surgery Jacobs School of Medicine and Biomedical Sciences University at Buffalo, The State University of New York 955 Main Street Buffalo, NY 14203. USA
| | - Song Yao
- Department of Cancer Prevention and Control Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Wesley L. Hicks
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Mukund Seshadri
- Department of Oral Oncology Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Elizabeth A. Repasky
- Department of Immunology Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | | | - Mark K. Farrugia
- Department of Radiation Medicine Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Han Yu
- Department of Biostatistics and Bioinformatics Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
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Tan X, Zhang J, Chen W, Chen T, Cui G, Liu Z, Hu R. Progress on Direct Regulation of Systemic Immunity by the Central Nervous System. World Neurosurg 2025; 196:123814. [PMID: 39983990 DOI: 10.1016/j.wneu.2025.123814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 02/11/2025] [Accepted: 02/12/2025] [Indexed: 02/23/2025]
Abstract
This article reviews the research progress on the direct regulation of the immune system by the central nervous system (CNS). The traditional "neuro-endocrine-immune" network model has confirmed the close connection between the CNS and the immune system. However, due to the complex mediating role of the endocrine system, its application in clinical treatment is limited. In recent years, the direct regulation of the peripheral immune system through the CNS has provided new methods for the clinical treatment of neuroimmune-related diseases. This article analyzes the changes in the peripheral immune system after CNS injury and summarizes the effects of various stimulation methods, including transcranial magnetic stimulation, transcranial electrical stimulation, deep brain stimulation, spinal cord stimulation, and vagus nerve stimulation, on the peripheral immune system. Additionally, it explores the clinical research progress and future development directions of these stimulation methods. It is proposed that these neural regulation techniques exhibit positive effects in reducing peripheral inflammation, protecting immune cells and organ functions, and improving immunosuppressive states, providing new perspectives and therapeutic potential for the treatment of immune-related diseases.
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Affiliation(s)
- Xiaotian Tan
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Junming Zhang
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Weiming Chen
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Tunan Chen
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Gaoyu Cui
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhi Liu
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Rong Hu
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
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Tintelnot J, Paschold L, Goekkurt E, Schultheiss C, Matschl U, Santos Cruz M, Bauer M, Wickenhauser C, Thuss-Patience P, Lorenzen S, Ettrich TJ, Riera-Knorrenschild J, Jacobasch L, Kretzschmar A, Kubicka S, Al-Batran SE, Reinacher-Schick A, Pink D, Bokemeyer C, Sinn M, Lindig U, Hinke A, Hegewisch-Becker S, Stein A, Binder M. Inflammatory Stress Determines the Need for Chemotherapy in Patients with HER2-Positive Esophagogastric Adenocarcinoma Receiving Targeted Therapy and Immunotherapy. Cancer Immunol Res 2025; 13:200-209. [PMID: 39527097 PMCID: PMC11788649 DOI: 10.1158/2326-6066.cir-24-0561] [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: 06/15/2024] [Revised: 08/10/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma, but long-term survival remains limited. In this study, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison with a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% confidence interval, 41%-71%) in the Ipi arm and 70% OS (95% confidence interval, 54%-82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analyses demonstrated elevated levels of normetanephrine, cortisol, and IL6 in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil to lymphocyte ratio that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low neutrophil to lymphocyte ratio characterized patients benefiting from immunotherapy and targeted therapy without the need for additional chemotherapy. These data suggest that patient selection based on inflammatory stress-driven immune changes could help customize first-line treatment in patients with advanced HER2-positive esophagogastric adenocarcinoma to potentially improve long-term survival.
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Affiliation(s)
- Joseph Tintelnot
- II. Medical Clinic and Polyclinic, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lisa Paschold
- Department of Internal Medicine IV - Oncology/Hematology, University Hospital, Martin-Luther University, Halle, Germany
| | - Eray Goekkurt
- II. Medical Clinic and Polyclinic, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hematology-Oncology Practice Eppendorf (HOPE), Hamburg, Germany
| | - Christoph Schultheiss
- Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
| | - Urte Matschl
- Department of Virus Immunology, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Mariana Santos Cruz
- II. Medical Clinic and Polyclinic, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marcus Bauer
- Institute of Pathology, University Hospital, Martin-Luther University, Halle, Germany
| | - Claudia Wickenhauser
- Institute of Pathology, University Hospital, Martin-Luther University, Halle, Germany
| | | | - Sylvie Lorenzen
- Rechts der Isar Hospital, Technical University of Munich, Munich, Germany
| | | | | | | | | | | | | | | | - Daniel Pink
- Klinik und Poliklinik für Innere Medizin C, University Greifswald, Greifswald, Germany
- Klinik für Hämatologie, Onkologie und Palliativmedizin, Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Bad-Saarow, Bad Saarow, Germany
| | - Carsten Bokemeyer
- II. Medical Clinic and Polyclinic, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marianne Sinn
- II. Medical Clinic and Polyclinic, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Alexander Stein
- II. Medical Clinic and Polyclinic, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mascha Binder
- Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland
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Wang R, Xu J, He M. Blood leukocyte-based clusters in patients with traumatic brain injury. Front Immunol 2025; 15:1504668. [PMID: 39850895 PMCID: PMC11754042 DOI: 10.3389/fimmu.2024.1504668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/16/2024] [Indexed: 01/25/2025] Open
Abstract
Background Leukocytes play an important role in inflammatory response after a traumatic brain injury (TBI). We designed this study to identify TBI phenotypes by clustering blood levels of various leukocytes. Methods TBI patients from the Medical Information Mart for Intensive Care-III (MIMIC-III) database were included. Blood levels of neutrophils, lymphocytes, monocytes, basophils, and eosinophils were collected by analyzing the first blood sample within 24 h since admission. Overall, TBI patients were divided into clusters following the K-means clustering method using blood levels of five types of leukocytes. The correlation between identified clusters and mortality was tested by univariate and multivariate logistic regression analyses. The Kaplan-Meier method was used to verify the survival difference between identified TBI clusters. Results A total of 172 (cluster 1), 791 (cluster 2), and 636 (cluster 3) TBI patients were divided into three clusters with the following percentages, 10.8%, 49.5%, and 39.8%, respectively. Cluster 1 had the lowest Glasgow Coma Scale (GCS) and the highest Injury Severity Score (ISS) while cluster 2 had the highest GCS and the lowest ISS. The mortality rates of the three clusters were 25.6%, 13.3%, and 18.1%, respectively. The multivariate logistic regression indicated that cluster 1 had a higher mortality risk (OR = 2.211, p = 0.003) than cluster 2, while cluster 3 did not show a significantly higher mortality risk than cluster 2 (OR = 1.285, p = 0.163). Kapan-Meier analysis showed that cluster 1 had shorter survival than cluster 2 and cluster 3. Conclusion Three TBI phenotypes with different inflammatory statuses and mortality rates were identified based on blood levels of leukocytes. This classification is helpful for physicians to evaluate the prognosis of TBI patients.
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Affiliation(s)
- Ruoran Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jianguo Xu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min He
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Lintecum K, Thumsi A, Dunn K, Druschel L, Chimene S, Prieto DF, Simmons A, Mantri S, Esrafili A, Swaminathan SJ, Trivedi M, Manjre S, Willingham C, Kizeev G, Davila A, Inamdar S, Mangal JL, Suresh AP, Kasthuri NM, Jaggarapu MMCS, Appel N, Khodaei T, Ng ND, Sundem A, Pathak S, Bjorklund G, Balmer T, Newbern J, Capadona J, Stabenfeldt SE, Acharya AP. Vaccines for immunological defense against traumatic brain injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.02.626331. [PMID: 39677609 PMCID: PMC11642756 DOI: 10.1101/2024.12.02.626331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Traumatic brain injury (TBI) and subsequent neurodegeneration is partially driven by chronic inflammation both locally and systemically. Yet, current clinical intervention strategies do not mitigate inflammation sequalae necessitating the development of innovative approaches to reduce inflammation and minimize deleterious effects of TBI. Herein, a subcutaneous formulation based on polymer of alpha-ketoglutarate (paKG) delivering glycolytic inhibitor PFK15 (PFKFB3 inhibitor, a rate limiting step in glycolysis), alpha-ketoglutarate (to fuel Krebs cycle) and peptide antigen from myelin proteolipid protein (PLP139-151) was utilized as the prophylactic immunosuppressive formulation in a mouse model of TBI. In vitro, the paKG(PFK15+PLP) vaccine formulation stimulated proliferation of immunosuppressive regulatory T cells and induced generation of T helper-2 cells. When given subcutaneously in the periphery to two weeks prior to mice sustaining a TBI, the active vaccine formulation increased frequency of immunosuppressive macrophages and dendritic cells in the periphery and the brain at day 7 post- TBI and by 28 days post-TBI enhanced PLP-specific immunosuppressive cells infiltrated the brain. While immunohistology measurements of neuroinflammation were not altered 28 days post-TBI, the vaccine formulation improved motor function and enhanced autophagy mediated genes in a spatial manner in the brain. Overall, these data suggest that the TBI vaccine formulation successfully induced an anti-inflammatory profile and decreased TBI-associated inflammation. Teaser In this study, a vaccine formulation was generated to develop central nervous specific immunosuppressive responses for TBI.
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Arcadio F, Seggio M, Pitruzzella R, Zeni L, Bossi AM, Cennamo N. An Efficient Bio-Receptor Layer Combined with a Plasmonic Plastic Optical Fiber Probe for Cortisol Detection in Saliva. BIOSENSORS 2024; 14:351. [PMID: 39056627 PMCID: PMC11274917 DOI: 10.3390/bios14070351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024]
Abstract
Cortisol is a clinically validated stress biomarker that takes part in many physiological and psychological functions related to the body's response to stress factors. In particular, it has emerged as a pivotal tool for understanding stress levels and overall well-being. Usually, in clinics, cortisol levels are monitored in blood or urine, but significant changes are also registered in sweat and saliva. In this work, a surface plasmon resonance probe based on a D-shaped plastic optical fiber was functionalized with a glucocorticoid receptor exploited as a highly efficient bioreceptor specific to cortisol. The developed plastic optical fiber biosensor was tested for cortisol detection in buffer and artificial saliva. The biosensor response showed very good selectivity towards other hormones and a detection limit of about 59 fM and 96 fM in phosphate saline buffer and artificial saliva, respectively. The obtained detection limit, with a rapid detection time (about 5 min) and a low-cost sensor system, paved the way for determining the cortisol concentration in saliva samples without any extraction process or sample pretreatment via a point-of-care test.
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Affiliation(s)
- Francesco Arcadio
- Department of Engineering, University of Campania Luigi Vanvitelli, Via Roma 29, 81031 Aversa, Italy; (F.A.); (R.P.); (L.Z.)
| | - Mimimorena Seggio
- Department of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy;
| | - Rosalba Pitruzzella
- Department of Engineering, University of Campania Luigi Vanvitelli, Via Roma 29, 81031 Aversa, Italy; (F.A.); (R.P.); (L.Z.)
| | - Luigi Zeni
- Department of Engineering, University of Campania Luigi Vanvitelli, Via Roma 29, 81031 Aversa, Italy; (F.A.); (R.P.); (L.Z.)
| | - Alessandra Maria Bossi
- Department of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy;
| | - Nunzio Cennamo
- Department of Engineering, University of Campania Luigi Vanvitelli, Via Roma 29, 81031 Aversa, Italy; (F.A.); (R.P.); (L.Z.)
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Ruiz-Pablos M, Paiva B, Zabaleta A. Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis. Front Immunol 2024; 15:1422940. [PMID: 39044822 PMCID: PMC11263040 DOI: 10.3389/fimmu.2024.1422940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/25/2024] [Indexed: 07/25/2024] Open
Abstract
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances. A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH. As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology. It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene. In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress. Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.
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Affiliation(s)
- Manuel Ruiz-Pablos
- Faculty of Biological Sciences, Universidad Complutense de Madrid, Madrid, Spain
| | - Bruno Paiva
- Centro de Investigación Médica Aplicada (CIMA), IdiSNA, Instituto de Investigación Sanitaria de Navarra, Clinica Universidad de Navarra, Pamplona, Spain
| | - Aintzane Zabaleta
- Centro de Investigación Médica Aplicada (CIMA), IdiSNA, Instituto de Investigación Sanitaria de Navarra, Clinica Universidad de Navarra, Pamplona, Spain
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El Baassiri MG, Raouf Z, Badin S, Escobosa A, Sodhi CP, Nasr IW. Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies. J Neuroinflammation 2024; 21:124. [PMID: 38730498 PMCID: PMC11083845 DOI: 10.1186/s12974-024-03118-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal, hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorption of nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI. These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers, lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive outcomes for TBI patients.
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Affiliation(s)
- Mahmoud G El Baassiri
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Zachariah Raouf
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Sarah Badin
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Alejandro Escobosa
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Chhinder P Sodhi
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Isam W Nasr
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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Gandasasmita N, Li J, Loane DJ, Semple BD. Experimental Models of Hospital-Acquired Infections After Traumatic Brain Injury: Challenges and Opportunities. J Neurotrauma 2024; 41:752-770. [PMID: 37885226 DOI: 10.1089/neu.2023.0453] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2023] Open
Abstract
Patients hospitalized after a moderate or severe traumatic brain injury (TBI) are at increased risk of nosocomial infections, including bacterial pneumonia and other upper respiratory tract infections. Infections represent a secondary immune challenge for vulnerable TBI patients that can lead to increased morbidity and poorer long-term prognosis. This review first describes the clinical significance of infections after TBI, delving into the known mechanisms by which a TBI can alter systemic immunological responses towards an immunosuppressive state, leading to promotion of increased vulnerability to infections. Pulmonary dysfunction resulting from respiratory tract infections is considered in the context of neurotrauma, including the bidirectional relationship between the brain and lungs. Turning to pre-clinical modeling, current laboratory approaches to study experimental TBI and lung infections are reviewed, to highlight findings from the limited key studies to date that have incorporated both insults. Then, practical decisions for the experimental design of animal studies of post-injury infections are discussed. Variables associated with the host animal, the infectious agent (e.g., species, strain, dose, and administration route), as well as the timing of the infection relative to the injury model are important considerations for model development. Together, the purpose of this review is to highlight the significant clinical need for increased pre-clinical research into the two-hit insult of a hospital-acquired infection after TBI to encourage further scientific enquiry in the field.
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Affiliation(s)
| | - Jian Li
- Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
- Department of Microbiology, Monash University, Melbourne, Victoria, Australia
| | - David J Loane
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Bridgette D Semple
- Department of Neuroscience, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Prahran, Victoria, Australia
- Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia
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Li Y, Qin S, Dong L, Qiao S, Wang X, Yu D, Gao P, Hou Y, Quan S, Li Y, Fan F, Zhao X, Ma Y, Gao GF. Long-term effects of Omicron BA.2 breakthrough infection on immunity-metabolism balance: a 6-month prospective study. Nat Commun 2024; 15:2444. [PMID: 38503738 PMCID: PMC10951309 DOI: 10.1038/s41467-024-46692-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: 07/28/2023] [Accepted: 03/06/2024] [Indexed: 03/21/2024] Open
Abstract
There have been reports of long coronavirus disease (long COVID) and breakthrough infections (BTIs); however, the mechanisms and pathological features of long COVID after Omicron BTIs remain unclear. Assessing long-term effects of COVID-19 and immune recovery after Omicron BTIs is crucial for understanding the disease and managing new-generation vaccines. Here, we followed up mild BA.2 BTI convalescents for six-month with routine blood tests, proteomic analysis and single-cell RNA sequencing (scRNA-seq). We found that major organs exhibited ephemeral dysfunction and recovered to normal in approximately six-month after BA.2 BTI. We also observed durable and potent levels of neutralizing antibodies against major circulating sub-variants, indicating that hybrid humoral immunity stays active. However, platelets may take longer to recover based on proteomic analyses, which also shows coagulation disorder and an imbalance between anti-pathogen immunity and metabolism six-month after BA.2 BTI. The immunity-metabolism imbalance was then confirmed with retrospective analysis of abnormal levels of hormones, low blood glucose level and coagulation profile. The long-term malfunctional coagulation and imbalance in the material metabolism and immunity may contribute to the development of long COVID and act as useful indicator for assessing recovery and the long-term impacts after Omicron sub-variant BTIs.
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Affiliation(s)
- Yanhua Li
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Shijie Qin
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China
- Institute of Pediatrics, Shenzhen Children's Hospital, Shenzhen, 518026, China
| | - Lei Dong
- Department of Clinical Laboratory, Air Force Medical Center, 100142, Beijing, China
| | - Shitong Qiao
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Xiao Wang
- School of Life Sciences, Yunnan University, Kunming, 650091, China
| | - Dongshan Yu
- Department of Infectious Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, 330008, China
| | - Pengyue Gao
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yali Hou
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, 030032, China
| | - Shouzhen Quan
- Department of Clinical Laboratory, Air Force Medical Center, 100142, Beijing, China
| | - Ying Li
- Department of Clinical Laboratory, Air Force Medical Center, 100142, Beijing, China
| | - Fengyan Fan
- Department of Clinical Laboratory, Air Force Medical Center, 100142, Beijing, China
| | - Xin Zhao
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 101408, Beijing, China.
- Beijing Life Science Academy, 102209, Beijing, China.
| | - Yueyun Ma
- Department of Clinical Laboratory, Air Force Medical Center, 100142, Beijing, China.
| | - George Fu Gao
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 101408, Beijing, China.
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, 030032, China.
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12
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Dee G, Ryznar R, Dee C. Epigenetic Changes Associated with Different Types of Stressors and Suicide. Cells 2023; 12:cells12091258. [PMID: 37174656 PMCID: PMC10177343 DOI: 10.3390/cells12091258] [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] [Received: 03/13/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Stress is associated with various epigenetic changes. Some stress-induced epigenetic changes are highly dynamic, whereas others are associated with lasting marks on the epigenome. In our study, a comprehensive narrative review of the literature was performed by investigating the epigenetic changes that occur with acute stress, chronic stress, early childhood stress, and traumatic stress exposures, along with examining those observed in post-mortem brains or blood samples of suicide completers and attempters. In addition, the transgenerational effects of these changes are reported. For all types of stress studies examined, the genes Nr3c1, OXTR, SLC6A4, and BDNF reproducibly showed epigenetic changes, with some modifications observed to be passed down to subsequent generations following stress exposures. The aforementioned genes are known to be involved in neuronal development and hormonal regulation and are all associated with susceptibility to mental health disorders including depression, anxiety, personality disorders, and PTSD (post-traumatic stress disorder). Further research is warranted in order to determine the scope of epigenetic actionable targets in individuals suffering from the long-lasting effects of stressful experiences.
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Affiliation(s)
- Garrett Dee
- College of Osteopathic Medicine, Rocky Vista University, Parker, CO 80112, USA
| | - Rebecca Ryznar
- Molecular Biology, Department of Biomedical Sciences, Rocky Vista University, Parker, CO 80112, USA
| | - Colton Dee
- College of Osteopathic Medicine, Des Moines University, Des Moines, IA 50312, USA
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13
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Towards a biomarker for acute arterial thrombosis using complete blood count and white blood cell differential parameters in mice. Sci Rep 2023; 13:4043. [PMID: 36899036 PMCID: PMC10006076 DOI: 10.1038/s41598-023-31122-9] [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: 06/30/2022] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about 6% and 28% to 150 [100-200] and 115 [100-127.5], which however were about 2.1-fold and 1.9-fold higher than in sham-operated mice (70 [50-100] and 60 [30-75], respectively). Lymphocyte counts (/µL) at 1- and 4-days after thrombosis (mean ± SD; 3513 ± 912 and 2590 ± 860) were ~ 38% and ~ 54% lower than those in the sham-operated mice (5630 ± 1602 and 5596 ± 1437, respectively), and ~ 39% and ~ 55% lower than those in non-operated mice (5791 ± 1344). Post-thrombosis monocyte-lymphocyte-ratio (MLR) was substantially higher at all three time-points (0.050 ± 0.02, 0.046 ± 0.025, and 0.050 ± 0.02) vs. sham (0.003 ± 0.021, 0.013 ± 0.004, and 0.010 ± 0.004). MLR was 0.013 ± 0.005 in non-operated mice. This is the first report on acute arterial thrombosis-related alterations in CBC and WBC differential parameters.
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Cai J, Yang Y, Han J, Gao Y, Li X, Ge X. KDM4A, involved in the inflammatory and oxidative stress caused by traumatic brain injury-hemorrhagic shock, partly through the regulation of the microglia M1 polarization. BMC Neurosci 2023; 24:17. [PMID: 36869312 PMCID: PMC9983262 DOI: 10.1186/s12868-023-00784-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 02/16/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Microglial polarization and the subsequent neuroinflammatory response and oxidative stress are contributing factors for traumatic brain injury (TBI) plus hemorrhagic shock (HS) induced brain injury. In the present work, we have explored whether Lysine (K)-specific demethylase 4 A (KDM4A) modulates microglia M1 polarization in the TBI and HS mice. RESULTS Male C57BL/6J mice were used to investigate the microglia polarization in the TBI + HS model in vivo. Lipopolysaccharide (LPS)-induced BV2 cells were used to examine the mechanism of KDM4A in regulating microglia polarization in vitro. We found that TBI + HS resulted in neuronal loss and microglia M1 polarization in vivo, reflected by the increased level of Iba1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, malondialdehyde (MDA) and the decreased level of reduced glutathione (GSH). Additionally, KDM4A was upregulated in response to TBI + HS and microglia were among the cell types showing the increased level of KDM4A. Similar to the results in vivo, KDM4A also highly expressed in LPS-induced BV2 cells. LPS-induced BV2 cells exhibited enhanced microglia M1 polarization, and enhanced level of pro-inflammatory cytokines, oxidative stress and reactive oxygen species (ROS), while this enhancement was abolished by the suppression of KDM4A. CONCLUSION Accordingly, our findings indicated that KDM4A was upregulated in response to TBI + HS and microglia were among the cell types showing the increased level of KDM4A. The important role of KDM4A in TBI + HS-induced inflammatory response and oxidative stress was at least partially realized through regulating microglia M1 polarization.
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Affiliation(s)
- Jimin Cai
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, 214000, Wuxi, Jiangsu, P.R. China
| | - Yang Yang
- Department of Neurosurgery, Central Hospital of Jinzhou, 121001, Jinzhou, Liaoning, P.R. China
| | - Jiahui Han
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, 214000, Wuxi, Jiangsu, P.R. China
| | - Yu Gao
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, 214000, Wuxi, Jiangsu, P.R. China
| | - Xin Li
- Department of Anesthesiology, Wuxi 9th People's Hospital Affiliated to Soochow University, 214000, Wuxi, Jiangsu, P.R. China.
| | - Xin Ge
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, 214000, Wuxi, Jiangsu, P.R. China.
- Orthopedic Institution of Wuxi City, 214000, Wuxi, Jiangsu, P.R. China.
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15
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Yoshida S, Hamada Y, Narita M, Sato D, Tanaka K, Mori T, Tezuka H, Suda Y, Tamura H, Aoki K, Kuzumaki N, Narita M. Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus. Mol Brain 2023; 16:18. [PMID: 36732798 PMCID: PMC9896675 DOI: 10.1186/s13041-023-01006-0] [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: 11/29/2022] [Accepted: 01/13/2023] [Indexed: 02/04/2023] Open
Abstract
A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.
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Affiliation(s)
- Sara Yoshida
- grid.412239.f0000 0004 1770 141XDepartment of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan ,grid.272242.30000 0001 2168 5385Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Yusuke Hamada
- grid.412239.f0000 0004 1770 141XDepartment of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan ,grid.272242.30000 0001 2168 5385Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Michiko Narita
- grid.272242.30000 0001 2168 5385Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Daisuke Sato
- grid.412239.f0000 0004 1770 141XDepartment of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan ,grid.272242.30000 0001 2168 5385Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Kenichi Tanaka
- grid.412239.f0000 0004 1770 141XDepartment of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan ,grid.272242.30000 0001 2168 5385Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Tomohisa Mori
- grid.412239.f0000 0004 1770 141XDepartment of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan
| | - Hiroyuki Tezuka
- grid.256115.40000 0004 1761 798XDepartment of Cellular Function Analysis, Research Promotion Headquarters, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-Cho, Toyoake, Aichi 470-1192 Japan
| | - Yukari Suda
- grid.412239.f0000 0004 1770 141XDepartment of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan ,grid.272242.30000 0001 2168 5385Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Hideki Tamura
- grid.412239.f0000 0004 1770 141XInstitute for Advanced Life Sciences, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan ,grid.412239.f0000 0004 1770 141XLaboratory of Biofunctional Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501 Japan
| | - Kazunori Aoki
- grid.272242.30000 0001 2168 5385Department of Immune Medicine, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045 Japan
| | - Naoko Kuzumaki
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501, Japan. .,Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
| | - Minoru Narita
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo, 142-8501, Japan. .,Division of Cancer Pathophysiology, National Cancer Center Research Institute (NCCRI), 5-1-1 Tsukiji, Chuo-Ku, Tokyo, 104-0045, Japan.
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Davis CK, Bathula S, Hsu M, Morris-Blanco KC, Chokkalla AK, Jeong S, Choi J, Subramanian S, Park JS, Fabry Z, Vemuganti R. An Antioxidant and Anti-ER Stress Combo Therapy Decreases Inflammation, Secondary Brain Damage and Promotes Neurological Recovery following Traumatic Brain Injury in Mice. J Neurosci 2022; 42:6810-6821. [PMID: 35882557 PMCID: PMC9436019 DOI: 10.1523/jneurosci.0212-22.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/01/2022] [Accepted: 07/14/2022] [Indexed: 11/21/2022] Open
Abstract
The complex pathophysiology of post-traumatic brain damage might need a polypharmacological strategy with a combination of drugs that target multiple, synergistic mechanisms. We currently tested a combination of apocynin (curtails formation of reactive oxygen species), tert-butylhydroquinone (promotes disposal of reactive oxygen species), and salubrinal (prevents endoplasmic reticulum stress) following a moderate traumatic brain injury (TBI) induced by controlled cortical impact in adult mice. Adult mice of both sexes treated with the above tri-combo showed alleviated motor and cognitive deficits, attenuated secondary lesion volume, and decreased oxidative DNA damage. Concomitantly, tri-combo treatment regulated post-TBI inflammatory response by decreasing the infiltration of T cells and neutrophils and activation of microglia in both sexes. Interestingly, sexual dimorphism was seen in the case of TBI-induced microgliosis and infiltration of macrophages in the tri-combo-treated mice. Moreover, the tri-combo treatment prevented TBI-induced white matter volume loss in both sexes. The beneficial effects of tri-combo treatment were long-lasting and were also seen in aged mice. Thus, the present study supports the tri-combo treatment to curtail oxidative stress and endoplasmic reticulum stress concomitantly as a therapeutic strategy to improve TBI outcomes.SIGNIFICANCE STATEMENT Of the several mechanisms that contribute to TBI pathophysiology, oxidative stress, endoplasmic reticulum stress, and inflammation play a major role. The present study shows the therapeutic potential of a combination of apocynin, tert-butylhydroquinone, and salubrinal to prevent oxidative stress and endoplasmic reticulum stress and the interrelated inflammatory response in mice subjected to TBI. The beneficial effects of the tri-combo include alleviation of TBI-induced motor and cognitive deficits and lesion volume. The neuroprotective effects of the tri-combo are also linked to its ability to prevent TBI-induced white matter damage. Importantly, neuroprotection by the tri-combo treatment was observed to be not dependent on sex or age. Our data demonstrate that a polypharmacological strategy is efficacious after TBI.
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Affiliation(s)
| | | | - Martin Hsu
- Department of Pathology and Laboratory Medicine
- Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin 53705
| | | | - Anil K Chokkalla
- Department of Neurological Surgery
- Cellular and Molecular Pathology Graduate Program
| | - Soomin Jeong
- Department of Neurological Surgery
- Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin 53705
| | | | | | | | - Zsuzsanna Fabry
- Department of Pathology and Laboratory Medicine
- Cellular and Molecular Pathology Graduate Program
- Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin 53705
| | - Raghu Vemuganti
- Department of Neurological Surgery
- Cellular and Molecular Pathology Graduate Program
- Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin 53705
- William S. Middleton Veterans Administration Hospital, Madison, Wisconsin 53705
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17
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Komoltsev IG, Gulyaeva NV. Brain Trauma, Glucocorticoids and Neuroinflammation: Dangerous Liaisons for the Hippocampus. Biomedicines 2022; 10:biomedicines10051139. [PMID: 35625876 PMCID: PMC9138485 DOI: 10.3390/biomedicines10051139] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/30/2022] [Accepted: 05/13/2022] [Indexed: 12/02/2022] Open
Abstract
Glucocorticoid-dependent mechanisms of inflammation-mediated distant hippocampal damage are discussed with a focus on the consequences of traumatic brain injury. The effects of glucocorticoids on specific neuronal populations in the hippocampus depend on their concentration, duration of exposure and cell type. Previous stress and elevated level of glucocorticoids prior to pro-inflammatory impact, as well as long-term though moderate elevation of glucocorticoids, may inflate pro-inflammatory effects. Glucocorticoid-mediated long-lasting neuronal circuit changes in the hippocampus after brain trauma are involved in late post-traumatic pathology development, such as epilepsy, depression and cognitive impairment. Complex and diverse actions of the hypothalamic–pituitary–adrenal axis on neuroinflammation may be essential for late post-traumatic pathology. These mechanisms are applicable to remote hippocampal damage occurring after other types of focal brain damage (stroke, epilepsy) or central nervous system diseases without obvious focal injury. Thus, the liaisons of excessive glucocorticoids/dysfunctional hypothalamic–pituitary–adrenal axis with neuroinflammation, dangerous to the hippocampus, may be crucial to distant hippocampal damage in many brain diseases. Taking into account that the hippocampus controls both the cognitive functions and the emotional state, further research on potential links between glucocorticoid signaling and inflammatory processes in the brain and respective mechanisms is vital.
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Affiliation(s)
- Ilia G. Komoltsev
- Department of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117465 Moscow, Russia;
- Moscow Research and Clinical Center for Neuropsychiatry, 115419 Moscow, Russia
| | - Natalia V. Gulyaeva
- Department of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117465 Moscow, Russia;
- Moscow Research and Clinical Center for Neuropsychiatry, 115419 Moscow, Russia
- Correspondence: ; Tel.: +7-495-9524007 or +7-495-3347020
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18
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Campbell B, Budreau D, Williams-Perez S, Chakravarty S, Galet C, McGonagill P. Admission Lymphopenia Predicts Infectious Complications and Mortality in Traumatic Brain Injury Victims. Shock 2022; 57:189-198. [PMID: 34618726 DOI: 10.1097/shk.0000000000001872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Traumatic brain injury (TBI) is a major cause of mortality and disability associated with increased risk of secondary infections. Identifying a readily available biomarker may help direct TBI patient care. Herein, we evaluated whether admission lymphopenia could predict outcomes of TBI patients. METHODS This is a 10-year retrospective review of TBI patients with a head Abbreviated Injury Score 2 to 6 and absolute lymphocyte counts (ALC) collected within 24 h of admission. Exclusion criteria were death within 24 h of admission and presence of bowel perforation on admission. Demographics, admission data, injury severity score, mechanism of injury, and outcomes were collected. Association between baseline variables and outcomes was analyzed. RESULTS We included 2,570 patients; 946 (36.8%) presented an ALC ≤1,000 on admission (lymphopenic group). Lymphopenic patients were significantly older, less likely to smoke, and more likely to have heart failure, hypertension, or chronic kidney disease. Lymphopenia was associated with increased risks of mortality (OR = 1.903 [1.389-2.608]; P < 0.001) and pneumonia (OR = 1.510 [1.081-2.111]; P = 0.016), increased LOS (OR = 1.337 [1.217-1.469]; P < 0.001), and likelihood of requiring additional healthcare resources at discharge (OR = 1.669 [1.344-2.073], P < 0.001). Additionally, lymphopenia increased the risk of early in-hospital death (OR = 1.459 [1.097-1.941]; P = 0.009). Subgroup analysis showed that lymphopenia was associated with mortality in polytrauma patients and those who presented with two or more concurrent types of TBI. In all subgroup analyses, lymphopenia was associated with longer length of stay and discharge requiring higher level of care. CONCLUSION A routine complete blood count with differential for all TBI patients may help predict patient outcomes and direct care accordingly.
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Affiliation(s)
| | - Daniel Budreau
- Department of Surgery, Acute Care Surgery Division, University of Iowa, Iowa City, Iowa
- Aurora BayCare Medical Center, Green Bay, Wisconsin
| | | | | | - Colette Galet
- Department of Surgery, Acute Care Surgery Division, University of Iowa, Iowa City, Iowa
| | - Patrick McGonagill
- Department of Surgery, Acute Care Surgery Division, University of Iowa, Iowa City, Iowa
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19
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Sribnick EA, Popovich PG, Hall MW. Central nervous system injury-induced immune suppression. Neurosurg Focus 2022; 52:E10. [PMID: 35104790 DOI: 10.3171/2021.11.focus21586] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/18/2021] [Indexed: 11/06/2022]
Abstract
Central nervous system trauma is a common cause of morbidity and mortality. Additionally, these injuries frequently occur in younger individuals, leading to lifetime expenses for patients and caregivers and the loss of opportunity for society. Despite this prevalence and multiple attempts to design a neuroprotectant, clinical trials for a pharmacological agent for the treatment of traumatic brain injury (TBI) or spinal cord injury (SCI) have provided disappointing results. Improvements in outcome from these disease processes in the past decades have been largely due to improvements in supportive care. Among the many challenges facing patients and caregivers following neurotrauma, posttraumatic nosocomial infection is a significant and potentially reversible risk factor. Multiple animal and clinical studies have provided evidence of posttraumatic systemic immune suppression, and injuries involving the CNS may be even more prone, leading to a higher risk for in-hospital infections following neurotrauma. Patients who have experienced neurotrauma with nosocomial infection have poorer recovery and higher risks of long-term morbidity and in-hospital mortality than patients without infection. As such, the etiology and reversal of postneurotrauma immune suppression is an important topic. There are multiple possible etiologies for these posttraumatic changes including the release of damage-associated molecular patterns, the activation of immunosuppressive myeloid-derived suppressor cells, and sympathetic nervous system activation. Postinjury systemic immunosuppression, particularly following neurotrauma, provides a challenge for clinicians but also an opportunity for improvement in outcome. In this review, the authors sought to outline the evidence of postinjury systemic immune suppression in both animal models and clinical research of TBI, TBI polytrauma, and SCI.
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Affiliation(s)
- Eric A Sribnick
- 1Department of Neurosurgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus.,2The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus
| | - Phillip G Popovich
- 3Department of Neuroscience.,4Center for Brain and Spinal Cord Repair.,5Belford Center for Spinal Cord Injury, and.,6Medical Scientist Training Program, The Ohio State University, College of Medicine, Columbus; and
| | - Mark W Hall
- 2The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus.,7Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio
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20
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Barton DJ, Kumar RG, Schuster AA, Juengst SB, Oh BM, Wagner AK. Acute Cortisol Profile Associations With Cognitive Impairment After Severe Traumatic Brain Injury. Neurorehabil Neural Repair 2021; 35:1088-1099. [PMID: 34689657 DOI: 10.1177/15459683211048771] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Cognitive impairments commonly occur after traumatic brain injury (TBI) and affect daily functioning. Cortisol levels, which are elevated during acute hospitalization for most individuals after severe TBI, can influence cognition, but this association has not been studied previously in TBI. OBJECTIVE We hypothesized that serum and cerebral spinal fluid (CSF) cortisol trajectories over days 0-5 post-injury are associated with cognition 6-month post-injury. METHODS We examined 94 participants with severe TBI, collected acute serum and/or CSF samples over days 0-5 post-injury, and compared cortisol levels to those in 17 healthy controls. N = 88 participants had serum, and n = 84 had CSF samples available for cortisol measurement and had neuropsychological testing 6 months post-injury. Group based trajectory analysis (TRAJ) was used to generate temporal serum and CSF cortisol profiles which were examined for associations with neuropsychological performance. We used linear regression to examine relationships between cortisol TRAJ groups and both overall and domain-specific cognition. RESULTS TRAJ analysis identified a high group and a decliner group for serum and a high group and low group for CSF cortisol. Multivariable analysis showed serum cortisol TRAJ group was associated with overall cognitive composites scores (P = .024) and with executive function (P = .039) and verbal fluency (P = .029) domain scores. CSF cortisol TRAJ group was associated with overall cognitive composite scores (P = .021) and domain scores for executive function (P = .041), verbal fluency (P = .031), and attention (P = .034). CONCLUSIONS High acute cortisol trajectories are associated with poorer cognition 6 months post-TBI.
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Affiliation(s)
- David J Barton
- Department of Emergency Medicine, 480740University of Pittsburgh, Pittsburgh, PA, USA
| | - Raj G Kumar
- Department of Physical Medicine & Rehabilitation, 171669University of Pittsburgh, Pittsburgh, PA, USA.,Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Alexandria A Schuster
- Department of Physical Medicine & Rehabilitation, 171669University of Pittsburgh, Pittsburgh, PA, USA
| | - Shannon B Juengst
- Department of Physical Medicine & Rehabilitation, University of Texas Southwestern, Dallas, TX, USA.,Department of Applied Clinical Research, University of Texas Southwestern, Dallas, TX, USA
| | - Byung-Mo Oh
- Department of Rehabilitation Medicine, Seoul National University, Seoul, KR
| | - Amy K Wagner
- Department of Physical Medicine & Rehabilitation, 171669University of Pittsburgh, Pittsburgh, PA, USA.,Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.,Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.,Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA
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21
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Corbett B, Luz S, Sotuyo N, Pearson-Leary J, Moorthy GS, Zuppa AF, Bhatnagar S. FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety. Physiol Behav 2021; 240:113556. [PMID: 34390688 DOI: 10.1016/j.physbeh.2021.113556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 10/20/2022]
Abstract
FTY720 (fingolimod) is an analog of sphingosine, a ubiquitous sphingolipid. Phosphorylated FTY720 (FTY720-P) non-selectively binds to sphingosine-1-phosphate receptors (S1PRs) and regulates multiple cellular processes including cell proliferation, inflammation, and vascular remodeling. We recently demonstrated that S1PR3 expression in the medial prefrontal cortex (mPFC) of rats promotes stress resilience and that S1PR3 expression in blood may serve as a biomarker for PTSD. Here we investigate the effects of FTY720 in regulating the stress response. We found that single and repeated intraperitoneal injections of FTY720 increased baseline plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. FTY720 reduced social anxiety- and despair-like behavior as assessed by increased social interaction time and reduced time spent immobile in the Porsolt forced swim test. In blood, FTY720 administration reduced lymphocyte and reticulocyte counts, but raised erythrocyte counts. FTY720 also reduced mRNA of angiopoietin 1, endothelin 1, plasminogen, TgfB2, Pdgfa, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced vascular remodeling. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced vascular remodeling as increased stress-induced blood vessel density in the brain contributes to behavior associated with vulnerability in rats. Together, these results demonstrate that FTY720 regulates baseline HPA axis activity but reduces social anxiety and despair, providing further evidence that S1PRs are important and novel regulators of stress-related functions.
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Affiliation(s)
- Brian Corbett
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Sandra Luz
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Nathaniel Sotuyo
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Jiah Pearson-Leary
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA
| | - Ganesh S Moorthy
- Center for Clinical Pharmacology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Athena F Zuppa
- Center for Clinical Pharmacology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Seema Bhatnagar
- Center for Stress Neurobiology, Children's Hospital of Philadelphia, 3615 CIvic Center Blvd, ARC Suite 402, Philadelphia, Pennsylvania,19104-4399, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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22
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McDonald SJ, Sharkey JM, Sun M, Kaukas LM, Shultz SR, Turner RJ, Leonard AV, Brady RD, Corrigan F. Beyond the Brain: Peripheral Interactions after Traumatic Brain Injury. J Neurotrauma 2021; 37:770-781. [PMID: 32041478 DOI: 10.1089/neu.2019.6885] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability, and there are currently no pharmacological treatments known to improve patient outcomes. Unquestionably, contributing toward a lack of effective treatments is the highly complex and heterogenous nature of TBI. In this review, we highlight the recent surge of research that has demonstrated various central interactions with the periphery as a potential major contributor toward this heterogeneity and, in particular, the breadth of research from Australia. We describe the growing evidence of how extracranial factors, such as polytrauma and infection, can significantly alter TBI neuropathology. In addition, we highlight how dysregulation of the autonomic nervous system and the systemic inflammatory response induced by TBI can have profound pathophysiological effects on peripheral organs, such as the heart, lung, gastrointestinal tract, liver, kidney, spleen, and bone. Collectively, this review firmly establishes TBI as a systemic condition. Further, the central and peripheral interactions that can occur after TBI must be further explored and accounted for in the ongoing search for effective treatments.
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Affiliation(s)
- Stuart J McDonald
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia.,Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Jessica M Sharkey
- Discipline of Anatomy and Pathology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Mujun Sun
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia
| | - Lola M Kaukas
- School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Sandy R Shultz
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia.,Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Renee J Turner
- Discipline of Anatomy and Pathology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Anna V Leonard
- Discipline of Anatomy and Pathology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Rhys D Brady
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia
| | - Frances Corrigan
- School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia
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23
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Cortisol Secretion and Subsequent Impaired Lymphopoiesis after Starvation Can Be Reduced by Moxibustion Treatment. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:8856687. [PMID: 33613686 PMCID: PMC7878081 DOI: 10.1155/2021/8856687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/15/2021] [Accepted: 01/22/2021] [Indexed: 11/29/2022]
Abstract
As a known steroid hormone, cortisol is involved in gluconeogenesis. Uninterrupted cortisol secretion has fatal effects, both physically and psychologically, because cortisol counteracts the immune response. Moxibustion (Mox) treatment is a traditional technique used in East Asia, which therapeutically transfers heat to certain points on the body surface. In the present study, the effect of Mox treatment on stress hormone secretion was investigated using a mouse model of starvation, in which Mox was applied on the Zhongwan acupoint (CV12). First, high cortisol levels induced by starvation were dose-dependently reduced by Mox treatment. In addition, the stress-induced decline in lymphoid progenitor cell production accompanied by altered cellularity in the thymus, bone marrow, and spleen was also significantly recovered by Mox treatment. Taken together, these findings indicated that Mox treatment reduces stress hormone secretion, which may rescue stress-induced lymphopoiesis impairment. These observations also suggested that enhanced resistance to stress may be one of the mechanisms underlying the immunomodulatory effects of Mox treatment.
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24
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Neutrophil-Lymphocyte Ratio as an Initial Screening Biomarker for Differential Diagnosis of Cushing's Syndrome from Nonfunctional Adenoma in Patients with an Adrenal Mass. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6635594. [PMID: 33628798 PMCID: PMC7899776 DOI: 10.1155/2021/6635594] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/25/2020] [Accepted: 02/01/2021] [Indexed: 02/07/2023]
Abstract
Objective Assessing excess adrenal hormones is important in patients with adrenal mass. Current screening tests for excess cortisol hormones are complex, so it cannot be done sometimes due to the limited medical resources. The aim of the study was to evaluate whether the neutrophil-lymphocyte ratio (NLR) can be used as an initial screening biomarker for Cushing's syndrome (CS) in patients with an adrenal mass. Methods This retrospective study included a total of 185 patients with CS and 185 patients with nonfunctional adrenal adenoma (matched 1 : 1 by sex, body mass index, and discharge date). The NLR was compared between the two groups. The association between NLR and serum and urinary cortisol concentrations was analyzed, and an NLR cut-off value for CS screening was calculated. Results NLR (3.38 (2.33, 5.45) vs. 2.13 (1.74, 3.00), P < 0.001) was significantly higher in the CS group than in the nonfunctional adenoma group. In CS patients, the NLR was positively associated with serum cortisol concentrations at 8 am, with 24-hour urine free cortisol and with serum cortisol after a 1 mg dexamethasone suppression test (P < 0.001 each). An NLR cut-off of 2.2 had a sensitivity of 80.0% and a specificity of 54.05%. The weighted Youden index for the NLR was similar to that of the 24-hour urine free cortisol and late-night serum cortisol tests, which are recommended initial tests for CS diagnosis. Conclusion The NLR may be useful for initial screening for CS among patients with an adrenal mass as an easy and convenient marker.
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25
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Faden AI, Barrett JP, Stoica BA, Henry RJ. Bidirectional Brain-Systemic Interactions and Outcomes After TBI. Trends Neurosci 2021; 44:406-418. [PMID: 33495023 DOI: 10.1016/j.tins.2020.12.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/23/2020] [Accepted: 12/31/2020] [Indexed: 12/16/2022]
Abstract
Traumatic brain injury (TBI) is a debilitating disorder associated with chronic progressive neurodegeneration and long-term neurological decline. Importantly, there is now substantial and increasing evidence that TBI can negatively impact systemic organs, including the pulmonary, gastrointestinal (GI), cardiovascular, renal, and immune system. Less well appreciated, until recently, is that such functional changes can affect both the response to subsequent insults or diseases, as well as contribute to chronic neurodegenerative processes and long-term neurological outcomes. In this review, we summarize evidence showing bidirectional interactions between the brain and systemic organs following TBI and critically assess potential underlying mechanisms.
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Affiliation(s)
- Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - James P Barrett
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bogdan A Stoica
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Rebecca J Henry
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA
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26
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Siebold L, Krueger AC, Abdala JA, Figueroa JD, Bartnik-Olson B, Holshouser B, Wilson CG, Ashwal S. Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury. Front Mol Neurosci 2020; 13:109. [PMID: 32670020 PMCID: PMC7332854 DOI: 10.3389/fnmol.2020.00109] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/22/2020] [Indexed: 12/21/2022] Open
Abstract
Aim: Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (CoSyn), a synthetic ACTH analog, on the early inflammatory response and functional outcome following experimental TBI. Methods: The controlled cortical impact model was used to induce TBI in mice. Mice were assigned to injury and treatment protocols resulting in four experimental groups including sham + saline, sham + CoSyn, TBI + saline, and TBI + CoSyn. Treatment was administered subcutaneously 3 h post-injury and daily injections were given for up to 7 days post-injury. The early inflammatory response was evaluated at 3 days post-injury through the evaluation of cytokine expression (IL1β and TNFα) and immune cell response. Quantification of immune cell response included cell counts of microglia/macrophages (Iba1+ cells) and neutrophils (MPO+ cells) in the cortex and hippocampus. Behavioral testing (n = 10–14 animals/group) included open field (OF) and novel object recognition (NOR) during the first week following injury and Morris water maze (MWM) at 10–15 days post-injury. Results: Immune cell quantification showed decreased accumulation of Iba1+ cells in the perilesional cortex and CA1 region of the hippocampus for CoSyn-treated TBI animals compared to saline-treated. Reduced numbers of MPO+ cells were also found in the perilesional cortex and hippocampus in CoSyn treated TBI mice compared to their saline-treated counterparts. Furthermore, CoSyn treatment reduced IL1β expression in the cortex of TBI mice. Behavioral testing showed a treatment effect of CoSyn for NOR with CoSyn increasing the discrimination ratio in both TBI and Sham groups, indicating increased memory performance. CoSyn also decreased latency to find platform during the early training period of the MWM when comparing CoSyn to saline-treated TBI mice suggesting moderate improvements in spatial memory following CoSyn treatment. Conclusion: Reduced microglia/macrophage accumulation and neutrophil infiltration in conjunction with moderate improvements in spatial learning in our CoSyn treated TBI mice suggests a beneficial anti-inflammatory effect of CoSyn following TBI.
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Affiliation(s)
- Lorraine Siebold
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States.,The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University, Loma Linda, CA, United States
| | - Amy C Krueger
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Jonathan A Abdala
- The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University, Loma Linda, CA, United States
| | - Johnny D Figueroa
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States.,Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Brenda Bartnik-Olson
- Department of Radiology, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Barbara Holshouser
- Department of Radiology, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Christopher G Wilson
- Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, United States.,The Lawrence D. Longo MD Center for Perinatal Biology, Loma Linda University, Loma Linda, CA, United States.,Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA, United States
| | - Stephen Ashwal
- Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, CA, United States
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Zhang B, Gao Y, Li Q, Sun D, Dong X, Li X, Xin W, Zhang J. Effects of Brain-Derived Mitochondria on the Function of Neuron and Vascular Endothelial Cell After Traumatic Brain Injury. World Neurosurg 2020; 138:e1-e9. [DOI: 10.1016/j.wneu.2019.11.172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/28/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022]
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28
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Doran SJ, Henry RJ, Shirey KA, Barrett JP, Ritzel RM, Lai W, Blanco JC, Faden AI, Vogel SN, Loane DJ. Early or Late Bacterial Lung Infection Increases Mortality After Traumatic Brain Injury in Male Mice and Chronically Impairs Monocyte Innate Immune Function. Crit Care Med 2020; 48:e418-e428. [PMID: 32149839 PMCID: PMC7541908 DOI: 10.1097/ccm.0000000000004273] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Respiratory infections in the postacute phase of traumatic brain injury impede optimal recovery and contribute substantially to overall morbidity and mortality. This study investigated bidirectional innate immune responses between the injured brain and lung, using a controlled cortical impact model followed by secondary Streptococcus pneumoniae infection in mice. DESIGN Experimental study. SETTING Research laboratory. SUBJECTS Adult male C57BL/6J mice. INTERVENTIONS C57BL/6J mice were subjected to sham surgery or moderate-level controlled cortical impact and infected intranasally with S. pneumoniae (1,500 colony-forming units) or vehicle (phosphate-buffered saline) at 3 or 60 days post-injury. MAIN RESULTS At 3 days post-injury, S. pneumoniae-infected traumatic brain injury mice (TBI + Sp) had a 25% mortality rate, in contrast to no mortality in S. pneumoniae-infected sham (Sham + Sp) animals. TBI + Sp mice infected 60 days post-injury had a 60% mortality compared with 5% mortality in Sham + Sp mice. In both studies, TBI + Sp mice had poorer motor function recovery compared with TBI + PBS mice. There was increased expression of pro-inflammatory markers in cortex of TBI + Sp compared with TBI + PBS mice after both early and late infection, indicating enhanced post-traumatic neuroinflammation. In addition, monocytes from lungs of TBI + Sp mice were immunosuppressed acutely after traumatic brain injury and could not produce interleukin-1β, tumor necrosis factor-α, or reactive oxygen species. In contrast, after delayed infection monocytes from TBI + Sp mice had higher levels of interleukin-1β, tumor necrosis factor-α, and reactive oxygen species when compared with Sham + Sp mice. Increased bacterial burden and pathology was also found in lungs of TBI + Sp mice. CONCLUSIONS Traumatic brain injury causes monocyte functional impairments that may affect the host's susceptibility to respiratory infections. Chronically injured mice had greater mortality following S. pneumoniae infection, which suggests that respiratory infections even late after traumatic brain injury may pose a more serious threat than is currently appreciated.
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Affiliation(s)
- Sarah J Doran
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Rebecca J Henry
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Kari Ann Shirey
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
| | - James P Barrett
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Rodney M Ritzel
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Wendy Lai
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
| | | | - Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Stefanie N Vogel
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
| | - David J Loane
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
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29
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Chen BY, Ghezzi C, Villegas B, Quon A, Radu CG, Witte ON, Clark PM. 18F-FAC PET Visualizes Brain-Infiltrating Leukocytes in a Mouse Model of Multiple Sclerosis. J Nucl Med 2020; 61:757-763. [PMID: 31653711 PMCID: PMC7198381 DOI: 10.2967/jnumed.119.229351] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 10/07/2019] [Indexed: 12/26/2022] Open
Abstract
Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2'-deoxy-2'-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures deoxyribonucleoside salvage and accumulates preferentially in immune cells. We hypothesized that 18F-FAC PET could noninvasively image brain-infiltrating leukocytes. Methods: Healthy mice were imaged with 18F-FAC PET to quantify if this radiotracer crosses the blood-brain barrier (BBB). Experimental autoimmune encephalomyelitis (EAE) is a mouse disease model with brain-infiltrating leukocytes. To determine whether 18F-FAC accumulates in brain-infiltrating leukocytes, EAE mice were analyzed with 18F-FAC PET, digital autoradiography, and immunohistochemistry, and deoxyribonucleoside salvage activity in brain-infiltrating leukocytes was analyzed ex vivo. Fingolimod-treated EAE mice were imaged with 18F-FAC PET to assess if this approach can monitor the effect of an immunomodulatory drug on brain-infiltrating leukocytes. PET scans of individuals injected with 2-chloro-2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosyl-adenine (18F-CFA), a PET radiotracer that measures deoxyribonucleoside salvage in humans, were analyzed to evaluate whether 18F-CFA crosses the human BBB. Results:18F-FAC accumulates in the healthy mouse brain at levels similar to 18F-FAC in the blood (2.54 ± 0.2 and 3.04 ± 0.3 percentage injected dose per gram, respectively) indicating that 18F-FAC crosses the BBB. EAE mice accumulate 18F-FAC in the brain at 180% of the levels of control mice. Brain 18F-FAC accumulation localizes to periventricular regions with significant leukocyte infiltration, and deoxyribonucleoside salvage activity is present at similar levels in brain-infiltrating T and innate immune cells. These data suggest that 18F-FAC accumulates in brain-infiltrating leukocytes in this model. Fingolimod-treated EAE mice accumulate 18F-FAC in the brain at 37% lower levels than control-treated EAE mice, demonstrating that 18F-FAC PET can monitor therapeutic interventions in this mouse model. 18F-CFA accumulates in the human brain at 15% of blood levels (0.08 ± 0.01 and 0.54 ± 0.07 SUV, respectively), indicating that 18F-CFA does not cross the BBB in humans. Conclusion:18F-FAC PET can visualize brain-infiltrating leukocytes in a mouse MS model and can monitor the response of these cells to an immunomodulatory drug. Translating this strategy into humans will require exploring additional radiotracers.
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Affiliation(s)
- Bao Ying Chen
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California
| | - Chiara Ghezzi
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California
| | - Brendon Villegas
- Department of Pulmonary and Critical Care Medicine, UCLA, Los Angeles, California
| | - Andrew Quon
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
- Ahmanson Translational Imaging Division, UCLA, Los Angeles, California
| | - Caius G Radu
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
- Ahmanson Translational Imaging Division, UCLA, Los Angeles, California
| | - Owen N Witte
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California; and
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, California
| | - Peter M Clark
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
- Crump Institute for Molecular Imaging, UCLA, Los Angeles, California
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California; and
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30
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Sun M, Brady RD, Wanrooy B, Mychasiuk R, Yamakawa GR, Casillas-Espinosa PM, Wong CHY, Shultz SR, McDonald SJ. Experimental traumatic brain injury does not lead to lung infection. J Neuroimmunol 2020; 343:577239. [PMID: 32302792 DOI: 10.1016/j.jneuroim.2020.577239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/23/2020] [Accepted: 04/08/2020] [Indexed: 12/13/2022]
Abstract
Traumatic brain injury (TBI) patients often experience post-traumatic infections, especially in the lung. Pulmonary infection is associated with unfavorable outcomes and increased mortality rates in TBI patients; however, our understanding of the underlying mechanisms is poor. Here we used a lateral fluid percussion injury (LFPI) model in rats to investigate whether TBI could lead to spontaneous lung infection. Analysis of bacterial load in lung tissue indicated no occurrence of spontaneous lung infection at 24 h, 48 h, and 7 d following LFPI. This may suggest that exogenous infectious agents play a crucial role in post-TBI infection in patients.
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Affiliation(s)
- Mujun Sun
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
| | - Rhys D Brady
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia.
| | - Brooke Wanrooy
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia.
| | - Richelle Mychasiuk
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
| | - Glenn R Yamakawa
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
| | - Pablo M Casillas-Espinosa
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia.
| | - Connie H Y Wong
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia.
| | - Sandy R Shultz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia.
| | - Stuart J McDonald
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC 3086, Australia.
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Gad S, Alkhalafawi A, Raza S, Hesham M, Sheta M. Value of Neutrophil to Lymphocyte Ratio in Early Prediction of Meconium Aspiration Syndrome. JOURNAL OF CHILD SCIENCE 2020. [DOI: 10.1055/s-0040-1720958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
AbstractMeconium aspiration syndrome (MAS) is a serious neonatal condition. Prediction of MAS is challenging particularly in low-resource setting. Neutrophil to lymphocyte ratio (NLR) is a new simple index used for diagnosis of many inflammatory conditions. The present study was an attempt to determine whether NLR can predict the occurrence of MAS. The present study included 101 children with meconium-stained amniotic fluid. They comprised 22 patients who developed MAS and 79 neonates who didn't have the condition. All neonates were subjected to careful analysis of maternal and perinatal history in addition to thorough clinical assessment and radiological and laboratory evaluation. Blood samples from the umbilical cord were collected at birth and were used to obtain complete blood counts and C-reactive protein (CRP) assay. Univariate analysis revealed that elevated CRP levels, increased NLR, and 5-minute Apgar score of <7 were significant risk factors for the occurrence of MAS. Multivariate analysis revealed that low 5-minute Apgar score and increased NLR remained as significant risk factors of MAS. Receiver operating characteristic curve analysis showed good performance of NLR in prediction of MAS. NLR is useful in prediction of MAS in term neonates with meconium-stained amniotic fluid.
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Affiliation(s)
- Suzan Gad
- Department of Pediatrics, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | | | - Syed Raza
- Department of Pediatrics, Sheikh Khalifa Medical City, Ajman, UAE
| | - Mervat Hesham
- Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mohamed Sheta
- Department of Pediatrics, Mansoura General Hospital, Mansoura, Egypt
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32
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Krämer TJ, Hack N, Brühl TJ, Menzel L, Hummel R, Griemert EV, Klein M, Thal SC, Bopp T, Schäfer MKE. Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-γ gene expression in acute experimental traumatic brain injury. J Neuroinflammation 2019; 16:163. [PMID: 31383034 PMCID: PMC6683516 DOI: 10.1186/s12974-019-1550-0] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 07/22/2019] [Indexed: 12/20/2022] Open
Abstract
Background Traumatic brain injury (TBI) is a major cause of death and disability. T cells were shown to infiltrate the brain during the first days after injury and to exacerbate tissue damage. The objective of this study was to investigate the hitherto unresolved role of immunosuppressive, regulatory T cells (Tregs) in experimental TBI. Methods “Depletion of regulatory T cell” (DEREG) and wild type (WT) C57Bl/6 mice, treated with diphtheria toxin (DTx) to deplete Tregs or to serve as control, were subjected to the controlled cortical impact (CCI) model of TBI. Neurological and motor deficits were examined until 5 days post-injury (dpi). At the 5 dpi endpoint, (immuno-) histological, protein, and gene expression analyses were carried out to evaluate the consequences of Tregs depletion. Comparison of parametric or non-parametric data between two groups was done using Student’s t test or the Mann-Whitney U test. For multiple comparisons, p values were calculated by one-way or two-way ANOVA followed by specific post hoc tests. Results The overall neurological outcome at 5 dpi was not different between DEREG and WT mice but more severe motor deficits occurred transiently at 1 dpi in DEREG mice. DEREG and WT mice did not differ in the extent of brain damage, blood-brain barrier (BBB) disruption, or neuronal excitotoxicity, as examined by lesion volumetry, immunoglobulin G (IgG) extravasation, or calpain-generated αII-spectrin breakdown products (SBDPs), respectively. In contrast, increased protein levels of glial fibrillary acidic protein (GFAP) and GFAP+ astrocytes in the ipsilesional brain tissue indicated exaggerated reactive astrogliosis in DEREG mice. T cell counts following anti-CD3 immunohistochemistry and gene expression analyses of Cd247 (CD3 subunit zeta) and Cd8a (CD8a) further indicated an increased number of T cells infiltrating the brain injury sites of DEREG mice compared to WT. These changes coincided with increased gene expression of pro-inflammatory interferon-γ (Ifng) in DEREG mice compared to WT in the injured brain. Conclusions The results show that the depletion of Tregs attenuates T cell brain infiltration, reactive astrogliosis, interferon-γ gene expression, and transiently motor deficits in murine acute traumatic brain injury.
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Affiliation(s)
- Tobias J Krämer
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1 (Bld. 505), 55131, Mainz, Germany
| | - Nathalia Hack
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1 (Bld. 505), 55131, Mainz, Germany
| | - Till J Brühl
- Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany
| | - Lutz Menzel
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1 (Bld. 505), 55131, Mainz, Germany
| | - Regina Hummel
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1 (Bld. 505), 55131, Mainz, Germany
| | - Eva-Verena Griemert
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1 (Bld. 505), 55131, Mainz, Germany
| | - Matthias Klein
- Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.,Research Center for Immunotherapy (FZI), Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Serge C Thal
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1 (Bld. 505), 55131, Mainz, Germany
| | - Tobias Bopp
- Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.,Research Center for Immunotherapy (FZI), Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Michael K E Schäfer
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1 (Bld. 505), 55131, Mainz, Germany. .,Research Center for Immunotherapy (FZI), Johannes Gutenberg-University Mainz, Mainz, Germany. .,Focus Program Translational Neurosciences (FTN), Johannes Gutenberg-University Mainz, Mainz, Germany.
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Sharma R, Shultz SR, Robinson MJ, Belli A, Hibbs ML, O'Brien TJ, Semple BD. Infections after a traumatic brain injury: The complex interplay between the immune and neurological systems. Brain Behav Immun 2019; 79:63-74. [PMID: 31029794 DOI: 10.1016/j.bbi.2019.04.034] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/29/2019] [Accepted: 04/24/2019] [Indexed: 12/21/2022] Open
Abstract
Traumatic brain injury (TBI) is a serious global health issue, being the leading cause of death and disability for individuals under the age of 45, and one of the largest causes of global neurological disability. In addition to the brain injury itself, it is increasingly appreciated that a TBI may also alter the systemic immune response in a way that renders TBI patients more vulnerable to infections in the acute post-injury period. Such infections pose an additional challenge to the patient, increasing rates of mortality and morbidity, and worsening neurological outcomes. Hospitalization, surgical interventions, and a state of immunosuppression induced by injury to the central nervous system (CNS), may all contribute to the high rate of infections seen in the population with TBI. Ongoing research to better understand the immunomodulators that underlie TBI-induced immunosuppression may aid in the development of effective therapeutic strategies to improve the recovery trajectory for patients. This review first describes the clinical scenario, posing the question of whether TBI patients are more susceptible to infections such as pneumonia, and if so, why? We then consider how cross-talk between the injured brain and the systemic immune system occurs, and further, how the additional immune challenge of an acquired infection can contribute to ongoing neuroinflammation and neurodegeneration after a TBI. Experimental models combining TBI with infection are discussed, as well as current treatment options available for this double-barreled insult. The aims of this review are to summarize current understanding of the bidirectional relationship between the CNS and the immune system when faced with a mechanical trauma combined with a concomitant infection, and to highlight key outstanding questions that remain in the field.
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Affiliation(s)
- Rishabh Sharma
- Department of Neuroscience, Central Clinical School at the Alfred Hospital, Monash University, Melbourne, VIC, Australia
| | - Sandy R Shultz
- Department of Neuroscience, Central Clinical School at the Alfred Hospital, Monash University, Melbourne, VIC, Australia; Department of Medicine (Royal Melbourne Hospital), Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia
| | - Marcus J Robinson
- Department of Immunology and Pathology, Central Clinical School at the Alfred Hospital, Monash University, Melbourne, VIC, Australia
| | - Antonio Belli
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Margaret L Hibbs
- Department of Immunology and Pathology, Central Clinical School at the Alfred Hospital, Monash University, Melbourne, VIC, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Central Clinical School at the Alfred Hospital, Monash University, Melbourne, VIC, Australia; Department of Medicine (Royal Melbourne Hospital), Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia
| | - Bridgette D Semple
- Department of Neuroscience, Central Clinical School at the Alfred Hospital, Monash University, Melbourne, VIC, Australia; Department of Medicine (Royal Melbourne Hospital), Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia.
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Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, Ma GX, Nguyen MT. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol 2019; 25:2279-2293. [PMID: 31148900 PMCID: PMC6529884 DOI: 10.3748/wjg.v25.i19.2279] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/27/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
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Affiliation(s)
- Olorunseun O Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Trisheena Harricharran
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Anna Galuza
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Oluwatoyin Odumuwagun
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Yin Tan
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Grace X Ma
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Minhhuyen T Nguyen
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, United States
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St-Amour I, Bosoi CR, Paré I, Ignatius Arokia Doss PM, Rangachari M, Hébert SS, Bazin R, Calon F. Peripheral adaptive immunity of the triple transgenic mouse model of Alzheimer's disease. J Neuroinflammation 2019; 16:3. [PMID: 30611289 PMCID: PMC6320637 DOI: 10.1186/s12974-018-1380-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 11/27/2018] [Indexed: 01/25/2023] Open
Abstract
Background Immunologic abnormalities have been described in peripheral blood and central nervous system of patients suffering from Alzheimer’s disease (AD), yet their role in the pathogenesis still remains poorly defined. Aim and methods We used the triple transgenic mouse model (3xTg-AD) to reproduce Aβ (amyloid plaques) and tau (neurofibrillary tangles) neuropathologies. We analyzed important features of the adaptive immune system in serum, primary (bone marrow) as well as secondary (spleen) lymphoid organs of 12-month-old 3xTg-AD mice using flow cytometry and ELISPOT. We further investigated serum cytokines of 9- and 13-month-old 3xTg-AD mice using multiplex ELISA. Results were compared to age-matched non-transgenic controls (NTg). Results In the bone marrow of 12-month-old 3xTg-AD mice, we detected decreased proportions of short-term reconstituting hematopoietic stem cells (0.58-fold, P = 0.0116), while lymphocyte, granulocyte, and monocyte populations remained unchanged. Our results also point to increased activation of both B and T lymphocytes. Indeed, we report elevated levels of plasma cells in bone marrow (1.3-fold, P = 0.0405) along with a 5.4-fold rise in serum IgG concentration (P < 0.0001) in 3xTg-AD animals. Furthermore, higher levels of interleukin (IL)-2 were detected in serum of 9- and 13-month-old 3xTg-AD mice (P = 0.0018). Along with increased concentrations of IL-17 (P = 0.0115) and granulocyte-macrophage colony-stimulating factor (P = 0.0085), these data support helper T lymphocyte activation with Th17 polarization. Conclusion Collectively, these results suggest that the 3xTg-AD model mimics modifications of the adaptive immunity changes previously observed in human AD patients and underscore the activation of both valuable and harmful pathways of immunity in AD.
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Affiliation(s)
- Isabelle St-Amour
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, QC, Québec, Canada.,Département de psychiatrie et neurosciences, Faculté de médecine, Université Laval, QC, Canada
| | - Cristina R Bosoi
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, QC, Québec, Canada.,Centre de Recherche de l'IUCPQ-Université Laval, QC, Québec, Canada
| | - Isabelle Paré
- Medical Affairs and Innovation, Héma-Québec, QC, Québec, Canada
| | - Prenitha Mercy Ignatius Arokia Doss
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, QC, Québec, Canada.,Département de psychiatrie et neurosciences, Faculté de médecine, Université Laval, QC, Canada
| | - Manu Rangachari
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, QC, Québec, Canada.,Département de psychiatrie et neurosciences, Faculté de médecine, Université Laval, QC, Canada
| | - Sébastien S Hébert
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, QC, Québec, Canada.,Département de psychiatrie et neurosciences, Faculté de médecine, Université Laval, QC, Canada
| | - Renée Bazin
- Medical Affairs and Innovation, Héma-Québec, QC, Québec, Canada.,Faculté de pharmacie, Université Laval, QC, Québec, Canada
| | - Frédéric Calon
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, QC, Québec, Canada. .,Faculté de pharmacie, Université Laval, QC, Québec, Canada.
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Lång M, Skrifvars MB, Siironen J, Tanskanen P, Ala-Peijari M, Koivisto T, Djafarzadeh S, Bendel S. A pilot study of hyperoxemia on neurological injury, inflammation and oxidative stress. Acta Anaesthesiol Scand 2018; 62:801-810. [PMID: 29464691 DOI: 10.1111/aas.13093] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/11/2018] [Accepted: 01/19/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Normobaric hyperoxia is used to alleviate secondary brain ischaemia in patients with traumatic brain injury (TBI), but clinical evidence is limited and hyperoxia may cause adverse events. METHODS An open label, randomised controlled pilot study comparing blood concentrations of reactive oxygen species (ROS), interleukin 6 (IL-6) and neuron-specific enolase (NSE) between two different fractions of inspired oxygen in severe TBI patients on mechanical ventilation. RESULTS We enrolled 27 patients in the Fi O2 0.40 group and 38 in the Fi O2 0.70 group; 19 and 23 patients, respectively, completed biochemical analyses. In baseline, there were no differences between Fi O2 0.40 and Fi O2 0.70 groups, respectively, in ROS (64.8 nM [22.6-102.1] vs. 64.9 nM [26.8-96.3], P = 0.80), IL-6 (group 92.4 pg/ml [52.9-171.6] vs. 94.3 pg/ml [54.8-133.1], P = 0.52) or NSE (21.04 ug/l [14.0-30.7] vs. 17.8 ug/l [14.1-23.9], P = 0.35). ROS levels did not differ at Day 1 (24.2 nM [20.6-33.5] vs. 29.2 nM [22.7-69.2], P = 0.10) or at Day 2 (25.4 nM [21.7-37.4] vs. 47.3 nM [34.4-126.1], P = 0.95). IL-6 concentrations did not differ at Day 1 (112.7 pg/ml [65.9-168.9) vs. 83.9 pg/ml [51.8-144.3], P = 0.41) or at Day 3 (55.0 pg/ml [34.2-115.6] vs. 49.3 pg/ml [34.4-126.1], P = 0.95). NSE levels did not differ at Day 1 (15.9 ug/l [9.0-24.3] vs. 15.3 ug/l [12.2-26.3], P = 0.62). There were no differences between groups in the incidence of pulmonary complications. CONCLUSION Higher fraction of inspired oxygen did not increase blood concentrations of markers of oxidative stress, inflammation or neurological injury or the incidence of pulmonary complications in severe TBI patients on mechanical ventilation.
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Affiliation(s)
- M. Lång
- Department of Intensive Care Medicine; Kuopio University Hospital; Kys Finland
| | - M. B. Skrifvars
- Department of Anaesthesiology, Intensive Care and Pain Medicine; Helsinki University and Helsinki University Hospital; Helsinki Finland
| | - J. Siironen
- Department of Neurosurgery; Helsinki University and Helsinki University Hospital; Helsinki Finland
| | - P. Tanskanen
- Department of Anaesthesiology, Intensive Care and Pain Medicine; Helsinki University and Helsinki University Hospital; Helsinki Finland
| | - M. Ala-Peijari
- Department of Intensive Care Medicine; Tampere University Hospital; Tampere Finland
| | - T. Koivisto
- Department of Neurosurgery; Kuopio University Hospital; Kys Finland
| | - S. Djafarzadeh
- Department of Intensive Care Medicine, Inselspital; Bern University Hospital; Bern Switzerland
| | - S. Bendel
- Department of Intensive Care Medicine; Kuopio University Hospital; Kys Finland
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37
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Sun M, McDonald SJ, Brady RD, O'Brien TJ, Shultz SR. The influence of immunological stressors on traumatic brain injury. Brain Behav Immun 2018; 69:618-628. [PMID: 29355823 DOI: 10.1016/j.bbi.2018.01.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 01/13/2018] [Accepted: 01/14/2018] [Indexed: 12/15/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and typically involves a robust immune response. Although a great deal of preclinical research has been conducted to identify an effective treatment, all phase III clinical trials have been unsuccessful to date. These translational shortcomings are in part due to a failure to recognize and account for the heterogeneity of TBI, including how extracranial factors can influence the aftermath of TBI. For example, most preclinical studies have utilized isolated TBI models in young adult males, while clinical trials typically involve highly heterogeneous patient populations (e.g., different mechanisms of injury, a range of ages, presence of polytrauma or infection). This paper will review the current, albeit limited literature related to how TBI is affected by common concomitant immunological stressors. In particular, discussion will focus on whether extracranial trauma (i.e., polytrauma), infection, and age/immunosenescence can influence TBI pathophysiology, and thereby may result in a different brain injury than what would have occurred in an isolated TBI. It is concluded that these immunological stressors are all likely to be TBI modifiers that should be further studied and could impact translational treatment strategies.
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Affiliation(s)
- Mujun Sun
- Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Stuart J McDonald
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia
| | - Rhys D Brady
- Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3052, Australia; Departments of Neuroscience and Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Terence J O'Brien
- Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3052, Australia; Departments of Neuroscience and Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Sandy R Shultz
- Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3052, Australia; Departments of Neuroscience and Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
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Lv J, Zeng Y, Qian Y, Dong J, Zhang Z, Zhang J. MicroRNA let-7c-5p improves neurological outcomes in a murine model of traumatic brain injury by suppressing neuroinflammation and regulating microglial activation. Brain Res 2018; 1685:91-104. [PMID: 29408500 DOI: 10.1016/j.brainres.2018.01.032] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 01/01/2018] [Accepted: 01/24/2018] [Indexed: 12/14/2022]
Abstract
MicroRNAs (miRNAs) are a class of non-coding small RNAs that regulate the expression of target genes. They derive from pre-miRNAs that are enzymatically processed by dicer to ∼22 nucleotide mature miRNAs. Members of the pre-miRNA lethal-7 (let-7) are known to regulate cell proliferation and apoptosis. Here, we showed that the level of let-7c-5p, a key member of the let-7 family, was rapidly reduced in the traumatically injured foci in brains of adult C57BL/6J mice and gradually recovered to the pre-injury level 14 days after traumatic brain injury (TBI) induction. This finding led us to test whether upregulating let-7c-5p in murine cerebral tissue by intracerebroventricular injection (ICV) of let-7c-5p mimic could improve the outcomes of mice subjected to controlled cortical impact (CCI). We found that let-7c-5p overexpression attenuated TBI-induced neurological dysfunction and brain edema. The improvements were attributed to let-7c-5p-mediated inhibiting neuroinflammation and attenuation of microglia/macrophage activation, both inhibiting M1 polarization and enhancing M2 polarization. In vitro experiments, we observed that let-7c-5p was decreased in primary microglia activated by LPS treatment or oxygen/glucose deprivation (OGD). Transfection of let-7c-5p mimic suppressed the release of inflammatory mediators in cultured activated primary microglia. In addition, the expressions of caspase-3, a let-7c-5p putative target gene, and the PKC-δ which mediates effect of caspase-3 were inhibited by let-7c-5p in a murine model of TBI. Taken together, these results define the biological activities of cerebral let-7c-5p and delineate its therapeutic potential for improving the neurological outcome of TBI.
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Affiliation(s)
- Jingfang Lv
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Laboratory of Neuro-Trauma, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China; Department of General Surgery, Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yong Zeng
- Laboratory of Neuro-Trauma, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China; Department of Neurosurgery, Tianjin First Center Hospital, Tianjin, China
| | - Yu Qian
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Laboratory of Neuro-Trauma, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China
| | - Jingfei Dong
- Blood Works Research Institute, Seattle, WA, USA; Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, USA
| | - Zhixiang Zhang
- Department of General Surgery, Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jianning Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Laboratory of Neuro-Trauma, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China.
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Stress Hormone Cortisol Enhances Bcl2 Like-12 Expression to Inhibit p53 in Hepatocellular Carcinoma Cells. Dig Dis Sci 2017; 62:3495-3500. [PMID: 29043595 DOI: 10.1007/s10620-017-4798-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/10/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The pathogenesis of hepatocellular carcinoma (HC) is unclear. It is suggested that psychological stress associates with the pathogenesis of liver cancer. Bcl2-like protein 12 (Bcl2L12) suppresses p53 protein. This study tests a hypothesis that the major stress hormone, cortisol, inhibits the expression of p53 in HC cells (HCC) via up regulating the expression of Bcl2L12. METHODS Peripheral blood samples were collected from patients with HC to be analyzed for the levels of cortisol. HCC were cultured to assess the role of cortisol in the regulation of the expression of Bcl2L12 and p53 in HCC. RESULTS We observed that the serum cortisol levels were higher in HC patients. Expression of Bcl2L12 in HCC was correlated with serum cortisol. Cortisol enhanced the Bcl2L12 expression in HCC. Bcl2L12 binding to the TP53 promoter was correlated with p53 expression in HCC. Cortisol increased the Bcl2L12 expression in HCC to inhibit p53 expression. CONCLUSIONS Stress hormone cortisol suppresses p53 in HCC via enhancing Bcl2L12 expression in HCC. The results suggest that cortisol may be a therapeutic target for the treatment of HC.
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Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflammation 2017; 14:167. [PMID: 28835272 PMCID: PMC5569493 DOI: 10.1186/s12974-017-0934-2] [Citation(s) in RCA: 175] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 08/07/2017] [Indexed: 12/25/2022] Open
Abstract
Background Neuroinflammation is an important secondary injury mechanism that has dual beneficial and detrimental roles in the pathophysiology of traumatic brain injury (TBI). Compelling data indicate that statins, a group of lipid-lowering drugs, also have extensive immunomodulatory and anti-inflammatory properties. Among statins, atorvastatin has been demonstrated as a neuroprotective agent in experimental TBI; however, there is a lack of evidence regarding its effects on neuroinflammation during the acute phase of TBI. The current study aimed to evaluate the effects of atorvastatin therapy on modulating the immune reaction, and to explore the possible involvement of peripheral leukocyte invasion and microglia/macrophage polarization in the acute period post-TBI. Methods C57BL/6 mice were subjected to TBI using a controlled cortical impact (CCI) device. Either atorvastatin or vehicle saline was administered orally starting 1 h post-TBI for three consecutive days. Short-term neurological deficits were evaluated using the modified neurological severity score (mNSS) and Rota-rod. Brain-invading leukocyte subpopulations were analyzed by flow cytometry and immunohistochemistry. Pro- and anti-inflammatory cytokines and chemokines were examined using enzyme-linked immunosorbent assay (ELISA). Markers of classically activated (M1) and alternatively activated (M2) microglia/macrophages were then determined by quantitative real-time PCR (qRT-PCR) and flow cytometry. Neuronal apoptosis was identified by double staining of terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) staining and immunofluorescence labeling for neuronal nuclei (NeuN). Results Acute treatment with atorvastatin at doses of 1 mg/kg/day significantly reduced neuronal apoptosis and improved behavioral deficits. Invasions of T cells, neutrophils and natural killer (NK) cells were attenuated profoundly after atorvastatin therapy, as was the production of pro-inflammatory cytokines (IFN-γ and IL-6) and chemokines (RANTES and IP-10). Notably, atorvastatin treatment significantly increased the proportion of regulatory T cells (Tregs) in both the peripheral spleen and brain, and at the same time, increased their main effector cytokines IL-10 and TGF-β1. We also found that atorvastatin significantly attenuated total microglia/macrophage activation but augmented the M2/M1 ratio by both inhibiting M1 polarization and enhancing M2 polarization. Conclusions Our data demonstrated that acute atorvastatin administration could modulate post-TBI neuroinflammation effectively, via a mechanism that involves altering peripheral leukocyte invasion and the alternative polarization of microglia/macrophages.
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Osier N, Dixon CE. Mini Review of Controlled Cortical Impact: A Well-Suited Device for Concussion Research. Brain Sci 2017; 7:E88. [PMID: 28726717 PMCID: PMC5532601 DOI: 10.3390/brainsci7070088] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 07/12/2017] [Accepted: 07/18/2017] [Indexed: 01/25/2023] Open
Abstract
Mild traumatic brain injury (mTBI) is increasingly recognized as a significant public health problem which warrants additional research. Part of the effort to understand mTBI and concussion includes modeling in animals. Controlled cortical impact (CCI) is a commonly employed and well-characterized model of experimental TBI that has been utilized for three decades. Today, several commercially available pneumatic- and electromagnetic-CCI devices exist as do a variety of standard and custom injury induction tips. One of CCI's strengths is that it can be scaled to a number of common laboratory animals. Similarly, the CCI model can be used to produce graded TBI ranging from mild to severe. At the mild end of the injury spectrum, CCI has been applied in many ways, including to study open and closed head mTBI, repeated injuries, and the long-term deficits associated with mTBI and concussion. The purpose of this mini-review is to introduce the CCI model, discuss ways the model can be applied to study mTBI and concussion, and compare CCI to alternative pre-clinical TBI models.
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Affiliation(s)
- Nicole Osier
- School of Nursing, Holistic Adult Health Division, University of Texas at Austin, Austin, TX 78701, USA.
- Dell Medical School, Department of Neurology, University of Texas at Austin, Austin, TX 78701, USA.
| | - C Edward Dixon
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15224, USA.
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15260, USA.
- VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
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Polesel DN, Nozoe KT, Tufik S, Andersen ML, Hachul H. Lack of sleep can jeopardize vaccine effectiveness. Am J Infect Control 2017; 45:96-97. [PMID: 27838162 DOI: 10.1016/j.ajic.2016.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 10/03/2016] [Indexed: 12/01/2022]
Affiliation(s)
| | - Karen Tieme Nozoe
- Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Sergio Tufik
- Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Monica Levy Andersen
- Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Helena Hachul
- Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, SP, Brazil; Department of Gynecology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
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