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Dai ZM, Xu ML, Zhang QQ, Zhu B, Wu JZ, Liu Q, Li Y, Li HB. Alterations of the gut commensal Akkermansia muciniphila in patients with COVID-19. Virulence 2025; 16:2505999. [PMID: 40360188 PMCID: PMC12091934 DOI: 10.1080/21505594.2025.2505999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/12/2024] [Accepted: 04/02/2025] [Indexed: 05/15/2025] Open
Abstract
Dysbiosis of gut microbiota is well established in coronavirus disease 2019 (COVID-19). While studies have attempted to establish a link between the gut commensal Akkermansia muciniphila (A. muciniphila) and COVID-19, the findings have been inconsistent and sometimes controversial. The intestinal microbial abundance information of COVID-19 patients was acquired and analysed from GMrepo database. Subsequently, A. muciniphila's metabolites, target-genes, and metabolite-target relationships was extracted from GutMGene database. Lastly, coronascape module in Metascape database is used for gene annotation and enrichment analysis in various host cells and tissues after SARS-CoV-2 infection. The results indicated that, in comparison to healthy people, A. muciniphila was significantly elevated in COVID-19 patients. This bacterium was found to be associated with heightened expression of IL-10, TLR2, TLR4, CLGN, CLDN4, TJP2, and TJP3, while concurrently experiencing a reduction in the expression of IL-12A and IL-12B in humans. The regulatory genes of A. muciniphila primarily enhance responses to viruses and cytokines, positively regulate cell migration, and control epithelial cell proliferation. Our study revealed a significant increase in the gut commensal A. muciniphila in COVID-19 patients. This bacterium can modulate host immune responses and may also serve as a probiotic with antiviral properties.
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Affiliation(s)
- Zhi-Ming Dai
- Department of Anesthesiology, The First People’s Hospital of Xianyang, Xianyang, China
| | - Meng-Lu Xu
- Department of Nephrology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, China
| | - Qing-Qing Zhang
- Department of Anesthesiology, Ganzhou Hospital of Guangdong Provincial People’s Hospital, Ganzhou Municipal Hospital, Ganzhou, China
| | - Bo Zhu
- Department of Anesthesiology, The First People’s Hospital of Xianyang, Xianyang, China
| | - Jun-Zhe Wu
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, China
| | - Qi Liu
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, China
| | - Ying Li
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, China
| | - Hong-Bao Li
- Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, China
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Guan H, Chen J, Kaur K, Amreen B, Lesseur C, Dolios G, Andra SS, Narasimhan S, Pulivarthi D, Midya V, De Witte LD, Bergink V, Rommel AS, Petrick LM. High-dimensional mediation analysis to elucidate the role of metabolites in the association between PFAS exposure and reduced SARS-CoV-2 IgG in pregnancy. THE SCIENCE OF THE TOTAL ENVIRONMENT 2025; 980:179520. [PMID: 40311333 DOI: 10.1016/j.scitotenv.2025.179520] [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: 02/04/2025] [Revised: 04/06/2025] [Accepted: 04/22/2025] [Indexed: 05/03/2025]
Abstract
We previously found that per- and polyfluoroalkyl substances (PFAS) mixture exposure is inversely associated with SARS-CoV-2 IgG (IgG) antibody levels in pregnant individuals. Here, we aim to identify metabolites mediating this relationship to elucidate the underlying biological pathways. This cross-sectional study included 59 pregnant participants from a US-based pregnancy cohort. Untargeted metabolomic profiling was performed using Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS), and Weighted Quantile Sum (WQS) regression was applied to assess the PFAS and metabolites mixture effects on IgG. Metabolite indices positively or negatively associated with IgG levels were constructed separately and their mediation effects were examined independently and jointly. The PFAS-index was negatively associated with IgG levels (beta = -0.315, p < 0.001), with PFHpS and PFHxS as major contributors. Two metabolites-indices were constructed, one positively (beta = 1.249, p < 0.001) and one negatively (beta = -1.200, p < 0.001) associated with IgG. Key contributors for these indices included trigonelline, adipate, p-octopamine, and n-acetylproline. Analysis of a single mediator showed that 74.6 % (95 % CI: 45.9 %, 98.0 %) and 68.6 % (95 % CI: 41.8 %, 94.1 %) of the PFAS index-IgG total effect were mediated by the negative and positive metabolites-indices, respectively. Joint analysis of the metabolites-indices indicated a cumulative mediation effect of 83.8 % (95 % CI: 58.1 %, 98.7 %). Enriched pathways associated with these metabolites-indices were phenylalanine, tyrosine, and tryptophan biosynthesis and arginine metabolism. We observed significant mediation effects of plasma metabolites on the PFAS-IgG relationship, suggesting that PFAS is associated with alteration in the balance of plasma metabolites that contributes to reduced plasma IgG production.
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Affiliation(s)
- Haibin Guan
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jia Chen
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Kirtan Kaur
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Bushra Amreen
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Corina Lesseur
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Georgia Dolios
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Syam S Andra
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Srinivasan Narasimhan
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Divya Pulivarthi
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Vishal Midya
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Lotje D De Witte
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Veerle Bergink
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Anna-Sophie Rommel
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Lauren M Petrick
- Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Bert Strassburger Metabolic Center, Sheba Medical Center, Tel-Hashomer, Israel.
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Nguyen HTT, Stoico MP, Le VQ, Thomsen JHD, Krarup KB, Kristjansen KA, Pedersen IS, Krarup HB. Metabolic signature of COVID-19 progression: potential prognostic markers for severity and outcome. Metabolomics 2025; 21:70. [PMID: 40399692 PMCID: PMC12095333 DOI: 10.1007/s11306-025-02264-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Accepted: 04/18/2025] [Indexed: 05/23/2025]
Abstract
INTRODUCTION There are significant challenges remain in accurately categorizing the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. OBJECTIVES We used an untargeted 1H NMR-based metabolomics to assess the metabolomic changes in serum samples from a Danish cohort of 106 COVID-19-infected patients with mild to fatal disease courses and from patients with fatal outcomes from other diseases. METHODS In total, 240 serum samples were used for this study. We used the data for multiple analyses (1) to construct a predictive model for disease severity and outcome, (2) to identify prognostic markers for subsequent disease severity and outcome, and (3) to understand the disease consequences in the metabolome and how recovery or death is reflected in the altered biological pathways. RESULTS Our results revealed distinct alterations in the serum metabolome that could differentiate patients with COVID-19 by severity (mild or severe) or outcome (death or survival). Using receiver operating characteristic (ROC) curve analysis and four machine learning algorithms (random forest, linear support vector machine, PLS-DA, and logistic regression), we identified two biomarker sets with relevant biological functions that predict subsequent disease severity and patient outcome. The range of these severity-associated biomarkers was equally broad and included inflammatory markers, amino acids, fluid balance, ketone bodies, glycolysis-related metabolites, lipoprotein particles, and fatty acid levels. CONCLUSIONS Our data suggest the potential benefits of broader testing of these metabolites from newly diagnosed patients to predict which COVID-19 patients will progress to severe disease and which patients will manifest severe symptoms to minimize mortality.
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Affiliation(s)
- Hien Thi Thu Nguyen
- Department of Molecular Diagnostics, Aalborg University Hospital, Reberbansgade 15, 9000, Aalborg, Denmark.
| | - Malene Pontoppidan Stoico
- Department of Molecular Diagnostics, Aalborg University Hospital, Reberbansgade 15, 9000, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | | | - Jakob Holm Dalsgaard Thomsen
- Department of Molecular Diagnostics, Aalborg University Hospital, Reberbansgade 15, 9000, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | | | | | - Inge Søkilde Pedersen
- Department of Molecular Diagnostics, Aalborg University Hospital, Reberbansgade 15, 9000, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Henrik Bygum Krarup
- Department of Molecular Diagnostics, Aalborg University Hospital, Reberbansgade 15, 9000, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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González Rosas Z, Martínez-Jiménez HS, Arroyo-Landín M, Fragoso G, Chávez-Canales M, Hernández M, Rosetti MF, López-Alvarenga JC, Sciutto E, Cárdenas G. Long-Term Neuropsychiatric Sequelae of COVID-19 in an Open Population: A Prospective Pilot Study. J Neuropsychiatry Clin Neurosci 2025:appineuropsych20240040. [PMID: 40384037 DOI: 10.1176/appi.neuropsych.20240040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
OBJECTIVE COVID-19 has been associated with a wide range of systemic and neurological complications, known as long COVID or postacute sequelae of COVID-19 (PASC). Such sequelae can be observed among all infected individuals, even among those with a mild disease course. Dysbiosis, a common condition associated with low-grade inflammation, has been proposed as a potential mechanism of PASC by altering levels of circulating lipopolysaccharide (LPS) and the tryptophan pathway metabolites kynurenine and quinolinic acid, known to affect neurocognitive function. The authors evaluated the evolution of neurological, neurocognitive, and neuropsychiatric COVID-19 sequelae and their relationship with circulating LPS and kynurenine and quinolinic acid levels. METHODS A prospective, longitudinal, and analytical study was conducted. Neurological, neurocognitive, and neuropsychiatric assessments of participants who had recovered from COVID-19 and did not require hospitalization during the acute stages of the infection were performed. Peripheral levels of LPS and tryptophan metabolites were measured 1, 3, 6, and 12 months after infection. RESULTS Of 95 participants recruited, 67 COVID-19-convalescent individuals and 20 COVID-19-free individuals were included. Significantly higher occurrences of asthenia, olfaction and taste alterations, headache, memory dysfunction, and systemic symptoms such as dyspnea, cough, and periodontal diseases were found among participants in the COVID-19-convalescent group compared with participants in the comparison group. A significant decrease in kynurenine levels, which correlated with cognitive impairment, was observed among PASC convalescents. CONCLUSIONS Significant neurocognitive and neuropsychiatric impairments were observed among COVID-19-convalescent individuals, along with decreased kynurenine levels, which recovered during a 12-month follow-up period.
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Affiliation(s)
- Zeltzin González Rosas
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Hanna Samara Martínez-Jiménez
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Manuel Arroyo-Landín
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Gladis Fragoso
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - María Chávez-Canales
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Marisela Hernández
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Marcos Francisco Rosetti
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Juan Carlos López-Alvarenga
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Edda Sciutto
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
| | - Graciela Cárdenas
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (González Rosas, Fragoso, Hernández, Sciutto); Department of Neurology, Instituto Nacional de Neurología y Neurocirugía, Mexico City (González Rosas, Martínez-Jiménez, Arroyo-Landín, Cárdenas); Department of Neurology, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Chávez-Canales); Department of Cellular Biology and Physiology, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, and Psychopathology and Development Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City (Rosetti); School of Medicine, University of Texas Rio Grande Valley, Edinburg, Texas (López-Alvarenga)
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Li L, Haijun W, Tianyu C, Wenjing W, Zi W, Yibing C. Metabolomics and machine learning identify urine metabolic characteristics and potential biomarkers for severe Mycoplasma pneumoniae pneumonia. Sci Rep 2025; 15:17090. [PMID: 40379752 PMCID: PMC12084370 DOI: 10.1038/s41598-025-01895-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 05/08/2025] [Indexed: 05/19/2025] Open
Abstract
To study the differences in the urine metabolome between pediatric patients with severe Mycoplasma pneumoniae pneumonia (SMPP) and those with general Mycoplasma pneumoniae pneumonia (GMPP) via non-targeted metabolomics method, and potential biomarkers were explored through machine learning (ML) algorithms. The urine metabonomics data of 48 children with SMPP and 85 children with GMPP were collected via high performance liquid chromatography‒mass spectrometry (HPLC-MS/MS). The differential metabolites between the two groups were obtained via principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), and the significant metabolic pathways were screened via enrichment analysis. Potential biomarkers were identified using the random forest algorithm, and their relationships with clinical indicators were subsequently analyzed. A total of 136 significantly differential metabolites were identified in the urine samples from SMPP and GMPP. Of these, 68 metabolites were upregulated, and 68 were downregulated, predominantly belonging to the amino acid group. A total of 6 differential metabolic pathways were enriched, including Galactose metabolism, Pantothenate and CoA biosynthesis, Cysteine and methionine metabolism, Biotin metabolism, Glycine, serine and threonine metabolism, Arginine biosynthesis. Three significant potential biomarkers were identified through machine learning: 3-Hydroxyanthranilic acid (3-HAA), L-Kynurenine, and 16(R)-HETE. The area under the receiver operating characteristic curve (AUC) for this three-metabolite panel was 0.9142. There are great differences in the urine metabolome between SMPP and GMPP children, with multiple metabolic pathways being abnormally expressed. Three metabolites have been identified as potential biomarkers for the early detection of SMPP.
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Affiliation(s)
- Lin Li
- Department of Emergency, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Wang Haijun
- Department of Emergency, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Chen Tianyu
- JIUHE Diagnostics Co., Ltd, Zhengzhou, 450016, China
| | - Wang Wenjing
- JIUHE Diagnostics Co., Ltd, Zhengzhou, 450016, China
| | - Wang Zi
- Department of Emergency, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Cheng Yibing
- Department of Emergency, Henan Province Engineering Research Center of Diagnosis and Treatment of Pediatric Infection and Critical Care, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
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Wang X, Li Y, Wang Q, Xia F, Chen W, You C, Ma L. Glucose concentration predicting mortality in patients with COVID-19: A propensity score-matched study. Am J Med Sci 2025:S0002-9629(25)01035-3. [PMID: 40374008 DOI: 10.1016/j.amjms.2025.05.003] [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: 07/10/2024] [Revised: 05/11/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025]
Abstract
BACKGROUND Patients with coronavirus disease-19 (COVID-19) often develop systemic inflammation, which is associated with increased mortality. Elevated blood glucose levels can exacerbate the cytokine storm, further worsening disease severity and accelerating patient death. Therefore, this study aims to investigate the association between glucose levels and mortality in hospitalized patients, providing insights into the importance of optimizing glucose management in hospitalized COVID-19 patients. METHODS A retrospective cohort study was conducted, involving adult COVID-19 patients in a university hospital. The primary outcome was in-hospital mortality. Propensity score matching (PSM) was utilized to match patients' baseline characteristics. Discrimination capacity of different models was assessed using C-statistics, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Trends in blood glucose over time were detected using the ordinary least squares model. RESULTS Among the 4583 COVID-19 patients during the study period, 2147 (46.8%) exhibited normal glycemia, while 2436 (53.2%) had admission hyperglycemia. After adjusting for confounding factors through multivariate regression analysis, patients with hyperglycemia showed significantly higher odds of in-hospital mortality (adjusted odds ratio [aOR]: 3.10, 95% CI: 2.25 to 4.28; P < 0.001). PSM analysis yielded similar results (aOR: 2.66, 95% CI: 2.09 to 3.41; P < 0.001). The incorporation of admission glucose significantly improved C-statistics (P < 0.001), IDI (P < 0.001), and NRI (P < 0.001) for predicting mortality. CONCLUSION This study concludes that blood glucose levels ≥ 6.1 mmol/L can independently predict all-cause mortality and clinical sequelae in COVID-19 patients. Furthermore, even a mild increase in blood glucose was associated with a significantly higher risk of mortality in these patients. These findings underscore the importance of managing hyperglycemia and monitoring blood glucose in individuals with COVID-19.
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Affiliation(s)
- Xing Wang
- Traumatic Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yue Li
- Research Core Facility of West China Hospital, Sichuan University
| | - Qiao Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fan Xia
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wuqian Chen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chao You
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lu Ma
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Zhang Y, Zhu F, Zhang Z, Wang J, Liao T, Xi Y, Liu D, Zhang H, Lin H, Mao J, Tang W, Zhao L, Yuan P, Yan L, Liu Q, Hong K, Qiao J. Alterations in Semen Quality and Immune-Related Factors in Men with Infertility who Recovered from COVID-19. MedComm (Beijing) 2025; 6:e70179. [PMID: 40276648 PMCID: PMC12019875 DOI: 10.1002/mco2.70179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 04/26/2025] Open
Abstract
The emergence of coronavirus disease 2019 (COVID-19) has triggered research into its impact on male reproductive health. However, studies exploring the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on semen quality in infertile men remain limited. Herein, we enrolled 781 male infertile patients who recovered from COVID-19 and analyzed their semen and blood samples collected at different time points. We found that SARS-CoV-2 RNA was undetectable in semen samples. Compared with pre-COVID-19 status, total sperm count, sperm concentration, vitality, motility, and percentage of sperm cells with normal morphology decreased significantly in the first month post-COVID-19. However, these alterations were reversed in the third month. Furthermore, seminal plasma samples exhibited reduced proinflammatory cytokine levels and notable changes in amino acid, nucleic acid, and carbohydrate metabolism by the third month compared with those in the first month. By contrast, no significant alterations in reproductive hormone levels were found. Vitality, progressive motility, and total motility negatively correlated with body temperature when it was above 38°C. In conclusion, semen quality initially decreases post-COVID-19 but reverses after approximately 3 months, with a decline related to inflammatory and fever. These findings may provide guidance to infertile male patients who need assisted reproductive technology.
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Affiliation(s)
- Ying Zhang
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
| | - Feiyin Zhu
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
| | - Zhe Zhang
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Jing Wang
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
| | - Tianyi Liao
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
| | - Yu Xi
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Defeng Liu
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Haitao Zhang
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Haocheng Lin
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Jiaming Mao
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Wenhao Tang
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Lianming Zhao
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Peng Yuan
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
| | - Liying Yan
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
| | - Qiang Liu
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
| | - Kai Hong
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- Department of UrologyPeking University Third HospitalBeijingChina
| | - Jie Qiao
- Department of Obstetrics and GynecologyCenter for Reproductive MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Female Fertility PromotionNational Clinical Research Center for Obstetrics and GynecologyKey Laboratory of Assisted Reproduction (Peking University)Ministry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyPeking University Third HospitalBeijingChina
- Peking‐Tsinghua Center for Life SciencesPeking UniversityBeijingChina
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8
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Chung KP, Chen YH, Chen YJ, Chien JY, Kuo HC, Huang YT, Ruan SY, Lin YL, Chen YF, Keng LT, Kuo LC, Ku SC, Kuo CH, Yu CJ. INCREASED CIRCULATORY KREBS CYCLE METABOLITES IN SEPSIS IS ASSOCIATED WITH INCREASED INTERLEUKIN-6 RELEASE AND WORSE SURVIVAL. Shock 2025; 63:723-732. [PMID: 39836931 DOI: 10.1097/shk.0000000000002550] [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] [Indexed: 01/23/2025]
Abstract
ABSTRACT Objective : Recent studies have proposed that Krebs cycle metabolites may serve as potential biomarkers for prognosis in sepsis. However, whether these metabolites are associated with disease severity and can be applied to improve the effectiveness of current prognosis assessment in sepsis remains unclear and is explored in this study. Methods : This prospective multicenter cohort study was conducted in medical intensive care units (ICUs). From December 2019 to September 2022, consecutive patients admitted to medical ICUs for sepsis were screened and recruited. Plasma samples were obtained for measurements of cytokines and Krebs cycle metabolites, including citrate/isocitrate, cis-aconitate, alpha-ketoglutarate, succinate, fumarate, and malate. Results : In total, 97 patients admitted for sepsis were enrolled in the study. The 28-day mortality rate was 17.5%, and nonsurvivors exhibited significantly increased plasma lactate levels and Sequential Organ Failure Assessment (SOFA) scores. Plasma levels of Krebs cycle metabolites were significantly correlated with both plasma lactate and interleukin-6 levels. Except for citrate/isocitrate, all Krebs cycle metabolites were significantly elevated in patients with acute kidney injury. Multivariate Cox proportional hazard models, adjusted for plasma lactate levels and SOFA scores, revealed that plasma levels of alpha-ketoglutarate (adjusted hazard ratio [HR]: 2.404, P = 0.002), fumarate (adjusted HR: 1.904, P = 0.001) and malate (adjusted HR: 1.327, P = 0.019) were associated with increased risk of 28-day mortality. Conclusions : Study findings indicate that Krebs cycle metabolites, particularly alpha-ketoglutarate, fumarate, and malate, when applied with SOFA score, might enhance prognostic assessment in patients with sepsis.
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Affiliation(s)
| | | | - Yi-Jung Chen
- Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jung-Yien Chien
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Han-Chun Kuo
- NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Sheng-Yuan Ruan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Li Lin
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Fu Chen
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Li-Ta Keng
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Lu-Cheng Kuo
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Chi Ku
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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9
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D’Alessandro A. Red blood cell metabolism: a window on systems health towards clinical metabolomics. Curr Opin Hematol 2025; 32:111-119. [PMID: 40085132 PMCID: PMC11949704 DOI: 10.1097/moh.0000000000000863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
PURPOSE OF REVIEW This review focuses on recent advances in the understanding of red blood cell (RBC) metabolism as a function of hypoxia and oxidant stress. In particular, we will focus on RBC metabolic alterations during storage in the blood bank, a medically relevant model of erythrocyte responses to energy and redox stress. RECENT FINDINGS Recent studies on over 13 000 healthy blood donors, as part of the Recipient Epidemiology and Donor Evaluation Study (REDS) III and IV-P RBC omics, and 525 diversity outbred mice have highlighted the impact on RBC metabolism of biological factors (age, BMI), genetics (sex, polymorphisms) and exposure (dietary, professional or recreational habits, drugs that are not grounds for blood donor deferral). SUMMARY We review RBC metabolism from basic biochemistry to storage biology, briefly discussing the impact of inborn errors of metabolism and genetic factors on RBC metabolism, as a window on systems metabolic health. Expanding on the concept of clinical chemistry towards clinical metabolomics, monitoring metabolism at scale in large populations (e.g., millions of blood donors) may thus provide insights into population health as a complementary tool to genetic screening and standard clinical measurements.
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Affiliation(s)
- Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver – Anschutz Medical Campus, Aurora, CO, USA
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10
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Shen W, Zhao S, Lyu S, Zhang M, Guo Q, Lou B, Ma W, Zhan J, Liu L, Li L. Integrating transcriptomics and metabolomics revealed pathogenic mechanism of Chinese soft-shell turtle (Trionyx sinensis) infected with Trionyx sinensis hemorrhagic syndrome virus (TSHSV). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2025; 166:105373. [PMID: 40258577 DOI: 10.1016/j.dci.2025.105373] [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: 11/13/2024] [Revised: 04/18/2025] [Accepted: 04/18/2025] [Indexed: 04/23/2025]
Abstract
Trionyx sinensis Hemorrhagic Syndrome Virus(TSHSV)seriously hinders the aquaculture of Chinese soft-shell turtle (Trionyx sinensis) due to its high mortality. However, the pathogenic mechanisms of TSHSV in T. sinensis are still unclear. In present study, transcriptomic and metabolomic analyses were performed on turtle livers following TSHSV infection. 734 up-regulated and 770 down-regulated differentially expressed genes (DEGs) were identified in different TSHSV challenge groups. These DEGs were categorized into 12 pathways related to virus infection and host immunity. Moreover, 27, 2679, and 4341 differentially expressed metabolites (DEMs) were identified in the D1, D3, and D5 groups, respectively. These DEMs were mapped into the pathways of energy metabolism, amino acid metabolism and fatty acid metabolism. Association analysis revealed TSHSV induced inflammatory responses, hepatocyte apoptosis, and ultimately led to liver tissue damage. Taurine supplementation promoted the survival rate of turtle after TSHSV infection and reduced the inflammatory response of liver by regulating the production of interferons, antioxidases, and the pro-inflammatory cytokine TNF-α. Collectively, our results provide comprehensive profiles of the transcriptome and metabolome in Chinese soft-shell turtle liver after TSHSV invasion, shedding light on the underlying pathogenic mechanism. The method of taurine supplementation might be a promising therapeutic strategy for protecting turtles from TSHSV.
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Affiliation(s)
- Weifeng Shen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Hydrobiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
| | - Shuang Zhao
- Xiamen Meliomics Technology Co. Ltd., Xiamen, Fujian, China
| | - Sunjian Lyu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Hydrobiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
| | | | - Qi Guo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Hydrobiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
| | - Bao Lou
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Hydrobiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China
| | - WenJun Ma
- Zhejiang aquatic technology extension station, Hangzhou, Zhejiang, China
| | - Jingjing Zhan
- Xiamen Meliomics Technology Co. Ltd., Xiamen, Fujian, China
| | - Li Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Hydrobiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China.
| | - Liang Li
- Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
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11
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Brinkman N, Teunis T, Choi S, Ring D, Brode WM. Factors associated with the presence and intensity of ongoing symptoms in Long COVID. PLoS One 2025; 20:e0319874. [PMID: 40267966 PMCID: PMC12017833 DOI: 10.1371/journal.pone.0319874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/10/2025] [Indexed: 04/25/2025] Open
Abstract
OBJECTIVE Identification of modifiable factors associated with symptom intensity among people seeking care for Post-Acute Sequelae of SARS-CoV-2 infection (PASC) could help guide the development of comprehensive, whole-person care pathways to alleviate symptoms irrespective of potential underlying pathophysiologies. We aimed to better define the key contributors to PASC, and sought the factors associated with PASC symptom presence and intensity. METHODS In this cross-sectional study, 249 patients presenting for PASC care at a dedicated Post-COVID-19 clinic completed a standardized screening assessment prior to initial visit and evaluation by a general internist or nurse practitioner. We measured 46 symptoms based on the WHO's Global COVID-19 Clinical Platform Case Report Form for Post COVID Condition and performed a factor analysis and item response theory based 2-parameter logistic model to develop a population-based t-score to measure PASC symptom presence and intensity (PASC-SPI). A multivariable linear regression analysis was used to assess factors associated with PASC-SPI, accounting for demographics, comorbidities, COVID-19 infection duration and severity, and mental health. RESULTS Greater PASC-SPI was associated with greater symptoms of anxiety, a longer duration of COVID-19 infection, and hypercholesterolemia. Lower PASC-SPI was associated with older age, self-reported 1-3 units of alcohol per week, and self-reported clinician confirmation of COVID-19 diagnosis. Symptoms of anxiety accounted for a considerably higher proportion of variation in PASC-SPI than other variables. CONCLUSION Symptoms of anxiety were the strongest correlate of PASC-SPI, highlighting it as both a potential neuroinflammatory marker of PASC and a modifiable component of the illness. This emphasizes the need for comprehensive, whole person treatment strategies that integrate evidence-based interventions to address the multifaceted nature of PASC.
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Affiliation(s)
- Niels Brinkman
- Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin,
| | - Teun Teunis
- Department of Orthopedic Surgery & Department of Plastic and Reconstructive Surgery, The University of Pittsburgh,
| | - Seung Choi
- The Center for Applied Psychometric Research, Educational Psychology Department, The University of Texas at Austin,
| | - David Ring
- Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin,
| | - W. Michael Brode
- Department of Internal Medicine & Department of Population Health, Dell Medical School, The University of Texas at Austin
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12
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Lage SL, Bricker-Holt K, Rocco JM, Rupert A, Donovan FX, Abramzon YA, Chandrasekharappa SC, McNinch C, Cook L, Amaral EP, Rosenfeld G, Dalhuisen T, Eun A, Hoh R, Fehrman E, Martin JN, Deeks SG, Henrich TJ, Peluso MJ, Sereti I. Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.16.25325949. [PMID: 40321289 PMCID: PMC12047922 DOI: 10.1101/2025.04.16.25325949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.
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Affiliation(s)
- Silvia Lucena Lage
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, USA
| | - Katherine Bricker-Holt
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, USA
| | - Joseph M. Rocco
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, USA
| | - Adam Rupert
- AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research; Frederick, USA
| | - Frank X. Donovan
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute; Bethesda, USA
| | - Yevgeniya A. Abramzon
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute; Bethesda, USA
| | | | - Colton McNinch
- Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Logan Cook
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, USA
| | - Eduardo Pinheiro Amaral
- Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, USA
| | - Gabriel Rosenfeld
- Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
| | - Thomas Dalhuisen
- Department of Medicine, University of California, San Francisco; San Francisco, USA
| | - Avery Eun
- Department of Medicine, University of California, San Francisco; San Francisco, USA
| | - Rebecca Hoh
- Department of Medicine, University of California, San Francisco; San Francisco, USA
| | - Emily Fehrman
- Department of Medicine, University of California, San Francisco; San Francisco, USA
| | - Jeffrey N. Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco; San Francisco, USA
| | - Steven G. Deeks
- Department of Medicine, University of California, San Francisco; San Francisco, USA
| | - Timothy J. Henrich
- Department of Medicine, University of California, San Francisco; San Francisco, USA
| | - Michael J. Peluso
- Department of Medicine, University of California, San Francisco; San Francisco, USA
| | - Irini Sereti
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, USA
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13
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Gong J, Ge L, Zeng Y, Yang C, Luo Y, Kang J, Zou T, Xu H. The influence of SARS-CoV-2 spike protein exposure on retinal development in the human retinal organoids. Cell Biosci 2025; 15:43. [PMID: 40217547 PMCID: PMC11987193 DOI: 10.1186/s13578-025-01383-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Pregnant women are considered a high-risk population for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as the virus can infect the placenta and embryos. Recently, SARS-CoV-2 has been widely reported to cause retinal pathological changes and to infect the embryonic retina. The infection of host cells by SARS-CoV-2 is primarily mediated through spike (S) protein, which also plays a crucial role in the pathogenesis of SARS-CoV-2. However, it remains poorly understood how the S protein of SARS-CoV-2 affects retinal development, and the underlying mechanism has not yet been clarified. METHODS We used human embryonic stem cell-derived retinal organoids (hEROs) as a model to study the effect of S protein exposure at different stages of retinal development. hEROs were treated with 2 μg/mL of S protein on days 90 and 280. Immunofluorescence staining, RNA sequencing, and RT-PCR were performed to assess the influence of S protein exposure on retinal development at both early and late stages. RESULTS The results showed that ACE2 and TMPRSS2, the receptors facilitating SARS-CoV-2 entry into host cells, were expressed in hEROs. Exposure to the S protein induced an inflammatory response in both the early and late stages of retinal development in the hEROs. Additionally, RNA sequencing indicated that early exposure of the S protein to hEROs affected nuclear components and lipid metabolism, while late-stages exposure resulted in changes to cell membrane components and the extracellular matrix. CONCLUSION This work highlights the differential effects of SARS-CoV-2 S protein exposure on retinal development at both early and late stages, providing insights into the cellular and molecular mechanisms underlying SARS-CoV-2-induced developmental impairments in the human retina.
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Affiliation(s)
- Jing Gong
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China
| | - Lingling Ge
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Yuxiao Zeng
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Cao Yang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Yushan Luo
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Jiahui Kang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Ting Zou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
- Department of Ophthalmology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
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14
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Nemkov T, Stauffer E, Cendali F, Stephenson D, Nader E, Robert M, Skinner S, Dzieciatkowska M, Hansen KC, Robach P, Millet G, Connes P, D'Alessandro A. Long-Distance Trail Running Induces Inflammatory-Associated Protein, Lipid, and Purine Oxidation in Red Blood Cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.09.648006. [PMID: 40291720 PMCID: PMC12027326 DOI: 10.1101/2025.04.09.648006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Ultra-endurance exercise places extreme physiological demands on oxygen transport, yet its impact on red blood cells (RBCs) remains underexplored. We conducted a multi-omics analysis of plasma and RBCs from endurance athletes before and after a 40-km trail race (MCC) and a 171-km ultramarathon (UTMB®). Ultra-running led to oxidative stress, metabolic shifts, and inflammation-driven RBC damage, including increased acylcarnitines, kynurenine accumulation, oxidative lipid and protein modifications, reduced RBC deformability, enhanced microparticle release, and decreased hematocrit - hallmarks of accelerated RBC aging and clearance. Post-race interleukin-6 strongly correlated with kynurenine elevation, mirroring inflammatory responses in severe infections. These findings challenge the assumption that RBC damage in endurance exercise is primarily mechanical, revealing systemic inflammation and metabolic remodeling as key drivers. This study underscores RBCs as both mediators and casualties of extreme exercise stress, with implications for optimizing athlete recovery, endurance training, and understanding inflammation-linked RBC dysfunction in clinical settings. Teaser Marathon running imparts molecular damage to red blood cells, the effects of which are exacerbated by increased distances of ultramarathons.
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15
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Jiang Y, Xu L, Zheng X, Shi H. Recent advances in nutritional metabolism studies on SARS-CoV-2 infection. INFECTIOUS MEDICINE 2025; 4:100162. [PMID: 39936106 PMCID: PMC11810712 DOI: 10.1016/j.imj.2025.100162] [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] [Received: 09/27/2024] [Revised: 11/19/2024] [Accepted: 11/27/2024] [Indexed: 02/13/2025]
Abstract
In the context of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), metabolic research has become crucial for in-depth exploration of viral infection mechanisms and in searching for therapeutic strategies. This paper summarizes the interrelationships between carbohydrate, lipid, and amino acid metabolism and COVID-19 infection, discussing their roles in infection progression. SARS-CoV-2 infection leads to insulin resistance and increased glycolysis, reducing glucose utilization and shifting metabolism to use fat as an energy source. Fat is crucial for viral replication, and imbalances in amino acid metabolism may interfere with immune regulation. Consequently, metabolic changes such as hyperglycemia, hypolipidemia, and deficiency of certain amino acids following SARS-CoV-2 infection can contribute to progression toward severe conditions. These metabolic pathways not only have potential value in prediction and diagnosis but also provide new perspectives for the development of therapeutic strategies. By monitoring metabolic changes, infection severity can be predicted early, and modulating these metabolic pathways may help reduce inflammatory responses, improve immune responses, and reduce the risk of thrombosis. Research on the relationship between metabolism and SARS-CoV-2 infection provides an important scientific basis for addressing the global challenge posed by COVID-19, however, further studies are needed to validate these findings and provide more effective strategies for disease control.
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Affiliation(s)
- Yufen Jiang
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Linle Xu
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xuexing Zheng
- School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Hongbo Shi
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
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16
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Wang P, Li ZY, Wang J, Liu KZ, Wang YR, Guo QY, Wen SL, Ni PL, Zhang QP, Wang T, Gong CM, Wan W, Yi XN, Ma ZJ, Li YQ, Lu LF, Feng RJ. Potential role for kynurenine pathway in increased COVID-19 mortality of patients with schizophrenia. J Psychiatr Res 2025; 183:289-295. [PMID: 40020648 DOI: 10.1016/j.jpsychires.2025.02.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 01/15/2025] [Accepted: 02/20/2025] [Indexed: 03/03/2025]
Abstract
Schizophrenia (SCZ) is a common psychiatric disorder that has complex pathological mechanisms. During the coronavirus disease 2019 (COVID-19) epidemic, patients with SCZ had substantially higher rates of infection with SARS-CoV-2, the virus that causes COVID-19, as well as higher COVID-19 mortality relative to patients without mental disorders. Previous studies suggested that COVID-19 and SCZ both involve the kynurenine metabolic pathway. This article reviews the characteristics of kynurenine metabolism in COVID-19 and SCZ, and considers the possibility that disordered kynurenine metabolism may be one cause of increased infection and COVID-19 mortality rates in the patients with SCZ. Several possible molecular mechanisms that could be involved in disease pathology are discussed.
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Affiliation(s)
- Peng Wang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Zhen-Ying Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Jie Wang
- Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, China
| | - Kun-Ze Liu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Ya-Ru Wang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Qing-Yun Guo
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Shi-Lei Wen
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China; Department of Human Anatomy and Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Pan-Li Ni
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Quan-Peng Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China; Department of Human Anatomy and Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Tan Wang
- The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Chun-Mei Gong
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Wei Wan
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China; Department of Human Anatomy and Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Xi-Nan Yi
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China; Department of Human Anatomy and Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Zhi-Jian Ma
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China; Department of Human Anatomy and Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Yun-Qing Li
- Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, China.
| | - Li-Fang Lu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China; Department of Human Anatomy and Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China.
| | - Ren-Jun Feng
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China; Department of Human Anatomy and Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China.
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17
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Chen Y, Jan J, Yang C, Yen T, Linh TTD, Annavajjula S, Satapathy MK, Tsao S, Hsieh C. Cognitive Sequelae of COVID-19: Mechanistic Insights and Therapeutic Approaches. CNS Neurosci Ther 2025; 31:e70348. [PMID: 40152069 PMCID: PMC11950837 DOI: 10.1111/cns.70348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 03/10/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND The COVID-19 pandemic has left an indelible mark on the world, with mounting evidence suggesting that it not only posed acute challenges to global healthcare systems but has also unveiled a complex array of long-term consequences, particularly cognitive impairment (CI). As the persistence of post-COVID-19 neurological syndrome could evolve into the next public health crisis, it is imperative to gain a better understanding of the intricate pathophysiology of CI in COVID-19 patients and viable treatment strategies. METHODS This comprehensive review explores the pathophysiology and management of cognitive impairment across the phases of COVID-19, from acute infection to Long-COVID, by synthesizing findings from clinical, preclinical, and mechanistic studies to identify key contributors to CI, as well as current therapeutic approaches. RESULTS Key mechanisms contributing to CI include persistent neuroinflammation, cerebrovascular complications, direct neuronal injury, activation of the kynurenine pathway, and psychological distress. Both pharmacological interventions, such as anti-inflammatory therapies and agents targeting neuroinflammatory pathways, and non-pharmacological strategies, including cognitive rehabilitation, show promise in addressing these challenges. Although much of the current evidence is derived from preclinical and animal studies, these findings provide foundational insights into potential treatment approaches. CONCLUSION By synthesizing current knowledge, this review highlights the importance of addressing COVID-19-related cognitive impairment and offers actionable insights for mitigation and recovery as the global community continues to grapple with the pandemic's long-term impact.
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Affiliation(s)
- Yu‐Hao Chen
- Section of Neurosurgery, Department of SurgeryDitmanson Medical Foundation, Chia‐Yi Christian HospitalChia‐Yi CityTaiwan
- Chung‐Jen Junior College of Nursing, Health Sciences and ManagementChia‐Yi CountryTaiwan
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Jing‐Shiun Jan
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Chih‐Hao Yang
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Ting‐Lin Yen
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
- Department of Medical ResearchCathay General HospitalTaipeiTaiwan
| | - Tran Thanh Duy Linh
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
- Family Medicine Training Center, University of Medicine and Pharmacy at Ho Chi Minh CityHo Chi Minh CityVietnam
| | - Saileela Annavajjula
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Mantosh Kumar Satapathy
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Shin‐Yi Tsao
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
- Division of Endocrinology and Metabolism, Department of Internal MedicineTaipeiTaiwan
| | - Cheng‐Ying Hsieh
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
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18
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Russkikh IV, Popov OS, Klochkova TG, Sushentseva NN, Apalko SV, Asinovskaya AY, Mosenko SV, Sarana AM, Shcherbak SG. Comparative metabolomic analysis reveals shared and unique features of COVID-19 cytokine storm and surgical sepsis. Sci Rep 2025; 15:6622. [PMID: 39994234 PMCID: PMC11850835 DOI: 10.1038/s41598-025-90426-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
The clinical manifestations of the cytokine storm (CS) associated with COVID-19 resemble the acute phase of sepsis. Metabolomics may contribute to understanding the specific pathobiology of these two syndromes. The aim of this study was to compare serum metabolomic profiles in CS associated with COVID-19 vs. septic surgery patients. In a retrospective cross-sectional study, serum samples from patients with CS associated with COVID-19, with and without comorbidity, as well as serum samples from patients with surgical sepsis were investigated. Targeted metabolomic analysis was performed on all samples using LC-MS/MS. Analysis revealed that similar alterations in the serum metabolome of patients with COVID-19 and surgical septic patients were associated with amino acid metabolism, nitrogen metabolism, inflammatory status, methionine cycle and glycolysis. The most significant difference was found for serum levels of metabolites of kynurenine synthesis, tricarboxylic acid cycle, gamma-aminobutyric acid and niacinamide. The metabolic pathway of cysteine and methionine metabolism was significantly disturbed in COVID-19 and surgical septic patients. For the first time, the similarities and differences between the serum metabolomic profiles of patients with CS associated with COVID-19 and patients with surgical sepsis were investigated for patients from the Northwest of the Russian Federation.
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Affiliation(s)
- Iana V Russkikh
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
| | - Oleg S Popov
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Tatiana G Klochkova
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation.
| | - Natalia N Sushentseva
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
| | - Svetlana V Apalko
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Anna Yu Asinovskaya
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Sergey V Mosenko
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Andrey M Sarana
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
| | - Sergey G Shcherbak
- Saint Petersburg State Health Care Establishment the City Hospital No. 40 of Health Department of the Saint Petersburg Kurortniy District Administration, St. Borisova, 9, 197706, Sestroretsk, Russian Federation
- Saint Petersburg State University, Government of the Russian Federation, 199034, Saint-Petersburg, Russian Federation
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19
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Kupriyanova Y, Yurchenko I, Bobrov P, Bartels F, Wierichs S, Jonuscheit M, Korzekwa B, Prystupa K, Schön M, Mendez D, Trenkamp S, Burkart V, Wagner R, Schrauwen-Hinderling V, Roden M. Alterations of hepatic lipid content following COVID-19 in persons with type 2 diabetes. BMJ Open Diabetes Res Care 2025; 13:e004727. [PMID: 39965871 PMCID: PMC11836859 DOI: 10.1136/bmjdrc-2024-004727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
INTRODUCTION The study aimed to assess the effect of COVID-19 on hepatic lipid (HL) content, fibrosis risk, and adiposity in persons with type 2 diabetes. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes with a history of mild COVID-19 (n=15, age 58±12 years, body mass index 30.9±5.2 kg/m2) were examined before (baseline) and 1 year (12±2 months) after (follow-up) recovery from COVID-19. Investigations for changes in metabolic risk comprised clinical examination, fasting blood sampling and MR-based measurements. Potential changes were corrected with the time course of the respective parameters in a group of participants who did not contract COVID-19 over the same time course (n=14, 61±6 years, 30.0±4.6 kg/m2). RESULTS COVID-19 resulted in a relative increase in HL content of 56% (95% CI 18%, 106%; p=0.04) measured as proton density fat fraction (HL-PDFF), corrected for the time course in the absence of COVID-19. While no changes in hepatic stiffness and volume, intramyocellular lipids, whole-body, subcutaneous and visceral adipose tissue volumes as well as homeostatic model assessment of insulin resistance and beta-cell function were observed. CONCLUSIONS History of COVID-19 in persons with type 2 diabetes is associated with higher HL-PDFF after 1 year following recovery from infection. TRIAL REGISTRATION NUMBER NCT01055093.
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Affiliation(s)
- Yuliya Kupriyanova
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Iryna Yurchenko
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Pavel Bobrov
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Frederik Bartels
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Stefan Wierichs
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Marc Jonuscheit
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Benedict Korzekwa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Katsiaryna Prystupa
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Martin Schön
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Dania Mendez
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Sandra Trenkamp
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Volker Burkart
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Robert Wagner
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Vera Schrauwen-Hinderling
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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20
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He L, Wang Y, Yuan F, Morrissey S, Geller AE, Hu X, Xu R, Ma X, Zhang HG, McLeish K, Huang J, Zhang X, Yan J. Metabolomics Profiling Reveals Critical Roles of Indoxyl Sulfate in the Regulation of Innate Monocytes in COVID-19. Cells 2025; 14:256. [PMID: 39996729 PMCID: PMC11853107 DOI: 10.3390/cells14040256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/03/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is intricately related to the reprogramming of host metabolism. However, existing studies have mainly focused on peripheral blood samples and barely identified specific metabolites that are critically involved in the pathology of coronavirus disease 2019 (COVID-19). In the current small-scale study, we performed metabolic profiling in plasma (n = 61) and paired bronchoalveolar lavage fluid (BALF) samples (n = 20) using parallel two-dimensional liquid chromatography-mass spectrometry (2DLC-MS). In addition, we studied how an identified metabolite regulates the immunopathogenesis of COVID-19. The results unveiled distinct metabolome changes between healthy donors, and moderate and severe patients in both plasma and BALF, indicating that locations and disease severity play critical roles in COVID-19 metabolic alteration. Notably, a vital metabolite, indoxyl sulfate, was found to be elevated in both the plasma and BALF of severe COVID-19 patients. Indoxyl sulfate selectively induced TNF-α production, reduced co-stimulatory signals, and enhanced apoptosis in human monocytes. Moreover, its levels negatively correlated with the strength of co-stimulatory signals and antigen presentation capability in monocytes of COVID-19 patients. Collectively, our findings suggest that the levels of indoxyl sulfate could potentially serve as a functional biomarker to monitor COVID-19 disease progression and guide more individualized treatment for COVID-19 patients.
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Affiliation(s)
- Liqing He
- Department of Chemistry, University of Louisville, Louisville, KY 40292, USA; (L.H.); (R.X.); (X.M.); (X.Z.)
| | - Yunke Wang
- Immuno-Oncology Program, Brown Cancer Center, Division of Immunotherapy, MD Department of Surgery, University of Louisville, Louisville, KY 40292, USA (X.H.)
| | - Fang Yuan
- Department of Chemistry, University of Louisville, Louisville, KY 40292, USA; (L.H.); (R.X.); (X.M.); (X.Z.)
| | - Samantha Morrissey
- Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40292, USA
| | - Anne E. Geller
- Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40292, USA
| | - Xiaoling Hu
- Immuno-Oncology Program, Brown Cancer Center, Division of Immunotherapy, MD Department of Surgery, University of Louisville, Louisville, KY 40292, USA (X.H.)
| | - Raobo Xu
- Department of Chemistry, University of Louisville, Louisville, KY 40292, USA; (L.H.); (R.X.); (X.M.); (X.Z.)
| | - Xipeng Ma
- Department of Chemistry, University of Louisville, Louisville, KY 40292, USA; (L.H.); (R.X.); (X.M.); (X.Z.)
| | - Huang-ge Zhang
- Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40292, USA
| | - Kenneth McLeish
- Division of Nephrology and Hypertension, Department of Medicine, University of Louisville, Louisville, KY 40292, USA;
| | - Jiapeng Huang
- Department of Anesthesiology and Perioperative Medicine, University of Louisville Hospital, Louisville, KY 40292, USA
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, KY 40292, USA; (L.H.); (R.X.); (X.M.); (X.Z.)
| | - Jun Yan
- Immuno-Oncology Program, Brown Cancer Center, Division of Immunotherapy, MD Department of Surgery, University of Louisville, Louisville, KY 40292, USA (X.H.)
- Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40292, USA
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21
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Li X, Edén A, Malwade S, Cunningham JL, Bergquist J, Weidenfors JA, Sellgren CM, Engberg G, Piehl F, Gisslen M, Kumlien E, Virhammar J, Orhan F, Rostami E, Schwieler L, Erhardt S. Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses. Brain Behav Immun 2025; 124:163-176. [PMID: 39615604 DOI: 10.1016/j.bbi.2024.11.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/31/2024] [Accepted: 11/27/2024] [Indexed: 12/09/2024] Open
Abstract
Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients. Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway. The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers. Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients. In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood-brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN. We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.
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Affiliation(s)
- Xueqi Li
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Arvid Edén
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41685, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Disease, Gothenburg, 41685, Sweden
| | - Susmita Malwade
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Janet L Cunningham
- Department of Medical Science, Psychiatry, Uppsala University, Uppsala 75185, Sweden; Department of Neuroscience, Karolinska Institute, Stockholm 17177, Sweden
| | - Jonas Bergquist
- Analytical Chemistry and Neurochemistry, Department of Chemistry─BMC, Uppsala University, Box 599, 751 24 Uppsala, Sweden; The ME/CFS Collaborative Research Centre at Uppsala University, 751 24 Uppsala, Sweden
| | | | - Carl M Sellgren
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
| | - Göran Engberg
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Institute of Sport Science and Innovations, Lithuanian Sports University, Kaunas, Lithuania
| | - Fredrik Piehl
- Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm 17177, Sweden; Division of Neurology, Karolinska University Hospital, Stockholm 17176, Sweden
| | - Magnus Gisslen
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41685, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Disease, Gothenburg, 41685, Sweden; Public Health Agency of Sweden, Solna, Sweden
| | - Eva Kumlien
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala 75185, Sweden
| | - Johan Virhammar
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala 75185, Sweden
| | - Funda Orhan
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Elham Rostami
- Department of Neuroscience, Karolinska Institute, Stockholm 17177, Sweden; Department of Medical Sciences, Neurology, Uppsala University, Uppsala 75185, Sweden
| | - Lilly Schwieler
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
| | - Sophie Erhardt
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
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22
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Subramaniam S, Napoleon MA, Lotfollahzadeh S, Kamal MH, Kurniawan H, Elsadawi M, Kenney D, Douam F, Bosmann M, Whelan S, Cabral H, Burks EJ, Zhao G, Kolachalama V, Ravid K, Chitalia V. Tryptophan metabolism reprogramming contributes to the prothrombotic milieu in mice and humans infected with SARS-CoV-2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.17.633602. [PMID: 39896681 PMCID: PMC11785031 DOI: 10.1101/2025.01.17.633602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
SARS-CoV-2 infection disturbs the coagulation balance in the blood, triggering thrombosis and contributing to organ failure. The role of prothrombotic metabolites in COVID-19-associated coagulopathy remains elusive. Leveraging K18-hACE2 mice infected with SARS-CoV-2, we observed higher levels of the tryptophan metabolite, kynurenine, compared to controls. SARS CoV-2 infected mice showed a significant upregulation of enzymes controlling Kynurenine biogenesis, such as indoleamine 2,3-dioxygenase (IDO-1) and tryptophan 2,3-dioxygenase levels in kidneys and liver, respectively, as well as changes in the enzymes involved in kynurenine catabolism, including kynurenine monooxygenase and kynurinase. Consistent with the agonistic role of these metabolites in Aryl Hydrocarbon Receptor (AHR) signaling, AHR activation and its downstream mediator, tissue factor (TF), a highly potent procoagulant factor, was observed in endothelial cells (ECs) of lungs and kidneys of infected mice. These findings were validated in humans, where compared to controls, sera of COVID-19 patients showed increased levels of Kynurenine, kynurenic acid, anthranilic acid, and quinolinic acid. Activation of the AHR-TF axis was noted in the kidneys and lungs of COVID-19 patients, and COVID-19 sera showed higher IDO-1 activity than controls. Levels of Kyn in COVID-19 patients correlated strongly with the TF inducing activity of COVID-19 sera on ECs. A specific IDO-1 inhibitor or AHR inhibitor separately or in combination suppressed COVID-19 sera-induced TF activity in ECs. Together, we identified IDO-1 as upregulated by SARS-CoV-2 infection, resulting in augmented Kyn and its prothrombotic catabolites, thereby suggesting the Kyn AHR-TF axis as possibly a new diagnostic and/or therapeutic target.
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23
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Lu Y, Wang Y, Ruan T, Wang Y, Ju L, Zhou M, Liu L, Yao D, Yao M. Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases. Front Immunol 2025; 16:1536020. [PMID: 39917294 PMCID: PMC11798928 DOI: 10.3389/fimmu.2025.1536020] [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: 11/28/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.
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24
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Kaur Sardarni U, Ambikan AT, Acharya A, Johnson SD, Avedissian SN, Végvári Á, Neogi U, Byrareddy SN. SARS-CoV-2 variants mediated tissue-specific metabolic reprogramming determines the disease pathophysiology in a hamster model. Brain Behav Immun 2025; 123:914-927. [PMID: 39481495 DOI: 10.1016/j.bbi.2024.10.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 09/28/2024] [Accepted: 10/26/2024] [Indexed: 11/02/2024] Open
Abstract
Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between tissues and SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed the presence of increased SARS-CoV-2 genomic RNA in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.
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Affiliation(s)
- Urvinder Kaur Sardarni
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Anoop T Ambikan
- The Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Samuel D Johnson
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sean N Avedissian
- Antiviral Pharmacology Laboratory, Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ákos Végvári
- Division of Chemistry I, Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ujjwal Neogi
- The Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, Campus Flemingsberg, Stockholm, Sweden.
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
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25
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Wang XS, Wang JY, Yu F, Shi D, Xie JJ, Li LJ, Wang BH. Microbiota-related metabolites correlated with the severity of COVID-19 patients. Hepatobiliary Pancreat Dis Int 2024:S1499-3872(24)00168-1. [PMID: 39734160 DOI: 10.1016/j.hbpd.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 12/18/2024] [Indexed: 12/31/2024]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is a global pandemic with high mortality, and the treatment options for the severe patients remain limited. Previous studies reported the altered gut microbiota in severe COVID-19. But there are no comprehensive data on the role of microbial metabolites in COVID-19 patients. METHODS We identified 153 serum microbial metabolites and assessed the changes in 72 COVID-19 patients upon admission and one-month after their discharge, comparing these changes to those in 133 healthy control individuals from the outpatient department during the same period. RESULTS Our study revealed that microbial metabolites varied across different stages and severity of COVID-19 patients. These altered microbial metabolites included tryptophan, bile acids, fatty acids, amino acids, vitamins and those containing benzene. A total of 13 distinct microbial metabolites were identified in COVID-19 patients compared to healthy controls. Notably, correlations were found among these disrupted metabolites and organ injury and inflammatory responses related to COVID-19. Furthermore, these metabolites did not restore to the normal levels one month after discharge. Importantly, two microbial metabolites were the core microbial metabolites related to the severity of COVID-19 patients. CONCLUSIONS The microbial metabolites were altered in the acute and recovery stage, correlating with disease severity of COVID-19. These results indicated the important role of gut microbiota in the progression of COVID-19, and facilitated the potential therapeutic microbial target for severe COVID-19 patients.
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Affiliation(s)
- Xiao-Sen Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jing-Yu Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Fei Yu
- Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiao-Jiao Xie
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Jinan Microecological Biomedicine Shandong Laboratory, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310000, China
| | - Bao-Hong Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Jinan Microecological Biomedicine Shandong Laboratory, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China; Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310000, China.
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26
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Guan H, Chen J, Kaur K, Amreen B, Lesseur C, Dolios G, Andra SS, Narasimhan S, Pulivarthi D, Midya V, De Witte LD, Bergink V, Rommel AS, Petrick LM. High-dimensional mediation analysis to elucidate the role of metabolites in the association between PFAS exposure and reduced SARS-CoV-2 IgG in pregnancy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.16.628663. [PMID: 39763891 PMCID: PMC11702545 DOI: 10.1101/2024.12.16.628663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
Objective We previously found that per- and polyfluoroalkyl substances (PFAS) mixture exposure is inversely associated with SARS-CoV-2 IgG (IgG) antibody levels in pregnant individuals. Here, we aim to identify metabolites mediating this relationship to elucidate the underlying biological pathways. Methods We included 59 pregnant participants from a US-based pregnancy cohort. Untargeted metabolomic profiling was performed using Liquid Chromatography-High Resolution Sass spectrometry (LC-HRMS), and weighted Quantile Sum (WQS) regression was applied to assess the PFAS and metabolites mixture effects on IgG. Metabolite indices positively or negatively associated with IgG levels were constructed separately and their mediation effects were examined independently and jointly. Results The PFAS-index was negatively associated with IgG levels (beta=-0.273, p=0.002), with PFHpS and PFHxS as major contributors. Two metabolite-indices were constructed, one positively (beta=1.260, p<0.001) and one negatively (beta=-0.997, p<0.001) associated with IgG. Key contributors for these indices included protoporphyrin, 5-hydroxytryptophan, n-acetylproline, and tyrosine. Analysis of single mediator showed that 48.9% (95%CI: 21.9%,125.0%) and 50.1% (95% CI: 8.1%, 90.1%) of the PFAS index-IgG total effect were mediated by the negative and positive metabolite-indices, respectively. Joint analysis of the metabolite-indices indicated a cumulative mediation effect of 73.6% (95%CI: 44.9%, 116.4%). Enriched pathways associated with these metabolites indices were phenylalanine, tyrosine, and tryptophan biosynthesis and arginine metabolism. Conclusions We observed significant mediation effects of plasma metabolites on the PFAS-IgG relationship, suggesting that PFAS disrupts the balance of plasma metabolites that contributes to reduced plasma IgG production.
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27
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Lee S, Lee J, Lyoo KS, Shin Y, Shin DM, Kim JW, Yang JS, Kim KC, Lee JY, Hwang GS. Unraveling metabolic signatures in SARS-CoV-2 variant infections using multiomics analysis. Front Immunol 2024; 15:1473895. [PMID: 39759510 PMCID: PMC11697598 DOI: 10.3389/fimmu.2024.1473895] [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: 07/31/2024] [Accepted: 11/18/2024] [Indexed: 01/07/2025] Open
Abstract
Introduction The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, notably delta and omicron, has significantly accelerated the global pandemic, worsening conditions worldwide. However, there is a lack of research concerning the molecular mechanisms related to immune responses and metabolism induced by these variants. Methods Here, metabolomics combined with transcriptomics was performed to elucidate the immunometabolic changes in the lung of hamsters infected with delta and omicron variants. Results Both variants caused acute inflammation and lung pathology in intranasally infected hamsters. Principal component analysis uncovered the delta variant significantly altered lung metabolite levels between the pre- and post-infection states. Additionally, metabolic pathways determined by assessment of metabolites and genes in lung revealed significant alterations in arginine biosynthesis, glutathione metabolism, and tryptophan metabolism upon infection with both variants and closely linked to inflammatory cytokines, indicating immune activation and oxidative stress in response to both variants. These metabolic changes were also evident in the serum, validating the presence of systemic alterations corresponding to those identified in lung. Notably, the delta variant induced a more robust metabolic regulation than the omicron variant. Discussion The study suggests that multi-omics is a valuable approach for understanding immunometabolic responses to infectious diseases, and providing insights for effective treatment strategies.
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Affiliation(s)
- Sunho Lee
- Integrated Metabolomics Research Group, Metropolitan Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Jueun Lee
- Integrated Metabolomics Research Group, Metropolitan Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea
| | - Kwang-Soo Lyoo
- College of Health Sciences, Wonkwang University, Iksan, Republic of Korea
| | - Yourim Shin
- Integrated Metabolomics Research Group, Metropolitan Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Dong-Min Shin
- Bioinformatics Department, Theragen Bio, Seongnam, Republic of Korea
| | - Jun-Won Kim
- National Institute of Infectious Diseases, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, Republic of Korea
| | - Jeong-Sun Yang
- National Institute of Infectious Diseases, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, Republic of Korea
| | - Kyung-Chang Kim
- National Institute of Infectious Diseases, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, Republic of Korea
| | - Joo-Yeon Lee
- National Institute of Infectious Diseases, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, Republic of Korea
| | - Geum-Sook Hwang
- Integrated Metabolomics Research Group, Metropolitan Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
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28
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Somova M, Simm S, Ehrhardt J, Schoon J, Burchardt M, Pinto PC. SARS-CoV-2 Spike Protein Amplifies the Immunogenicity of Healthy Renal Epithelium in the Presence of Renal Cell Carcinoma. Cells 2024; 13:2038. [PMID: 39768130 PMCID: PMC11674446 DOI: 10.3390/cells13242038] [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: 10/29/2024] [Revised: 12/06/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025] Open
Abstract
Renal cell carcinoma (RCC) is the most common form of kidney cancer, known for its immune evasion and resistance to chemotherapy. Evidence indicates that the SARS-CoV-2 virus may worsen outcomes for RCC patients, as well as patients with diminished renal function. Evidence suggests that the SARS-CoV-2 virus may exacerbate outcomes in RCC patients and those with impaired renal function. This study explored the unidirectional effects of RCC cells and the SARS-CoV-2 spike protein (S protein) on human renal proximal tubule epithelial cells (RPTECs) using a microphysiological approach. We co-cultured RCC cells (Caki-1) with RPTEC and exposed them to the SARS-CoV-2 S protein under dynamic 3D conditions. The impact on metabolic activity, gene expression, immune secretions, and S protein internalization was evaluated. The SARS-CoV-2 S protein was internalized by RPTEC but poorly interacted with RCC cells. RPTECs exposed to RCC cells and the S protein exhibited upregulated expression of genes involved in immunogenic pathways, particularly those related to antigen processing and presentation via the major histocompatibility complex I (MHCI). Additionally, increased TNF-α secretion suggested a pro-inflammatory response. Metabolic shifts toward glycolysis were observed in RCC co-culture, while the presence of the S protein led to minor changes. The presence of RCC cells amplified the immune-modulatory effects of the SARS-CoV-2 S protein on the renal epithelium, potentially exacerbating renal inflammation and fostering tumor-supportive conditions. These findings suggest that COVID-19 infections can impact renal function in the presence of kidney cancer.
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MESH Headings
- Humans
- Carcinoma, Renal Cell/immunology
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/virology
- Spike Glycoprotein, Coronavirus/immunology
- Spike Glycoprotein, Coronavirus/metabolism
- Kidney Neoplasms/immunology
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/pathology
- Kidney Neoplasms/virology
- SARS-CoV-2/immunology
- COVID-19/immunology
- COVID-19/virology
- COVID-19/metabolism
- Epithelial Cells/metabolism
- Epithelial Cells/virology
- Epithelial Cells/immunology
- Kidney Tubules, Proximal/immunology
- Kidney Tubules, Proximal/metabolism
- Kidney Tubules, Proximal/pathology
- Cell Line, Tumor
- Epithelium/metabolism
- Epithelium/virology
- Epithelium/pathology
- Coculture Techniques
- Kidney/pathology
- Kidney/virology
- Kidney/immunology
- Kidney/metabolism
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Affiliation(s)
- Maryna Somova
- Department of Urology, University Medicine Greifswald, DZ7 J05.15, Fleischmannstraße 8, 17475 Greifswald, Germany
| | - Stefan Simm
- Institute of Bioinformatics, University Medicine Greifswald, Fleischmannstraße 8, 17475 Greifswald, Germany
- Institute for Bioanalysis, Coburg University of Applied Sciences and Arts, Friedrich-Streib-Str. 2, 96450 Coburg, Germany
| | - Jens Ehrhardt
- Department of Obstetrics and Gynecology, University Medicine Greifswald, Fleischmannstraße 8, 17475 Greifswald, Germany
| | - Janosch Schoon
- Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine, University Medicine Greifswald, Fleischmannstraße 8, 17475 Greifswald, Germany
| | - Martin Burchardt
- Department of Urology, University Medicine Greifswald, DZ7 J05.15, Fleischmannstraße 8, 17475 Greifswald, Germany
| | - Pedro Caetano Pinto
- Department of Urology, University Medicine Greifswald, DZ7 J05.15, Fleischmannstraße 8, 17475 Greifswald, Germany
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29
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Said M, Ferrara BT, Aprodu A, Cabreiro F, Thompson EP, Everett J. Transcriptional analysis of C. elegans fmos at different life stages and their roles in ageing. Mol Genet Genomics 2024; 299:113. [PMID: 39636438 PMCID: PMC11621177 DOI: 10.1007/s00438-024-02201-x] [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: 09/15/2022] [Accepted: 10/22/2024] [Indexed: 12/07/2024]
Abstract
Flavin-containing monooxygenases (FMOs) are present in most organisms including plants, fungi, bacteria, invertebrates and vertebrates, where they catalyse the oxidative metabolism of a range of xenobiotics and endogenous metabolites. FMOs have been associated with ageing and longevity in the mouse and in C. elegans. As all five FMOs of C. elegans share an evolutionary root with mouse and human FMO5, it was of interest to discover if effects on ageing and longevity persisted across the whole group. We therefore investigated the impact of fmo gene knockout (KO) in C. elegans. We found that fmo-1, fmo-3 and fmo-4 KO significantly extended C. elegans lifespan relative to wild type and, as previously reported, FMO-2 over-expression did likewise. The transcription levels of C. elegans fmo genes were determined throughout the life cycle (embryo, larva and adult) in wild type and in each mutant to discover if their expression was related to stages in ageing, and expression levels were compared to those in human and mouse. In wild type worms, fmo-1 and fmo-4 were the mostly highly transcribed genes (especially at the larval stage), whereas fmo-2 and fmo-3 were the least transcribed, at all stages. Notably, the knockout of fmo-4 led to a 17- to 30-fold up-regulation of fmo-2, along with significantly increased levels of the other fmos. This parallels recent findings in the long-lived C. elegans tald-1 mutant where fmo-2 was also significantly up-regulated and reinforces its importance in lifespan extension.
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Affiliation(s)
- Mohamed Said
- Faculty of Engineering and Science, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK
- Faculty of Pharmacy, October University for Modern Sciences and Arts, 6th October City, Egypt
| | - Bill T Ferrara
- Faculty of Engineering and Science, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK
| | - Andreea Aprodu
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany
| | - Filipe Cabreiro
- Institute of Clinical Sciences, Imperial College London, London, W12 0NN, UK
- Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany
| | - Elinor P Thompson
- Faculty of Engineering and Science, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK.
| | - Jeremy Everett
- Faculty of Engineering and Science, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK.
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30
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Sun J, Peters M, Yu LR, Vijay V, Bidarimath M, Agrawal M, Flores-Torres AS, Green AM, Burkhart K, Oliphant J, Smallwood HS, Beger RD. Untargeted metabolomics and lipidomics in COVID-19 patient plasma reveals disease severity biomarkers. Metabolomics 2024; 21:3. [PMID: 39636373 DOI: 10.1007/s11306-024-02195-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/29/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION Coronavirus disease 2019 (COVID-19) has widely varying clinical severity. Currently, no single marker or panel of markers is considered standard of care for prediction of COVID-19 disease progression. The goal of this study is to gain mechanistic insights at the molecular level and to discover predictive biomarkers of severity of infection and outcomes among COVID-19 patients. METHOD This cohort study (n = 76) included participants aged 16-78 years who tested positive for SARS-CoV-2 and enrolled in Memphis, TN between August 2020 to July 2022. Clinical outcomes were classified as Non-severe (n = 39) or Severe (n = 37). LC/HRMS-based untargeted metabolomics/lipidomics was conducted to examine the difference in plasma metabolome and lipidome between the two groups. RESULTS Metabolomics data indicated that the kynurenine pathway was activated in Severe participants. Significant increases in short chain acylcarnitines, and short and medium chain acylcarnitines containing OH-FA chain in Severe vs. Non-severe group, which indicates that (1) the energy pathway switched to FA β-oxidation to maintain the host energy homeostasis and to provide energy for virus proliferation; (2) ROS status was aggravated in Severe vs. Non-severe group. Based on PLS-DA and correlation analysis to severity score, IL-6, and creatine, a biomarker panel containing glucose (pro-inflammation), ceramide and S1P (inflammation related), 4-hydroxybutyric acid (oxidative stress related), testosterone sulfate (immune related), and creatine (kidney function), was discovered. This novel biomarker panel plus IL-6 with an AUC of 0.945 provides a better indication of COVID-19 clinical outcomes than that of IL-6 alone or the three clinical biomarker panel (IL-6, glucose and creatine) with AUCs of 0.875 or 0.892.
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Affiliation(s)
- Jinchun Sun
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
| | - Megan Peters
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Li-Rong Yu
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Vikrant Vijay
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Mallikarjun Bidarimath
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Mona Agrawal
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, USA
| | | | - Amanda M Green
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, USA
- Department of Infectious Disease, St Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Keith Burkhart
- Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA
| | - Jessica Oliphant
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
| | - Heather S Smallwood
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, USA
- Children's Foundation Research Institute, Memphis, TN, 38105, USA
| | - Richard D Beger
- Division of Systems Biology, National Center for Toxicological Research, United States Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA
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Li ZY, Li YQ, Zhou JR, Wang J, Liu KZ, Wang P, Gong CM, Wang H, Zhang YJ, Cao Y, Gu Y, Zhang HB, Lu H, Lu LF, Feng RJ. Causes and countermeasures for the increased infection and COVID-19 mortality rates in patients with schizophrenia. IBRO Neurosci Rep 2024; 17:456-462. [PMID: 39634030 PMCID: PMC11616062 DOI: 10.1016/j.ibneur.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/25/2024] [Accepted: 11/13/2024] [Indexed: 12/07/2024] Open
Abstract
Schizophrenia (SCZ) is a common psychiatric disorder that has a complex pathological mechanism. During the Coronavirus disease 2019 (COVID-19) epidemic, patients with SCZ had substantially higher rates of infection with SARS-CoV-2, the virus that causes COVID-19, as well as higher COVID-19 mortality relative to patients with other mental disorders. However, the reasons for these increased rates in patients with SCZ remain unknown. In this review, we hypothesize that certain molecular pathways exhibit abnormal function in both COVID-19 and SCZ, with a focus on those related to energy metabolism dysregulation, immune system disruption, and abnormalities of the central nervous system. We review that dysregulation of energy metabolism can result in disruptions to the immune system and abnormalities within the central nervous system (CNS). Furthermore, immune system disturbances may also contribute to CNS abnormalities in both SCZ and COVID-19. We also discuss macro-factors associated with the high infection and mortality rates of COVID-19 in patients with SCZ, including sociodemographic factors, reduced access to psychiatric healthcare, structural barriers to COVID-19 vaccination, and proposed approaches to mitigate these macro-factors.
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Affiliation(s)
- Zhen-Ying Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
| | - Yu-Qian Li
- The First Clinical College & The Second Clinical College, Hainan Medical University, Haikou, China
| | - Jing-Ru Zhou
- The First Clinical College & The Second Clinical College, Hainan Medical University, Haikou, China
| | - Jie Wang
- Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, China
| | - Kun-Ze Liu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
| | - Peng Wang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
| | - Chun-Mei Gong
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
| | - Han Wang
- Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Yu-Jing Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
| | - Yu Cao
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
| | - Yue Gu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
| | - Han-Bo Zhang
- The First Clinical College & The Second Clinical College, Hainan Medical University, Haikou, China
| | - Hui Lu
- The First Clinical College & The Second Clinical College, Hainan Medical University, Haikou, China
| | - Li-Fang Lu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
- Department of Medical Physiology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Ren-Jun Feng
- Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Brain Science Research Transformation in Tropical Environment of Hainan Province, School of Basic Medicine and Life Sciences, Hainan Medical University, China
- Department of Human Anatomy, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
- Department of Biology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China
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32
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Dylla L, Higgins HM, Poisson SN, Vu T, Reisz JA, Herson PS, Monte A. Sex Differences in Tryptophan Metabolism via the Kynurenine Pathway in Acute Ischemic Stroke. Clin Ther 2024; 46:960-966. [PMID: 39603869 PMCID: PMC11637908 DOI: 10.1016/j.clinthera.2024.10.015] [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: 07/27/2024] [Revised: 10/16/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024]
Abstract
PURPOSE Females are at increased lifetime risk of stroke and experience worse outcomes compared with males. Tryptophan metabolism through the kynurenine pathway, resulting in decreased tryptophan concentrations, is associated with poor outcomes (larger infarct volume, higher National Institutes of Health Stroke Scale [NIHSS] score, and increased early mortality). This metabolic pathway activity varies by sex in healthy adults. However, evaluation of potential sex differences in tryptophan metabolism after an acute ischemic stroke (AIS) is lacking and could contribute to the disparate outcomes by sex. This study characterized sex differences in tryptophan metabolism via the kynurenine pathway in patients with AIS. METHODS Whole blood from patients with AIS enrolled in the University of Colorado Health Emergency Medicine Specimen Bank was analyzed using high-throughput mass spectrometry-based metabolomics at the time of arrival to the emergency department and at 12, 24, and 48 hours thereafter. Descriptive statistics characterized the cohort and metabolite levels. Potential sex differences in tryptophan metabolites at individual time points and their change over time were estimated using linear regression models to control for known factors influencing metabolite levels, initial NIHSS score, therapeutic interventions, and time to last known well (or symptom onset). A multivariable linear regression model examined the interaction effect between sex and metabolite level (at 12 hours after admission) on 24-hour NIHSS score while controlling for initial metabolite level, initial NIHSS score, time to last known well, factors influencing metabolite level, and factors influencing neurologic outcomes. FINDINGS After adjusting for covariates, females with AIS had significantly lower levels of tryptophan at 12 hours after admission compared with males (point estimate, -5.80; P = 0.03). Females and males neither differ in levels of tryptophan, kynurenine, quinolinic acid, or kynurenic acid at any other time point nor did they differ in change in metabolite concentration over time. Only increased quinolinic acid levels across both sexes at 12 hours after admission were associated with increased 24-hour NIHSS scores (point estimate, 0.49; P = 0.0002). IMPLICATIONS Overall, females and males have similar levels and changes in tryptophan and kynurenine pathway metabolites after an AIS. However, females have lower levels of tryptophan early after a stroke. Increased quinolinic acid levels across both sexes were associated with worsening neurologic function as measured by an NIHSS score. Future evaluation of alternative metabolic pathways downstream of tryptophan is needed to explain differences in tryptophan levels but similar levels of downstream kynurenine metabolites in females and males with AIS.
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Affiliation(s)
- Layne Dylla
- Department of Emergency Medicine, Yale School of Medicine, New Haven, Connecticut; Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado.
| | - Hannah M Higgins
- Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, Colorado
| | - Sharon N Poisson
- Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado
| | - Thao Vu
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado
| | - Julie A Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado
| | - Paco S Herson
- Department of Neurological Surgery, The Ohio State University, Columbus, Ohio
| | - Andrew Monte
- Rocky Mountain Poisson and Drug, Denver Health, Denver, Colorado
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D'Alessandro A. It's in your blood: The impact of age, sex, genetic factors and exposures on stored red blood cell metabolism. Transfus Apher Sci 2024; 63:104011. [PMID: 39423666 PMCID: PMC11606750 DOI: 10.1016/j.transci.2024.104011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2024]
Abstract
Transfusion of packed red blood cell (RBCs) saves millions of lives yearly worldwide, making packed RBCs the most commonly administered drug in hospitals after vaccines. However, not all blood units are created equal. By examining blood products as they age in blood banks, transfusion scientists are gaining insights into the intricacies of human chemical individuality as regulated by biological factors (such as sex, age, and body mass index), genetic and non-genetic factors like environmental, dietary, and other exposures. Here, we review recent literature on this topic, with an emphasis on studies linking genetic traits to the metabolic heterogeneity of blood products, the hemolytic propensity of stored RBCs, and transfusion outcomes in both healthy autologous and non-autologous patients requiring transfusion. Given the role of RBCs as a simplified model of eukaryotic cells, and RBC storage as a medically relevant application modeling erythrocyte responses to oxidant stress, these insights have the potential not only to guide the development of precision transfusion strategies, but also to identify novel mechanisms of RBC metabolic regulation relevant to responses to hypoxia and oxidant stress in human (patho)physiology.
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Affiliation(s)
- Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA.
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34
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Garbsch R, Schäfer H, Mooren FC, Schmitz B. Analysis of fat oxidation capacity during cardiopulmonary exercise testing indicates long-lasting metabolic disturbance in patients with post-covid-19 syndrome. Clin Nutr 2024; 43:26-35. [PMID: 39423759 DOI: 10.1016/j.clnu.2024.10.010] [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: 07/01/2024] [Revised: 10/01/2024] [Accepted: 10/07/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND & AIMS Post-COVID-19 Syndrome (PCS) is characterized by symptoms including fatigue, reduced physical performance, dyspnea, cognitive impairment, and psychological distress. The mechanisms underlying the onset and severity of PCS point to mitochondrial dysfunction as significant contributor. This study examined fat oxidation as a function of mitochondrial capacity during exercise. METHODS Single-center prospective cohort study during inpatient rehabilitation. Cardiopulmonary exercise testing and assessment of fatigue using questionnaires were performed at admission and discharge. Detailed spirometric breath-by-breath data were used to calculate substrate oxidation rates. RESULTS Patients (N = 187; 38 % women; 49.7 ± 11.4 years) were referred to rehabilitation 253.4 ± 130.6 days after infection. Lead symptoms included fatigue/exercise intolerance (79.9 %), shortness of breath (77.0 %), and cognitive dysfunction (55.1 %). Fat oxidation capacity was disturbed in PCS patients overall (AUC: 11.3 [10.7-11.9]) compared to healthy controls (p < 0.0001), with hospitalization during acute infection predicting the level of disturbance (p < 0.0001). Low exercise capacity and high fatigue scores resulted in reduced fat oxidation (both p < 0.0001). In particular, younger males were affected by significantly reduced fat oxidation capacity (sex: p = 0.002; age: p < 0.001). Metabolic disturbance was significantly improved during exercise-based rehabilitation (AUC: 14.9 [14.4-15.4]; p < 0.0001), even for the group of younger impaired males (+44.2 %; p < 0.0001). Carbohydrate oxidation was not impaired. CONCLUSIONS PCS-specific restrictions in fat oxidation may indicate persistent mitochondrial dysfunction. Clinical assessment of PCS patients should include detailed breath-by-breath analysis during exercise to identify metabolic alterations especially in the group of younger males identified in this report. Exercise-based rehabilitation results in improved exercise capacity and fat oxidation and thus likely mitochondrial function. CLINICAL TRIALS NCT06468722.
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Affiliation(s)
- René Garbsch
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany
| | - Hendrik Schäfer
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany
| | - Frank C Mooren
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany
| | - Boris Schmitz
- Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany; DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany.
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35
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Maguire C, Chen J, Rouphael N, Pickering H, Phan HV, Glascock A, Chu V, Dandekar R, Corry D, Kheradmand F, Baden LR, Selaky R, McComsey GA, Haddad EK, Cairns CB, Pulendran B, Fernandez-Sesma A, Simon V, Metcalf JP, Higuita NIA, Messer WB, David MM, Nadeau KC, Kraft M, Bime C, Schaenman J, Erle D, Calfee CS, Atkinson MA, Brackenridge SC, Ehrlich LIR, Montgomery RR, Shaw AC, Hough CL, Geng LN, Hafler DA, Augustine AD, Becker PM, Peters B, Ozonoff A, Kim-Schulze SH, Krammer F, Bosinger S, Eckalbar W, Altman MC, Wilson M, Guan L, Kleinstein SH, IMPACC Network, Smolen KK, Reed EF, Levy O, Maecker H, Hunt P, Steen H, Diray-Arce J, Langelier CR, Melamed E. Chronic Viral Reactivation and Associated Host Immune Response and Clinical Outcomes in Acute COVID-19 and Post-Acute Sequelae of COVID-19. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.14.622799. [PMID: 39605478 PMCID: PMC11601417 DOI: 10.1101/2024.11.14.622799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Chronic viral infections are ubiquitous in humans, with individuals harboring multiple latent viruses that can reactivate during acute illnesses. Recent studies have suggested that SARS-CoV-2 infection can lead to reactivation of latent viruses such as Epstein-Barr Virus (EBV) and cytomegalovirus (CMV), yet, the extent and impact of viral reactivation in COVID-19 and its effect on the host immune system remain incompletely understood. Here we present a comprehensive multi-omic analysis of viral reactivation of all known chronically infecting viruses in 1,154 hospitalized COVID-19 patients, from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, who were followed prospectively for twelve months. We reveal significant reactivation of Herpesviridae, Enteroviridae, and Anelloviridae families during acute stage of COVID-19 (0-40 days post-hospitalization), each exhibiting distinct temporal dynamics. We also show that viral reactivation correlated with COVID-19 severity, demographic characteristics, and clinical outcomes, including mortality. Integration of cytokine profiling, cellular immunophenotyping, metabolomics, transcriptomics, and proteomics demonstrated virus-specific host responses, including elevated pro-inflammatory cytokines (e.g. IL-6, CXCL10, and TNF), increased activated CD4+ and CD8+ T-cells, and upregulation of cellular replication genes, independent of COVID-19 severity and SARS-CoV-2 viral load. Notably, persistent Anelloviridae reactivation during convalescence (≥3 months post-hospitalization) was associated with Post-Acute Sequelae of COVID-19 (PASC) symptoms, particularly physical function and fatigue. Our findings highlight a remarkable prevalence and potential impact of chronic viral reactivation on host responses and clinical outcomes during acute COVID-19 and long term PASC sequelae. Our data provide novel immune, transcriptomic, and metabolomic biomarkers of viral reactivation that may inform novel approaches to prognosticate, prevent, or treat acute COVID-19 and PASC.
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Affiliation(s)
- Cole Maguire
- The University of Texas at Austin, Austin, TX 78712, USA
| | - Jing Chen
- Clinical and Data Coordinating Center (CDCC) Precision Vaccines Program, Boston Children’s Hospital, Boston, MA 02115, USA
| | | | - Harry Pickering
- David Geffen School of Medicine at the University of California Los Angeles, Los Angeles CA 90095, USA
| | - Hoang Van Phan
- University of California San Francisco, San Francisco, CA 94115, USA
| | | | - Victoria Chu
- University of California San Francisco, San Francisco, CA 94115, USA
| | - Ravi Dandekar
- University of California San Francisco, San Francisco, CA 94115, USA
| | - David Corry
- Baylor College of Medicine and the Center for Translational Research on Inflammatory Diseases, Houston, TX 77030, USA
| | - Farrah Kheradmand
- Baylor College of Medicine and the Center for Translational Research on Inflammatory Diseases, Houston, TX 77030, USA
| | - Lindsey R. Baden
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Rafick Selaky
- Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA
| | - Grace A. McComsey
- Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA
| | - Elias K. Haddad
- Drexel University, Tower Health Hospital, Philadelphia, PA 19104, USA
| | - Charles B. Cairns
- Drexel University, Tower Health Hospital, Philadelphia, PA 19104, USA
| | - Bali Pulendran
- Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | | | - Viviana Simon
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jordan P. Metcalf
- Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA
| | | | | | - Mark M. David
- Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | - Kari C. Nadeau
- Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | | | - Chris Bime
- University of Arizona, Tucson AZ 85721, USA
| | - Joanna Schaenman
- David Geffen School of Medicine at the University of California Los Angeles, Los Angeles CA 90095, USA
| | - David Erle
- University of California San Francisco, San Francisco, CA 94115, USA
| | - Carolyn S. Calfee
- University of California San Francisco, San Francisco, CA 94115, USA
| | | | | | | | | | | | | | - Linda N Geng
- Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | | | - Alison D. Augustine
- National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD 20814, USA
| | - Patrice M. Becker
- National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD 20814, USA
| | - Bjoern Peters
- La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Al Ozonoff
- Clinical and Data Coordinating Center (CDCC) Precision Vaccines Program, Boston Children’s Hospital, Boston, MA 02115, USA
| | | | - Florian Krammer
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Walter Eckalbar
- University of California San Francisco, San Francisco, CA 94115, USA
| | - Matthew C. Altman
- Benaroya Research Institute, University of Washington, Seattle, WA 98101, USA
| | - Michael Wilson
- University of California San Francisco, San Francisco, CA 94115, USA
| | - Leying Guan
- Yale School of Public Health, New Haven, CT 06510, USA
| | | | | | - Kinga K. Smolen
- Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Elaine F. Reed
- David Geffen School of Medicine at the University of California Los Angeles, Los Angeles CA 90095, USA
| | - Ofer Levy
- Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA
| | - Holden Maecker
- Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | - Peter Hunt
- University of California San Francisco, San Francisco, CA 94115, USA
| | - Hanno Steen
- Precision Vaccines Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Joann Diray-Arce
- Clinical and Data Coordinating Center (CDCC) Precision Vaccines Program, Boston Children’s Hospital, Boston, MA 02115, USA
- Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | | | - Esther Melamed
- The University of Texas at Austin, Austin, TX 78712, USA
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Ai N, Zhang Y, Yang J, Zhang Y, Zhao X, Feng H. Genetically predicted blood metabolites mediate the association between circulating immune cells and severe COVID-19: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e40509. [PMID: 39560514 PMCID: PMC11575977 DOI: 10.1097/md.0000000000040509] [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: 08/21/2024] [Accepted: 10/24/2024] [Indexed: 11/20/2024] Open
Abstract
Investigating the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19 and revealing the role of blood metabolite-mediated circulating immune cells in disease onset and progression. Genetic variation data of 731 circulating immune cells, 1400 blood metabolites, and severe COVID-19 from genome-wide association study open-access database (https://gwas.mrcieu.ac.uk) were used as instrumental variables for bidirectional and two-step Mendelian randomization analysis. The study identified 11 circulating immune cells with unidirectional causality to severe COVID-19. Two-step Mendelian randomization analysis showed 10 blood metabolites were causally associated with severe COVID-19, and blood Myristate and Citrulline to phosphate ratio mediated the association of circulating effector memory double negative % DN and CD8dim natural killer T cell % T cells, respectively, with severe COVID-19 (Myristate mediated effect ratio was 10.20%, P = .011; Citrulline to phosphate ratio mediated effect ratio was -9.21%, P = .017). This study provides genetic evidence assessing the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19, elucidates the role of blood metabolite-mediated circulating immune cells in severe COVID-19 development, and offers new insights into severe COVID-19 etiology and related preventive and targeted therapeutic strategies.
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Affiliation(s)
- Ning Ai
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yan Zhang
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jing Yang
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yu Zhang
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xuejing Zhao
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Huifen Feng
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Mendes LT, Gama-Almeida MC, Reis DL, Silva ACPE, Neris RLS, Galliez RM, Castiñeiras TMPP, on behalf of the UFRJ COVID-19 Working Group, Ludwig C, Valente AP, Costa dos Santos Junior G, El-Bacha T, Assunção-Miranda I. Longitudinal 1H NMR-Based Metabolomics in Saliva Unveils Signatures of Transition from Acute to Post-Acute Phase of SARS-CoV-2 Infection. Viruses 2024; 16:1769. [PMID: 39599883 PMCID: PMC11598993 DOI: 10.3390/v16111769] [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: 09/13/2024] [Revised: 11/07/2024] [Accepted: 11/09/2024] [Indexed: 11/29/2024] Open
Abstract
COVID-19 can range from a mild to severe acute respiratory syndrome and also could result in multisystemic damage. Additionally, many people develop post-acute symptoms associated with immune and metabolic disturbances in response to viral infection, requiring longitudinal and multisystem studies to understand the complexity of COVID-19 pathophysiology. Here, we conducted a 1H Nuclear Magnetic Resonance metabolomics in saliva of symptomatic subjects presenting mild and moderate respiratory symptoms to investigate prospective changes in the metabolism induced after acute-phase SARS-CoV-2 infection. Saliva from 119 donors presenting non-COVID and COVID-19 respiratory symptoms were evaluated in the acute phase (T1) and the post-acute phase (T2). We found two clusters of metabolite fluctuation in the COVID-19 group. Cluster 1, metabolites such as glucose, (CH3)3 choline-related metabolites, 2-hydroxybutyrate, BCAA, and taurine increased in T2 relative to T1, and in cluster 2, acetate, creatine/creatinine, phenylalanine, histidine, and lysine decreased in T2 relative to T1. Metabolic fluctuations in the COVID-19 group were associated with overweight/obesity, vaccination status, higher viral load, and viral clearance of the respiratory tract. Our data unveil metabolic signatures associated with the transition to the post-acute phase of SARS-CoV-2 infection that may reflect tissue damage, inflammatory process, and activation of tissue repair cascade. Thus, they contribute to describing alterations in host metabolism that may be associated with prolonged symptoms of COVID-19.
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Affiliation(s)
- Luiza Tomé Mendes
- LaRIV-Laboratory of Cellular Response to Viral Infections, Instituto de Microbiologia Paulo de Góes, Departamento de Virologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil; (L.T.M.); (A.C.P.e.S.); (R.L.S.N.)
| | - Marcos C. Gama-Almeida
- LeBioME-Bioactives, Mitochondrial and Placental Metabolism Core, Institute of Nutrition Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil; (M.C.G.-A.); (D.L.R.)
| | - Desirée Lopes Reis
- LeBioME-Bioactives, Mitochondrial and Placental Metabolism Core, Institute of Nutrition Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil; (M.C.G.-A.); (D.L.R.)
| | - Ana Carolina Pires e Silva
- LaRIV-Laboratory of Cellular Response to Viral Infections, Instituto de Microbiologia Paulo de Góes, Departamento de Virologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil; (L.T.M.); (A.C.P.e.S.); (R.L.S.N.)
| | - Rômulo Leão Silva Neris
- LaRIV-Laboratory of Cellular Response to Viral Infections, Instituto de Microbiologia Paulo de Góes, Departamento de Virologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil; (L.T.M.); (A.C.P.e.S.); (R.L.S.N.)
| | - Rafael Mello Galliez
- Núcleo de Enfrentamento e Estudos de Doenças Infecciosas Emergentes e Reemergentes (NEEDIER), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-599, Brazil; (R.M.G.); (T.M.P.P.C.)
| | - Terezinha Marta Pereira Pinto Castiñeiras
- Núcleo de Enfrentamento e Estudos de Doenças Infecciosas Emergentes e Reemergentes (NEEDIER), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-599, Brazil; (R.M.G.); (T.M.P.P.C.)
| | | | - Christian Ludwig
- Department of Metabolism and Systems Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK;
| | - Ana Paula Valente
- National Center for Nuclear Magnetic Resonance—Jiri Jonas, Institute of Medical Biochemistry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil;
| | - Gilson Costa dos Santos Junior
- LabMet-Laboratory of Metabolomics, Instituto de Biologia Roberto Alcantara Gomes (IBRAG), Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil;
| | - Tatiana El-Bacha
- LeBioME-Bioactives, Mitochondrial and Placental Metabolism Core, Institute of Nutrition Josué de Castro, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil; (M.C.G.-A.); (D.L.R.)
| | - Iranaia Assunção-Miranda
- LaRIV-Laboratory of Cellular Response to Viral Infections, Instituto de Microbiologia Paulo de Góes, Departamento de Virologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil; (L.T.M.); (A.C.P.e.S.); (R.L.S.N.)
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Chen X, Xu D, Yu J, Song XJ, Li X, Cui YL. Tryptophan Metabolism Disorder-Triggered Diseases, Mechanisms, and Therapeutic Strategies: A Scientometric Review. Nutrients 2024; 16:3380. [PMID: 39408347 PMCID: PMC11478743 DOI: 10.3390/nu16193380] [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: 09/05/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Tryptophan is widely present in foods such as peanuts, milk, and bananas, playing a crucial role in maintaining metabolic homeostasis in health and disease. Tryptophan metabolism is involved in the development and progression of immune, nervous, and digestive system diseases. Although some excellent reviews on tryptophan metabolism exist, there has been no systematic scientometric study as of yet. METHODS This review provides and summarizes research hotspots and potential future directions by analyzing annual publications, topics, keywords, and highly cited papers sourced from Web of Science spanning 1964 to 2022. RESULTS This review provides a scientometric overview of tryptophan metabolism disorder-triggered diseases, mechanisms, and therapeutic strategies. CONCLUSIONS The gut microbiota regulates gut permeability, inflammation, and host immunity by directly converting tryptophan to indole and its derivatives. Gut microbial metabolites regulate tryptophan metabolism by activating specific receptors or enzymes. Additionally, the kynurenine (KYN) pathway, activated by indoleamine-2, 3-dioxygenase (IDO) and tryptophan 2, 3-dioxygenase, affects the migration and invasion of glioma cells and the development of COVID-19 and depression. The research and development of IDO inhibitors help to improve the effectiveness of immunotherapy. Tryptophan metabolites as potential markers are used for disease therapy, guiding clinical decision-making. Tryptophan metabolites serve as targets to provide a new promising strategy for neuroprotective/neurotoxic imbalance affecting brain structure and function. In summary, this review provides valuable guidance for the basic research and clinical application of tryptophan metabolism.
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Affiliation(s)
- Xue Chen
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; (X.C.); (D.X.); (J.Y.); (X.-J.S.); (X.L.)
- State Key Laboratory of Component-Based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Dong Xu
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; (X.C.); (D.X.); (J.Y.); (X.-J.S.); (X.L.)
- State Key Laboratory of Component-Based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jie Yu
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; (X.C.); (D.X.); (J.Y.); (X.-J.S.); (X.L.)
- State Key Laboratory of Component-Based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xu-Jiao Song
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; (X.C.); (D.X.); (J.Y.); (X.-J.S.); (X.L.)
- State Key Laboratory of Component-Based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xue Li
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; (X.C.); (D.X.); (J.Y.); (X.-J.S.); (X.L.)
- State Key Laboratory of Component-Based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yuan-Lu Cui
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; (X.C.); (D.X.); (J.Y.); (X.-J.S.); (X.L.)
- State Key Laboratory of Component-Based Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
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Chatterjee B, Thakur SS. Valuable Contributions and Lessons Learned from Proteomics and Metabolomics Studies of COVID-19. J Proteome Res 2024; 23:4171-4187. [PMID: 39157976 DOI: 10.1021/acs.jproteome.4c00340] [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] [Indexed: 08/20/2024]
Abstract
The COVID-19 pandemic caused by the SARS-CoV-2 virus infected more than 775,686,716 humans and was responsible for the death of more than 7,054,093 individuals. COVID-19 has taught us that the development of vaccines, repurposing of drugs, and understanding the mechanism of a disease can be done within a short time. The COVID-19 proteomics and metabolomics has contributed to its diagnosis, understanding of its progression, host-virus interaction, disease mechanism, and also in the search of suitable anti-COVID therapeutics. Mass spectrometry based proteomics was used to find the potential biomarkers of different stages of COVID-19 including severe and nonsevere cases in the blood serum. Notably, protein-protein interaction techniques to understand host-virus interactions were also significantly useful. The single-cell proteomics studies were carried out to ascertain the changes in immune cell composition and its activation in mild COVID-19 patients versus severe COVID-19 patients using whole-blood and peripheral-blood mononuclear cells. Modern technologies were helpful to deal with the pandemic; however, there is still scope for further development. Further, attempts were made to understand the protein-protein, metabolite-metabolite, and protein-metabolite interactomes, derived from proteins and metabolite fingerprints of COVID-19 patients by reanalysis of COVID-19 public mass spectrometry based proteomics and metabolomics studies. Further, some of these interactions were supported by the literature as validations in the COVID-19 studies.
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Affiliation(s)
| | - Suman S Thakur
- Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India
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Njomen E, Hayward RE, DeMeester KE, Ogasawara D, Dix MM, Nguyen T, Ashby P, Simon GM, Schreiber SL, Melillo B, Cravatt BF. Multi-tiered chemical proteomic maps of tryptoline acrylamide-protein interactions in cancer cells. Nat Chem 2024; 16:1592-1604. [PMID: 39138346 PMCID: PMC11684312 DOI: 10.1038/s41557-024-01601-1] [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: 06/05/2023] [Accepted: 07/12/2024] [Indexed: 08/15/2024]
Abstract
Covalent chemistry is a versatile approach for expanding the ligandability of the human proteome. Activity-based protein profiling (ABPP) can infer the specific residues modified by electrophilic compounds through competition with broadly reactive probes. However, the extent to which such residue-directed platforms fully assess the protein targets of electrophilic compounds in cells remains unclear. Here we evaluate a complementary protein-directed ABPP method that identifies proteins showing stereoselective reactivity with alkynylated, chiral electrophilic compounds-termed stereoprobes. Integration of protein- and cysteine-directed data from cancer cells treated with tryptoline acrylamide stereoprobes revealed generally well-correlated ligandability maps and highlighted features, such as protein size and the proteotypicity of cysteine-containing peptides, that explain gaps in each ABPP platform. In total, we identified stereoprobe binding events for >300 structurally and functionally diverse proteins, including compounds that stereoselectively and site-specifically disrupt MAD2L1BP interactions with the spindle assembly checkpoint complex leading to delayed mitotic exit in cancer cells.
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Affiliation(s)
- Evert Njomen
- Department of Chemistry, Scripps Research, La Jolla, CA, USA.
| | | | | | | | - Melissa M Dix
- Department of Chemistry, Scripps Research, La Jolla, CA, USA
| | | | | | | | - Stuart L Schreiber
- Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA
| | - Bruno Melillo
- Department of Chemistry, Scripps Research, La Jolla, CA, USA.
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
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Dehhaghi M, Heydari M, Panahi HKS, Lewin SR, Heng B, Brew BJ, Guillemin GJ. The roles of the kynurenine pathway in COVID-19 neuropathogenesis. Infection 2024; 52:2043-2059. [PMID: 38802702 PMCID: PMC11499433 DOI: 10.1007/s15010-024-02293-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: 03/07/2024] [Accepted: 05/07/2024] [Indexed: 05/29/2024]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the highly contagious respiratory disease Corona Virus Disease 2019 (COVID-19) that may lead to various neurological and psychological disorders that can be acute, lasting days to weeks or months and possibly longer. The latter is known as long-COVID or more recently post-acute sequelae of COVID (PASC). During acute COVID-19 infection, a strong inflammatory response, known as the cytokine storm, occurs in some patients. The levels of interferon-γ (IFN-γ), interferon-β (IFN-β), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are particularly increased. These cytokines are known to activate the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), catalysing the first step of tryptophan (Trp) catabolism through the kynurenine pathway (KP) leading to the production of several neurotoxic and immunosuppressive metabolites. There is already data showing elevation in KP metabolites both acutely and in PASC, especially regarding cognitive impairment. Thus, it is likely that KP involvement is significant in SARS-CoV-2 pathogenesis especially neurologically.
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Affiliation(s)
- Mona Dehhaghi
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mostafa Heydari
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran
| | - Hamed Kazemi Shariat Panahi
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Sharon R Lewin
- Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, VIC, Australia
| | - Benjamin Heng
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
| | - Bruce J Brew
- Peter Duncan Neurosciences Unit, St. Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia.
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia.
- Departments of Neurology and Immunology, St. Vincent's Hospital, Sydney, NSW, Australia.
- University of Notre Dame, Darlinghurst, Sydney, NSW, Australia.
| | - Gilles J Guillemin
- Peter Duncan Neurosciences Unit, St. Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Institut Pertanian Bogor University, Bogor, Indonesia
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Elahi S, Rezaeifar M, Osman M, Shahbaz S. Exploring the role of galectin-9 and artemin as biomarkers in long COVID with chronic fatigue syndrome: links to inflammation and cognitive function. Front Immunol 2024; 15:1443363. [PMID: 39386210 PMCID: PMC11461188 DOI: 10.3389/fimmu.2024.1443363] [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: 06/03/2024] [Accepted: 09/03/2024] [Indexed: 10/12/2024] Open
Abstract
This study aimed to assess plasma galectin-9 (Gal-9) and artemin (ARTN) concentrations as potential biomarkers to differentiate individuals with Long COVID (LC) patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) from SARS-CoV-2 recovered (R) and healthy controls (HCs). Receiver operating characteristic (ROC) curve analysis determined a cut-off value of plasma Gal-9 and ARTN to differentiate LC patients from the R group and HCs in two independent cohorts. Positive correlations were observed between elevated plasma Gal-9 levels and inflammatory markers (e.g. SAA and IP-10), as well as sCD14 and I-FABP in LC patients. Gal-9 also exhibited a positive correlation with cognitive failure scores, suggesting its potential role in cognitive impairment in LC patients with ME/CFS. This study highlights plasma Gal-9 and/or ARTN as sensitive screening biomarkers for discriminating LC patients from controls. Notably, the elevation of LPS-binding protein in LC patients, as has been observed in HIV infected individuals, suggests microbial translocation. However, despite elevated Gal-9, we found a significant decline in ARTN levels in the plasma of people living with HIV (PLWH). Our study provides a novel and important role for Gal-9/ARTN in LC pathogenesis.
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Affiliation(s)
- Shokrollah Elahi
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, Edmonton, AB, Canada
- Women and Children Health Research Institute, Edmonton, AB, Canada
- Cancer Research Institute of Northern Alberta, Edmonton, AB, Canada
- Glycomics Institute of Alberta, Edmonton, AB, Canada
- Alberta Transplant Institute, Edmonton, AB, Canada
| | - Maryam Rezaeifar
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
| | - Mohammed Osman
- Li Ka Shing Institute of Virology, Edmonton, AB, Canada
- Women and Children Health Research Institute, Edmonton, AB, Canada
- Department of Medicine, Division of Rheumatology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Shima Shahbaz
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
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Oropeza-Valdez JJ, Padron-Manrique C, Vázquez-Jiménez A, Soberon X, Resendis-Antonio O. Exploring metabolic anomalies in COVID-19 and post-COVID-19: a machine learning approach with explainable artificial intelligence. Front Mol Biosci 2024; 11:1429281. [PMID: 39314212 PMCID: PMC11417410 DOI: 10.3389/fmolb.2024.1429281] [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: 05/07/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, has led to significant challenges worldwide, including diverse clinical outcomes and prolonged post-recovery symptoms known as Long COVID or Post-COVID-19 syndrome. Emerging evidence suggests a crucial role of metabolic reprogramming in the infection's long-term consequences. This study employs a novel approach utilizing machine learning (ML) and explainable artificial intelligence (XAI) to analyze metabolic alterations in COVID-19 and Post-COVID-19 patients. Samples were taken from a cohort of 142 COVID-19, 48 Post-COVID-19, and 38 control patients, comprising 111 identified metabolites. Traditional analysis methods, like PCA and PLS-DA, were compared with ML techniques, particularly eXtreme Gradient Boosting (XGBoost) enhanced by SHAP (SHapley Additive exPlanations) values for explainability. XGBoost, combined with SHAP, outperformed traditional methods, demonstrating superior predictive performance and providing new insights into the metabolic basis of the disease's progression and aftermath. The analysis revealed metabolomic subgroups within the COVID-19 and Post-COVID-19 conditions, suggesting heterogeneous metabolic responses to the infection and its long-term impacts. Key metabolic signatures in Post-COVID-19 include taurine, glutamine, alpha-Ketoglutaric acid, and LysoPC a C16:0. This study highlights the potential of integrating ML and XAI for a fine-grained description in metabolomics research, offering a more detailed understanding of metabolic anomalies in COVID-19 and Post-COVID-19 conditions.
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Affiliation(s)
- Juan José Oropeza-Valdez
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
- Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Cristian Padron-Manrique
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Aarón Vázquez-Jiménez
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Xavier Soberon
- Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
- Departamento de Ingeniería Celular y Biocatálisis, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Colonia Chamilpa, Cuernavaca, México
| | - Osbaldo Resendis-Antonio
- Human Systems Biology Laboratory. Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
- Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
- Coordinación de la Investigación Científica – Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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Sevim Bayrak C, Forst CV, Jones DR, Gresham DJ, Pushalkar S, Wu S, Vogel C, Mahal LK, Ghedin E, Ross T, García-Sastre A, Zhang B. Patient subtyping analysis of baseline multi-omic data reveals distinct pre-immune states associated with antibody response to seasonal influenza vaccination. Clin Immunol 2024; 266:110333. [PMID: 39089348 PMCID: PMC11340208 DOI: 10.1016/j.clim.2024.110333] [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: 06/18/2024] [Revised: 07/26/2024] [Accepted: 07/27/2024] [Indexed: 08/03/2024]
Abstract
Understanding the molecular mechanisms underpinning diverse vaccination responses is critical for developing efficient vaccines. Molecular subtyping can offer insights into heterogeneous nature of responses and aid in vaccine design. We analyzed multi-omic data from 62 haemagglutinin seasonal influenza vaccine recipients (2019-2020), including transcriptomics, proteomics, glycomics, and metabolomics data collected pre-vaccination. We performed a subtyping analysis on the integrated data revealing five subtypes with distinct molecular signatures. These subtypes differed in the expression of pre-existing adaptive or innate immunity signatures, which were linked to significant variation in baseline immunoglobulin A (IgA) and hemagglutination inhibition (HAI) titer levels. It is worth noting that these differences persisted through day 28 post-vaccination, indicating the effect of initial immune state on vaccination response. These findings highlight the significance of interpersonal variation in baseline immune status as a crucial factor in determining the effectiveness of seasonal vaccines. Ultimately, incorporating molecular profiling could enable personalized vaccine optimization.
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Affiliation(s)
- Cigdem Sevim Bayrak
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai, New York, NY, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Christian V Forst
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai, New York, NY, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Microbiology, Icahn School of Medicine at Mt Sinai, New York, NY, USA
| | - Drew R Jones
- Department of Biochemistry and Molecular Pharmacology, New York University Langone Health, NY, New York, USA
| | - David J Gresham
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Smruti Pushalkar
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Shaohuan Wu
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Christine Vogel
- Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
| | - Lara K Mahal
- Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Elodie Ghedin
- Systems Genomics Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD, USA
| | - Ted Ross
- Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA; Department of Infectious Diseases, University of Georgia, Athens, GA, USA
| | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai, New York, NY, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Eslami Z, Joshaghani H. Investigating the Role of Serotonin Levels in Cognitive Impairments Associated with Long COVID-19. Chonnam Med J 2024; 60:141-146. [PMID: 39381125 PMCID: PMC11458317 DOI: 10.4068/cmj.2024.60.3.141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/02/2024] [Accepted: 09/12/2024] [Indexed: 10/10/2024] Open
Abstract
This study aimed to investigate the activation of the inflammation process, triggered as an immune response to combat the invasion by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named 'coronavirus disease 2019' (COVID-19). Several mechanisms contribute to the reduction in serotonin levels, such as the impaired absorption of dietary tryptophan, hindered serotonin transport via platelets, and increased activity of an enzyme responsible for breaking down serotonin. Individuals seeking treatment for long COVID-19 had lower serotonin levels in their blood than those who had fully recovered from the infection. Furthermore, patients with long COVID-19 also had reduced tryptophan levels. The potential benefits of dietary supplementation with tryptophan or the use of selective serotonin reuptake inhibitors (SSRIs) to improve cognitive impairments and depressive and anxiety disorders in long-term COVID-19 patients. The findings support the immune response's pivotal role in modulating serotonin levels and further highlight the intricate connection between the immune system and neurotransmitter regulation.
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Affiliation(s)
- Zahra Eslami
- Department of Clinical Biochemistry, Hamadan University of Medical Science, Hamadan, Iran
| | - Hamidreza Joshaghani
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Golestan, Iran
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Alves LDF, Moore JB, Kell DB. The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects. Int J Mol Sci 2024; 25:9082. [PMID: 39201768 PMCID: PMC11354673 DOI: 10.3390/ijms25169082] [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: 07/19/2024] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters and receptors display micromolar binding constants; these are consistent with its typically micromolar tissue concentrations but far above its serum/plasma concentration (normally tens of nanomolar), suggesting large gaps in our knowledge of its transport and mechanisms of action, in that the main influx transporters characterized to date are equilibrative, not concentrative. In addition, it is a substrate of a known anion efflux pump (ABCC4), whose in vivo activity is largely unknown. Exogeneous addition of L-tryptophan or L-kynurenine leads to the production of KYNA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation pathways, it might be added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show that it has valuable bioactivity. Given the above, we review its potential utility as a nutraceutical, finding it significantly worthy of further study and development.
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Affiliation(s)
- Luana de Fátima Alves
- The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Søltofts Plads, 2800 Kongens Lyngby, Denmark
| | - J. Bernadette Moore
- School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK;
- Department of Biochemistry, Cell & Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St., Liverpool L69 7ZB, UK
| | - Douglas B. Kell
- The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Building 220, Søltofts Plads, 2800 Kongens Lyngby, Denmark
- Department of Biochemistry, Cell & Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown St., Liverpool L69 7ZB, UK
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D’Amato M, Grignano MA, Iadarola P, Rampino T, Gregorini M, Viglio S. The Impact of Serum/Plasma Proteomics on SARS-CoV-2 Diagnosis and Prognosis. Int J Mol Sci 2024; 25:8633. [PMID: 39201322 PMCID: PMC11354567 DOI: 10.3390/ijms25168633] [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: 06/17/2024] [Revised: 07/19/2024] [Accepted: 08/05/2024] [Indexed: 09/02/2024] Open
Abstract
While COVID-19's urgency has diminished since its emergence in late 2019, it remains a significant public health challenge. Recent research reveals that the molecular intricacies of this virus are far more complex than initially understood, with numerous post-translational modifications leading to diverse proteoforms and viral particle heterogeneity. Mass spectrometry-based proteomics of patient serum/plasma emerges as a promising complementary approach to traditional diagnostic methods, offering insights into SARS-CoV-2 protein dynamics and enhancing understanding of the disease and its long-term consequences. This article highlights key findings from three years of pandemic-era proteomics research. It delves into biomarker discovery, diagnostic advancements, and drug development efforts aimed at monitoring COVID-19 onset and progression and exploring treatment options. Additionally, it examines global protein abundance and post-translational modification profiling to elucidate signaling pathway alterations and protein-protein interactions during infection. Finally, it explores the potential of emerging multi-omics analytic strategies in combatting SARS-CoV-2.
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Affiliation(s)
- Maura D’Amato
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; (M.D.); (S.V.)
| | - Maria Antonietta Grignano
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (M.A.G.); (T.R.); (M.G.)
| | - Paolo Iadarola
- Department of Biology and Biotechnologies “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy
| | - Teresa Rampino
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (M.A.G.); (T.R.); (M.G.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Marilena Gregorini
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (M.A.G.); (T.R.); (M.G.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Simona Viglio
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; (M.D.); (S.V.)
- Lung Transplantation Unit, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy
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48
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Shafqat A, Masters MC, Tripathi U, Tchkonia T, Kirkland JL, Hashmi SK. Long COVID as a disease of accelerated biological aging: An opportunity to translate geroscience interventions. Ageing Res Rev 2024; 99:102400. [PMID: 38945306 DOI: 10.1016/j.arr.2024.102400] [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: 04/21/2024] [Revised: 06/12/2024] [Accepted: 06/27/2024] [Indexed: 07/02/2024]
Abstract
It has been four years since long COVID-the protracted consequences that survivors of COVID-19 face-was first described. Yet, this entity continues to devastate the quality of life of an increasing number of COVID-19 survivors without any approved therapy and a paucity of clinical trials addressing its biological root causes. Notably, many of the symptoms of long COVID are typically seen with advancing age. Leveraging this similarity, we posit that Geroscience-which aims to target the biological drivers of aging to prevent age-associated conditions as a group-could offer promising therapeutic avenues for long COVID. Bearing this in mind, this review presents a translational framework for studying long COVID as a state of effectively accelerated biological aging, identifying research gaps and offering recommendations for future preclinical and clinical studies.
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Affiliation(s)
- Areez Shafqat
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
| | - Mary Clare Masters
- Division of Infectious Diseases, Northwestern University, Chicago, IL, USA
| | - Utkarsh Tripathi
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Tamara Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - James L Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA; Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Shahrukh K Hashmi
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Research and Innovation Center, Department of Health, Abu Dhabi, UAE; College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates
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49
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Essex M, Millet Pascual-Leone B, Löber U, Kuhring M, Zhang B, Brüning U, Fritsche-Guenther R, Krzanowski M, Fiocca Vernengo F, Brumhard S, Röwekamp I, Anna Bielecka A, Lesker TR, Wyler E, Landthaler M, Mantei A, Meisel C, Caesar S, Thibeault C, Corman VM, Marko L, Suttorp N, Strowig T, Kurth F, Sander LE, Li Y, Kirwan JA, Forslund SK, Opitz B. Gut microbiota dysbiosis is associated with altered tryptophan metabolism and dysregulated inflammatory response in COVID-19. NPJ Biofilms Microbiomes 2024; 10:66. [PMID: 39085233 PMCID: PMC11291933 DOI: 10.1038/s41522-024-00538-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 07/22/2024] [Indexed: 08/02/2024] Open
Abstract
The clinical course of COVID-19 is variable and often unpredictable. To test the hypothesis that disease progression and inflammatory responses associate with alterations in the microbiome and metabolome, we analyzed metagenome, metabolome, cytokine, and transcriptome profiles of repeated samples from hospitalized COVID-19 patients and uninfected controls, and leveraged clinical information and post-hoc confounder analysis. Severe COVID-19 was associated with a depletion of beneficial intestinal microbes, whereas oropharyngeal microbiota disturbance was mainly linked to antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine and reduced levels of several other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Moreover, reduced concentrations of various tryptophan metabolites were associated with depletion of Faecalibacterium, and tryptophan decrease and kynurenine increase were linked to enhanced production of inflammatory cytokines. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.
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Affiliation(s)
- Morgan Essex
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Belén Millet Pascual-Leone
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ulrike Löber
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Mathias Kuhring
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité, BIH Metabolomics Platform, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité, Core Unit Bioinformatics, Berlin, Germany
| | - Bowen Zhang
- Department of Computational Biology for Individualized Infection Medicine, Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz-Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, joint ventures between the Helmholtz Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- College of Life Sciences, Beijing Normal University, Beijing, China
| | - Ulrike Brüning
- Berlin Institute of Health (BIH) at Charité, BIH Metabolomics Platform, Berlin, Germany
| | | | - Marta Krzanowski
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Facundo Fiocca Vernengo
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sophia Brumhard
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ivo Röwekamp
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Agata Anna Bielecka
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
| | - Till Robin Lesker
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
| | - Emanuel Wyler
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Markus Landthaler
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Christian Meisel
- Labor Berlin-Charité Vivantes GmbH, Berlin, Germany
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sandra Caesar
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Charlotte Thibeault
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Victor M Corman
- Labor Berlin-Charité Vivantes GmbH, Berlin, Germany
- Institute of Virology, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Infection Research (DZIF), Berlin, Germany
| | - Lajos Marko
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
| | - Norbert Suttorp
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Lung Research (DZL), Berlin, Germany
| | - Till Strowig
- Department of Computational Biology for Individualized Infection Medicine, Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz-Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- Department of Microbial Immune Regulation, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany
| | - Florian Kurth
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Leif E Sander
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Lung Research (DZL), Berlin, Germany
| | - Yang Li
- Department of Computational Biology for Individualized Infection Medicine, Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz-Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, joint ventures between the Helmholtz Center for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Jennifer A Kirwan
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité, BIH Metabolomics Platform, Berlin, Germany
- University of Nottingham School of Veterinary Medicine and Science, Loughborough, UK
| | - Sofia K Forslund
- Experimental and Clinical Research Center (ECRC), a cooperation of the Max Delbrück Center and Charité-Universitätsmedizin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Bastian Opitz
- Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité-Universitätsmedizin Berlin, a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- Labor Berlin-Charité Vivantes GmbH, Berlin, Germany.
- German Center for Lung Research (DZL), Berlin, Germany.
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50
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Tsuge M, Ichihara E, Hasegawa K, Kudo K, Tanimoto Y, Nouso K, Oda N, Mitsumune S, Kimura G, Yamada H, Takata I, Mitsuhashi T, Taniguchi A, Tsukahara K, Aokage T, Hagiya H, Toyooka S, Tsukahara H, Maeda Y. Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients. Int J Mol Sci 2024; 25:8370. [PMID: 39125944 PMCID: PMC11313210 DOI: 10.3390/ijms25158370] [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: 07/03/2024] [Revised: 07/28/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
This study investigated the correlation between oxidative stress and blood amino acids associated with nitric oxide metabolism in adult patients with coronavirus disease (COVID-19) pneumonia. Clinical data and serum samples were prospectively collected from 100 adult patients hospitalized for COVID-19 between July 2020 and August 2021. Patients with COVID-19 were categorized into three groups for analysis based on lung infiltrates, oxygen inhalation upon admission, and the initiation of oxygen therapy after admission. Blood data, oxidative stress-related biomarkers, and serum amino acid levels upon admission were compared in these groups. Patients with lung infiltrations requiring oxygen therapy upon admission or starting oxygen post-admission exhibited higher serum levels of hydroperoxides and lower levels of citrulline compared to the control group. No remarkable differences were observed in nitrite/nitrate, asymmetric dimethylarginine, and arginine levels. Serum citrulline levels correlated significantly with serum lactate dehydrogenase and C-reactive protein levels. A significant negative correlation was found between serum levels of citrulline and hydroperoxides. Levels of hydroperoxides decreased, and citrulline levels increased during the recovery period compared to admission. Patients with COVID-19 with extensive pneumonia or poor oxygenation showed increased oxidative stress and reduced citrulline levels in the blood compared to those with fewer pulmonary complications. These findings suggest that combined oxidative stress and abnormal citrulline metabolism may play a role in the pathogenesis of COVID-19 pneumonia.
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Affiliation(s)
- Mitsuru Tsuge
- Department of Pediatrics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan;
| | - Eiki Ichihara
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan; (E.I.); (A.T.)
| | - Kou Hasegawa
- Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (K.H.); (H.H.)
| | - Kenichiro Kudo
- Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center, Okayama 701-1192, Japan; (K.K.); (S.M.)
| | - Yasushi Tanimoto
- Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center, Okayama 701-0304, Japan; (Y.T.); (G.K.)
| | - Kazuhiro Nouso
- Department of Gastroenterology, Okayama City Hospital, Okayama 700-0962, Japan;
| | - Naohiro Oda
- Department of Internal Medicine, Fukuyama City Hospital, Fukuyama 721-0971, Japan; (N.O.); (I.T.)
| | - Sho Mitsumune
- Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center, Okayama 701-1192, Japan; (K.K.); (S.M.)
| | - Goro Kimura
- Department of Allergy and Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center, Okayama 701-0304, Japan; (Y.T.); (G.K.)
| | - Haruto Yamada
- Department of Infectious Disease, Okayama City Hospital, Okayama 700-0962, Japan;
| | - Ichiro Takata
- Department of Internal Medicine, Fukuyama City Hospital, Fukuyama 721-0971, Japan; (N.O.); (I.T.)
| | - Toshiharu Mitsuhashi
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan;
| | - Akihiko Taniguchi
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan; (E.I.); (A.T.)
| | - Kohei Tsukahara
- Department of Emergency, Critical Care and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (K.T.); (T.A.)
| | - Toshiyuki Aokage
- Department of Emergency, Critical Care and Disaster Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (K.T.); (T.A.)
| | - Hideharu Hagiya
- Department of General Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; (K.H.); (H.H.)
| | - Shinichi Toyooka
- Department of General Thoracic Surgery and Breast and Endocrine Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan;
| | - Hirokazu Tsukahara
- Department of Pediatrics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan;
| | - Yoshinobu Maeda
- Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan;
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