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Schrier MS, Smirnova MI, Nemeth DP, Deth RC, Quan N. Flavins and Flavoproteins in the Neuroimmune Landscape of Stress Sensitization and Major Depressive Disorder. J Inflamm Res 2025; 18:681-699. [PMID: 39839188 PMCID: PMC11748166 DOI: 10.2147/jir.s501652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 01/08/2025] [Indexed: 01/23/2025] Open
Abstract
Major Depressive Disorder (MDD) is a common and severe neuropsychiatric condition resulting in irregular alterations in affect, mood, and cognition. Besides the well-studied neurotransmission-related etiologies of MDD, several biological systems and phenomena, such as the hypothalamic-pituitary-adrenal (HPA) axis, reactive oxygen species (ROS) production, and cytokine signaling, have been implicated as being altered and contributing to depressive symptoms. However, the manner in which these factors interact with each other to induce their effects on MDD development has been less clear, but is beginning to be understood. Flavins are potent biomolecules that regulate many redox activities, including ROS generation and energy production. Studies have found that circulating flavin levels are modulated during stress and MDD. Flavins are also known for their importance in immune responses. This review offers a unique perspective that considers the redox-active cofactors, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), as vital substrates for linking MDD-related maladaptive processes together, by permitting stress-induced enhancement of microglial interleukin-1 beta (IL-1β) signaling.
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Affiliation(s)
- Matt Scott Schrier
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, USA
| | - Maria Igorevna Smirnova
- The International Max Planck Research School (IMPRS) for Synapses and Circuits, Jupiter, FL, USA
- Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL, USA
- Department of Biological Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Jupiter, FL, USA
| | - Daniel Paul Nemeth
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, USA
| | - Richard Carlton Deth
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA
| | - Ning Quan
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, USA
- Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL, USA
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2
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Kelly C, Trumpff C, Acosta C, Assuras S, Baker J, Basarrate S, Behnke A, Bo K, Bobba-Alves N, Champagne FA, Conklin Q, Cross M, De Jager P, Engelstad K, Epel E, Franklin SG, Hirano M, Huang Q, Junker A, Juster RP, Kapri D, Kirschbaum C, Kurade M, Lauriola V, Li S, Liu CC, Liu G, McEwen B, McGill MA, McIntyre K, Monzel AS, Michelson J, Prather AA, Puterman E, Rosales XQ, Shapiro PA, Shire D, Slavich GM, Sloan RP, Smith JLM, Spann M, Spicer J, Sturm G, Tepler S, de Schotten MT, Wager TD, Picard M. A platform to map the mind-mitochondria connection and the hallmarks of psychobiology: the MiSBIE study. Trends Endocrinol Metab 2024; 35:884-901. [PMID: 39389809 PMCID: PMC11555495 DOI: 10.1016/j.tem.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/16/2024] [Accepted: 08/16/2024] [Indexed: 10/12/2024]
Abstract
Health emerges from coordinated psychobiological processes powered by mitochondrial energy transformation. But how do mitochondria regulate the multisystem responses that shape resilience and disease risk across the lifespan? The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was established to address this question and determine how mitochondria influence the interconnected neuroendocrine, immune, metabolic, cardiovascular, cognitive, and emotional systems among individuals spanning the spectrum of mitochondrial energy transformation capacity, including participants with rare mitochondrial DNA (mtDNA) lesions causing mitochondrial diseases (MitoDs). This interdisciplinary effort is expected to generate new insights into the pathophysiology of MitoDs, provide a foundation to develop novel biomarkers of human health, and integrate our fragmented knowledge of bioenergetic, brain-body, and mind-mitochondria processes relevant to medicine and public health.
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Affiliation(s)
- Catherine Kelly
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Caroline Trumpff
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Carlos Acosta
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Stephanie Assuras
- Department of Clinical Neuropsychology, Division of Cognitive Neuroscience, Columbia University Irving Medical Center, New York, NY, USA
| | - Jack Baker
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Sophia Basarrate
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Alexander Behnke
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA; Clinical and Biological Psychology, Institute of Psychology and Education, Ulm University, Ulm, Germany
| | - Ke Bo
- Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA
| | - Natalia Bobba-Alves
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Quinn Conklin
- Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Marissa Cross
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Philip De Jager
- Center for Translational and Computational Neuroimmunology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
| | - Kris Engelstad
- H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia Translational Neuroscience Initiative, Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Elissa Epel
- Weill Institute for Neurosciences, Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Soah G Franklin
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Michio Hirano
- H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia Translational Neuroscience Initiative, Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Qiuhan Huang
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Alex Junker
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Robert-Paul Juster
- Department of Psychiatry and Addiction, University of Montreal, Montreal, Quebec, Canada
| | - Darshana Kapri
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Clemens Kirschbaum
- Faculty of Psychology, Institute of Biopsychology, Technical University Dresden, Dresden, Germany
| | - Mangesh Kurade
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Vincenzo Lauriola
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Shufang Li
- H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia Translational Neuroscience Initiative, Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Cynthia C Liu
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Grace Liu
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Bruce McEwen
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA
| | - Marlon A McGill
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Kathleen McIntyre
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Anna S Monzel
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Jeremy Michelson
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Aric A Prather
- Weill Institute for Neurosciences, Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Eli Puterman
- School of Kinesiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Xiomara Q Rosales
- H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia Translational Neuroscience Initiative, Department of Neurology, Columbia University Medical Center, New York, NY, USA
| | - Peter A Shapiro
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA; Consultation-Liaison Psychiatry, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - David Shire
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - George M Slavich
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA
| | - Richard P Sloan
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Janell L M Smith
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Marisa Spann
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Julie Spicer
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gabriel Sturm
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Sophia Tepler
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA
| | - Michel Thiebaut de Schotten
- Brain Connectivity and Behavior Laboratory, Paris, France; Groupe d'Imagerie Neurofonctionnelle, Institut des Maladies Neurodégénératives-UMR 5293, CNRS, CEA University of Bordeaux, Bordeaux, France
| | - Tor D Wager
- Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, USA
| | - Martin Picard
- Division of Behavioral Medicine, Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA; H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia Translational Neuroscience Initiative, Department of Neurology, Columbia University Medical Center, New York, NY, USA; Robert N. Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, NY, USA; New York State Psychiatric Institute, New York, NY, USA.
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3
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Lingampelly SS, Naviaux JC, Heuer LS, Monk JM, Li K, Wang L, Haapanen L, Kelland CA, Van de Water J, Naviaux RK. Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder. Commun Biol 2024; 7:536. [PMID: 38729981 PMCID: PMC11549098 DOI: 10.1038/s42003-024-06102-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 03/22/2024] [Indexed: 05/12/2024] Open
Abstract
Classical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns (n = 205) and 5-year-old children (n = 53). Eighty percent of the metabolic impact in ASD was caused by 14 shared biochemical pathways that led to decreased anti-inflammatory and antioxidant defenses, and to increased physiologic stress molecules like lactate, glycerol, cholesterol, and ceramides. CIRCOS plots and a new metabolic network parameter,V ° net, revealed differences in both the kind and degree of network connectivity. Of 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was most changed. Purine network hub analysis revealed a 17-fold reversal in typically developing children. This purine network reversal did not occur in ASD. These results revealed previously unknown metabolic phenotypes, identified new developmental states of the metabolic correlation network, and underscored the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorder.
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Grants
- UL1 TR001442 NCATS NIH HHS
- 7274 Autism Speaks (Autism Speaks Inc.)
- This work was funded in part by philanthropic gifts to the Naviaux Lab from the UCSD Christini Fund, the Lennox Foundation, the William Wright Family Foundation, Malone Family Foundation, the Brain Foundation, the Westreich Foundation, the Aloe family, the Harb family, Marc Spilo and all the others who contributed to the Aloe family autism research fund, the N of One Autism Research Foundation, the UCSD Mitochondrial Disease Research Fund, the JMS Fund, Linda Clark, Jeanne Conrad, David Cannistraro, the Kirby and Katie Mano Family, Simon and Evelyn Foo, Wing-kun Tam, Gita and Anurag Gupta, the Brent Kaufman Family, and the Daniel and Kelly White Family, and grassroots support from over 2000 individuals from around the world who have each provided gifts in the past year to support Naviaux Lab research. The REDCap software system used in this study was provided by the UCSD Clinical and Translational Research Center and supported by Award Number UL1TR001442 from the National Center for Research Resources. Financial supporters for this study had no role in study design, data collection, analysis, interpretation, writing, or publication of this work.
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Affiliation(s)
- Sai Sachin Lingampelly
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
| | - Jane C Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
- Department of Neuroscience, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
| | - Luke S Heuer
- The UC Davis MIND Institute, University of California, Davis, Davis, CA, 95616, USA
| | - Jonathan M Monk
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
| | - Kefeng Li
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
- Macao Polytechnic University, Macau, China
| | - Lin Wang
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA
| | - Lori Haapanen
- The UC Davis MIND Institute, University of California, Davis, Davis, CA, 95616, USA
| | - Chelsea A Kelland
- The UC Davis MIND Institute, University of California, Davis, Davis, CA, 95616, USA
| | - Judy Van de Water
- The UC Davis MIND Institute, University of California, Davis, Davis, CA, 95616, USA
- Department of Rheumatology and Allergy, School of Veterinary Medicine, University of California, Davis, Davis, CA, 95616, USA
| | - Robert K Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA.
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA.
- Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA.
- Department of Pathology, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA.
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4
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Yagin FH, Shateri A, Nasiri H, Yagin B, Colak C, Alghannam AF. Development of an expert system for the classification of myalgic encephalomyelitis/chronic fatigue syndrome. PeerJ Comput Sci 2024; 10:e1857. [PMID: 38660205 PMCID: PMC11041999 DOI: 10.7717/peerj-cs.1857] [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: 07/17/2023] [Accepted: 01/14/2024] [Indexed: 04/26/2024]
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe condition with an uncertain origin and a dismal prognosis. There is presently no precise diagnostic test for ME/CFS, and the diagnosis is determined primarily by the presence of certain symptoms. The current study presents an explainable artificial intelligence (XAI) integrated machine learning (ML) framework that identifies and classifies potential metabolic biomarkers of ME/CFS. Metabolomic data from blood samples from 19 controls and 32 ME/CFS patients, all female, who were between age and body mass index (BMI) frequency-matched groups, were used to develop the XAI-based model. The dataset contained 832 metabolites, and after feature selection, the model was developed using only 50 metabolites, meaning less medical knowledge is required, thus reducing diagnostic costs and improving prognostic time. The computational method was developed using six different ML algorithms before and after feature selection. The final classification model was explained using the XAI approach, SHAP. The best-performing classification model (XGBoost) achieved an area under the receiver operating characteristic curve (AUCROC) value of 98.85%. SHAP results showed that decreased levels of alpha-CEHC sulfate, hypoxanthine, and phenylacetylglutamine, as well as increased levels of N-delta-acetylornithine and oleoyl-linoloyl-glycerol (18:1/18:2)[2], increased the risk of ME/CFS. Besides the robustness of the methodology used, the results showed that the combination of ML and XAI could explain the biomarker prediction of ME/CFS and provided a first step toward establishing prognostic models for ME/CFS.
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Affiliation(s)
- Fatma Hilal Yagin
- Department of Biostatistics and Medical Informatics, Inonu University, Malatya, Türkiye
| | - Ahmadreza Shateri
- Electrical and Computer Engineering Department, Semnan University, Semnan, Iran
| | - Hamid Nasiri
- Department of Computer Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Burak Yagin
- Department of Biostatistics and Medical Informatics, Inonu University, Malatya, Türkiye
| | - Cemil Colak
- Department of Biostatistics and Medical Informatics, Inonu University, Malatya, Türkiye
| | - Abdullah F. Alghannam
- Lifestyle and Health Research Center, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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5
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Pan LA, Naviaux JC, Wang L, Li K, Monk JM, Lingampelly SS, Segreti AM, Bloom K, Vockley J, Tarnopolsky MA, Finegold DN, Peters DG, Naviaux RK. Metabolic features of treatment-refractory major depressive disorder with suicidal ideation. Transl Psychiatry 2023; 13:393. [PMID: 38097555 PMCID: PMC10721812 DOI: 10.1038/s41398-023-02696-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/18/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023] Open
Abstract
Peripheral blood metabolomics was used to gain chemical insight into the biology of treatment-refractory Major Depressive Disorder with suicidal ideation, and to identify individualized differences for personalized care. The study cohort consisted of 99 patients with treatment-refractory major depressive disorder and suicidal ideation (trMDD-SI n = 52 females and 47 males) and 94 age- and sex-matched healthy controls (n = 48 females and 46 males). The median age was 29 years (IQR 22-42). Targeted, broad-spectrum metabolomics measured 448 metabolites. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) were measured as biomarkers of mitochondrial dysfunction. The diagnostic accuracy of plasma metabolomics was over 90% (95%CI: 0.80-1.0) by area under the receiver operator characteristic (AUROC) curve analysis. Over 55% of the metabolic impact in males and 75% in females came from abnormalities in lipids. Modified purines and pyrimidines from tRNA, rRNA, and mRNA turnover were increased in the trMDD-SI group. FGF21 was increased in both males and females. Increased lactate, glutamate, and saccharopine, and decreased cystine provided evidence of reductive stress. Seventy-five percent of the metabolomic abnormalities found were individualized. Personalized deficiencies in CoQ10, flavin adenine dinucleotide (FAD), citrulline, lutein, carnitine, or folate were found. Pathways regulated by mitochondrial function dominated the metabolic signature. Peripheral blood metabolomics identified mitochondrial dysfunction and reductive stress as common denominators in suicidal ideation associated with treatment-refractory major depressive disorder. Individualized metabolic differences were found that may help with personalized management.
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Affiliation(s)
- Lisa A Pan
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- School of Public Health, Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Panomics Mental Health Initiative, Pittsburgh, PA, USA.
- New Hope Molecular, LLC, Pittsburgh, PA, USA.
- New Hope Molecular, LLC, 750 Washington Rd, Suite 19, Pittsburgh, PA, 15228, USA.
| | - Jane C Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, USA
- Department of Neurosciences, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Lin Wang
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Kefeng Li
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Jonathan M Monk
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Sai Sachin Lingampelly
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, USA
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA
| | - Anna Maria Segreti
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kaitlyn Bloom
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jerry Vockley
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Mark A Tarnopolsky
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - David N Finegold
- School of Public Health, Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Panomics Mental Health Initiative, Pittsburgh, PA, USA
- New Hope Molecular, LLC, Pittsburgh, PA, USA
| | - David G Peters
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- School of Public Health, Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Panomics Mental Health Initiative, Pittsburgh, PA, USA
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert K Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, USA.
- Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA.
- Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, CA, USA.
- Department of Pathology, University of California, San Diego School of Medicine, San Diego, CA, USA.
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6
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Alitalo O, González-Hernández G, Rosenholm M, Kohtala P, Matsui N, Müller HK, Theilmann W, Klein A, Kärkkäinen O, Rozov S, Rantamäki T, Kohtala S. Linking Hypothermia and Altered Metabolism with TrkB Activation. ACS Chem Neurosci 2023; 14:3212-3225. [PMID: 37551888 PMCID: PMC10485900 DOI: 10.1021/acschemneuro.3c00350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 07/13/2023] [Indexed: 08/09/2023] Open
Abstract
Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β). Increased TrkB, GSK3β, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.
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Affiliation(s)
- Okko Alitalo
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
- SleepWell
Research Program, Faculty of Medicine, University
of Helsinki, Helsinki 00014, Finland
| | - Gemma González-Hernández
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
- SleepWell
Research Program, Faculty of Medicine, University
of Helsinki, Helsinki 00014, Finland
| | - Marko Rosenholm
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
- SleepWell
Research Program, Faculty of Medicine, University
of Helsinki, Helsinki 00014, Finland
- Center
for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Piia Kohtala
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
- SleepWell
Research Program, Faculty of Medicine, University
of Helsinki, Helsinki 00014, Finland
- Department
of Psychiatry, Weill Cornell Medicine, New York, New York 10021, United States
| | - Nobuaki Matsui
- Faculty
of Pharmacy, Gifu University of Medical
Science, 4-3-3 Nijigaoka,
Kani, Gifu 509-0293, Japan
| | - Heidi Kaastrup Müller
- Translational
Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus N 8200, Denmark
| | - Wiebke Theilmann
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
| | - Anders Klein
- Novo
Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK-2200, Denmark
- Department
of Drug Design & Pharmacology, University
of Copenhagen, Copenhagen DK-2100, Denmark
| | - Olli Kärkkäinen
- School
of Pharmacy, University of Eastern Finland, Kuopio 70210, Finland
- Afekta
Technologies Ltd., Kuopio 70210, Finland
| | - Stanislav Rozov
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
- SleepWell
Research Program, Faculty of Medicine, University
of Helsinki, Helsinki 00014, Finland
| | - Tomi Rantamäki
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
- SleepWell
Research Program, Faculty of Medicine, University
of Helsinki, Helsinki 00014, Finland
| | - Samuel Kohtala
- Laboratory
of Neurotherapeutics, Drug Research Program, Division of Pharmacology
and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
- SleepWell
Research Program, Faculty of Medicine, University
of Helsinki, Helsinki 00014, Finland
- Department
of Psychiatry, Weill Cornell Medicine, New York, New York 10021, United States
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7
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Zhang H, Tang X, Feng C, Gao Y, Hong Q, Zhang J, Zhang X, Zheng Q, Lin J, Liu X, Shen L. The use of data independent acquisition based proteomic analysis and machine learning to reveal potential biomarkers for autism spectrum disorder. J Proteomics 2023; 278:104872. [PMID: 36898611 DOI: 10.1016/j.jprot.2023.104872] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 02/08/2023] [Accepted: 03/03/2023] [Indexed: 03/12/2023]
Abstract
Autism spectrum disorder (ASD) is a complex neurological developmental disorder in children, and is associated with social isolation and restricted interests. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. We performed data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis of plasma from children with ASD and controls. The result showed that 45 differentially expressed proteins (DEPs) were identified between autistic subjects and controls. Among these, only one DEP was down-regulated in ASD; other DEPs were up-regulated in ASD children's plasma. These proteins are found associated with complement and coagulation cascades, vitamin digestion and absorption, cholesterol metabolism, platelet degranulation, selenium micronutrient network, extracellular matrix organization and inflammatory pathway, which have been reported to be related to ASD. After MRM verification, five key proteins in complement pathway (PLG, SERPINC1, and A2M) and inflammatory pathway (CD5L, ATRN, SERPINC1, and A2M) were confirmed to be significantly up-regulated in ASD group. Through the screening of machine learning model and MRM verification, we found that two proteins (biotinidase and carbonic anhydrase 1) can be used as early diagnostic markers of ASD (AUC = 0.8, p = 0.0001). SIGNIFICANCE: ASD is the fastest growing neurodevelopmental disorder in the world and has become a major public health problem worldwide. Its prevalence has been steadily increasing, with a global prevalence rate of 1%. Early diagnosis and intervention can achieve better prognosis. In this study, data independent acquisition (DIA) and multiple reaction monitoring (MRM) analysis was applied to analyze the plasma proteome of ASD patients (31 (±5) months old), and 378 proteins were quantified. 45 differentially expressed proteins (DEPs) were identified between the ASD group and the control group. They mainly were associated with platelet degranulation, ECM proteoglycar, complement and coagulation cascades, selenium micronutrient network, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), cholesterol metabolism, vitamin metabolism, and inflammatory pathway. Through the integrated machine learning methods and the MRM verification of independent samples, it is considered that biotinidase and carbon anhydrase 1 have the potential to become biomarkers for the early diagnosis of ASD. These results complement proteomics database of the ASD patients, broaden our understanding of ASD, and provide a panel of biomarkers for the early diagnosis of ASD.
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Affiliation(s)
- Huajie Zhang
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China
| | - Xiaoxiao Tang
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China
| | - Chengyun Feng
- Maternal and Child Health Hospital of Baoan, Shenzhen 518100, PR China
| | - Yan Gao
- Maternal and Child Health Hospital of Baoan, Shenzhen 518100, PR China
| | - Qi Hong
- Maternal and Child Health Hospital of Baoan, Shenzhen 518100, PR China
| | - Jun Zhang
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China
| | - Xinglai Zhang
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China
| | - Qihong Zheng
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China
| | - Jing Lin
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China
| | - Xukun Liu
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China
| | - Liming Shen
- College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518071, PR China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research, Institutions, Shenzhen 518055, PR China; Shenzhen Key Laboratory of Marine Biotechnology and Ecology, Shenzhen 518071, PR China.
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8
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Naviaux RK. Mitochondrial and metabolic features of salugenesis and the healing cycle. Mitochondrion 2023; 70:131-163. [PMID: 37120082 DOI: 10.1016/j.mito.2023.04.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/24/2023] [Accepted: 04/23/2023] [Indexed: 05/01/2023]
Abstract
Pathogenesis and salugenesis are the first and second stages of the two-stage problem of disease production and health recovery. Salugenesis is the automatic, evolutionarily conserved, ontogenetic sequence of molecular, cellular, organ system, and behavioral changes that is used by living systems to heal. It is a whole-body process that begins with mitochondria and the cell. The stages of salugenesis define a circle that is energy- and resource-consuming, genetically programmed, and environmentally responsive. Energy and metabolic resources are provided by mitochondrial and metabolic transformations that drive the cell danger response (CDR) and create the three phases of the healing cycle: Phase 1-Inflammation, Phase 2-Proliferation, and Phase 3-Differentiation. Each phase requires a different mitochondrial phenotype. Without different mitochondria there can be no healing. The rise and fall of extracellular ATP (eATP) signaling is a key driver of the mitochondrial and metabolic reprogramming required to progress through the healing cycle. Sphingolipid and cholesterol-enriched membrane lipid rafts act as rheostats for tuning cellular sensitivity to purinergic signaling. Abnormal persistence of any phase of the CDR inhibits the healing cycle, creates dysfunctional cellular mosaics, causes the symptoms of chronic disease, and accelerates the process of aging. New research reframes the rising tide of chronic disease around the world as a systems problem caused by the combined action of pathogenic triggers and anthropogenic factors that interfere with the mitochondrial functions needed for healing. Once chronic pain, disability, or disease is established, salugenesis-based therapies will start where pathogenesis-based therapies end.
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Affiliation(s)
- Robert K Naviaux
- The Mitochondrial and Metabolic Disease Center, Departments of Medicine, and Pediatrics, University of California, San Diego School of Medicine, 214 Dickinson St., Bldg CTF, Rm C107, MC#8467, San Diego, CA 92103.
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9
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Kurniansyah N, Wallace DA, Zhang Y, Yu B, Cade B, Wang H, Ochs-Balcom HM, Reiner AP, Ramos AR, Smith JD, Cai J, Daviglus M, Zee PC, Kaplan R, Kooperberg C, Rich SS, Rotter JI, Gharib SA, Redline S, Sofer T. An integrated multi-omics analysis of sleep-disordered breathing traits implicates P2XR4 purinergic signaling. Commun Biol 2023; 6:125. [PMID: 36721044 PMCID: PMC9889381 DOI: 10.1038/s42003-023-04520-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 01/23/2023] [Indexed: 02/01/2023] Open
Abstract
Sleep Disordered Breathing (SDB) is a common disease associated with increased risk for cardiometabolic, cardiovascular, and cognitive diseases. How SDB affects the molecular environment is still poorly understood. We study the association of three SDB measures with gene expression measured using RNA-seq in multiple blood tissues from the Multi-Ethnic Study of Atherosclerosis. We develop genetic instrumental variables for the associated transcripts as polygenic risk scores (tPRS), then generalize and validate the tPRS in the Women's Health Initiative. We measure the associations of the validated tPRS with SDB and serum metabolites in Hispanic Community Health Study/Study of Latinos. Here we find differential gene expression by blood cell type in relation to SDB traits and link P2XR4 expression to average oxyhemoglobin saturation during sleep and butyrylcarnitine (C4) levels. These findings can be used to develop interventions to alleviate the effect of SDB on the human molecular environment.
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Affiliation(s)
- Nuzulul Kurniansyah
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA
| | - Danielle A Wallace
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA
| | - Ying Zhang
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Brian Cade
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA
| | - Heming Wang
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA
| | - Heather M Ochs-Balcom
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Alexander P Reiner
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Alberto R Ramos
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua D Smith
- Northwest Genomic Center, University of Washington, Seattle, WA, USA
| | - Jianwen Cai
- Department of Biostatistics, University of North Carolina, at Chapel Hill, NC, USA
| | - Martha Daviglus
- Institute for Minority Health Research, University of Illinois at Chicago, Chicago, IL, USA
| | - Phyllis C Zee
- Division of Sleep Medicine, Department of Neurology, Northwestern University, Chicago, IL, USA
| | - Robert Kaplan
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Epidemiology & Population Health, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Sina A Gharib
- Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Susan Redline
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA
- Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA
| | - Tamar Sofer
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
- Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
- Departments of Medicine and of Biostatistics, Harvard University, Boston, MA, USA.
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10
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De Vitis C, Capalbo C, Torsello A, Napoli C, Salvati V, Loffredo C, Blandino G, Piaggio G, Auciello FR, Pelliccia F, Salerno G, Simmaco M, Di Magno L, Canettieri G, Coluzzi F, Mancini R, Rocco M, Sciacchitano S. Opposite Effect of Thyroid Hormones on Oxidative Stress and on Mitochondrial Respiration in COVID-19 Patients. Antioxidants (Basel) 2022; 11:antiox11101998. [PMID: 36290721 PMCID: PMC9598114 DOI: 10.3390/antiox11101998] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 01/08/2023] Open
Abstract
Background: Thyroid hormones (TH)s are master regulators of mitochondrial activity and biogenesis. Nonthyroidal illness syndrome (NTIS) is generally considered an adaptative response to reduced energy that is secondary to critical illness, including COVID-19. COVID-19 has been associated with profound changes in the cell energy metabolism, especially in the cells of the immune system, with a central role played by the mitochondria, considered the power units of every cell. Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects and alters mitochondrial functions, both to influence its intracellular survival and to evade host immunity. Aim of the study: This study was undertaken to analyze the oxidative balance and mitochondrial respiration in COVID-19 patients with and without NTIS to elucidate the role that thyroid hormones (TH)s play in this context. Methods: In our cohort of 54 COVID-19 patients, admitted to our University Hospital during the COVID-19 pandemic, we evaluated the generation of reactive oxygen species (ROS) by measuring the serum levels of derivatives of reactive oxygen metabolites (dROMs), and we analyzed the antioxidant capacity by measuring the serum biological antioxidant potential (BAP). We then analyzed the mitochondrial respiration in peripheral blood mononuclear cells (PBMC)s of 28 of our COVID-19 patients, using the seahorse instrument (Agilent). Results were correlated with the serum levels of THs and, in particular, of FT3. In addition, the role of T3 on bioelectrical impedance analysis (BIA) and mitochondrial respiration parameters was directly evaluated in two COVID-19 patients with NTIS, in which treatment with synthetic liothyronine (LT3) was given both in vivo and in vitro. Results: In our COVID-19 patients with NTIS, the dROMs values were significantly lower and the BAP values were significantly higher. Consequently, the oxidative stress index (OSi), measured as BAP/dROMs ratio was reduced compared to that observed in COVID-19 patients without NTIS, indicating a protective role exerted by NTIS on oxidative stress. In our COVID-19 patients, the mitochondrial respiration, measured in PBMCs, was reduced compared to healthy controls. Those with NTIS showed a reduced maximal respiratory capacity and a reduced proton leak, compared to those with normal FT3 serum values. Such lowered mitochondrial respiratory capacity makes the cells more vulnerable to bioenergetic exhaustion. In a pilot study involving two COVID-19 patients with NTIS, we could reinforce our previous observation regarding the role of T3 in the maintenance of adequate peripheral hydroelectrolytic balance. In addition, in these two patients, we demonstrated that by treating their PBMCs with LT3, both in vitro and in vivo, all mitochondrial respiration parameters significantly increased. Conclusions: Our results regarding the reduction in the serum levels of the reactive oxygen species (ROS) of COVID-19 patients with NTIS support the hypothesis that NTIS could represent an adaptative response to severe COVID-19. However, beside this beneficial effect, we demonstrate that, in the presence of an acute reduction of FT3 serum levels, the mitochondrial respiration is greatly impaired, with a consequent establishment of a hypoenergetic state of the immune cells that may hamper their capacity to react to massive viral infection.
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Affiliation(s)
- Claudia De Vitis
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Carlo Capalbo
- Department of Medical Oncology, Sant’Andrea University Hospital, 00189 Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Alessandra Torsello
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Christian Napoli
- Department of Surgical and Medical Science and Translational Medicine, Sapienza University of Rome, 00181 Rome, Italy
| | - Valentina Salvati
- Scientific Direction, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Chiara Loffredo
- Unit of Anesthesia, Intensive Care and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Giovanni Blandino
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Giulia Piaggio
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Roma, Italy
| | - Francesca Romana Auciello
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Flaminia Pelliccia
- Unit of Anesthesia, Intensive Care and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Gerardo Salerno
- Department of Neuroscience, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, 00189 Rome, Italy
| | - Maurizio Simmaco
- Department of Neuroscience, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, 00189 Rome, Italy
| | - Laura Di Magno
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Gianluca Canettieri
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Pasteur Institute, Cenci-Bolognetti Foundation, 00161 Rome, Italy
| | - Flaminia Coluzzi
- Unit of Anesthesia, Intensive Care and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
- Department Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, 04100 Latina, Italy
| | - Rita Mancini
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Monica Rocco
- Department of Surgical and Medical Science and Translational Medicine, Sapienza University of Rome, 00181 Rome, Italy
- Unit of Anesthesia, Intensive Care and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Salvatore Sciacchitano
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Correspondence:
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11
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Li K, Schön M, Naviaux JC, Monk JM, Alchus-Laiferová N, Wang L, Straka I, Matejička P, Valkovič P, Ukropec J, Tarnopolsky MA, Naviaux RK, Ukropcová B. Cerebrospinal fluid and plasma metabolomics of acute endurance exercise. FASEB J 2022; 36:e22408. [PMID: 35713567 DOI: 10.1096/fj.202200509r] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/05/2022] [Accepted: 05/28/2022] [Indexed: 11/11/2022]
Abstract
Metabolomics has emerged as a powerful new tool in precision medicine. No studies have yet been published on the metabolomic changes in cerebrospinal fluid (CSF) produced by acute endurance exercise. CSF and plasma were collected from 19 young active adults (13 males and 6 females) before and 60 min after a 90-min monitored outdoor run. The median age, BMI, and VO2 max of subjects was 25 years (IQR 22-31), 23.2 kg/m2 (IQR 21.7-24.5), and 47 ml/kg/min (IQR 38-51), respectively. Targeted, broad-spectrum metabolomics was performed by liquid chromatography, tandem mass spectrometry (LC-MS/MS). In the CSF, purines and pyrimidines accounted for 32% of the metabolic impact after acute endurance exercise. Branch chain amino acids, amino acid neurotransmitters, fatty acid oxidation, phospholipids, and Krebs cycle metabolites traceable to mitochondrial function accounted for another 52% of the changes. A narrow but important channel of metabolic communication was identified between the brain and body by correlation network analysis. By comparing these results to previous work in experimental animal models, we found that over 80% of the changes in the CSF correlated with a cascade of mitochondrial and metabolic changes produced by ATP signaling. ATP is released as a co-neurotransmitter and neuromodulator at every synapse studied to date. By regulating brain mitochondrial function, ATP release was identified as an early step in the kinetic cascade of layered benefits produced by endurance exercise.
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Affiliation(s)
- Kefeng Li
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, California, USA.,Department of Medicine, University of California, San Diego School of Medicine, San Diego, California, USA
| | - Martin Schön
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jane C Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, California, USA.,Department of Neurosciences, University of California, San Diego School of Medicine, San Diego, California, USA
| | - Jonathan M Monk
- Department of Bioengineering, University of California, San Diego School of Medicine, San Diego, California, USA
| | - Nikoleta Alchus-Laiferová
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.,Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Lin Wang
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, California, USA.,Department of Medicine, University of California, San Diego School of Medicine, San Diego, California, USA
| | - Igor Straka
- 2nd Department of Neurology, Faculty of Medicine, Comenius University and University Hospital Bratislava, Bratislava, Slovakia
| | - Peter Matejička
- 2nd Department of Neurology, Faculty of Medicine, Comenius University and University Hospital Bratislava, Bratislava, Slovakia
| | - Peter Valkovič
- 2nd Department of Neurology, Faculty of Medicine, Comenius University and University Hospital Bratislava, Bratislava, Slovakia.,Centre of Experimental Medicine, Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jozef Ukropec
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Mark A Tarnopolsky
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Robert K Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, California, USA.,Department of Medicine, University of California, San Diego School of Medicine, San Diego, California, USA.,Department of Pediatrics, University of California, San Diego School of Medicine, San Diego, California, USA.,Department of Pathology, University of California, San Diego School of Medicine, San Diego, California, USA
| | - Barbara Ukropcová
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.,Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
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12
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Disruption of Alternative Splicing in the Amygdala of Pigs Exposed to Maternal Immune Activation. IMMUNO 2021. [DOI: 10.3390/immuno1040035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The inflammatory response of gestating females to infection or stress can disrupt gene expression in the offspring’s amygdala, resulting in lasting neurodevelopmental, physiological, and behavioral disorders. The effects of maternal immune activation (MIA) can be impacted by the offspring’s sex and exposure to additional stressors later in life. The objectives of this study were to investigate the disruption of alternative splicing patterns associated with MIA in the offspring’s amygdala and characterize this disruption in the context of the second stress of weaning and sex. Differential alternative splicing was tested on the RNA-seq profiles of a pig model of viral-induced MIA. Compared to controls, MIA was associated with the differential alternative splicing (FDR-adjusted p-value < 0.1) of 292 and 240 genes in weaned females and males, respectively, whereas 132 and 176 genes were differentially spliced in control nursed female and male, respectively. The majority of the differentially spliced (FDR-adjusted p-value < 0.001) genes (e.g., SHANK1, ZNF672, KCNA6) and many associated enriched pathways (e.g., Fc gamma R-mediated phagocytosis, non-alcoholic fatty liver disease, and cGMP-PKG signaling) have been reported in MIA-related disorders including autism and schizophrenia in humans. Differential alternative splicing associated with MIA was detected in the gene MAG across all sex-stress groups except for unstressed males and SLC2A11 across all groups except unstressed females. Precise understanding of the effect of MIA across second stressors and sexes necessitates the consideration of splicing isoform profiles.
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13
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Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A 2021; 118:e2024358118. [PMID: 34400495 PMCID: PMC8403932 DOI: 10.1073/pnas.2024358118] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called "long COVID-19," reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, postexertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities. However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases. We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.
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Affiliation(s)
- Bindu D Paul
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
| | | | - Anthony L Komaroff
- Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02120
| | - Solomon H Snyder
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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14
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Schmidt RJ, Liang D, Busgang SA, Curtin P, Giulivi C. Maternal Plasma Metabolic Profile Demarcates a Role for Neuroinflammation in Non-Typical Development of Children. Metabolites 2021; 11:545. [PMID: 34436486 PMCID: PMC8400060 DOI: 10.3390/metabo11080545] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 11/16/2022] Open
Abstract
Maternal and cord plasma metabolomics were used to elucidate biological pathways associated with increased diagnosis risk for autism spectrum disorders (ASD). Metabolome-wide associations were assessed in both maternal and umbilical cord plasma in relation to diagnoses of ASD and other non-typical development (Non-TD) compared to typical development (TD) in the Markers of Autism risk in Babies: Learning Early Signs (MARBLES) cohort study of children born to mothers who already have at least one child with ASD. Analyses were stratified by sample matrix type, machine mode, and annotation confidence level. Dimensionality reduction techniques were used [i.e, principal component analysis (PCA) and random subset weighted quantile sum regression (WQSRS)] to minimize the high multiple comparison burden. With WQSRS, a metabolite mixture obtained from the negative mode of maternal plasma decreased the odds of Non-TD compared to TD. These metabolites, all related to the prostaglandin pathway, underscored the relevance of neuroinflammation status. No other significant findings were observed. Dimensionality reduction strategies provided confirming evidence that a set of maternal plasma metabolites are important in distinguishing Non-TD compared to TD diagnosis. A lower risk for Non-TD was linked to anti-inflammatory elements, thereby linking neuroinflammation to detrimental brain function consistent with studies ranging from neurodevelopment to neurodegeneration.
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Affiliation(s)
- Rebecca J. Schmidt
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA;
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
| | - Donghai Liang
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA;
| | - Stefanie A. Busgang
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (S.A.B.); (P.C.)
| | - Paul Curtin
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (S.A.B.); (P.C.)
| | - Cecilia Giulivi
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
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15
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Ju J, Yang X, Jiang J, Wang D, Zhang Y, Zhao X, Fang X, Liao H, Zheng L, Li S, Hou ST, Liang L, Pan Y, Li H, Li N. Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder. Front Cell Neurosci 2021; 15:718720. [PMID: 34483844 PMCID: PMC8416256 DOI: 10.3389/fncel.2021.718720] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/22/2021] [Indexed: 12/27/2022] Open
Abstract
Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2±) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2± mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids and that increasing evidence has linked dysregulation of lipid metabolism to ASD, we performed lipidomic analysis and discovered decreased levels of certain species of sphingomyelin, hexosyl ceramide and their common precursor, ceramide, in 16p11.2± striatum, all of which are major myelin components. We further identified lack of ceramide synthase 2 as the possible reason behind the decrease in these lipid species. Taken together, our data suggest a role for myelin and myelin lipids in ASD development.
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Affiliation(s)
- Jun Ju
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xiuyan Yang
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jian Jiang
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Dilong Wang
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yumeng Zhang
- Wolfson Institute for Biomedical Research, Division of Medicine, Faculty of Medical Sciences, University College London, London, United Kingdom
| | - Xiaofeng Zhao
- Institute of Developmental and Regenerative Biology, Zhejiang Key Laboratory of Organ Development and Regeneration, Hangzhou Normal University, Hangzhou, China
| | - Xiaoyi Fang
- Department of Neonatology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Huanquan Liao
- The Clinical Neuroscience Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Lei Zheng
- Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Sheng-Tao Hou
- Brain Research Centre and Department of Biology, Southern University of Science and Technology, Shenzhen, China
| | - Liyang Liang
- Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Huiliang Li
- Wolfson Institute for Biomedical Research, Division of Medicine, Faculty of Medical Sciences, University College London, London, United Kingdom
| | - Ningning Li
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- China-UK Institute for Frontier Science, Shenzhen, China
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16
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Stanton JE, Malijauskaite S, McGourty K, Grabrucker AM. The Metallome as a Link Between the "Omes" in Autism Spectrum Disorders. Front Mol Neurosci 2021; 14:695873. [PMID: 34290588 PMCID: PMC8289253 DOI: 10.3389/fnmol.2021.695873] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/14/2021] [Indexed: 12/26/2022] Open
Abstract
Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal composition, only. Still, few have considered the links between other "omes," which may together result in an individual's specific pathologies. In particular, ASD have been reported to have multitudes of possible causal effects. Metallomics data focusing on metal deficiencies and dyshomeostasis can be linked to functions of metalloenzymes, metal transporters, and transcription factors, thus affecting the proteome and transcriptome. Furthermore, recent studies in ASD have emphasized the gut-brain axis, with alterations in the microbiome being linked to changes in the metabolome and inflammatory processes. However, the microbiome and other "omes" are heavily influenced by the metallome. Thus, here, we will summarize the known implications of a changed metallome for other "omes" in the body in the context of "omics" studies in ASD. We will highlight possible connections and propose a model that may explain the so far independently reported pathologies in ASD.
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Affiliation(s)
- Janelle E Stanton
- Department of Biological Sciences, University of Limerick, Limerick, Ireland.,Bernal Institute, University of Limerick, Limerick, Ireland
| | - Sigita Malijauskaite
- Bernal Institute, University of Limerick, Limerick, Ireland.,Department of Chemical Sciences, University of Limerick, Limerick, Ireland
| | - Kieran McGourty
- Bernal Institute, University of Limerick, Limerick, Ireland.,Department of Chemical Sciences, University of Limerick, Limerick, Ireland.,Health Research Institute, University of Limerick, Limerick, Ireland
| | - Andreas M Grabrucker
- Department of Biological Sciences, University of Limerick, Limerick, Ireland.,Bernal Institute, University of Limerick, Limerick, Ireland.,Health Research Institute, University of Limerick, Limerick, Ireland
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17
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Pietrowski MJ, Gabr AA, Kozlov S, Blum D, Halle A, Carvalho K. Glial Purinergic Signaling in Neurodegeneration. Front Neurol 2021; 12:654850. [PMID: 34054698 PMCID: PMC8160300 DOI: 10.3389/fneur.2021.654850] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/16/2021] [Indexed: 12/15/2022] Open
Abstract
Purinergic signaling regulates neuronal and glial cell functions in the healthy CNS. In neurodegenerative diseases, purinergic signaling becomes dysregulated and can affect disease-associated phenotypes of glial cells. In this review, we discuss how cell-specific expression patterns of purinergic signaling components change in neurodegeneration and how dysregulated glial purinergic signaling and crosstalk may contribute to disease pathophysiology, thus bearing promising potential for the development of new therapeutical options for neurodegenerative diseases.
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Affiliation(s)
- Marie J Pietrowski
- Microglia and Neuroinflammation Laboratory, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Amr Ahmed Gabr
- Microglia and Neuroinflammation Laboratory, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.,Department of Physiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Stanislav Kozlov
- Microglia and Neuroinflammation Laboratory, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - David Blum
- University of Lille, Inserm, CHU Lille, U1172 LilNCog - Lille Neuroscience and Cognition, Lille, France.,Alzheimer and Tauopathies, Labex DISTALZ, Lille, France
| | - Annett Halle
- Microglia and Neuroinflammation Laboratory, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.,Institute of Neuropathology, University of Bonn, Bonn, Germany
| | - Kevin Carvalho
- University of Lille, Inserm, CHU Lille, U1172 LilNCog - Lille Neuroscience and Cognition, Lille, France.,Alzheimer and Tauopathies, Labex DISTALZ, Lille, France
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