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Braverman EL, Mognol GP, Minn AJ, Vignali DAA, Varner JA. One Step Ahead: Preventing Tumor Adaptation to Immune Therapy. Am Soc Clin Oncol Educ Book 2025; 45:e481556. [PMID: 40334183 DOI: 10.1200/edbk-25-481556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.
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Affiliation(s)
- Erica L Braverman
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Giuliana P Mognol
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
| | - Andy J Minn
- Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA
| | - Judith A Varner
- Moores Cancer Center, University of California, San Diego, La Jolla, CA
- Department of Pathology, University of California, San Diego, La Jolla, CA
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Presicce P, Morselli M, Jeong A, Altendahl M, Martinez G, Del Vecchio G, Devaskar SU, Pellegrini M, Afshar Y, Kallapur SG. Placental Privilege: Evidence of organ resilience in severe COVID-19 in pregnancy. Placenta 2025:S0143-4004(25)00156-0. [PMID: 40383676 DOI: 10.1016/j.placenta.2025.05.003] [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: 12/18/2024] [Revised: 03/27/2025] [Accepted: 05/08/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND COVID-19 infection in pregnancy is associated with preterm birth and an increased risk of severe disease, needing intensive care admission for management of maternal multi-organ failure. The placenta, a fetal organ, functions as a barrier at the maternal interface and expresses the SARS-CoV-2 viral receptors. However, placental infection and transplacental transfer of virus are rare, suggesting placental resistance to viral infection. Here, we seek to determine the impact of severe COVID-19 infection on maternal, newborn, and placental outcomes. METHODS A prospectively recruited cohort of pregnant COVID-19 patients (n = 204) at a quaternary perinatal academic center were retrospectively analyzed. During pregnancy umbilical artery (UA) Doppler assessment was performed to assess placental function. At delivery, maternal and fetal outcomes were assessed, with paired maternal peripheral blood and placenta samples collected (n = 26) for bulk RNA sequencing (RNA-seq). Post-sequencing analysis with single cell deconvolution and pathway analysis was performed. RESULTS Maternally-indicated preterm births were more frequent in severe, but not asymptomatic or mild/moderate COVID-19 infection. In severe COVID-19 infection, UA Doppler assessment was normal. Rates of fetal growth restriction and placenta:birth weight ratios were similar between groups. RNA-seq showed a distinct adaptive immune activation signature in peripheral blood while placental transcripts showed no significant changes in immune cell types. CONCLUSION Despite multi-organ failure, severe COVID-19 did not significantly impact placental function and transcriptomics with iatrogenic preterm birth indicated for maternal-indications.
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Affiliation(s)
- Pietro Presicce
- Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
| | - Marco Morselli
- Department of Chemistry, Life Sciences and Environmental Sustainability (S.C.V.S.A.), University of Parma, Parma, Italy
| | - Anhyo Jeong
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
| | - Marie Altendahl
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
| | - Guadalupe Martinez
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
| | - Giorgia Del Vecchio
- Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
| | - Sherin U Devaskar
- Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology Medicine at the University of California Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences - Collaboratory at the University of California Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, USA
| | - Yalda Afshar
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, USA
| | - Suhas G Kallapur
- Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA.
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Hakimi P, Zaboli KA, Golbabapour‐Samakoush M, Azizimohammadi S, Soleimani F, Salmani MH, Teimoori‐Toolabi L. HLA Polymorphisms and COVID-19 Susceptibility and Severity: Insights From an Iranian Patients Cohort. J Cell Mol Med 2025; 29:e70570. [PMID: 40366340 PMCID: PMC12077277 DOI: 10.1111/jcmm.70570] [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: 11/26/2024] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 05/15/2025] Open
Abstract
The HLA system is a crucial immune response component against infectious agents, including SARS-CoV-2. Certain polymorphisms may impart varying levels of protection or vulnerability to COVID-19. This research aims to understand the possible relationship between HLA polymorphisms and the susceptibility to COVID-19 and its severity. We recruited 290 hospitalised Iranian COVID-19 patients (130 severe and 160 moderate). Using PCR-SSP methods, we conducted a detailed analysis of polymorphisms in HLA class I (HLA-A, HLA-B, and HLA-C) and II (HLA-DRB1 and HLA-DQB1) molecules at low resolution. The study found that certain HLA alleles, including HLA-B*49, HLA-B*52, HLA-C*12, HLA-DRB1*04, and HLA-DQB1*05, were associated with disease susceptibility. Additionally, HLA-A*23, DRB1*10, and DRB1*13 were indicators of disease severity. The study also noted that individuals carrying the HLA-A*23 allele showed a significant decrease in lymphocyte levels and an elevated likelihood of developing thrombosis. We hypothesise that a maladaptive immune response may occur based on these findings. This might be due to the strong affinity of the HLA-A*23 allele group for presenting a wide range of SARS-CoV-2 peptides. Such a presentation possibly leads to a cytokine storm, followed by lymphocyte apoptosis and an increase in platelet count.
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Affiliation(s)
- Pooria Hakimi
- Molecular Medicine Department, Biotechnology Research CenterPasteur Institute of IranTehranIran
| | - Kasra Arbabi Zaboli
- Molecular Medicine Department, Biotechnology Research CenterPasteur Institute of IranTehranIran
| | | | | | - Fatemeh Soleimani
- Molecular Medicine Department, Biotechnology Research CenterPasteur Institute of IranTehranIran
| | | | - Ladan Teimoori‐Toolabi
- Molecular Medicine Department, Biotechnology Research CenterPasteur Institute of IranTehranIran
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Liu H, Ramirez BM, Wong TS, Weiss CM, Lloyd KCK, Gong Q, Coffey LL. Severe Acute Respiratory Syndrome Coronavirus 2 Variant Infection Dynamics and Pathogenesis in Transgenic K18-h ACE2 and Inbred Immunocompetent C57BL/6J Mice. Viruses 2025; 17:500. [PMID: 40284943 PMCID: PMC12031173 DOI: 10.3390/v17040500] [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: 01/20/2025] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
The global impact of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), persists in part due to the emergence of new variants. Understanding variant-specific infection dynamics and pathogenesis in murine models is crucial for identifying phenotypic changes and guiding the development of countermeasures. To address the limitations of earlier studies that investigated only a few variants or used small sample sizes, we evaluated clinical disease, infection kinetics, viral titers, cellular localization, and histopathologic changes in the lungs and brains of transgenic B6.Cg-Tg(K18-ACE2)2Prlmn/J ("K18") and corresponding genetic control (C57BL/6J) mice expressing human angiotensin-converting enzyme 2 (hACE2). Six SARS-CoV-2 variants were assessed: B.1 (WA1-like), alpha, beta, delta, omicron, and omicron XBB.1.5, using cohorts of ≥18 mice. Following intranasal inoculation with B.1, alpha, beta, or delta variants, K18 mice experienced rapid weight loss and reached euthanasia criteria by 5-6 days post-inoculation (dpi). In contrast, K18 mice inoculated with both omicron variants recovered to their starting weight within 4-6 dpi. Infectious SARS-CoV-2 was detected in the oropharynx at 1 and2 dpi, in the lungs at 2, 4, and 6 dpi, and in the brain at 4 and 6 dpi for all variants except omicron. SARS-CoV-2 nucleoprotein was detected, and interstitial pneumonia of varying severity was observed in K18 mice infected with all variants. Brain lesions were identified in mice infected with the B.1, beta, and delta variants 6 dpi. As K18 mice express hACE2 in the brain-a feature not present in humans-we also compared infection dynamics of three variants to those of a mouse-adapted WA1 strain in C57BL/6J mice lacking the human ACE2 gene. C57BL/6J mice did not experience lethal disease, exhibited milder pneumonia, and had no evidence of neuroinvasion despite similar infection kinetics to K18 mice. These findings demonstrate contrasting phenotypes across the two models and reduced tropism and pathology of omicron compared to earlier variants in both models. This comprehensive analysis of SARS-CoV-2 variants in two mouse models provides valuable insights for model and variant selection for future studies.
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Affiliation(s)
- Hongwei Liu
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Brianna M. Ramirez
- Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA 95616, USA; (B.M.R.); (Q.G.)
| | - Talia S. Wong
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Christopher M. Weiss
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Kevin C. K. Lloyd
- Mouse Biology Program, University of California, Davis, CA 95616, USA
- Department of Surgery, School of Medicine, University of California, Davis, CA 95616, USA
| | - Qizhi Gong
- Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA 95616, USA; (B.M.R.); (Q.G.)
| | - Lark L. Coffey
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
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Xin J, Xu Z, Zhang F, Sun Y, Wang X, Wu C, Zhao L. Mendelian randomization-based observational cohort study on drug targets: Impact of antihypertensive and lipid-lowering therapies on inflammatory cytokines. Medicine (Baltimore) 2025; 104:e41771. [PMID: 40068040 PMCID: PMC11903001 DOI: 10.1097/md.0000000000041771] [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: 01/17/2025] [Revised: 02/17/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
This study assesses the causal effects of antihypertensive and lipid-lowering drugs on inflammatory cytokines using a Mendelian randomization (MR) approach. We conducted a drug-targeted MR analysis using data from large-scale genome-wide association studies and eQTL datasets. SNPs near drug target genes served as instrumental variables to investigate the impact of antihypertensive (angiotensin-converting enzyme inhibitors [ACEIs], ARBs) and lipid-lowering drugs (HMGCR inhibitors, proprotein convertase subtilisin/Kexin type 9 [PCSK9] inhibitors, Niemann-Pick C1-like 1 inhibitors) on inflammatory cytokines. Sensitivity analyses, including leave-one-out and MR-Egger tests, were performed to confirm the robustness of the findings. ACEIs were associated with decreased levels of IL-1β, TNF-α, and CRP. ARBs did not show significant effects on inflammatory cytokines. HMGCR inhibitors significantly reduced MCP-1, MIP-1β, TNF-α, and IFN-γ, while PCSK9 inhibitors were linked to reductions in IL-1β and IL-6. Sensitivity analyses supported the reliability of these findings. The study demonstrated distinct anti-inflammatory effects of ACEIs, HMGCR inhibitors, and PCSK9 inhibitors. These findings support the potential use of these drugs to mitigate inflammation-related complications in patients with chronic conditions.
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Affiliation(s)
- Jiechen Xin
- Department of Critical Care Medicine, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Zhibin Xu
- Department of Organ Transplantation, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Feng Zhang
- Department of Critical Care Medicine, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Yue Sun
- Department of Critical Care Medicine, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Xiaoyan Wang
- Department of Critical Care Medicine, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Chaojun Wu
- Department of Critical Care Medicine, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Longshu Zhao
- Department of Critical Care Medicine, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
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Cao Z, Rao H, Yang W, Hu X, Kang X, Gong D, Song X, Ren Y, Peng C, Li Y, Pei J. Luteolin Mitigates Acute Lung Injury Through Immune Modulation and Antinecroptosis Effects by Targeting the BTK and FLT3 Signaling Pathways. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:5180-5193. [PMID: 39885663 DOI: 10.1021/acs.jafc.4c06704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2025]
Abstract
Overactive immune responses and lung cell damage exacerbate acute lung injury (ALI). Luteolin, a flavonoid commonly found in traditional herbs, shows potential as an anti-ALI agent in pharmacological and clinical research, although its biological mechanism is not fully understood. This study aims to investigate whether luteolin can ameliorate ALI through its immune-modulatory and antinecroptosis mechanisms. We found that luteolin significantly inhibits the cellular activity of the FLT3-dependent monocyte cell line MOLM-13 and BTK-dependent B-cell line TMD-8. Through molecular docking and HTRF detection, it was confirmed that luteolin inhibits BTK and FLT3 enzyme activity by binding to their kinase domains, with IC50 values of 0.78 and 0.35 μM, respectively. In a TNF-α-induced lung epithelial cell injury model, luteolin reduced the increased expression of IL1B, IL6, and CXCL8 mRNAs by blocking the necroptosis signal TNF-α/BTK/MLKL. Furthermore, using a Balb/c mouse ALI model with intratracheal LPS infusion (5 mg/kg), it was observed that luteolin improved lung function and pathology, regulated immune cell infiltration, and reduced cell death in pulmonary tissues by inhibiting BTK and FLT3 protein phosphorylation. In conclusion, luteolin acts as a natural BTK and FLT3 inhibitor, effectively preventing ALI both in vivo and in vitro through its immune-modulating and antinecroptosis properties.
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Affiliation(s)
- Zhixing Cao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Huanan Rao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wenya Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaoxue Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xin Kang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Daoyin Gong
- Department of Pathology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Xiaominting Song
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yali Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuzhi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jin Pei
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
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Mirzababaei A, Shiraseb F, Mohamadi A, Mehri Hajmir M, Ebrahimi S, Zarrinvafa Z, Kazemian E, Mehrvar A, Mirzaei K. The association between nutrient patterns and hospital stay duration and symptoms in COVID-19 in Iranian patients: cross-sectional study. Front Nutr 2025; 12:1542449. [PMID: 40098737 PMCID: PMC11911187 DOI: 10.3389/fnut.2025.1542449] [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: 12/09/2024] [Accepted: 02/07/2025] [Indexed: 03/19/2025] Open
Abstract
Background An excessively reactive immune system results in the cytokine storm COVID-19. A healthy diet is essential to maintain the balance between the immune system and inflammatory and oxidative stress. Associations between single foods and nutrients and COVID-19 have been examined. However, no prior study has examined associations between nutrient patterns and COVID-19. This study assessed the link between nutrient patterns and the COVID-19 severity and length of hospital stay in Iranian adults. Methods This cross-sectional study included 107 Iranian adults aged 20-60 years, who were admitted to Amir Alam Hospital in Tehran, Iran, due to COVID-19. Data on their symptoms were collected through a demographic questionnaire and verified against their hospital records. Three non-consecutive 24-h dietary recalls were used to collect participants' food and beverage intake. Principal component analysis (PCA) was used to derive nutrient patterns. Result A total of 95 Covid patients with a mean age of 46.2 years were included. Four major dietary patterns were identified using the Scree Plot chart, including high carbohydrate and high minerals pattern; high protein and high vitamins pattern; high fat pattern; and poor nutrient pattern. Adherence to the poor nutrient patterns was associated with a higher number of hospitalization days and lower appetite (p < 0.05). The poor dietary patterns were associated with an increased likelihood of headache, fever, and respiratory distress syndrome (RDS). Also, headaches were more common with adherence to the high-fat pattern (p < 0.05). Conclusion The findings of this study show that a poor nutrient pattern is related to longer hospital stays and reduced appetite. It also connected to an increased likelihood of symptoms including headaches, fever, and respiratory distress syndrome. A strong association was found between respiratory distress syndrome, headaches, and a high-fat diet was found. Further studies with prospective designs are needed to better understand and validate these findings.
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Affiliation(s)
- Atieh Mirzababaei
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Shiraseb
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Mohamadi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
- Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahya Mehri Hajmir
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, The George Washington University, Washington, DC, United States
| | - Sara Ebrahimi
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, VIC, Australia
| | - Zeinab Zarrinvafa
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Elham Kazemian
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Amir Mehrvar
- Department of Orthopedics, Taleghani Hospital Research Development Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
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Chakraborty C, Bhattacharya M, Das A, Saha A. Regulation of miRNA in Cytokine Storm (CS) of COVID-19 and Other Viral Infection: An Exhaustive Review. Rev Med Virol 2025; 35:e70026. [PMID: 40032584 DOI: 10.1002/rmv.70026] [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: 10/12/2024] [Revised: 01/29/2025] [Accepted: 02/18/2025] [Indexed: 03/05/2025]
Abstract
In the initial stage of the COVID-19 pandemic, high case fatality was noted. The case fatality during this was associated with the cytokine storm (CS) or cytokine storm syndrome (CSS). Sometimes, virus infections are due to the excessive secretion of pro-inflammatory cytokines, leading to cytokine storms, which might be directed to ARDS, multi-organ failure, and death. However, it was noted that several miRNAs are involved in regulating cytokines during SARS-CoV-2 and other viruses such as IFNs, ILs, GM-CSF, TNF, etc. The article spotlighted several miRNAs involved in regulating cytokines associated with the cytokine storm caused by SARS-CoV-2 and other viruses (influenza virus, MERS-CoV, SARS-CoV, dengue virus). Targeting those miRNAs might help in the discovery of novel therapeutics, considering CS or CSS associated with different virus infections.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
| | | | - Arpita Das
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
| | - Abinit Saha
- Deparment of Zoology, J.K. College, Purulia, India
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Hinojosa-Gutiérrez LR, González-Sánchez AL, Rios-Muñoz JA, Aguilar-Guerrero R, Macías-Cervantes HE. Visceral fat as the main tomographic risk factor for COVID-19 mortality. Heart Lung 2025; 70:191-196. [PMID: 39705967 DOI: 10.1016/j.hrtlng.2024.12.005] [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: 09/18/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Obesity is a risk factor for COVID-19 mortality; a BMI >35 increases the risk of death up to 12-fold; two previous studies have examined the association between visceral fat quantified by tomography and the risk of severe COVID-19, but not its association with mortality. OBJECTIVE Examine whether tomographic findings differentiated data from patients who died of COVID-19 pneumonia from those who survived in a cohort of patients at a tertiary hospital. METHODS This was a case-control study (1:1) in which we recruited data from patients at a tertiary care hospital in Mexico. Cases (N = 213) were data from patients with COVID-19 pneumonia discharged due to death, and controls (N = 216) were data from patients discharged due to improvement. All had chest computed tomography (CT) scans in the Picture Archiving and Communication System (PACS) platform. Multivariate analysis was used to identify tomographic variables associated with mortality, and odds ratios were calculated. As tomographic variables, we refer to the total severity score, the total percentage of pulmonary involvement, the pattern of involvement, the location of the lesions, and subcutaneous and visceral fat. RESULTS A total of 429 sets of data from Mexican patients were analyzed, with an overall age of 57 years (18-93). Sixty-three percent were male, and arterial hypertension was the most common comorbidity in 48.3 %. An odds ratio (OR) of 8.79 (95 % CI 1.44-53.73) was found for visceral fat and mortality; the rest of the tomographic variables did not show a statistically significant association. CONCLUSION Visceral fat was the most significant tomographic risk factor for mortality in patients with COVID-19 pneumonia.
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Affiliation(s)
- Luis Ricardo Hinojosa-Gutiérrez
- Radiology Physician, Radiology Departament, Unidad Medica de Alta Especialidad, Hospital de Especialidades No 1, Centro Médico Nacional del Bajío, Boulevard Adolfo López Mateos esquina Insurgentes S/N, Colonia Los Paraísos, CP 37260, León, Guanajuato, Mexico.
| | - Adriana Lizbeth González-Sánchez
- Radiology Physician, Radiology Departament, Unidad Medica de Alta Especialidad, Hospital de Especialidades No 1, Centro Médico Nacional del Bajío, Boulevard Adolfo López Mateos esquina Insurgentes S/N, Colonia Los Paraísos, CP 37260, León, Guanajuato, Mexico.
| | - Jair Antonio Rios-Muñoz
- Radiology Physician, Radiology Departament, Unidad Medica de Alta Especialidad, Hospital de Especialidades No 1, Centro Médico Nacional del Bajío, Boulevard Adolfo López Mateos esquina Insurgentes S/N, Colonia Los Paraísos, CP 37260, León, Guanajuato, Mexico.
| | - Rodolfo Aguilar-Guerrero
- Internal Medicina Physician, Internal Medicine Department, Unidad Medica de Alta Especialidad, Hospital de Especialidades No 1, Centro Médico Nacional del Bajío, Boulevard Adolfo López Mateos esquina Insurgentes S/N, Colonia Los Paraísos, CP 37260, León, Guanajuato, Mexico.
| | - Hilda Elizabeth Macías-Cervantes
- Internal Medicina Physician, Internal Medicine Department, Unidad Medica de Alta Especialidad, Hospital de Especialidades No 1, Centro Médico Nacional del Bajío, Boulevard Adolfo López Mateos esquina Insurgentes S/N, Colonia Los Paraísos, CP 37260, León, Guanajuato, Mexico.
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Shivshankar P, Mueller-Ortiz SL, Domozhirov AY, Bi W, Collum SD, Doursout MF, Patel M, LeFebvre IN, Akkanti B, Yau S, Huang HJ, Hussain R, Karmouty-Quintana H. Complement activity and autophagy are dysregulated in the lungs of patients with nonresolvable COVID-19 requiring lung transplantation. Respir Res 2025; 26:68. [PMID: 40016722 PMCID: PMC11866606 DOI: 10.1186/s12931-025-03152-6] [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: 09/16/2024] [Accepted: 02/11/2025] [Indexed: 03/01/2025] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) pandemic has challenged the current understanding of the complement cascade mechanisms of host immune responses during infection-induced nonresolvable lung disease. While the complement system is involved in opsonization and phagocytosis of the invading pathogens, uncontrolled complement activation also leads to aberrant autophagic response and tissue damage. Our recent study revealed unique pathologic and fibrotic signature genes associated with epithelial bronchiolization in the lung tissues of patients with nonresolvable COVID-19 (NR-COVID-19) requiring lung transplantation. However, there is a knowledge gap if complement components are modulated to contribute to tissue damage and the fibrotic phenotype during NR-COVID-19. We, therefore, aimed to study the role of the complement factors and their corresponding regulatory proteins in the pathogenesis of NR-COVID-19. We further examined the association of complement components with mediators of the host autophagic response. We observed significant upregulation of the expression of the classical pathway factor C1qrs and alternative complement factors C3 and C5a, as well as the anaphylatoxin receptor C5aR1, in NR-COVID-19 lung tissues. Of note, complement regulatory protein, decay accelerating factor (DAF; CD55) was significantly downregulated at both transcript and protein levels in the NR-COVID-19 lungs, indicating a dampened host protective response. Furthermore, we observed significantly decreased levels of the autophagy mediators PPARγ and LC3a/b, which was corroborated by decreased expression of factor P and the C3b receptor CR1, indicating impaired clearance of damaged cells that may contribute to the fibrotic phenotype in NR-COVID-19 patients. Thus, our study revealed previously unrecognized complement dysregulation associated with impaired cell death and clearance of damaged cells, which may promote NR-COVID-19 in patients, ultimately necessitating lung transplantation. The identified network of dysregulated complement cascade activity indicates the interplay of regulatory factors and the receptor-mediated modulation of host immune and autophagic responses as potential therapeutic targets for treating NR-COVID-19.
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Affiliation(s)
- Pooja Shivshankar
- Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX, USA.
- Hans J. Müller-Eberhard and Irma Gigli Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX, USA.
- Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, UTHealth-McGovern Medical School, 1825 Pressler Street, #407-07, Houston, TX, 77030, USA.
| | - Stacey L Mueller-Ortiz
- Hans J. Müller-Eberhard and Irma Gigli Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX, USA
| | - Aleksey Y Domozhirov
- Hans J. Müller-Eberhard and Irma Gigli Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, UTHealth-McGovern Medical School, Houston, TX, USA
| | - Weizhen Bi
- Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Scott D Collum
- Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX, USA
| | | | - Manish Patel
- Center for Advanced Cardiopulmonary Therapies and Transplantation at UTHealth/McGovern Medical School, Houston, TX, USA
| | - Isabella N LeFebvre
- Center for Advanced Cardiopulmonary Therapies and Transplantation at UTHealth/McGovern Medical School, Houston, TX, USA
| | - Bindu Akkanti
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Suite 6.214, Houston, TX, 77030, USA
| | - Simon Yau
- Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston, TX, USA
| | - Howard J Huang
- Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston, TX, USA
| | - Rahat Hussain
- Center for Advanced Cardiopulmonary Therapies and Transplantation at UTHealth/McGovern Medical School, Houston, TX, USA
| | - Harry Karmouty-Quintana
- Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX, USA.
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Suite 6.214, Houston, TX, 77030, USA.
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11
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Yang Q, Guo H, Li H, Li Z, Ni F, Wen Z, Liu K, Kong H, Wei W. The CXCL8/MAPK/hnRNP-K axis enables susceptibility to infection by EV-D68, rhinovirus, and influenza virus in vitro. Nat Commun 2025; 16:1715. [PMID: 39962077 PMCID: PMC11832783 DOI: 10.1038/s41467-025-57094-0] [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: 03/06/2024] [Accepted: 02/11/2025] [Indexed: 02/20/2025] Open
Abstract
Respiratory viruses pose an ongoing threat to human health with excessive cytokine secretion contributing to severe illness and mortality. However, the relationship between cytokine secretion and viral infection remains poorly understood. Here we elucidate the role of CXCL8 as an early response gene to EV-D68 infection. Silencing CXCL8 or its receptors, CXCR1/2, impedes EV-D68 replication in vitro. Upon recognition of CXCL8 by CXCR1/2, the MAPK pathway is activated, facilitating the translocation of nuclear hnRNP-K to the cytoplasm. This translocation increases the recognition of viral RNA by hnRNP-K in the cytoplasm, promoting the function of the 5' untranslated region in the viral genome. Moreover, our investigations also reveal the importance of the CXCL8 signaling pathway in the replication of both influenza virus and rhinovirus. In summary, our findings hint that these viruses exploit the CXCL8/MAPK/hnRNP-K axis to enhance viral replication in respiratory cells in vitro.
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Affiliation(s)
- Qingran Yang
- Department of Respiration, Children's Medical Center, First Hospital, Jilin University, Changchun, Jilin, China
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Haoran Guo
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Huili Li
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Zhaoxue Li
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Fushun Ni
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Zhongmei Wen
- Center for Pathogen Biology and Infectious Diseases, Department of Respiratory Medicine, First Hospital, Jilin University, Changchun, Jilin, China
| | - Kai Liu
- Department of Chemistry, Tsinghua University, Beijing, China
| | - Huihui Kong
- Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, China
| | - Wei Wei
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China.
- Cancer Center, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, First Hospital, Jilin University, Changchun, Jilin, China.
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12
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Mo J, Deng Q, Huang Y, Jia X, Xie F, Zhou B, Gao H, Wu Y, Yuan J. Study on the Optimization of an Extraction Process of Two Triterpenoid Saponins in the Root of Rosa laevigata Michx. and Their Protective Effect on Acute Lung Injury. Pharmaceuticals (Basel) 2025; 18:253. [PMID: 40006066 PMCID: PMC11859398 DOI: 10.3390/ph18020253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/24/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Objectives: Kajiichigoside F1 and rosamultin are natural triterpenoid saponins found in the root of Rosa laevigata Michx. These compounds are isomers, making their separation challenging. Nonetheless, they have been reported to exhibit significant anti-inflammatory activity, although their mechanism of action remains unclear. This study aimed to optimize the extraction process of echinacoside and rosamultin from R. laevigata and to elucidate the anti-inflammatory mechanisms of these saponins in an LPS-induced acute lung injury (ALI) model. Methods: The extraction process was optimized using a single-factor experiment and the Box-Behnken response surface methodology, with the content of kajiichigoside F1, rosamultin, and their total content serving as evaluation indices. The acute lung injury model was induced by LPS, and lung tissue damage was assessed through hematoxylin and eosin (HE) staining. The secretion of relevant inflammatory factors was quantified using enzyme-linked immunosorbent assay (ELISA), and the expression levels of associated proteins were analyzed via Western blotting. Results: The optimal extraction conditions were determined to be an ethanol volume fraction of 80.0%, a solid-liquid ratio of 1:25, an extraction duration of 80 min, and three extraction cycles. Kajiichigoside F1 and rosamultin were found to mitigate alveolar inflammation in mice with acute lung injury (ALI) by effectively reducing the expression of the pro-inflammatory cytokines TNF-α and IL-6. Additionally, these compounds down-regulated the expression of phosphorylated NF-κB p65 and NF-κB IκBα proteins, thereby alleviating inflammatory symptoms. Conclusions: Kajiichigoside F1 and rosamultin attenuate the inflammatory response in acute lung injury induced by lipopolysaccharide (LPS) stimulation through modulation of the NF-κB signaling pathway. This study preliminarily elucidates their anti-inflammatory mechanism, suggesting that both compounds possess therapeutic potential for ALI. These findings provide significant guidance for the future development of active components derived from the root of R. laevigata and establish a foundation for enhancing the quality standards of its medicinal materials.
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Affiliation(s)
- Jingya Mo
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
| | - Qiaoyu Deng
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
| | - Yuanyuan Huang
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
| | - Xuegong Jia
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
| | - Fengfeng Xie
- Guangxi Key Laboratory of Zhuangyao Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China;
| | - Bei Zhou
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
| | - Hongwei Gao
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
| | - Yanchun Wu
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
| | - Jingquan Yuan
- Zhuangyao Medical Research Institute of Traditional Chinese Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China; (J.M.); (Q.D.); (Y.H.); (X.J.); (B.Z.)
- Guangxi Key Laboratory of Zhuangyao Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530200, China;
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13
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Jermakow N, Brodaczewska K, Kot J, Lubas A, Kłos K, Siewiera J. Bayesian Modeling of the Impact of HBOT on the Reduction in Cytokine Storms. J Clin Med 2025; 14:1180. [PMID: 40004710 PMCID: PMC11856955 DOI: 10.3390/jcm14041180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/29/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Since the initial identification of SARS-CoV-2 infections, numerous clinical challenges have arisen, revealing both acute and long-term effects associated with COVID-19. These effects impact various systems within the body, including the respiratory, cardiovascular, and nervous systems. Background/Objectives: This study aimed to investigate the immunological and inflammatory parameters in patients with severe COVID-19 and evaluate the effects of hyperbaric oxygen therapy (HBOT) on these parameters. Methods: This study enrolled thirty patients from the Military Medical Institute-National Research Institute in Warsaw, who were hospitalized for SARS-CoV-2 infection. Patients were screened for eligibility based on pre-defined inclusion criteria. The subjects were randomly assigned to one of two groups: hyperbaric oxygen therapy (HBOT) or a control group. Immune profiling was performed, measuring cytokine concentrations and leukocyte subpopulations in serum samples. Outcomes were assessed using Bayesian modeling. Results: Bayesian regression analysis confirmed previous findings, indicating that HBOT may reduce inflammatory cytokine levels while improving oxygen saturation (SpO2) in patients with moderate and severe COVID-19. Moreover, the analysis suggested a higher probability of HBOT success in modulating the immune response and reducing inflammatory parameters, particularly in T lymphocyte subpopulations. Conclusions: Hyperbaric oxygen therapy (HBOT) may serve as an effective adjunctive treatment for patients with COVID-19 by enhancing oxygen saturation and modulating the immune response. Further studies are needed to elucidate the underlying mechanisms of HBOT on inflammatory and immunological parameters in COVID-19 patients.
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Affiliation(s)
- Natalia Jermakow
- Department of Hyperbaric Medicine, Military Institute of Medicine, National Science Institute, Szaserów 128, 04-141 Warsaw, Poland;
| | - Klaudia Brodaczewska
- The Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, National Science Institute, Szaserów 128, 04-141 Warsaw, Poland;
| | - Jacek Kot
- National Centre for Hyperbaric Medicine, Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Powstania Styczniowego 9B, 81-519 Gdynia, Poland;
| | - Arkadiusz Lubas
- Department of Internal Diseases Nephrology and Dialysis, Military Institute of Medicine, National Science Institute, Szaserów 128, 04-141 Warsaw, Poland;
| | - Krzysztof Kłos
- Department of Infectious Diseases and Allergology, Military Institute of Medicine, National Science Institute, Szaserów 128, 04-141 Warsaw, Poland;
| | - Jacek Siewiera
- Department of Hyperbaric Medicine, Military Institute of Medicine, National Science Institute, Szaserów 128, 04-141 Warsaw, Poland;
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14
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Su E, Song X, Wei L, Xue J, Cheng X, Xie S, Jiang H, Liu M. Endothelial GSDMD underlies LPS-induced systemic vascular injury and lethality. JCI Insight 2025; 10:e182398. [PMID: 39927458 PMCID: PMC11948583 DOI: 10.1172/jci.insight.182398] [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: 04/25/2024] [Accepted: 12/17/2024] [Indexed: 02/11/2025] Open
Abstract
Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.
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Affiliation(s)
- Enyong Su
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoyue Song
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Lili Wei
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Cardiology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Shanghai, China
| | - Junqiang Xue
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Xuelin Cheng
- Department of Health Management Center, Zhongshan Hospital, and
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shiyao Xie
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hong Jiang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai, China
| | - Ming Liu
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Health Management Center, Zhongshan Hospital, and
- Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai, China
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15
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Moharram FA, Ibrahim RR, Mahgoub S, Abdel-Aziz MS, Said AM, Huang HC, Chen LY, Lai KH, Hashad N, Mady MS. Secondary metabolites of Alternaria alternate appraisal of their SARS-CoV-2 inhibitory and anti-inflammatory potentials. PLoS One 2025; 20:e0313616. [PMID: 39854441 PMCID: PMC11760621 DOI: 10.1371/journal.pone.0313616] [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: 09/05/2024] [Accepted: 10/28/2024] [Indexed: 01/26/2025] Open
Abstract
This study identifies the secondary metabolites from Alternaria alternate and evaluates their ACE-2: Spike RBD (SARS-CoV-2) inhibitory activity confirmed via immunoblotting in human lung microvascular endothelial cells. In addition, their in vitro anti-inflammatory potential was assessed using a cell-based assay in LPS-treated RAW 264.7 macrophage cells. Two novel compounds, altenuline (1), phthalic acid bis (7'/7'' pentyloxy) isohexyl ester (2), along with 1-deoxyrubralactone (3) alternariol-5-O-methyl ether (4) and alternariol (5) were identified. Molecular docking and in vitro studies showed that compounds 2 and 4 were promising to counteract SARS-CoV-2 attachment to human ACE-2. Thus, they are considered promising natural anti-viral agents. SwissADME in silico analysis was conducted to predict the drug-like potential. Immunoblotting analysis confirmed that the tested compounds (1-4) demonstrated downregulation of ACE-2 expression in the endothelial cells from the lungs with variable degrees. Furthermore, the tested compounds (1-4) showed promising anti-inflammatory activities through TNF-α: TNFR2 inhibitory activity and their inhibitory effect on the proinflammatory cytokines (TNF-α and IL-6) in LPS-stimulated monocytes. In conclusion, our study, for the first time, provides beneficial experimental confirmation for the efficiency of the A. alternate secondary metabolites for the treatment of COVID-19 as they hinder SARS-CoV-2 infection and lower inflammatory responses initiated by SARS-CoV-2. A. alternate and its metabolites are considered in developing preventative and therapeutic tactics for COVID-19.
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Affiliation(s)
- Fatma A. Moharram
- Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Reham R. Ibrahim
- Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Shahenda Mahgoub
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Mohamed S. Abdel-Aziz
- Genetic Engineering and Biotechnology Division, Microbial Chemistry Department, National Research Centre, Giza, Egypt
| | - Ahmed M. Said
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Hui-Chi Huang
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Lo-Yun Chen
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Kuei-Hung Lai
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- PhD Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Nashwa Hashad
- Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Mohamed S. Mady
- Department of Pharmacognosy, Faculty of Pharmacy, Helwan University, Cairo, Egypt
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16
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Roe K. Lethal Synergistic Infections by Two Concurrent Respiratory Pathogens. Arch Med Res 2025; 56:103101. [PMID: 39454459 DOI: 10.1016/j.arcmed.2024.103101] [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: 06/19/2024] [Revised: 09/08/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024]
Abstract
Lethal synergistic infections by concurrent pathogens have occurred in humans, including human immunodeficiency virus and Mycobacterium tuberculosis infections, or in animal or human models of influenza virus, or bacteria, e.g., Streptococcus pneumoniae, concurrent with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the intracellular synergistic interaction possibilities between two respiratory viral pathogens, or between viral and fungal pathogens, merits additional examination. The requirements for synergistic concurrent pathogen infections are: a) relatively little detrimental interference between two pathogens, b) one pathogen having the capability of directly or indirectly assisting the second pathogen by direct immuno-manipulation or indirect provision of infection opportunities and/or metabolic assistance, c) substantial human or environmental prevalence, possibly including a prevalence in any type of health-care facilities or other locations having congregations of potentially infected human or animal vectors and d) substantial transmissibility of the pathogens, which would make their concurrent pathogen infections much more probable. A new definition of pathogen synergy is proposed: "pathogen synergy is an interaction of two or more pathogens during concurrent infections causing an increased infection severity compared to mono-infections by the individual pathogens." Non-respiratory pathogens can also concurrently infect organs besides the lungs. However, the air-transmissible respiratory pathogens, particularly the RNA viruses, can enable highly widespread and synergistic concurrent infections. For instance, certain strains of coronaviruses, influenza viruses and similar respiratory viruses, are highly transmissible and/or widely prevalent in various vectors for transmission to humans and have numerous capabilities for altering lung immune defenses.
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Affiliation(s)
- Kevin Roe
- Retired, United States Patent and Trademark Office, San Jose, CA, USA.
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17
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Wang Z, Liu J, Mou Y, Li Y, Liao W, Yao M, Wang T, Shen H, Sun Q, Tang J. Extinguishing the flames of inflammation: retardant effect of chlorquinaldol on NLRP3-driven diseases. Mol Med 2024; 30:245. [PMID: 39701924 DOI: 10.1186/s10020-024-01016-1] [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: 05/05/2023] [Accepted: 11/26/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND NLRP3 inflammasome immoderate activation results in the occurrence of various inflammatory diseases, but the clinic medications targeting NLRP3 inflammasome are still not available currently. The strategy of drug repurposing can reorient the direction of therapy, which is an indispensable method of drug research. In this study, an antimicrobial agent chlorquinaldol (CQ) was conducted to assess the effect on NLRP3 inflammasome and novel clinical value on NLRP3-driven diseases. METHODS The effect of CQ on NLRP3 inflammasome activation and pyroptosis was studied in mouse and human macrophages. ASC oligomerization, intracellular potassium, reactive oxygen species production, and NLRP3-ASC interaction were used to evaluate the suppression mechanism of CQ on inflammasome activation. Finally, the ameliorative effects of CQ in the model of LPS-induced peritonitis, dextran sodium sulfate (DSS)-induced colitis, and monosodium urate (MSU)-induced gouty arthritis were evaluated in vivo. RESULTS CQ is a highly powerful NLRP3 inhibitor that has feeble impact on the NLRC4 or AIM2 inflammasome activation in mouse and human macrophages. Further study indicated that CQ exhibits its suppression effect on NLRP3 inflammasome by blocking NLRP3-ASC interaction and hydroxyl on the benzene ring is vital for the assembly and activation of NLRP3 inflammasome. Furthermore, in vivo experiments demonstrated that administration of CQ has outstanding therapeutic action on LPS-induced peritonitis, DSS-induced colitis, and MSU-induced gouty inflammation in mice. CONCLUSIONS Collectively, the current study discoveries the antimicrobial agent CQ as a potentially specific NLRP3 inhibitor, and its use provides a feasible therapeutic approach for the treatment of NLRP3-driven diseases.
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Affiliation(s)
- Zhilei Wang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
| | - Jingwen Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Yu Mou
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Yuchen Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Wenhao Liao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Menglin Yao
- National Traditional Chinese Medicine Clinical Research Base of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Ting Wang
- National Traditional Chinese Medicine Clinical Research Base of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Hongping Shen
- National Traditional Chinese Medicine Clinical Research Base of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Qin Sun
- National Traditional Chinese Medicine Clinical Research Base of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Jianyuan Tang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
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Gasparello J, Papi C, Marzaro G, Macone A, Zurlo M, Finotti A, Agostinelli E, Gambari R. Aged Garlic Extract (AGE) and Its Constituent S-Allyl-Cysteine (SAC) Inhibit the Expression of Pro-Inflammatory Genes Induced in Bronchial Epithelial IB3-1 Cells by Exposure to the SARS-CoV-2 Spike Protein and the BNT162b2 Vaccine. Molecules 2024; 29:5938. [PMID: 39770027 PMCID: PMC11677098 DOI: 10.3390/molecules29245938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/07/2024] [Accepted: 12/11/2024] [Indexed: 01/05/2025] Open
Abstract
Garlic (Allium sativum L.) is a species of the onion family (Alliaceae) widely used as a food and a folk medicine. The objective of this study was to determine the effects of AGE (aged garlic extract) on pro-inflammatory genes relevant to COVID-19. To this aim, we treated bronchial epithelial IB3-1 cells with SARS-CoV-2 spike protein (S-protein) or with the COVID-19 BNT162b2 vaccine in the absence or in the presence of AGE. The results obtained demonstrated that AGE is a potent inhibitor of the S-protein-induced expression of the IL-1β, IL-6 and IL-8 genes. Bio-Plex analysis demonstrated that AGE reduced release of IL-6 and IL-8, which were highly induced by S-protein. No inhibition of cells' growth, toxicity and pro-apoptotic effects were found in AGE-treated cells. The effects of one of the major AGE constituents (S-allyl cysteine, SAC) were studied on the same experimental model systems. SAC was able to inhibit the S-protein-induced expression of IL-1β, IL-6 and IL-8 genes and extracellular release of IL-6 and IL-8, confirming that S-allyl-cysteine is one of the constituents of AGE that is responsible for inhibiting S-protein-induced pro-inflammatory genes. Docking experiments suggest that a possible mechanism of action of SAC is an interference with the activity of Toll-like receptors (TLRs), particularly TLR4, thereby inhibiting NF-κB- and NF-κB-regulated genes, such as IL-1β, IL-6 and IL-8 genes. These results suggest that both AGE and SAC deserve further experimental efforts to verify their effects on pro-inflammatory genes in SARS-CoV-2-infected cells.
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Affiliation(s)
- Jessica Gasparello
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (A.F.)
| | - Chiara Papi
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (A.F.)
| | - Giovanni Marzaro
- Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy;
| | - Alberto Macone
- Department of Biochemical Sciences ‘A. Rossi Fanelli’, Sapienza University of Rome, 00185 Rome, Italy;
| | - Matteo Zurlo
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (A.F.)
| | - Alessia Finotti
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (A.F.)
| | - Enzo Agostinelli
- Department of Sensory Organs, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy
- International Polyamines Foundation ‘ETS-ONLUS’, Via del Forte Tiburtino 98, 00159 Rome, Italy
| | - Roberto Gambari
- Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (A.F.)
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19
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George Pryzdial EL, Perrier JR, Rashid MU, West HE, Sutherland MR. Viral coagulation: pushing the envelope. J Thromb Haemost 2024; 22:3366-3382. [PMID: 39260743 DOI: 10.1016/j.jtha.2024.08.014] [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: 02/27/2024] [Revised: 07/11/2024] [Accepted: 08/19/2024] [Indexed: 09/13/2024]
Abstract
Many virus types affect the blood clotting system with correlations to pathology that range widely from thrombosis to hemorrhage linking to inflammation. Here we overview the intricate crosstalk induced by infection between proteins on the virus encoded by either the host or virus genomes, coagulation proteins, platelets, leukocytes, and endothelial cells. For blood-borne viruses with an outer covering acquired from the host cell, the envelope, a key player may be the cell-derived trigger of coagulation on the virus surface, tissue factor (TF). TF is a multifunctional transmembrane cofactor that accelerates factor (F)VIIa-dependent activation of FX to FXa, leading to clot formation. However, the nascent TF/FVIIa/FXa complex also facilitates G protein-coupled modulation of cells via protease-activated receptor 2. As a viral envelope constituent, TF can bypass the physiological modes of regulation, thereby initiating the activation of neighboring platelets, leukocytes, and endothelial cells. A thromboinflammatory environment is predicted due to feedback amplification in response to cellular release of cytokines, procoagulant proteins, neutrophil extracellular traps, and stimulus-induced accessibility of adhesive receptors, resulting in cellular aggregates. The pathobiological effects of thromboinflammation ultimately contribute to innate and adaptive immunity for viral clearance. In contrast, the preceding stages of viral infection may be enhanced via the TF-protease axis.
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Affiliation(s)
- Edward Louis George Pryzdial
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada.
| | - John Ruggles Perrier
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Mahamud-Ur Rashid
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Henry Euan West
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Michael Ross Sutherland
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
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20
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Navacchia ML, Cinti C, Marchesi E, Perrone D. Insights into SARS-CoV-2: Small-Molecule Hybrids for COVID-19 Treatment. Molecules 2024; 29:5403. [PMID: 39598790 PMCID: PMC11596935 DOI: 10.3390/molecules29225403] [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: 10/18/2024] [Revised: 11/08/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
The advantages of a treatment modality that combines two or more therapeutic agents with different mechanisms of action encourage the study of hybrid functional compounds for pharmacological applications. Molecular hybridization, resulting from a covalent combination of two or more pharmacophore units, has emerged as a promising approach to overcome several issues and has also been explored for the design of new drugs for COVID-19 treatment. In this review, we presented an overview of small-molecule hybrids from both natural products and synthetic sources reported in the literature to date with potential antiviral anti-SARS-CoV-2 activity.
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Affiliation(s)
- Maria Luisa Navacchia
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), 40129 Bologna, Italy;
| | - Caterina Cinti
- Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), 40129 Bologna, Italy;
| | - Elena Marchesi
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Daniela Perrone
- Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy
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21
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Carolin A, Yan K, Bishop CR, Tang B, Nguyen W, Rawle DJ, Suhrbier A. Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice. PLoS One 2024; 19:e0302344. [PMID: 39531435 PMCID: PMC11556745 DOI: 10.1371/journal.pone.0302344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in severe disease, often characterised by a 'cytokine storm' and the associated acute respiratory distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout the course of infection. Although blood biomarkers of severe disease are well studied, less well understood are the inflammatory signatures in lung tissues associated with mild disease or silent infections, wherein infection and inflammation are rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq and histological analyses of lungs over time in an omicron BA.1/K18-hACE2 mouse infection model, which displays these latter features. Although robust infection was evident at 2 days post infection (dpi), viral RNA was largely cleared by 10 dpi. Acute inflammatory signatures showed a slightly different pattern of cytokine signatures compared with severe infection models, and where much diminished 30 dpi and absent by 66 dpi. Cellular deconvolution identified significantly increased abundance scores for a number of anti-inflammatory pro-resolution cell types at 5/10 dpi. These included type II innate lymphoid cells, T regulatory cells, and interstitial macrophages. Genes whose expression trended downwards over 2-66 dpi included biomarkers of severe disease and were associated with 'cytokine storm' pathways. Genes whose expression trended upward during this period were associated with recovery of ciliated cells, AT2 to AT1 transition, reticular fibroblasts and innate lymphoid cells, indicating a return to homeostasis. Very few differentially expressed host genes were identified at 66 dpi, suggesting near complete recovery. The parallels between mild or subclinical infections in humans and those observed in this BA.1/K18-hACE2 mouse model are discussed with reference to the concept of "protective inflammation".
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Affiliation(s)
- Agnes Carolin
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Kexin Yan
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Cameron R. Bishop
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Bing Tang
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Wilson Nguyen
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Daniel J. Rawle
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Andreas Suhrbier
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- GVN Centre of Excellence, Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia
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22
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Yan HW, Feng YD, Tang N, Cao FC, Lei YF, Cao W, Li XQ. Viral myocarditis: From molecular mechanisms to therapeutic prospects. Eur J Pharmacol 2024; 982:176935. [PMID: 39182550 DOI: 10.1016/j.ejphar.2024.176935] [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: 06/19/2024] [Revised: 08/10/2024] [Accepted: 08/22/2024] [Indexed: 08/27/2024]
Abstract
Myocarditis is characterized as local or diffuse inflammatory lesions in the myocardium, primarily caused by viruses and other infections. It is a common cause of sudden cardiac death and dilated cardiomyopathy. In recent years, the global prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the widespread vaccination have coincided with a notable increase in the number of reported cases of myocarditis. In light of the potential threat that myocarditis poses to global public health, numerous studies have sought to elucidate the pathogenesis of this condition. However, despite these efforts, effective treatment strategies remain elusive. To collate the current research advances in myocarditis, and thereby provide possible directions for further research, this review summarizes the mechanisms involved in viral invasion of the organism and primarily focuses on how viruses trigger excessive inflammatory responses and in result in different types of cell death. Furthermore, this article outlines existing therapeutic approaches and potential therapeutic targets for the acute phase of myocarditis. In particular, immunomodulatory treatments are emphasized and suggested as the most extensively studied and clinically promising therapeutic options.
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Affiliation(s)
- Han-Wei Yan
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China.
| | - Ying-Da Feng
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China.
| | - Na Tang
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China.
| | - Feng-Chuan Cao
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China.
| | - Ying-Feng Lei
- Department of Microbiology, Air Force Medical University, Xi'an, Shaanxi, 710032, China.
| | - Wei Cao
- Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China; Department of Pharmacy, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Xiao-Qiang Li
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, Shaanxi, 710032, China.
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23
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Hu Z, Wang W, Lin Y, Guo H, Chen Y, Wang J, Yu F, Rao L, Fan Z. Extracellular Vesicle-Inspired Therapeutic Strategies for the COVID-19. Adv Healthc Mater 2024; 13:e2402103. [PMID: 38923772 DOI: 10.1002/adhm.202402103] [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] [Indexed: 06/28/2024]
Abstract
Emerging infectious diseases like coronavirus pneumonia (COVID-19) present significant challenges to global health, extensively affecting both human society and the economy. Extracellular vesicles (EVs) have demonstrated remarkable potential as crucial biomedical tools for COVID-19 diagnosis and treatment. However, due to limitations in the performance and titer of natural vesicles, their clinical use remains limited. Nonetheless, EV-inspired strategies are gaining increasing attention. Notably, biomimetic vesicles, inspired by EVs, possess specific receptors that can act as "Trojan horses," preventing the virus from infecting host cells. Genetic engineering can enhance these vesicles by enabling them to carry more receptors, significantly increasing their specificity for absorbing the novel coronavirus. Additionally, biomimetic vesicles inherit numerous cytokine receptors from parent cells, allowing them to effectively mitigate the "cytokine storm" by adsorbing pro-inflammatory cytokines. Overall, this EV-inspired strategy offers new avenues for the treatment of emerging infectious diseases. Herein, this review systematically summarizes the current applications of EV-inspired strategies in the diagnosis and treatment of COVID-19. The current status and challenges associated with the clinical implementation of EV-inspired strategies are also discussed. The goal of this review is to provide new insights into the design of EV-inspired strategies and expand their application in combating emerging infectious diseases.
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Affiliation(s)
- Ziwei Hu
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Wei Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Ying Lin
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Hui Guo
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, P. R. China
| | - Yiwen Chen
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Junjie Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Feng Yu
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Lang Rao
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, P. R. China
| | - Zhijin Fan
- Institute for Engineering Medicine, Kunming Medical University, Kunming, 650500, P. R. China
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24
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McCubbin S, Meade A, Harrison DA, Cooper RL. Acute lipopolysaccharide (LPS)-induced cell membrane hyperpolarization is independent of voltage gated and calcium activated potassium channels. Comp Biochem Physiol C Toxicol Pharmacol 2024; 285:110004. [PMID: 39154976 DOI: 10.1016/j.cbpc.2024.110004] [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: 06/13/2024] [Revised: 07/29/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
The gram-negative toxin lipopolysaccharides (LPS) are known to trigger inflammatory cytokines in mammals, which can result in pathological responses. Upon treatment of bacterial sepsis with antibiotics, the lysing bacteria can present a surge in LPS, inducing a cytokine storm. However, LPS can also have direct cellular effects, including transient rapid hyperpolarizing of the membrane potential, blocking glutamate receptors and even promoting release of glutamate. The detailed mechanism of action for these immediate responses is still unresolved. In addressing the membrane hyperpolarization, voltage gated K+ channel blockers 4-aminopyridine (4-AP, 3 mM), quinidine hydrochloride monohydrate (0.1 mM) and tetraethylammonium (TEA, 20 mM) were examined along with RNAi knockdowns of potential calcium activated K+ channels. The immediate responses of LPS were not blocked. Even in the presence of glutamate, the membrane still hyperpolarizes with LPS. When the driving gradient for the ionotropic glutamate receptors is enhanced during hyperpolarization, spontaneous quantal responses are dampened in amplitude. Thus, glutamate receptors are blocked, and the mechanism of hyperpolarization remains unresolved. The larval Drosophila glutamatergic neuromuscular junction is used as a model synaptic preparation to address the direct rapid actions by LPS.
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Affiliation(s)
- Shelby McCubbin
- Department of Biology, University of Kentucky, Lexington, KY 40506-0025, USA.
| | - Alexis Meade
- Department of Biology, University of Kentucky, Lexington, KY 40506-0025, USA.
| | - Douglas A Harrison
- Department of Biology, University of Kentucky, Lexington, KY 40506-0025, USA.
| | - Robin L Cooper
- Department of Biology, University of Kentucky, Lexington, KY 40506-0025, USA.
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25
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Günter M, Mueller KAL, Salazar MJ, Gekeler S, Prang C, Harm T, Gawaz MP, Autenrieth SE. Immune signature of patients with cardiovascular disease predicts increased risk for a severe course of COVID-19. Eur J Immunol 2024; 54:e2451145. [PMID: 39094122 DOI: 10.1002/eji.202451145] [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: 03/15/2024] [Revised: 07/16/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024]
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can lead to life-threatening clinical manifestations. Patients with cardiovascular disease (CVD) are at higher risk for severe courses of COVID-19. So far, however, there are hardly any strategies for predicting the course of SARS-CoV-2 infection in CVD patients at hospital admission. Thus, we investigated whether this prediction is achievable by prospectively analysing the blood immunophenotype of 94 nonvaccinated participants, including uninfected and acutely SARS-CoV-2-infected CVD patients and healthy donors, using a 36-colour spectral flow cytometry panel. Unsupervised data analysis revealed little differences between healthy donors and CVD patients, whereas the distribution of the cell populations changed dramatically in SARS-CoV-2-infected CVD patients. The latter had more mature NK cells, activated monocyte subsets, central memory CD4+ T cells, and plasmablasts but fewer dendritic cells, CD16+ monocytes, innate lymphoid cells, and CD8+ T-cell subsets. Moreover, we identified an immune signature characterised by CD161+ T cells, intermediate effector CD8+ T cells, and natural killer T (NKT) cells that is predictive for CVD patients with a severe course of COVID-19. Thus, intensified immunophenotype analyses can help identify patients at risk of severe COVID-19 at hospital admission, improving clinical outcomes through specific treatment.
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Affiliation(s)
- Manina Günter
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
- German Cancer Research Centre, Research Group Dendritic Cells in Infection and Cancer, Heidelberg, Germany
| | - Karin Anne Lydia Mueller
- Department of Cardiology and Angiology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Mathew J Salazar
- German Cancer Research Centre, Research Group Dendritic Cells in Infection and Cancer, Heidelberg, Germany
| | - Sarah Gekeler
- Department of Cardiology and Angiology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Carolin Prang
- Department of Cardiology and Angiology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Tobias Harm
- Department of Cardiology and Angiology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Meinrad Paul Gawaz
- Department of Cardiology and Angiology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Stella E Autenrieth
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Eberhard Karls University Tuebingen, Tuebingen, Germany
- German Cancer Research Centre, Research Group Dendritic Cells in Infection and Cancer, Heidelberg, Germany
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26
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Azadinejad H, Feizollahi P, Rezaeimanesh A, Salari F, Gorgin Karaji A. Relationship Between IL-10 Single Nucleotide Polymorphisms (rs1800871, rs1800872, and rs1800896) and the Severity of COVID-19. Genet Test Mol Biomarkers 2024; 28:438-444. [PMID: 39253838 DOI: 10.1089/gtmb.2024.0276] [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: 09/11/2024] Open
Abstract
Background: Interleukin-10 (IL-10) is an anti-inflammatory cytokine whose levels are elevated in patients with severe COVID-19. IL-10 polymorphisms may play a role in increasing IL-10 levels and the severity of COVID-19. This study aimed to investigate the relationship between IL-10 single nucleotide polymorphisms (SNPs) (rs1800896 [-1082 C < T], rs1800871 [-819 A > G], and rs1800872 [-592 T > G]) and the severity of COVID-19 in patients from Kermanshah Province, Iran. Methods: A total of 150 patients with mild COVID-19 (84 men and 66 women aged 40.1 ± 12.44 years) and 143 patients with severe COVID-19 (76 men and 67 women aged 61.04 ± 15.65 years) participated in this study. Blood samples were collected from the patients, DNA was extracted, and the genotype of each SNPs was determined using the polymerase chain reaction-restriction fragment length polymorphism method. Result: The results of this study did not show a significant relationship between the genotypes of the three studied SNPs and the severity of COVID-19 (p > 0.05). Conclusion: According to our findings, these SNPs were not associated with COVID-19 severity in patients in Kermanshah.
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Affiliation(s)
- Hossein Azadinejad
- Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parisa Feizollahi
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Immunology, School of Medicine, Tarbiat Modares University of Medical Science, Tehran, Iran
| | - Alireza Rezaeimanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farhad Salari
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Gorgin Karaji
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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27
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Li C, He H, Wang Y, Huang L, Chen Z, Zhang Q, Cai Y, Zhai T, Wu X, Zhan Q. Outcomes and inflammation changes in different types of immunocompromised patients with critically ill COVID-19 admitted to ICU: a national multicenter study. BMC Pulm Med 2024; 24:548. [PMID: 39482633 PMCID: PMC11529014 DOI: 10.1186/s12890-024-03362-6] [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: 07/25/2024] [Accepted: 10/22/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Immunocompromised patients face higher risks of Severe Acute Respiratory Syndrome Coronavirus 2 infection and co-infections, leading to a possibility of high disease severity and poor outcomes. Conversely, immunosuppression can mitigate the excessive inflammatory response induced by the virus, potentially reducing disease severity. This study aims to investigate the prognostic differences and early inflammatory response characteristics in various types of immunocompromised patients with severe coronavirus disease 2019 (COVID-19) admitted to intensive care unit (ICU), summarize their clinical features, and explore potential mechanisms. METHODS A retrospective analysis was conducted on critically ill COVID-19 patients admitted to the ICU of 59 medical centers in mainland China during the Omicron outbreak from November 2022 to February 2023. Patients were categorized into two groups based on their immunosuppression status: immunocompromised and immunocompetent. Immunocompromised patients were further subdivided by etiology into cancer patients, solid organ transplant (SOT) patients, and other immunocompromised groups, with immunocompetent patients serving as controls. The mortality rates, respiratory support, complications, and early inflammatory cytokine dynamics upon ICU admission among different populations were analyzed. RESULTS A total of 2030 critically ill COVID-19 patients admitted to ICU were included, with 242 in the immunocompromised group and 1788 in the immunocompetent group. Cancer patients had a higher median age of 69 years (IQR 59, 77), while SOT patients were generally younger and had less severe illness upon ICU admission, with a median APACHE II score of 12.0 (IQR 8.0, 20.0). Cancer patients had a twofold increased risk of death (OR = 2.02, 95% CI 1.18-3.46, P = 0.010) compared to immunocompetent patients. SOT and cancer patients exhibited higher C-reactive protein and serum ferritin levels than the immunocompetent group in their early days of ICU admission. The CD8+ T cells dynamics were inversely correlated in cancer and SOT patients, with Interleukin-6 levels consistently lower in the SOT group compared to both immunocompetent and cancer patients. CONCLUSION Critically ill COVID-19 patients admitted to the ICU exhibit distinct clinical outcomes based on their immunosuppression status, with cancer patients facing the highest mortality rate due to variations in inflammatory responses linked to their immunosuppression mechanisms. Monitoring dynamic changes in inflammatory markers and immune cells, particularly CD8+ T lymphocytes and IL-6, may offer valuable prognostic insights for these patients.
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Affiliation(s)
- Chunyan Li
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Hangyong He
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Yuqiong Wang
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship School of Clinical Medicine, Peking University, Beijing, China
| | - Linna Huang
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ziying Chen
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship School of Clinical Medicine, Peking University, Beijing, China
| | - Qi Zhang
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Ying Cai
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Tianshu Zhai
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xiaojing Wu
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China.
| | - Qingyuan Zhan
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China.
- National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, Chinese Academy of Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
- China-Japan Friendship School of Clinical Medicine, Peking University, Beijing, China.
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Yoo JW, Kim WY, Chung CR, Cho YJ, Lee J, Jegal Y, Kim J, Joh JS, Park TY, Baek AR, Park JH, Chae G, Hwang JH, Song JW. Early pulmonary fibrosis-like changes between delta and pre-delta periods in patients with severe COVID-19 pneumonia on mechanical ventilation. Sci Rep 2024; 14:26101. [PMID: 39478105 PMCID: PMC11525473 DOI: 10.1038/s41598-024-77405-7] [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: 02/13/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
It remains unclear whether pulmonary fibrosis-like changes differ in patients with different SARS-CoV-2 variants. This study aimed to compare pulmonary fibrotic changes between two SARS-CoV-2 variant periods (delta vs. pre-delta) in critically ill patients with SARS-CoV-2 pneumonia. Clinical data and chest CT images of patients with SARS-CoV-2 pneumonia receiving mechanical ventilation were collected from 10 hospitals in South Korea over two periods: delta (July-December, 2021; n = 64) and pre-delta (February, 2020-June, 2021; n = 120). Fibrotic changes on chest CT were evaluated through visual assessment. Of 184 patients, the mean age was 64.6 years, and 60.5% were ale. Fibrosis-like changes on chest CT (median 51 days from enrollment to follow up CT scan, interquartile range 27-76 days) were identified in 75.3%. Delta group showed more fibrosis-like changes (≥ 2) (69.8% vs. 43.1%, P = 0.001) and more frequent reticulation and architectural distortion+/-parenchymal band than pre-delta group. Even after propensity score matching with clinical variables, delta group had more severe (≥ 2) fibrosis-like changes (71.4% vs. 38.8%, P = 0.001), and more frequent reticulation and architectural distortion+/-parenchymal band than pre-delta group. Our data suggest that critically ill patients with SARS-CoV-2 in delta period had more severe pulmonary fibrosis-like changes than those in pre-delta period.
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Affiliation(s)
- Jung-Wan Yoo
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - Won-Young Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Chi Ryang Chung
- Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Young-Jae Cho
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jinwoo Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yangjin Jegal
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Junghyun Kim
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Republic of Korea
| | - Joon-Sung Joh
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, National Medical Center, Seoul, Republic of Korea
| | - Tae Yun Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Ae-Rin Baek
- Division of Allergy and Pulmonology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea
| | - Joo Hun Park
- Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Ganghee Chae
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Jung Hwa Hwang
- Department of Radiology, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Jin Woo Song
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu 05505, Seoul, Republic of Korea.
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Sayan M, Altinisik HB, Sayan O. Neutrophil-platelet ratio as a predictor of acute kidney injury in severe COVID-19. Medicine (Baltimore) 2024; 103:e40053. [PMID: 39465828 PMCID: PMC11479445 DOI: 10.1097/md.0000000000040053] [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: 02/02/2024] [Accepted: 06/18/2024] [Indexed: 10/29/2024] Open
Abstract
Acute kidney injury (AKI) is one of the most seen complications of coronavirus-2019 (COVID-19) infection. Patients with AKI caused by COVID-19 likely have higher neutrophil counts and lower platelet and lymphocyte levels. Therefore, the predictive value of many inflammation indexes calculated from the total blood count has been investigated to predict the AKI in COVID-19. According to our clinical experience, we thought that neutrophilia and thrombocytopenia may be more common in the development of AKI. For this reason, this study aimed to evaluate the predictive value of the neutrophil-to-platelet ratio (NPR) for AKI in severe COVID-19 patients. This retrospective study included 334 severe COVID-19 patients followed up in the intensive care unit (ICU). Predictive factors for AKI were analyzed. ROC curve analysis was performed to determine the inflammation indexes' cutoff values for the AKI prediction. Multivariate analyses were performed to determine correlations between the inflammation indexes and AKI. In this study, AKI was determined at the rate of 43% (n:145). Independent risk factors affecting AKI were determined to be age (HR = 1.047, 95% confidence interval [CI]: 1.021-1.072, P < .001), the need for invasive mechanical ventilation (HR = 3.003, 95% CI: 1.645-5.481, P = .001) and the need for vasopressor (HR = 8.111, 95% CI: 3.786-17.375, P < .001). The optimal cutoff values predicting AKI were determined to be 3.9 for the NPR (AUC = 0.679, 95% CI: 0.622-0.737, P < .001) with 71.7% sensitivity and 61.9% specificity, 16.1 for the neutrophil-to-lymphocyte ratio (NLR) (AUC = 0.634, 95% CI: 0.575-0.694, P < .001) with 65.5% sensitivity and 56.1% specificity, and 3872.5 × 109L for the systemic inflammatory index (SII) (AUC = 0.566, 95% CI: 0.504-0.629, P = .038) with 60% sensitivity and 55.6% specificity. In the regression model, only NPR values above the cutoff were related to AKI (HR = 3.817, 95% CI: 1.782-8.177, P = .001). The NPR has more predictive value than the NLPR, NLR, and SII in developing AKI in severe COVID-19 patients in the ICU. NPR is a new helpful index that can help clinicians predict early AKI in critical COVID-19.
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Affiliation(s)
- Mihrican Sayan
- Department of Anesthesiology and Reanimation, Lapseki State Hospital, Canakkale, Turkey
| | | | - Ozan Sayan
- Department of Anesthesiology and Reanimation, Canakkale Onsekiz Mart University, Canakkale, Turkey
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30
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Xu R, Xia C, He X, Hu C, Li Y, Zhang Y, Chen Z. siRNA Nanoparticle Dry Powder Formulation with High Transfection Efficiency and Pulmonary Deposition for Acute Lung Injury Treatment. ACS APPLIED MATERIALS & INTERFACES 2024; 16:54344-54358. [PMID: 39325628 DOI: 10.1021/acsami.4c04241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
Abstract
Acute lung injury (ALI) is a severe inflammatory syndrome, which was caused by diverse factors. The COVID-19 pandemic has resulted in a higher mortality rate of these conditions. Currently, effective treatments are lacking. Although siRNA nucleotide-based drugs are promising therapeutic approaches, their poor stability and inability to efficiently reach target cells limit their clinical translation. This study identified a peptide from known cell-penetrating peptides that can form an efficient anti-inflammatory complex with TNF-α siRNA, termed SAR6EW/TNF-α siRNA. This complex can effectively transport TNF-α siRNA into the cytoplasm and achieve potent gene silencing in vitro as well as in vivo. By using lactose and triarginine as coexcipients and optimizing the spray-drying process, a powder was produced with micrometer-scale spherical and porous structures, enhancing aerosol release and lung delivery efficiency. The dry powder formulation and process preserve the stability and integrity of the siRNA. When administered intratracheally to ALI model mice, the complex powder demonstrated specific pulmonary gene silencing activity and significantly reduced inflammation symptoms caused by ALI, suggesting a potential strategy for the clinical therapeutic approach of respiratory diseases.
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Affiliation(s)
- Rui Xu
- College of pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Chenjie Xia
- College of pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiongxiong He
- College of pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Changhui Hu
- College of pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yinjia Li
- College of pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yufeng Zhang
- Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin 214400, China
| | - Zhipeng Chen
- College of pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
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31
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Roy A, Paul I, Luharuka S, Ray S. An in-silico scaffold- hopping approach to design novel inhibitors against gp130: A potential therapeutic application in cancer and Covid-19. Mol Divers 2024; 28:3129-3151. [PMID: 37934366 DOI: 10.1007/s11030-023-10737-0] [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: 01/05/2023] [Accepted: 09/25/2023] [Indexed: 11/08/2023]
Abstract
An upregulation of the gp130-signalling cascade has been reported in multiple cancers, making gp130 an attractive target for the development of anticancer drugs. An inverted-funnel-like approach was utilised along with various structure-based drug designing strategies to discover and optimise novel potential inhibitors of gp130. The study resulted in the discovery of 2 ligands- 435 and 510, both of which exhibit a very high-binding affinity towards the gp130 D1 domain which controls cytokine recognition and interaction thus being involved in complexation. The two resulting complexes remained stable over time with the ligands maintaining a steady interaction with the target. This inference is drawn from their RMSD, Rg, SASA and RMSF analysis. We also tested the protein folding patterns based on their principal component analysis, energy of surface and landscape. The leads also displayed a more favourable ADMET profile than their parent compounds. The two lead candidates show a better therapeutic profile in comparison to the two existing drugs- bazedoxifene and raloxifene. Both these potential leads can be addressed for their activity in-vitro and can be used as a potential anti-cancer treatment as well as to combat Covid-19 related cytokine storm.
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Affiliation(s)
- Alankar Roy
- Amity Institute of Biotechnology, Amity University, Kolkata, India
| | - Ishani Paul
- Amity Institute of Biotechnology, Amity University, Kolkata, India
| | - Shreya Luharuka
- Amity Institute of Biotechnology, Amity University, Kolkata, India
| | - Sujay Ray
- Amity Institute of Biotechnology, Amity University, Kolkata, India.
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32
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Guo M, Shang S, Li M, Cai G, Li P, Chen X, Li Q. Understanding autoimmune response after SARS-CoV-2 infection and the pathogenesis/mechanisms of long COVID. MEDICAL REVIEW (2021) 2024; 4:367-383. [PMID: 39444797 PMCID: PMC11495526 DOI: 10.1515/mr-2024-0013] [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: 02/05/2024] [Accepted: 05/04/2024] [Indexed: 10/25/2024]
Abstract
COVID-19 posed a major challenge to the healthcare system and resources worldwide. The popularization of vaccines and the adoption of numerous prevention and control measures enabled the gradual end of the COVID-19 pandemic. However, successive occurrence of autoimmune diseases in patients with COVID-19 cannot be overlooked. Long COVID has been the major focus of research due to the long duration of different symptoms and the variety of systems involved. Autoimmunity may play a crucial role in the pathogenesis of long COVID. Here, we reviewed several autoimmune disorders occurring after COVID-19 infection and the pathogenesis of long COVID.
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Affiliation(s)
- Ming Guo
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Shunlai Shang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
- Department of Nephrology, China-Japan Friendship Hospital, Beijing, China
| | - Mengfei Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Ping Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
- Haihe Laboratory of CellEcosystem, China
| | - Qinggang Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China
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33
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Rawle DJ, Hugo LE, Cox AL, Devine GJ, Suhrbier A. Generating prophylactic immunity against arboviruses in vertebrates and invertebrates. Nat Rev Immunol 2024; 24:621-636. [PMID: 38570719 DOI: 10.1038/s41577-024-01016-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/29/2024] [Indexed: 04/05/2024]
Abstract
The World Health Organization recently declared a global initiative to control arboviral diseases. These are mainly caused by pathogenic flaviviruses (such as dengue, yellow fever and Zika viruses) and alphaviruses (such as chikungunya and Venezuelan equine encephalitis viruses). Vaccines represent key interventions for these viruses, with licensed human and/or veterinary vaccines being available for several members of both genera. However, a hurdle for the licensing of new vaccines is the epidemic nature of many arboviruses, which presents logistical challenges for phase III efficacy trials. Furthermore, our ability to predict or measure the post-vaccination immune responses that are sufficient for subclinical outcomes post-infection is limited. Given that arboviruses are also subject to control by the immune system of their insect vectors, several approaches are now emerging that aim to augment antiviral immunity in mosquitoes, including Wolbachia infection, transgenic mosquitoes, insect-specific viruses and paratransgenesis. In this Review, we discuss recent advances, current challenges and future prospects in exploiting both vertebrate and invertebrate immune systems for the control of flaviviral and alphaviral diseases.
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Affiliation(s)
- Daniel J Rawle
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Leon E Hugo
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Abigail L Cox
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Gregor J Devine
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- GVN Centre of Excellence, Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia
| | - Andreas Suhrbier
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- GVN Centre of Excellence, Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia.
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Liang Y, Quan X, Gu R, Meng Z, Gan H, Wu Z, Sun Y, Pan H, Han P, Liu S, Dou G. Repurposing existing drugs for the treatment ofCOVID-19/SARS-CoV-2: A review of pharmacological effects and mechanism of action. Heliyon 2024; 10:e35988. [PMID: 39247343 PMCID: PMC11379597 DOI: 10.1016/j.heliyon.2024.e35988] [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: 02/26/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 09/10/2024] Open
Abstract
Following the coronavirus disease-2019 outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an ongoing need to seek drugs that target COVID-19. First off, novel drugs have a long development cycle, high investment cost, and are high risk. Second, novel drugs must be evaluated for activity, efficacy, safety, and metabolic performance, contributing to the development cycle, investment cost, and risk. We searched the Cochrane COVID-19 Study Register (including PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and WHO COVID-19 Coronaviral Disease Global Literature to identify completed and ongoing studies as of February 20, 2024. We evaluated the pharmacological effects, in vivo and in vitro data of the 16 candidates in the paper. The difficulty of studying these candidates in clinical trials involving COVID-19 patients, dosage of repurposed drugs, etc. is discussed in detail. Ultimately, Metformin is more suitable for prophylactic administration or mildly ill patients; the combination of Oseltamivir, Tamoxifen, and Dexamethasone is suitable for moderately and severely ill patients; and more clinical trials are needed for Azvudine, Ribavirin, Colchicine, and Cepharanthine to demonstrate efficacy.
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Affiliation(s)
- Yutong Liang
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Xiaoxiao Quan
- Beijing Institute of Radiation Medicine, Beijing, China
- Scientific Experimental Center of Guangxi University of Chinese Medicine, Nanning, China
| | - Ruolan Gu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Zhiyun Meng
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Hui Gan
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Zhuona Wu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Yunbo Sun
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Huajie Pan
- General Internal Medicine Department, Jingnan Medical District, PLA General Hospital, Beijing, China
| | - Peng Han
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Shuchen Liu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Guifang Dou
- Beijing Institute of Radiation Medicine, Beijing, China
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35
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Silawal S, Gögele C, Pelikan P, Werner C, Levidou G, Mahato R, Schulze-Tanzil G. A Histological Analysis and Detection of Complement Regulatory Protein CD55 in SARS-CoV-2 Infected Lungs. Life (Basel) 2024; 14:1058. [PMID: 39337843 PMCID: PMC11432792 DOI: 10.3390/life14091058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND A complement imbalance in lung alveolar tissue can play a deteriorating role in COVID-19, leading to acute respiratory distress syndrome (ARDS). CD55 is a transmembrane glycoprotein that inhibits the activation of the complement system at the intermediate cascade level, blocking the activity of the C3 convertase. OBJECTIVE In our study, lung specimens from COVID-19 and ARDS-positive COVID+/ARDS+ patients were compared with COVID-19 and ARDS-negative COVID-/ARDS- as well as COVID-/ARDS+ patients. METHODS Histochemical staining and immunolabeling of CD55 protein were performed. RESULTS The COVID-/ARDS- specimen showed higher expression and homogeneous distribution of glycosaminoglycans as well as compactly arranged elastic and collagen fibers of the alveolar walls in comparison to ARDS-affected lungs. In addition, COVID-/ARDS- lung tissues revealed stronger and homogenously distributed CD55 expression on the alveolar walls in comparison to the disrupted COVID-/ARDS+ lung tissues. CONCLUSIONS Even though the collapse of the alveolar linings and the accumulation of cellular components in the alveolar spaces were characteristic of COVID+/ARDS+ lung tissues, evaluating CD55 expression could be relevant to understand its relation to the disease. Furthermore, targeting CD55 upregulation as a potential therapy could be an option for post-infectious complications of COVID-19 and other inflammatory lung diseases in the future.
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Affiliation(s)
- Sandeep Silawal
- Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, General Hospital Nuremberg, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany
| | - Clemens Gögele
- Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, General Hospital Nuremberg, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany
| | - Petr Pelikan
- Institute for Pathology, Paracelsus Medical University, Nuremberg, General Hospital, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany
| | - Christian Werner
- Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, General Hospital Nuremberg, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany
| | - Georgia Levidou
- Institute for Pathology, Paracelsus Medical University, Nuremberg, General Hospital, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany
| | - Raman Mahato
- Department of Emergency and Intensive Care Medicine, Klinikum Ernst von Bergmann, Charlottenstraße 72, 14467 Potsdam, Germany
| | - Gundula Schulze-Tanzil
- Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, General Hospital Nuremberg, Prof. Ernst Nathan Str. 1, 90419 Nuremberg, Germany
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36
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Aphale P, Sanap A, Sharma D, Kharat A, Kheur S, Gawade C, Somasundaram I, Bhonde R. Stem Cell Secretome Modulated by Arsenicum album 30C Ameliorates Lipopolysaccharide-induced Cytokine Storm in Blood Mononuclear Cells in vitro. HOMEOPATHY 2024; 113:132-141. [PMID: 38061387 DOI: 10.1055/s-0043-1776039] [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] [Indexed: 07/28/2024]
Abstract
BACKGROUND The therapeutic effectiveness of mesenchymal stem cells (MSCs) and their secretome can be enhanced by means of physical, chemical and biological preconditioning. Arsenicum album 30C (AA30) has been one of the leading homeopathic medicines used in prophylaxis against SARS-CoV-2 infection. AIMS This study aimed to investigate whether AA30 preconditioning could influence the growth factors and cytokine profile of the human dental pulp-derived MSC (DPD-MSC) secretome. Also, to test the efficacy of the AA30-preconditioned DPD-MSC secretome in ameliorating the lipopolysaccharide (LPS)-induced cytokine storm in human peripheral blood mononuclear cells (PBMCs) as an in-vitro cellular model. METHODS The cytotoxicity of AA30 was assessed in DPD-MSCs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Growth factors and cytokine levels in the AA30-preconditioned DPD-MSC secretome were analysed by fluorescence-activated cell sorting (FACS) analysis. The angiogenic potential of the AA30-preconditioned DPD-MSC secretome was assessed by chick yolk-sac membrane (YSM) assay. Culture medium with 0.001% ethanol was used as vehicle control. The efficacy of the AA30-preconditioned DPD-MSC secretome in ameliorating the cytokine storm was assessed in LPS pre-treated PBMCs. The mRNA and protein expression of inflammatory markers such as IL-1β, IL-6 and IL-10 were analysed by using RT-PCR and FACS analysis respectively. RESULTS AA30 did not exhibit cytotoxicity in the concentration range of 1% to 50%. Furthermore, the AA30-preconditioned DPD-MSC secretome exhibited a significant increase in the levels of angiogenic factors, such as human angiopoietin-2, EPO and PDGF-AA, and decreased levels of cytokines, such as TNF-α, CXCL-8 and IL-6. The AA30-preconditioned DPD-MSC secretome showed augmented angiogenesis compared to vehicle controls. The DPD-MSC secretome ameliorated LPS-induced mRNA and protein expression of IL-1β, IL-6 and IL-10 in PBMCs. CONCLUSION The AA30-preconditioned DPD-MSC secretome augmented angiogenesis and ameliorated the LPS-induced cytokine storm in human PBMCs in vitro. Our data demonstrate that AA30 preconditioning enhances the therapeutic potency of MSCs and their secretome.
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Affiliation(s)
- Parth Aphale
- Dr D. Y. Patil Homeopathic Medical College and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Dharmendra Sharma
- Dr D. Y. Patil Homeopathic Medical College and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Avinash Kharat
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Supriya Kheur
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Chinmay Gawade
- Dr D. Y. Patil Homeopathic Medical College and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Indumati Somasundaram
- Department of Biotechnology Engineering, Kolhapur Institute of Technology's College of Engineering, Kolhapur, India
| | - Ramesh Bhonde
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
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Liu Z, Ye Y, Ma Y, Hu B, Zhu J. Inhaled heparin: Past, present, and future. Drug Discov Today 2024; 29:104065. [PMID: 38901669 DOI: 10.1016/j.drudis.2024.104065] [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: 03/10/2024] [Revised: 05/30/2024] [Accepted: 06/13/2024] [Indexed: 06/22/2024]
Abstract
While heparin has traditionally served as a key anticoagulant in clinical practice for nearly a century, recent years have witnessed a growing interest in its role as a potent antiinflammatory and antiviral agent, as well as an anticancer agent. To address challenges with injection-based delivery, exploring patient-friendly routes such as oral and pulmonary delivery is crucial. This review specifically highlights the multiple therapeutic benefits of inhaled heparin. In summary, this review serves as a valuable source of information, providing deep insights into the diverse therapeutic advantages of inhaled heparin and its potential applications within clinical contexts.
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Affiliation(s)
- Zhewei Liu
- University of Nottingham Ningbo China, 199 Taikang East Road, Ningbo 315100, China
| | - Yuqing Ye
- University of Nottingham Ningbo China, 199 Taikang East Road, Ningbo 315100, China; University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 3K7, Canada
| | - Ying Ma
- Ningbo Inhale Pharma, 2260 Yongjiang Avenue, Ningbo National High-Tech Zone, Ningbo 315000, China; University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 3K7, Canada
| | - Binjie Hu
- University of Nottingham Ningbo China, 199 Taikang East Road, Ningbo 315100, China
| | - Jesse Zhu
- University of Nottingham Ningbo China, 199 Taikang East Road, Ningbo 315100, China; University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 3K7, Canada; Eastern Institute of Technology, 568 Tongxin Road, Ningbo 315000, China.
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Markovič R, Ternar L, Trstenjak T, Marhl M, Grubelnik V. Cardiovascular Comorbidities in COVID-19: Comprehensive Analysis of Key Topics. Interact J Med Res 2024; 13:e55699. [PMID: 39046774 PMCID: PMC11306943 DOI: 10.2196/55699] [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: 12/21/2023] [Revised: 03/22/2024] [Accepted: 05/23/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND The interrelation between COVID-19 and various cardiovascular and metabolic disorders has been a critical area of study. There is a growing need to understand how comorbidities such as cardiovascular diseases (CVDs) and metabolic disorders affect the risk and severity of COVID-19. OBJECTIVE The objective of this study is to systematically analyze the association between COVID-19 and cardiovascular and metabolic disorders. The focus is on comorbidity, examining the roles of CVDs such as embolism, thrombosis, hypertension, and heart failure, as well as metabolic disorders such as disorders of glucose and iron metabolism. METHODS Our study involved a systematic search in PubMed for literature published from 2000 to 2022. We established 2 databases: one for COVID-19-related articles and another for CVD-related articles, ensuring all were peer-reviewed. In terms of data analysis, statistical methods were applied to compare the frequency and relevance of MeSH (Medical Subject Headings) terms between the 2 databases. This involved analyzing the differences and ratios in the usage of these terms and employing statistical tests to determine their significance in relation to key CVDs within the COVID-19 research context. RESULTS The study revealed that "Cardiovascular Diseases" and "Nutritional and Metabolic Diseases" were highly relevant as level 1 Medical Subject Headings descriptors in COVID-19 comorbidity research. Detailed analysis at level 2 and level 3 showed "Vascular Disease" and "Heart Disease" as prominent descriptors under CVDs. Significantly, "Glucose Metabolism Disorders" were frequently associated with COVID-19 comorbidities such as embolism, thrombosis, and heart failure. Furthermore, iron deficiency (ID) was notably different in its occurrence between COVID-19 and CVD articles, underlining its significance in the context of COVID-19 comorbidities. Statistical analysis underscored these differences, highlighting the importance of both glucose and iron metabolism disorders in COVID-19 research. CONCLUSIONS This work lays the foundation for future research that utilizes a knowledge-based approach to elucidate the intricate relationships between these conditions, aiming to develop more effective health care strategies and interventions in the face of ongoing pandemic challenges.
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Affiliation(s)
- Rene Markovič
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
- Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor, Slovenia
| | - Luka Ternar
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Tim Trstenjak
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Marko Marhl
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Faculty of Education, University of Maribor, Maribor, Slovenia
| | - Vladimir Grubelnik
- Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor, Slovenia
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Corrao S, Raspanti M, Agugliaro F, Gervasi F, Di Bernardo F, Natoli G, Argano C. Safety of High-Dose Vitamin C in Non-Intensive Care Hospitalized Patients with COVID-19: An Open-Label Clinical Study. J Clin Med 2024; 13:3987. [PMID: 38999551 PMCID: PMC11242388 DOI: 10.3390/jcm13133987] [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: 05/11/2024] [Revised: 06/30/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024] Open
Abstract
Background: Vitamin C has been used as an antioxidant and has been proven effective in boosting immunity in different diseases, including coronavirus disease (COVID-19). An increasing awareness was directed to the role of intravenous vitamin C in COVID-19. Methods: In this study, we aimed to assess the safety of high-dose intravenous vitamin C added to the conventional regimens for patients with different stages of COVID-19. An open-label clinical trial was conducted on patients with COVID-19. One hundred four patients underwent high-dose intravenous administration of vitamin C (in addition to conventional therapy), precisely 10 g in 250 cc of saline solution in slow infusion (60 drops/min) for three consecutive days. At the same time, 42 patients took the standard-of-care therapy. Results: This study showed the safety of high-dose intravenous administration of vitamin C. No adverse reactions were found. When we evaluated the renal function indices and estimated the glomerular filtration rate (eGRF, calculated with the CKD-EPI Creatinine Equation) as the main side effect and contraindication related to chronic renal failure, no statistically significant differences between the two groups were found. High-dose vitamin C treatment was not associated with a statistically significant reduction in mortality and admission to the intensive care unit, even if the result was bound to the statistical significance. On the contrary, age was independently associated with admission to the intensive care unit and in-hospital mortality as well as noninvasive ventilation (N.I.V.) and continuous positive airway pressure (CPAP) (OR 2.17, 95% CI 1.41-3.35; OR 7.50, 95% CI 1.97-28.54; OR 8.84, 95% CI 2.62-29.88, respectively). When considering the length of hospital stay, treatment with high-dose vitamin C predicts shorter hospitalization (OR -4.95 CI -0.21--9.69). Conclusions: Our findings showed that an intravenous high dose of vitamin C is configured as a safe and promising therapy for patients with moderate to severe COVID-19.
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Affiliation(s)
- Salvatore Corrao
- Department of Internal Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; (F.A.); (G.N.); (C.A.)
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy
| | - Massimo Raspanti
- Cardiology and Intensive Care Unit, A. Aiello Hospital, 91026 Mazzara del Vallo, Italy;
| | - Federica Agugliaro
- Department of Internal Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; (F.A.); (G.N.); (C.A.)
| | - Francesco Gervasi
- Specialized Laboratory of Oncology, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy;
| | - Francesca Di Bernardo
- Department of Microbiology and Virology, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy;
| | - Giuseppe Natoli
- Department of Internal Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; (F.A.); (G.N.); (C.A.)
| | - Christiano Argano
- Department of Internal Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; (F.A.); (G.N.); (C.A.)
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Su L, Yu T, Zhang C, Huo P, Zhao Z. A prediction model for secondary invasive fungal infection among severe SARS-CoV-2 positive patients in ICU. Front Cell Infect Microbiol 2024; 14:1382720. [PMID: 39040601 PMCID: PMC11260608 DOI: 10.3389/fcimb.2024.1382720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Background The global COVID-19 pandemic has resulted in over seven million deaths, and IFI can further complicate the clinical course of COVID-19. Coinfection of COVID-19 and IFI (secondary IFI) pose significant threats not only to healthcare systems but also to patient lives. After the control measures for COVID-19 were lifted in China, we observed a substantial number of ICU patients developing COVID-19-associated IFI. This creates an urgent need for predictive assessment of COVID-19 patients in the ICU environment for early detection of suspected fungal infection cases. Methods This study is a single-center, retrospective research endeavor. We conducted a case-control study on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients. The cases consisted of patients who developed any secondary IFI during their ICU stay at Jilin University China-Japan Union Hospital in Changchun, Jilin Province, China, from December 1st, 2022, to August 31st, 2023. The control group consisted of SARS-CoV-2 positive patients without secondary IFI. Descriptive and comparative analyses were performed, and a logistic regression prediction model for secondary IFI in COVID-19 patients was established. Additionally, we observed an increased incidence of COVID-19-associated pulmonary aspergillosis (CAPA) during this pandemic. Therefore, we conducted a univariate subgroup analysis on top of IFI, using non-CAPA patients as the control subgroup. Results From multivariate analysis, the prediction model identified 6 factors that are significantly associated with IFI, including the use of broad-spectrum antibiotics for more than 2 weeks (aOR=4.14, 95% CI 2.03-8.67), fever (aOR=2.3, 95%CI 1.16-4.55), elevated log IL-6 levels (aOR=1.22, 95% CI 1.04-1.43) and prone position ventilation (aOR=2.38, 95%CI 1.15-4.97) as independent risk factors for COVID-19 secondary IFI. High BMI (BMI ≥ 28 kg/m2) (aOR=0.85, 95% CI 0.75-0.94) and the use of COVID-19 immunoglobulin (aOR=0.45, 95% CI 0.2-0.97) were identified as independent protective factors against COVID-19 secondary IFI. The Receiver Operating Curve (ROC) area under the curve (AUC) of this model was 0.81, indicating good classification. Conclusion We recommend paying special attention for the occurrence of secondary IFI in COVID-19 patients with low BMI (BMI < 28 kg/m2), elevated log IL-6 levels and fever. Additionally, during the treatment of COVID-19 patients, we emphasize the importance of minimizing the duration of broad-spectrum antibiotic use and highlight the potential of immunoglobulin application in reducing the incidence of IFI.
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Affiliation(s)
- Leilei Su
- Department of Critical Care Medicine, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Tong Yu
- Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, United States
| | - Chunmei Zhang
- Department of Critical Care Medicine, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Pengfei Huo
- Department of Critical Care Medicine, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhongyan Zhao
- Department of Critical Care Medicine, China-Japan Union Hospital of Jilin University, Changchun, China
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Peskersoy C, Oguzhan A, Akcay C, Dincturk BA, Can HS, Kamer EK, Haciyanli M. Evaluation of oral health status and immunological parameters of hospitalized COVID-19 patients during acute and recovery phases: A randomized clinical trial. J Dent Sci 2024; 19:1515-1524. [PMID: 39035327 PMCID: PMC11259628 DOI: 10.1016/j.jds.2024.01.022] [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: 01/13/2024] [Revised: 01/27/2024] [Indexed: 07/23/2024] Open
Abstract
Background/purpose It is known that COVID-19 patients show many clinical oral symptoms due to the immunological mechanisms triggered by the virus. Aim of this study is to analyze the antibody response to SARS-CoV-2, and to evaluate the oral health status of hospitalized patients. Materials and methods 160 patients with COVID-19 confirmed by SARS-CoV-2-specific RT-PCR testing and 160 healthy volunteers (HI) with similar age, gender and systemic status were included to compare the bio-chemical and oral manifestations. Oropharyngeal swab specimens were collected to evaluate the salivary interleukins (IL-1, IL-6, IL-10) and immunoglobulins (sIgA, sIgG, sIgM). Oral findings (DMFT, plaque index, salivary flow rate), socio-demographic information and systemic conditions were also recorded. Chi-square, Mann-Whitney U and Spearman's ratio tests were applied to determine the possible correlations between the factors (P = 0.05). Results The mean DMFT scores of COVID-19 patients (12.71 ± 7.3) were significantly higher than the HI (7.39 ± 2.8), whereas cases of total or partial edentulism were more common among COVID-19 patients (P < 0.05). While plaque index scores were similar for both groups (P > 0.05), salivary parameters were found statistically different (P < 0.05). Severe and moderate cases showed higher proinflammatory interleukin levels (IL-1 = 68.74 pg/ml, IL-6 = 53.31 pg/ml) amongst all (P < 0.05). While secretory immunoglobulins were almost depleted at baseline, (sIgA = 0.11 mg/ml, sIgG = 0.21 mg/ml, sIgM = 0.08 mg/ml) they reached to threshold levels after 4 weeks. Conclusion Higher proinflammatory interleukin levels indicated that traces of ongoing "Cytokine Storm" in COVID-19 patients which can also be observed in oral environment. Poor oral hygiene and malnutrition due to edentulism can pave the way for having a severe COVID-19 infection.
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Affiliation(s)
- Cem Peskersoy
- Ege University, Faculty of Dentistry, Department of Restorative Dentistry, Izmir, Turkey
| | - Aybeniz Oguzhan
- Ege University, Faculty of Dentistry, Department of Restorative Dentistry, Izmir, Turkey
| | - Cagri Akcay
- Izmir Katip Celebi University Faculty of Medicine, Department of Surgery and Infectious Diseases, Izmir, Turkey
| | - Beyza A. Dincturk
- Dokuz Eylul University, Faculty of Dentistry, Department of Restorative Dentistry, Izmir, Turkey
| | - Hulya S.E. Can
- Gazi University, Faculty of Dentistry, Department of Restorative Dentistry, Ankara, Turkey
| | - Erdinc K. Kamer
- Health Sciences University, Faculty of Medicine, Department of Surgery, Izmir, Turkey
| | - Mehmet Haciyanli
- Izmir Katip Celebi University, Faculty of Medicine, Department of Surgery, Izmir, Turkey
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Gulati N, Chellappan DK, MacLoughlin R, Gupta G, Singh SK, Oliver BG, Dua K, Dureja H. Advances in nano-based drug delivery systems for the management of cytokine influx-mediated inflammation in lung diseases. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3695-3707. [PMID: 38078921 DOI: 10.1007/s00210-023-02882-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/30/2023] [Indexed: 05/23/2024]
Abstract
Asthma, lung cancer, cystic fibrosis, tuberculosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and COVID-19 are few examples of inflammatory lung conditions that cause cytokine release syndrome. It can initiate a widespread inflammatory response and may activate several inflammatory pathways that cause multiple organ failures leading to increased number of deaths and increased prevalence rates around the world. Nanotechnology-based therapeutic modalities such as nanoparticles, liposomes, nanosuspension, monoclonal antibodies, and vaccines can be used in the effective treatment of inflammatory lung diseases at both cellular and molecular levels. This would also help significantly in the reduction of patient mortality. Therefore, nanotechnology could be a potent platform for repurposing current medications in the treatment of inflammatory lung diseases. The aim and approach of this article are to highlight the clinical manifestations of cytokine storm in inflammatory lung diseases along with the advances and potential applications of nanotechnology-based therapeutics in the management of cytokine storm. Further in-depth studies are required to understand the molecular pathophysiology, and how nanotechnology-based therapeutics can help to effectively combat this problem.
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Affiliation(s)
- Nisha Gulati
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Ronan MacLoughlin
- Research and Development, Science and Emerging Technologies, Aerogen Limited, Galway Business Park, Galway, H91 HE94, Ireland
- School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, D02YN77, Ireland
- School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin, D02 PN40, Ireland
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, India
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, Australia
| | - Brian G Oliver
- Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW, 2007, Australia
- Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, 2037, Australia
| | - Kamal Dua
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India.
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, Australia.
- Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW, 2007, Australia.
- Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, 2037, Australia.
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India.
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, Australia.
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Dinneen B, Stack J. Atypical antinuclear matrix protein 2-positive dermatomyositis presenting with anasarca and bulbar weakness after COVID-19 infection requiring mechanical ventilation. Arch Rheumatol 2024; 39:312-313. [PMID: 38933725 PMCID: PMC11196233 DOI: 10.46497/archrheumatol.2024.10520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 10/30/2023] [Indexed: 06/28/2024] Open
Affiliation(s)
- Brona Dinneen
- Department of Rheumatology, The Mater Misericordiae University Hospital, Dublin, Ireland
| | - John Stack
- Department of Rheumatology, The Mater Misericordiae University Hospital, Dublin, Ireland
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Živanović J, Baralić K, Živančević K, Božić D, Marić Đ, Miljaković EA, Đorđević AB, Ćurčić M, Bulat Z, Antonijević B, Đukić-Ćosić D. In silico analysis of the impact of toxic metals on COVID-19 complications: molecular insights. Arh Hig Rada Toksikol 2024; 75:102-109. [PMID: 38963144 PMCID: PMC11223505 DOI: 10.2478/aiht-2024-75-3819] [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: 01/01/2024] [Revised: 01/01/2024] [Accepted: 05/01/2024] [Indexed: 07/05/2024] Open
Abstract
COVID-19 can cause a range of complications, including cardiovascular, renal, and/or respiratory insufficiencies, yet little is known of its potential effects in persons exposed to toxic metals. The aim of this study was to answer this question with in silico toxicogenomic methods that can provide molecular insights into COVID-19 complications owed to exposure to arsenic, cadmium, lead, mercury, nickel, and chromium. For this purpose we relied on the Comparative Toxicogenomic Database (CTD), GeneMANIA, and ToppGene Suite portal and identified a set of five common genes (IL1B, CXCL8, IL6, IL10, TNF) for the six metals and COVID-19, all of which code for pro-inflammatory and anti-inflammatory cytokines. The list was expanded with additional 20 related genes. Physical interactions are the most common between the genes affected by the six metals (77.64 %), while the dominant interaction between the genes affected by each metal separately is co-expression (As 56.35 %, Cd 64.07 %, Pb 71.5 %, Hg 81.91 %, Ni 64.28 %, Cr 88.51 %). Biological processes, molecular functions, and pathways in which these 25 genes participate are closely related to cytokines and cytokine storm implicated in the development of COVID-19 complications. In other words, our findings confirm that exposure to toxic metals, alone or in combinations, might escalate COVID-19 severity.
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Affiliation(s)
- Jovana Živanović
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Katarina Baralić
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Katarina Živančević
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
- University of Belgrade, Faculty of Biology, Ivan Đaja Institute for Physiology and Biochemistry, Belgrade, Serbia
| | - Dragica Božić
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Đurđica Marić
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Evica Antonijević Miljaković
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Aleksandra Buha Đorđević
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Marijana Ćurčić
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Zorica Bulat
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Biljana Antonijević
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
| | - Danijela Đukić-Ćosić
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović”, Belgrade, Serbia
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Loucera-Muñecas C, Canal-Rivero M, Ruiz-Veguilla M, Carmona R, Bostelmann G, Garrido-Torres N, Dopazo J, Crespo-Facorro B. Aripiprazole as protector against COVID-19 mortality. Sci Rep 2024; 14:12362. [PMID: 38811612 PMCID: PMC11137032 DOI: 10.1038/s41598-024-60297-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 04/21/2024] [Indexed: 05/31/2024] Open
Abstract
The relation of antipsychotics with severe Coronavirus Disease 19 (COVID-19) outcomes is a matter of debate since the beginning of the pandemic. To date, controversial results have been published on this issue. We aimed to prove whether antipsychotics might exert adverse or protective effects against fatal outcomes derived from COVID-19. A population-based retrospective cohort study (January 2020 to November 2020) comprising inpatients (15,968 patients) who were at least 18 years old and had a laboratory-confirmed COVID-19 infection. Two sub-cohorts were delineated, comprising a total of 2536 inpatients: individuals who either had no prescription medication or were prescribed an antipsychotic within the 15 days preceding hospitalization. We conducted survival and odds ratio analyses to assess the association between antipsychotic use and mortality, reporting both unadjusted and covariate-adjusted results. We computed the average treatment effects, using the untreated group as the reference, and the average treatment effect on the treated, focusing solely on the antipsychotic-treated population. Among the eight antipsychotics found to be in use, only aripiprazole showed a significant decrease in the risk of death from COVID-19 [adjusted odds ratio (OR) = 0.86; 95% CI, 0.79-0.93, multiple-testing adjusted p-value < 0.05]. Importantly, these findings were consistent for both covariate-adjusted and unadjusted analyses. Aripiprazole has been shown to have a differentiated beneficial effect in protecting against fatal clinical outcome in COVID-19 infected individuals. We speculate that the differential effect of aripiprazole on controlling immunological pathways and inducible inflammatory enzymes, that are critical in COVID19 illness, may be associated with our findings herein.
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Affiliation(s)
- C Loucera-Muñecas
- Computational Medicine Platform, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain
| | - M Canal-Rivero
- Hospital Universitario Virgen del Rocío, Av. Manuel Siurot, s/n, 41013, Sevilla, Spain.
- Centro Investigación Biomédica en Red Salud Mental, CIBERSAM, Madrid, Spain.
- Instituto de Biomedicina de Sevilla (IBiS), HUVR/CSIC/Universidad de Sevilla, Seville, Spain.
| | - M Ruiz-Veguilla
- Hospital Universitario Virgen del Rocío, Av. Manuel Siurot, s/n, 41013, Sevilla, Spain
- Centro Investigación Biomédica en Red Salud Mental, CIBERSAM, Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), HUVR/CSIC/Universidad de Sevilla, Seville, Spain
- Department of Psychiatry, Universidad de Sevilla, Seville, Spain
| | - R Carmona
- Computational Medicine Platform, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain
| | - G Bostelmann
- Computational Medicine Platform, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain
| | - N Garrido-Torres
- Hospital Universitario Virgen del Rocío, Av. Manuel Siurot, s/n, 41013, Sevilla, Spain
- Centro Investigación Biomédica en Red Salud Mental, CIBERSAM, Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), HUVR/CSIC/Universidad de Sevilla, Seville, Spain
| | - J Dopazo
- Computational Medicine Platform, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Seville, Spain
- FPS, ELIXIR-Es, Hospital Virgen del Rocío, Seville, Spain
| | - B Crespo-Facorro
- Hospital Universitario Virgen del Rocío, Av. Manuel Siurot, s/n, 41013, Sevilla, Spain
- Centro Investigación Biomédica en Red Salud Mental, CIBERSAM, Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), HUVR/CSIC/Universidad de Sevilla, Seville, Spain
- Department of Psychiatry, Universidad de Sevilla, Seville, Spain
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Zhao G, Gentile ME, Xue L, Cosgriff CV, Weiner AI, Adams-Tzivelekidis S, Wong J, Li X, Kass-Gergi S, Holcomb NP, Basal MC, Stewart KM, Planer JD, Cantu E, Christie JD, Crespo MM, Mitchell MJ, Meyer NJ, Vaughan AE. Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation. Nat Commun 2024; 15:4235. [PMID: 38762489 PMCID: PMC11102455 DOI: 10.1038/s41467-024-48589-3] [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: 04/27/2023] [Accepted: 05/06/2024] [Indexed: 05/20/2024] Open
Abstract
Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing 'M1-like' macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.
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Affiliation(s)
- Gan Zhao
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Maria E Gentile
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Lulu Xue
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Christopher V Cosgriff
- Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Aaron I Weiner
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Stephanie Adams-Tzivelekidis
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Joanna Wong
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xinyuan Li
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sara Kass-Gergi
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Nicolas P Holcomb
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Maria C Basal
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kathleen M Stewart
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Joseph D Planer
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Edward Cantu
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jason D Christie
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Maria M Crespo
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Nuala J Meyer
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Andrew E Vaughan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Ghazanfari D, Courreges MC, Belinski LE, Hogrell MJ, Lloyd J, C Bergmeier S, McCall KD, Goetz DJ. Mechanistic insights into SARS-CoV-2 spike protein induction of the chemokine CXCL10. Sci Rep 2024; 14:11179. [PMID: 38750069 PMCID: PMC11096305 DOI: 10.1038/s41598-024-61906-6] [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: 01/20/2023] [Accepted: 05/10/2024] [Indexed: 05/18/2024] Open
Abstract
During a SARS-CoV-2 infection, macrophages recognize viral components resulting in cytokine production. While this response fuels virus elimination, overexpression of cytokines can lead to severe COVID-19. Previous studies suggest that the spike protein (S) of SARS-CoV-2 can elicit cytokine production via the transcription factor NF-κB and the toll-like receptors (TLRs). In this study, we found that: (i) S and the S2 subunit induce CXCL10, a chemokine implicated in severe COVID-19, gene expression by human macrophage cells (THP-1); (ii) a glycogen synthase kinase-3 inhibitor attenuates this induction; (iii) S and S2 do not activate NF-κB but do activate the transcription factor IRF; (iv) S and S2 do not require TLR2 to elicit CXCL10 production or activate IRF; and (v) S and S2 elicit CXCL10 production by peripheral blood mononuclear cells (PBMCs). We also discovered that the cellular response, or lack thereof, to S and S2 is a function of the recombinant S and S2 used. While such a finding raises the possibility of confounding LPS contamination, we offer evidence that potential contaminating LPS does not underly induced increases in CXCL10. Combined, these results provide insights into the complex immune response to SARS-CoV-2 and suggest possible therapeutic targets for severe COVID-19.
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Affiliation(s)
- Davoud Ghazanfari
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
| | | | - Lydia E Belinski
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA
| | - Michael J Hogrell
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA
| | - Jacob Lloyd
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
| | - Stephen C Bergmeier
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA
| | - Kelly D McCall
- Department of Specialty Medicine, Ohio University, Athens, OH, 45701, USA
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA
- The Diabetes Institute, Ohio University, Athens, OH, 45701, USA
- Molecular and Cellular Biology Program, Ohio University College of Arts & Sciences, Athens, OH, 45701, USA
- Department of Biological Sciences, Ohio University College of Arts & Sciences, Athens, OH, 45701, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, 45701, USA
| | - Douglas J Goetz
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA.
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA.
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48
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Saito S, Bozorgmehr N, Sligl W, Osman M, Elahi S. The Role of Coinhibitory Receptors in B Cell Dysregulation in SARS-CoV-2-Infected Individuals with Severe Disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1540-1552. [PMID: 38517295 DOI: 10.4049/jimmunol.2300783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 03/01/2024] [Indexed: 03/23/2024]
Abstract
Severe SARS-CoV-2 infection is associated with significant immune dysregulation involving different immune cell subsets. In this study, when analyzing critically ill COVID-19 patients versus those with mild disease, we observed a significant reduction in total and memory B cell subsets but an increase in naive B cells. Moreover, B cells from COVID-19 patients displayed impaired effector functions, evidenced by diminished proliferative capacity, reduced cytokine, and Ab production. This functional impairment was accompanied by an increased apoptotic potential upon stimulation in B cells from severely ill COVID-19 patients. Our further studies revealed the expansion of B cells expressing coinhibitory molecules (PD-1, PD-L1, TIM-1, VISTA, CTLA-4, and Gal-9) in intensive care unit (ICU)-admitted patients but not in those with mild disease. The coinhibitory receptor expression was linked to altered IgA and IgG expression and increased the apoptotic capacity of B cells. Also, we found a reduced frequency of CD24hiCD38hi regulatory B cells with impaired IL-10 production. Our mechanistic studies revealed that the upregulation of PD-L1 was linked to elevated plasma IL-6 levels in COVID-19 patients. This implies a connection between the cytokine storm and altered B cell phenotype and function. Finally, our metabolomic analysis showed a significant reduction in tryptophan but elevation of kynurenine in ICU-admitted COVID-19 patients. We found that kynurenine promotes PD-L1 expression in B cells, correlating with increased IL-6R expression and STAT1/STAT3 activation. Our observations provide novel insights into the complex interplay of B cell dysregulation, implicating coinhibitory receptors, IL-6, and kynurenine in impaired B cell effector functions, potentially contributing to the pathogenesis of COVID-19.
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Affiliation(s)
- Suguru Saito
- School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton, AB, Canada
| | - Najmeh Bozorgmehr
- School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton, AB, Canada
| | - Wendy Sligl
- Department of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Infectious Diseases, University of Alberta, Edmonton, AB, Canada
| | - Mohammed Osman
- Department of Medicine, Division of Rheumatology, University of Alberta, Edmonton, AB, Canada
| | - Shokrollah Elahi
- School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton, AB, Canada
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada
- Women and Children Health Research Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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49
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Riyaz Tramboo S, Elkhalifa AM, Quibtiya S, Ali SI, Nazir Shah N, Taifa S, Rakhshan R, Hussain Shah I, Ahmad Mir M, Malik M, Ramzan Z, Bashir N, Ahad S, Khursheed I, Bazie EA, Mohamed Ahmed E, Elderdery AY, Alenazy FO, Alanazi A, Alzahrani B, Alruwaili M, Manni E, E. Hussein S, Abdalhabib EK, Nabi SU. The critical impacts of cytokine storms in respiratory disorders. Heliyon 2024; 10:e29769. [PMID: 38694122 PMCID: PMC11058722 DOI: 10.1016/j.heliyon.2024.e29769] [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: 01/16/2024] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 05/03/2024] Open
Abstract
Cytokine storm (CS) refers to the spontaneous dysregulated and hyper-activated inflammatory reaction occurring in various clinical conditions, ranging from microbial infection to end-stage organ failure. Recently the novel coronavirus involved in COVID-19 (Coronavirus disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has been associated with the pathological phenomenon of CS in critically ill patients. Furthermore, critically ill patients suffering from CS are likely to have a grave prognosis and a higher case fatality rate. Pathologically CS is manifested as hyper-immune activation and is clinically manifested as multiple organ failure. An in-depth understanding of the etiology of CS will enable the discovery of not just disease risk factors of CS but also therapeutic approaches to modulate the immune response and improve outcomes in patients with respiratory diseases having CS in the pathogenic pathway. Owing to the grave consequences of CS in various diseases, this phenomenon has attracted the attention of researchers and clinicians throughout the globe. So in the present manuscript, we have attempted to discuss CS and its ramifications in COVID-19 and other respiratory diseases, as well as prospective treatment approaches and biomarkers of the cytokine storm. Furthermore, we have attempted to provide in-depth insight into CS from both a prophylactic and therapeutic point of view. In addition, we have included recent findings of CS in respiratory diseases reported from different parts of the world, which are based on expert opinion, clinical case-control research, experimental research, and a case-controlled cohort approach.
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Affiliation(s)
- Shahana Riyaz Tramboo
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Ahmed M.E. Elkhalifa
- Department of Public Health, College of Health Sciences, Saudi Electronic University, Riyadh, 11673, Saudi Arabia
- Department of Haematology, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Syed Quibtiya
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Medical College, Srinagar, 190011, Jammu & Kashmir, India
| | - Sofi Imtiyaz Ali
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Naveed Nazir Shah
- Department of Chest Medicine, Govt. Medical College, Srinagar, 191202, Jammu & Kashmir, India
| | - Syed Taifa
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Rabia Rakhshan
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu & Kashmir, 190006, India
| | - Iqra Hussain Shah
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Muzafar Ahmad Mir
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Masood Malik
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Zahid Ramzan
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Nusrat Bashir
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Shubeena Ahad
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Ibraq Khursheed
- Department of Zoology, Central University of Kashmir, 191201, Nunar, Ganderbal, Jammu & Kashmir, India
| | - Elsharif A. Bazie
- Pediatric Department, Faculty of Medicine, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Elsadig Mohamed Ahmed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, 61922, Saudi Arabia
- Department of Clinical Chemistry, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Abozer Y. Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Fawaz O. Alenazy
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Awadh Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Muharib Alruwaili
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Emad Manni
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Sanaa E. Hussein
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Ezeldine K. Abdalhabib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Showkat Ul Nabi
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
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50
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Bishop CR, Yan K, Nguyen W, Rawle DJ, Tang B, Larcher T, Suhrbier A. Microplastics dysregulate innate immunity in the SARS-CoV-2 infected lung. Front Immunol 2024; 15:1382655. [PMID: 38803494 PMCID: PMC11128561 DOI: 10.3389/fimmu.2024.1382655] [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: 02/06/2024] [Accepted: 04/24/2024] [Indexed: 05/29/2024] Open
Abstract
Introduction Global microplastic (MP) pollution is now well recognized, with humans and animals consuming and inhaling MPs on a daily basis, with a growing body of concern surrounding the potential impacts on human health. Methods Using a mouse model of mild COVID-19, we describe herein the effects of azide-free 1 μm polystyrene MP beads, co-delivered into lungs with a SARS-CoV-2 omicron BA.5 inoculum. The effect of MPs on the host response to SARS-CoV-2 infection was analysed using histopathology and RNA-Seq at 2 and 6 days post-infection (dpi). Results Although infection reduced clearance of MPs from the lung, virus titres and viral RNA levels were not significantly affected by MPs, and overt MP-associated clinical or histopathological changes were not observed. However, RNA-Seq of infected lungs revealed that MP exposure suppressed innate immune responses at 2 dpi and increased pro-inflammatory signatures at 6 dpi. The cytokine profile at 6 dpi showed a significant correlation with the 'cytokine release syndrome' signature observed in some COVID-19 patients. Discussion The findings are consistent with the recent finding that MPs can inhibit phagocytosis of apoptotic cells via binding of Tim4. They also add to a growing body of literature suggesting that MPs can dysregulate inflammatory processes in specific disease settings.
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Affiliation(s)
- Cameron R. Bishop
- Inflammation Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Kexin Yan
- Inflammation Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Wilson Nguyen
- Inflammation Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Daniel J. Rawle
- Inflammation Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Bing Tang
- Inflammation Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Thibaut Larcher
- Institut National de Recherche Agronomique, Unité Mixte de Recherche, Oniris, Nantes, France
| | - Andreas Suhrbier
- Inflammation Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Australian Infectious Disease Research Centre, Global Virus Network (GVN) Center of Excellence, Brisbane, QLD, Australia
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