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Kumar N, Segovia D, Kumar P, Atti HB, Kumar S, Mishra J. Mucosal implications of oral Jak3-targeted drugs in COVID patients. Mol Med 2025; 31:203. [PMID: 40410684 PMCID: PMC12100796 DOI: 10.1186/s10020-025-01260-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Accepted: 05/12/2025] [Indexed: 05/25/2025] Open
Abstract
The JAK family, particularly JAK3, plays a crucial role in immune signaling and inflammatory responses. Dysregulated JAK3 activation in SARS-CoV-2 infections has been associated with severe inflammation and respiratory complications, making JAK inhibitors a viable therapeutic option. However, their use raises concerns regarding immunosuppression, which could increase susceptibility to secondary infections. While long-term adverse effects are less of a concern in acute COVID-19 treatment, patient selection and monitoring remain critical. Furthermore, adverse effects associated with oral JAK3 inhibitors necessitate the exploration of alternative strategies to optimize therapeutic efficacy while minimizing risks. This review highlights the role of JAK3 in immune and epithelial cells, examines the adverse effects of oral JAK3 inhibitors in COVID-19 and other treatments, and discusses alternative therapeutic strategies for improving patient outcomes.
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Affiliation(s)
- Narendra Kumar
- ILR-College of Pharmacy, Texas A&M University Health Science Center, Kingsville, TX, USA.
| | - Daniel Segovia
- ILR-College of Pharmacy, Texas A&M University Health Science Center, Kingsville, TX, USA
| | - Priyam Kumar
- University of Pennsylvania, Philadelphia, PA, USA
| | - Hima Bindu Atti
- ILR-College of Pharmacy, Texas A&M University Health Science Center, Kingsville, TX, USA
| | - Soaham Kumar
- Veterans Memorial High School, Corpus Christi, TX, USA
| | - Jayshree Mishra
- ILR-College of Pharmacy, Texas A&M University Health Science Center, Kingsville, TX, USA.
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2
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Yasir M, Choe J, Hassan M, Kloczkowski A, Chun W. Recent advances and future perspectives in small molecule JAK2 inhibitors. Future Med Chem 2025:1-17. [PMID: 40392133 DOI: 10.1080/17568919.2025.2507564] [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: 03/28/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025] Open
Abstract
The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is essential for controlling immune function, blood cell formation, and cell growth. Dysregulation of this pathway is implicated in various diseases, including hematologic malignancies, autoimmune disorders, and chronic inflammatory conditions. This review provides a comprehensive overview of the structural and functional aspects of JAK/STAT signaling, with a particular focus on the role of JAK2. This manuscript explores the primary regulators of the JAK/STAT pathway, such as Suppressors Of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS), and Protein Tyrosine Phosphatases (PTPs), which play a crucial role in maintaining cellular balance and stability. Additionally, the therapeutic landscape of JAK2 inhibitors is explored, covering both approved and investigational drugs, including their mechanisms of action, efficacy, and safety profiles. Emerging strategies such as drug repositioning using computational approaches and experimental validation are also highlighted. By integrating insights from molecular docking studies, machine learning models, and kinase assays, this review emphasizes the potential of JAK2 inhibitors in disease management.
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Affiliation(s)
- Muhammad Yasir
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Jongseon Choe
- Department of Microbiology and Immunology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, OH, USA
| | - Wanjoo Chun
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
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Ebrahim N, Al Saihati HA, Alali Z, Mahmoud SYM, Rabaan AA, Dessouky AA, Salim RF, Shamaa AA, Abdallah AN, Elsherbiny NM, Othman G, Badawy AA, Di Leva G, Badr OA. Lyophilized MSC-EVs attenuates COVID-19 pathogenesis by regulating the JAK/STAT pathway. Stem Cell Res Ther 2025; 16:244. [PMID: 40369583 PMCID: PMC12079845 DOI: 10.1186/s13287-025-04284-8] [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: 11/13/2024] [Accepted: 03/19/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND The JAK/STAT signaling pathway plays a crucial role in the release of interferons (IFNs) and the proinflammatory response during SARS-CoV-2 infection, contributing to the cytokine storm characteristic of severe COVID-19 cases. STAT3, a key protein in this pathway, has been implicated in promoting inflammation, making its inhibition a potential therapeutic strategy to mitigate disease severity. Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs), enriched with immunomodulatory and antiviral miRNAs, offer a promising therapeutic approach by modulating gene expression and regulating inflammatory responses. This study investigates the ability of Lyophilized MSC-EVs to inhibit the JAK/STAT pathway, highlighting their potential application in COVID-19 management. METHODS Male Syrian hamsters were used as an experimental model, housed under controlled laboratory conditions. SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020) was propagated in Vero E6 cells, and viral titers were determined using plaque assays. Hamsters were intranasally challenged with the virus and treated intraperitoneally with 0.5 mL of lyophilized human Wharton's jelly-derived MSC-extracellular vesicles (MSC-EVs). Histopathological evaluations were performed on lung tissues using H&E, Masson's trichrome, and immunohistochemical staining. Morphometric analyses were conducted to assess lung injury and fibrosis. Western blotting was employed to evaluate protein expression. All procedures adhered to ethical and biosafety guidelines. RESULTS The administration of MSC-EVs significantly upregulated the expression levels of miRNA-146a, miRNA-124, miRNA-155, miRNA-29b, miRNA-7, miRNA-145 and miRNA-18a compared to their levels in the COVID-19 group, suggesting a targeted release of miRNA-cargo from the MSC-EVs into the lung tissue of the animals. MSC-EVs impaired the activation of the STAT3/STAT1 signaling pathway and reduced the cytokine storm and coagulopathy associated with COVID-19. CONCLUSIONS These findings suggest that MSC-EVs have the potential to effectively mitigate the pathogenesis of COVID-19 by targeting the JAK/STAT signaling pathway. Further research is needed to fully understand the mechanisms underlying the therapeutic effects of MSC-EVs and their clinical application in combating the COVID-19 pandemic.
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Affiliation(s)
- Nesrine Ebrahim
- Department of Medical Histology and Cell Biology Faculty of Medicine, Benha University, Benha, Egypt
- Stem Cell Unit, Faculty of Medicine, Benha University, Benha, Egypt
- Faculty of Medicine, Benha National University, Obour, Egypt
- Keele University, Keele, UK
| | - Hajir A Al Saihati
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Albatin, Hafar Al-Batin, Saudi Arabia.
| | - Zahraa Alali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Al Batin, P.O Box 1803, 31991, Hafr Al Batin, Saudi Arabia
| | - Sabry Younis Mohamed Mahmoud
- Biology Department, College of Sciences, University of Hafr Al Batin, P. O. Box 1803, 31991, Hafar Al Batin, Saudi Arabia
| | - Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, 31311, Dhahran, Saudi Arabia
- College of Medicine, Alfaisal University, 11533, Riyadh, Saudi Arabia
- Department of Public Health and Nutrition, The University of Haripur, Haripur, 22610, Pakistan
| | - Arigue A Dessouky
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Rabab F Salim
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Banha, Egypt
| | - Ashraf A Shamaa
- Anesthesiology & Radiology, Faculty of Vet. Men, Cairo University, P. O. Box 12211, Giza, Egypt
| | - Ahmed N Abdallah
- Hormones Department, National Research Centre, Medical Research and Clinical Studies Institute, Cairo, Egypt
| | - Nehal M Elsherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Gamal Othman
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Diriyah, Saudi Arabia
| | - Abdelnaser A Badawy
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Gianpiero Di Leva
- School of Life Sciences, Keele University Staffordshire, Keele, ST5 5BG, UK
| | - Omnia A Badr
- Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Benha, Egypt.
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Guo M, Shu L, He Z. Genomic and GEO data integration identifies PDGFB as a potential therapeutic target for sepsis. Sci Rep 2025; 15:12615. [PMID: 40221544 PMCID: PMC11993713 DOI: 10.1038/s41598-025-96655-7] [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: 01/13/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
Sepsis is a major contributor to global health loss, yet effective therapeutic options remain scarce. This study aims to identify potential therapeutic targets for sepsis. We integrated data from the druggable genome, expression quantitative trait loci (eQTLs) from human blood, and genome-wide association studies on sepsis. Mendelian randomization (MR) was employed to investigate causal relationships between drug target genes and sepsis. The eQTLGen Consortium data served as the discovery set and was validated using genotype-tissue expression (GTEx) eQTLs. Sensitivity and colocalization analyses were conducted to support causal inferences. Additionally, phenome-wide MR (Phe-MR) was used to assess potential side effects of druggable genes. The expression levels of the target genes were validated using the GSE154918 dataset. In the discovery MR analysis phase, we identified 26 potential targets with significant expression in blood (PFDR < 0.05). PDGFB and BPI were further validated in the replication MR analysis. Colocalization analysis provided strong evidence (PPH4 > 0.75) supporting PDGFB as a therapeutic candidate for sepsis. Phe-MR analysis suggested that targeting PDGFB is unlikely to cause adverse effects. PDGFB downregulation was confirmed in sepsis groups via the GEO dataset. PDGFB is identified as a promising druggable target for sepsis treatment, supported by strong evidence of its therapeutic potential.
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Affiliation(s)
- Mingjun Guo
- Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, China
| | - Lei Shu
- Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, China
| | - Zhihui He
- Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, No.138 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan Province, China.
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Li X, Qi X, Wang B, Fu L, Chen X, Luo X, Chen X, Lu Y. Efficacy of nintedanib as a host-directed therapy candidate in the treatment of tuberculosis. J Antimicrob Chemother 2025; 80:452-464. [PMID: 39656809 DOI: 10.1093/jac/dkae429] [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: 04/14/2024] [Accepted: 11/12/2024] [Indexed: 12/17/2024] Open
Abstract
BACKGROUND The lengthy duration and high frequency of drug resistance associated with currently used antimycobacterial drug treatments have intensified the need for alternative therapies against Mycobacterium tuberculosis, the causative agent of TB. METHODS MICs and intracellular macrophage cfu counts were tested to evaluate the antibacterial activity of nintedanib and pirfenidone against drug-susceptible and -resistant M. tuberculosis. A chronic murine model of pulmonary infection was used to assay the therapeutic efficacy of nintedanib. Macrophage transcriptome deep sequencing, a confocal assay, siRNA knockdown, Western blotting, quantitative RT-PCR and a cfu assay were used to investigate the antibacterial mechanism of nintedanib. RESULTS The MIC90 of nintedanib against M. tuberculosis standard strain H37Rv was 23.56-40.51 mg/L. TB murine model studies showed that nintedanib, coadministered with isoniazid, rifampicin and pyrazinamide, shortened treatment duration, and ameliorated pulmonary inflammation and fibrosis. In mechanism studies, transcriptome sequencing analysis revealed that nintedanib may eliminate M. tuberculosis through up-regulating macrophage autophagy. Furthermore, inhibition of autophagy by using siRNA targeting ATG5 or the autophagy inhibitor 3-methyladenine almost completely abolished nintedanib-mediated suppression of M. tuberculosis. Nintedanib induced autophagy by the JAK2/STAT3/Beclin1 pathway. When JAK2 or Beclin1 were knocked down through siRNA, nintedanib no longer inhibited M. tuberculosis. JAK2 activator coumermycin A1 and STAT3 agonist colivelin also reversed this phenotype. CONCLUSIONS In vitro activity of nintedanib against drug-susceptible and -resistant M. tuberculosis and efficacy in murine infections warrant the continued clinical evaluation of nintedanib as a new adjuvant therapy for standard treatment of TB.
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Affiliation(s)
- Xinda Li
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xueting Qi
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Bin Wang
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Lei Fu
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xi Chen
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xiaoyi Luo
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Xiaoyou Chen
- Infectious Diseases Department, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yu Lu
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
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Zhou X, Wu Y, Zhu Z, Lu C, Zhang C, Zeng L, Xie F, Zhang L, Zhou F. Mucosal immune response in biology, disease prevention and treatment. Signal Transduct Target Ther 2025; 10:7. [PMID: 39774607 PMCID: PMC11707400 DOI: 10.1038/s41392-024-02043-4] [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: 06/01/2024] [Revised: 09/05/2024] [Accepted: 10/27/2024] [Indexed: 01/11/2025] Open
Abstract
The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensive understanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remains incomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on the dynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures and functions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanisms involved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-related diseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immune responses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines and inhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention and treatment.
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Affiliation(s)
- Xiaoxue Zhou
- School of Medicine, Hangzhou City University, Hangzhou, China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yuchen Wu
- The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhipeng Zhu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Chu Lu
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Chunwu Zhang
- The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Linghui Zeng
- School of Medicine, Hangzhou City University, Hangzhou, China
| | - Feng Xie
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Fangfang Zhou
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
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Fan Z, Zhao H, Zhou J, Li D, Fan Y, Bi Y, Ji S. A versatile attention-based neural network for chemical perturbation analysis and its potential to aid surgical treatment: an experimental study. Int J Surg 2024; 110:7671-7686. [PMID: 39017949 PMCID: PMC11634177 DOI: 10.1097/js9.0000000000001781] [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: 02/21/2024] [Accepted: 05/30/2024] [Indexed: 07/18/2024]
Abstract
Deep learning models have emerged as rapid, accurate, and effective approaches for clinical decisions. Through a combination of drug screening and deep learning models, drugs that may benefit patients before and after surgery can be discovered to reduce the risk of complications or speed recovery. However, most existing drug prediction methods have high data requirements and lack interpretability, which has a limited role in adjuvant surgical treatment. To address these limitations, the authors propose the attention-based convolution transpositional interfusion network (ACTIN) for flexible and efficient drug discovery. ACTIN leverages the graph convolution and the transformer mechanism, utilizing drug and transcriptome data to assess the impact of chemical pharmacophores containing certain elements on gene expression. Remarkably, just with only 393 training instances, only one-tenth of the other models, ACTIN achieves state-of-the-art performance, demonstrating its effectiveness even with limited data. By incorporating chemical element embedding disparity and attention mechanism-based parameter analysis, it identifies the possible pharmacophore containing certain elements that could interfere with specific cell lines, which is particularly valuable for screening useful pharmacophores for new drugs tailored to adjuvant surgical treatment. To validate its reliability, the authors conducted comprehensive examinations by utilizing transcriptome data from the lung tissue of fatal COVID-19 patients as additional input for ACTIN, the authors generated novel lead chemicals that align with clinical evidence. In summary, ACTIN offers insights into the perturbation biases of elements within pharmacophore on gene expression, which holds the potential for guiding the development of new drugs that benefit surgical treatment.
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Affiliation(s)
- Zheqi Fan
- Department of Orthopaedics, The First Medical Centre, Chinese PLA General Hospital, Beijing
| | - Houming Zhao
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing
| | - Jingcheng Zhou
- Senior Department of Otolaryngology-Head and Neck Surgery, The Sixth Medical Center, Chinese PLA General Hospital, Beijing
| | - Dingchang Li
- Department of General Surgery, The First Medical Centre, Chinese PLA General Hospital, Beijing
| | - Yunlong Fan
- Department of Dermatology, The Seventh Medical Center, Chinese PLA General Hospital, Beijing
| | - Yiming Bi
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Shuaifei Ji
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, People’s Republic of China
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Balaji D, Balakrishnan R, Srinivasan D, Subbarayan R, Shrestha R, Srivastava N, Chauhan A. The Impact of SARS-CoV-2 on Liver Diseases and Potential Phytochemical Treatments. INFECTIOUS MICROBES AND DISEASES 2024; 6:177-188. [DOI: 10.1097/im9.0000000000000161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Abstract
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has brought about numerous challenges. One of these challenges is the impact of SARS-CoV-2 on the liver. Although this virus primarily affects the lungs, it can induce elevated transaminase levels and the development of scar tissue in the liver, exacerbating preexisting liver conditions. Individuals with preexisting conditions, such as nonalcoholic fatty liver disease, alcohol-induced liver disease and hepatocellular carcinoma, face an increased risk of mortality from COVID-19. However, drugs currently used to treat COVID-19 have undesirable side effects, which make them unsuitable for patients with preexisting liver conditions. In this review, we explore the potential of phytochemicals, such as apigenin, berberine, curcumin, epigallocatechin-3-gallate, quercetin, resveratrol and silymarin, for treatment of the liver conditions, including nonalcoholic fatty liver disease, alcohol-induced liver disease and hepatocellular carcinoma. We also discuss significant associations between phytochemicals and COVID-19 by depicting their molecular interactions. Based on the discussed overlapping functions, it is important to assess the therapeutic efficacy of phytochemicals that possess hepatoprotective properties as potential alternative treatments for COVID-19.
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Affiliation(s)
- Dhanvee Balaji
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Ranjith Balakrishnan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | - Dhasarathdev Srinivasan
- Centre for Advanced Biotherapeutics and Regenerative Medicine, Faculty of Research, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
| | | | | | | | - Ankush Chauhan
- Centre for Herbal Pharmacology and Environmental Sustainability, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India
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Attiq A, Afzal S, Wahab HA, Ahmad W, Kandeel M, Almofti YA, Alameen AO, Wu YS. Cytokine Storm-Induced Thyroid Dysfunction in COVID-19: Insights into Pathogenesis and Therapeutic Approaches. Drug Des Devel Ther 2024; 18:4215-4240. [PMID: 39319193 PMCID: PMC11421457 DOI: 10.2147/dddt.s475005] [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: 04/22/2024] [Accepted: 08/26/2024] [Indexed: 09/26/2024] Open
Abstract
Angiotensin-converting enzyme 2 receptors (ACE2R) are requisite to enter the host cells for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). ACE2R is constitutive and functions as a type I transmembrane metallo-carboxypeptidase in the renin-angiotensin system (RAS). On thyroid follicular cells, ACE2R allows SARS-CoV-2 to invade the thyroid gland, impose cytopathic effects and produce endocrine abnormalities, including stiff back, neck pain, muscle ache, lethargy, and enlarged, inflamed thyroid gland in COVID-19 patients. Further damage is perpetuated by the sudden bursts of pro-inflammatory cytokines, which is suggestive of a life-threatening syndrome known as a "cytokine storm". IL-1β, IL-6, IFN-γ, and TNF-α are identified as the key orchestrators of the cytokine storm. These inflammatory mediators upregulate transcriptional turnover of nuclear factor-kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK), paving the pathway for cytokine storm-induced thyroid dysfunctions including euthyroid sick syndrome, autoimmune thyroid diseases, and thyrotoxicosis in COVID-19 patients. Targeted therapies with corticosteroids (dexamethasone), JAK inhibitor (baricitinib), nucleotide analogue (remdesivir) and N-acetyl-cysteine have demonstrated effectiveness in terms of attenuating the severity and frequency of cytokine storm-induced thyroid dysfunctions, morbidity and mortality in severe COVID-19 patients. Here, we review the pathogenesis of cytokine storms and the mechanisms and pathways that establish the connection between thyroid disorder and COVID-19. Moreover, cross-talk interactions of signalling pathways and therapeutic strategies to address COVID-19-associated thyroid diseases are also discussed herein.
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Affiliation(s)
- Ali Attiq
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang, 11800, Malaysia
| | - Sheryar Afzal
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al Ahsa, 31982, Saudi Arabia
| | - Habibah A Wahab
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang, 11800, Malaysia
| | - Waqas Ahmad
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang, 11800, Malaysia
| | - Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al Ahsa, 31982, Saudi Arabia
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrel Sheikh, 6860404, Egypt
| | - Yassir A Almofti
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al Ahsa, 31982, Saudi Arabia
- Department of Biochemistry, Molecular Biology and Bioinformatics, College of Veterinary Medicine, University of Bahri, Khartoum, 12217, Sudan
| | - Ahmed O Alameen
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al Ahsa, 31982, Saudi Arabia
- Department of Physiology, Faculty of Veterinary Medicine, University of Khartoum, Shambat, 13314, Sudan
| | - Yuan Seng Wu
- Sunway Microbiome Centre, School of Medical and Life Sciences, Sunway University, Subang Jaya, Selangor, 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Subang Jaya, Selangor, 47500, Malaysia
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Nisar H, Wajid B, Anwar F, Ahmad A, Javaid A, Attique SA, Nisar W, Saeed A, Shahid S, Sadaf S. Bioinformatics and systems biology analysis revealed PMID26394986-Compound-10 as potential repurposable drug against covid-19. J Biomol Struct Dyn 2024; 42:7972-7985. [PMID: 37534820 DOI: 10.1080/07391102.2023.2242500] [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: 02/02/2023] [Accepted: 07/24/2023] [Indexed: 08/04/2023]
Abstract
The global health pandemic known as COVID-19, which stems from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a significant concern worldwide. Several treatment methods exist for COVID-19; however, there is an urgent demand for previously established drugs and vaccines to effectively combat the disease. Since, discovering new drugs poses a significant challenge, making the repurposing of existing drugs can potentially reduce time and costs compared to developing entirely new drugs from scratch. The objective of this study is to identify hub genes and associated repurposed drugs targeting them. We analyzed differentially expressed genes (DEGs) by analyzing RNA-seq transcriptomic datasets and integrated with genes associated with COVID-19 present in different databases. We detected 173 Covid-19 associated genes for the construction of a protein-protein interaction (PPI) network which resulted in the identification of the top 10 hub genes/proteins (STAT1, IRF7, MX1, IRF9, ISG15, OAS3, OAS2, OAS1, IRF3, and IRF1). Hub genes were subjected to GO functional and KEGG pathway enrichment analyses, which indicated some key roles and signaling pathways that were strongly related to SARS-CoV-2 infections. We conducted drug repurposing analysis using CMap, TTD, and DrugBank databases with these 10 hub genes, leading to the identification of Piceatannol, CKD-712, and PMID26394986-Compound-10 as top-ranked candidate drugs. Finally, drug-gene interactions analysis through molecular docking and validated via molecular dynamic simulation for 80 ns suggests PMID26394986-Compound-10 as the only potential drug. Our research demonstrates how in silico analysis might produce repurposing candidates to help respond faster to new disease outbreaks.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Haseeb Nisar
- Department of Life-Sciences, University of Management and Technology, Lahore, Pakistan
| | - Bilal Wajid
- Ibn Sina Research & Development Division, Sabz-Qalam, Lahore, Pakistan
- Department of Electrical Engineering, University of Engineering and Technology, Lahore, Pakistan
| | | | - Ashfaq Ahmad
- Department of Bioinformatics, Hazara University, Mansehra, Pakistan
| | - Anum Javaid
- School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Syed Awais Attique
- Bioinformatics Institute, Agency for Science, Technology and Research (A(*)STAR), Singapore, Singapore
| | - Wardah Nisar
- Department of Public Health, University of Health Sciences, Lahore, Pakistan
| | - Amir Saeed
- Department of Bioinformatics, Hazara University, Mansehra, Pakistan
| | - Samiah Shahid
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Saima Sadaf
- School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
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11
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Lv Y, Qi J, Babon JJ, Cao L, Fan G, Lang J, Zhang J, Mi P, Kobe B, Wang F. The JAK-STAT pathway: from structural biology to cytokine engineering. Signal Transduct Target Ther 2024; 9:221. [PMID: 39169031 PMCID: PMC11339341 DOI: 10.1038/s41392-024-01934-w] [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: 04/08/2024] [Revised: 06/12/2024] [Accepted: 07/16/2024] [Indexed: 08/23/2024] Open
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway serves as a paradigm for signal transduction from the extracellular environment to the nucleus. It plays a pivotal role in physiological functions, such as hematopoiesis, immune balance, tissue homeostasis, and surveillance against tumors. Dysregulation of this pathway may lead to various disease conditions such as immune deficiencies, autoimmune diseases, hematologic disorders, and cancer. Due to its critical role in maintaining human health and involvement in disease, extensive studies have been conducted on this pathway, ranging from basic research to medical applications. Advances in the structural biology of this pathway have enabled us to gain insights into how the signaling cascade operates at the molecular level, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced comprehension of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed us to engineer cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. In this review, we outline the structural basis that governs key nodes in this pathway, offering a comprehensive overview of the signal transduction process. Furthermore, we explore recent advances in cytokine engineering for therapeutic development in this pathway.
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Affiliation(s)
- You Lv
- Center for Molecular Biosciences and Non-communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi, 710054, China
- Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China
| | - Jianxun Qi
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100080, China
| | - Jeffrey J Babon
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
| | - Longxing Cao
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China
| | - Guohuang Fan
- Immunophage Biotech Co., Ltd, No. 10 Lv Zhou Huan Road, Shanghai, 201112, China
| | - Jiajia Lang
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jin Zhang
- Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China
| | - Pengbing Mi
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Bostjan Kobe
- School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, 4072, Australia.
| | - Faming Wang
- Center for Molecular Biosciences and Non-communicable Diseases Research, Xi'an University of Science and Technology, Xi'an, Shaanxi, 710054, China.
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12
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Fujimoto K, Kameda Y, Nagano Y, Deguchi S, Yamamoto T, Krol RP, Gee P, Matsumura Y, Okamoto T, Nagao M, Takayama K, Yokokawa R. SARS-CoV-2-induced disruption of a vascular bed in a microphysiological system caused by type-I interferon from bronchial organoids. LAB ON A CHIP 2024; 24:3863-3879. [PMID: 38252025 DOI: 10.1039/d3lc00768e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
Blood vessels show various COVID-19-related conditions including thrombosis and cytokine propagation. Existing in vitro blood vessel models cannot represent the consequent changes in the vascular structure or determine the initial infection site, making it difficult to evaluate how epithelial and endothelial tissues are damaged. Here, we developed a microphysiological system (MPS) that co-culture the bronchial organoids and the vascular bed to analyze infection site and interactions. In this system, virus-infected organoids caused damage in vascular structure. However, vasculature was not damaged or infected when the virus was directly introduced to vascular bed. The knockout of interferon-related genes and inhibition of the JAK/STAT pathway reduced the vascular damage, indicating the protective effect of interferon response suppression. The results demonstrate selective infection of bronchial epithelial cells and vascular damage by cytokines and also indicate the applicability of MPS to investigate how the infection influences vascular structure and functions.
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Affiliation(s)
- Kazuya Fujimoto
- Department of Micro Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto 615-8540, Japan.
| | - Yoshikazu Kameda
- Department of Micro Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto 615-8540, Japan.
| | - Yuta Nagano
- Department of Micro Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto 615-8540, Japan.
| | - Sayaka Deguchi
- Center for iPS cell Research and Application (CiRA), Kyoto University, Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Takuya Yamamoto
- Center for iPS cell Research and Application (CiRA), Kyoto University, Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto, 606-8507, Japan.
- Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
- Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Rafal P Krol
- Research and Development Center, CiRA Foundation, Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto, 606-8397, Japan
| | - Peter Gee
- MaxCyte Inc., Gaithersburg, MD 20878, USA
| | - Yasufumi Matsumura
- Department of Clinical Laboratory medicine, Kyoto University Graduate School of Medicine, Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Toru Okamoto
- Department of Microbiology, School of Medicine, Juntendo University, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Miki Nagao
- Department of Clinical Laboratory medicine, Kyoto University Graduate School of Medicine, Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Kazuo Takayama
- Center for iPS cell Research and Application (CiRA), Kyoto University, Shogoin-Kawahara-cho 53, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Ryuji Yokokawa
- Department of Micro Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto 615-8540, Japan.
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13
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Chung YS, Lam CY, Tan PH, Tsang HF, Wong SCC. Comprehensive Review of COVID-19: Epidemiology, Pathogenesis, Advancement in Diagnostic and Detection Techniques, and Post-Pandemic Treatment Strategies. Int J Mol Sci 2024; 25:8155. [PMID: 39125722 PMCID: PMC11312261 DOI: 10.3390/ijms25158155] [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: 06/14/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
At present, COVID-19 remains a public health concern due to the ongoing evolution of SARS-CoV-2 and its prevalence in particular countries. This paper provides an updated overview of the epidemiology and pathogenesis of COVID-19, with a focus on the emergence of SARS-CoV-2 variants and the phenomenon known as 'long COVID'. Meanwhile, diagnostic and detection advances will be mentioned. Though many inventions have been made to combat the COVID-19 pandemic, some outstanding ones include multiplex RT-PCR, which can be used for accurate diagnosis of SARS-CoV-2 infection. ELISA-based antigen tests also appear to be potential diagnostic tools to be available in the future. This paper also discusses current treatments, vaccination strategies, as well as emerging cell-based therapies for SARS-CoV-2 infection. The ongoing evolution of SARS-CoV-2 underscores the necessity for us to continuously update scientific understanding and treatments for it.
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Affiliation(s)
| | | | | | | | - Sze-Chuen Cesar Wong
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; (Y.-S.C.); (C.-Y.L.); (P.-H.T.); (H.-F.T.)
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14
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Hu Y, Hao C, Wang D, Guo M, Chu H, Jin X, Zu S, Ding X, Zhang H, Hu H. Porcine deltacoronavirus nucleocapsid protein antagonizes JAK-STAT signaling pathway by targeting STAT1 through KPNA2 degradation. J Virol 2024; 98:e0033424. [PMID: 38829137 PMCID: PMC11264599 DOI: 10.1128/jvi.00334-24] [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: 02/19/2024] [Accepted: 05/09/2024] [Indexed: 06/05/2024] Open
Abstract
Porcine deltacoronavirus (PDCoV) is an enteric pathogenic coronavirus that causes acute and severe watery diarrhea in piglets and has the ability of cross-species transmission, posing a great threat to swine production and public health. The interferon (IFN)-mediated signal transduction represents an important component of virus-host interactions and plays an essential role in regulating viral infection. Previous studies have suggested that multifunctional viral proteins encoded by coronaviruses antagonize the production of IFN via various means. However, the function of these viral proteins in regulating IFN-mediated signaling pathways is largely unknown. In this study, we demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I IFN-mediated JAK-STAT signaling pathway. We identified that PDCoV infection stimulated but delayed the production of IFN-stimulated genes (ISGs). In addition, PDCoV inhibited JAK-STAT signal transduction by targeting the nuclear translocation of STAT1 and ISGF3 formation. Further evidence showed that PDCoV N is the essential protein involved in the inhibition of type I IFN signaling by targeting STAT1 nuclear translocation via its C-terminal domain. Mechanistically, PDCoV N targets STAT1 by interacting with it and subsequently inhibiting its nuclear translocation. Furthermore, PDCoV N inhibits STAT1 nuclear translocation by specifically targeting KPNA2 degradation through the lysosomal pathway, thereby inhibiting the activation of downstream sensors in the JAK-STAT signaling pathway. Taken together, our results reveal a novel mechanism by which PDCoV N interferes with the host antiviral response.IMPORTANCEPorcine deltacoronavirus (PDCoV) is a novel enteropathogenic coronavirus that receives increased attention and seriously threatens the pig industry and public health. Understanding the underlying mechanism of PDCoV evading the host defense during infection is essential for developing targeted drugs and effective vaccines against PDCoV. This study demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I interferon signaling by targeting STAT1, which is a crucial signal sensor in the JAK-STAT signaling pathway. Further experiments suggested that PDCoV N-mediated inhibition of the STAT1 nuclear translocation involves the degradation of KPNA2, and the lysosome plays a role in KPNA2 degradation. This study provides new insights into the regulation of PDCoV N in the JAK-STAT signaling pathway and reveals a novel mechanism by which PDCoV evades the host antiviral response. The novel findings may guide us to discover new therapeutic targets and develop live attenuated vaccines for PDCoV infection.
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Affiliation(s)
- Yating Hu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
| | - Chenlin Hao
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
| | - Donghan Wang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
| | - Meng Guo
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
| | - Hongyan Chu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
| | - Xiaohui Jin
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
- Henan Province Key Laboratory of Animal Food Pathogens Surveillance, Zhengzhou, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou, China
| | - Shaopo Zu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
- Henan Province Key Laboratory of Animal Food Pathogens Surveillance, Zhengzhou, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou, China
| | - Xueyan Ding
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
- Henan Province Key Laboratory of Animal Food Pathogens Surveillance, Zhengzhou, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou, China
| | - Honglei Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
- Henan Province Key Laboratory of Animal Food Pathogens Surveillance, Zhengzhou, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou, China
| | - Hui Hu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China
- Henan Province Key Laboratory of Animal Food Pathogens Surveillance, Zhengzhou, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou, China
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15
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Gong Q, Fu M, Wang J, Zhao S, Wang H. Potential Immune-Inflammatory Proteome Biomarkers for Guiding the Treatment of Patients with Primary Acute Angle-Closure Glaucoma Caused by COVID-19. J Proteome Res 2024; 23:2587-2597. [PMID: 38836775 PMCID: PMC11232099 DOI: 10.1021/acs.jproteome.4c00325] [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: 04/16/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/06/2024]
Abstract
Primary acute angle-closure glaucoma (PAACG) is a sight-threatening condition that can lead to blindness. With the increasing incidence of COVID-19, a multitude of people are experiencing acute vision loss and severe swelling of the eyes and head. These patients were then diagnosed with acute angle closure, with or without a history of PACG. However, the mechanism by which viral infection causes PACG has not been clarified. This is the first study to explore the specific inflammatory proteomic landscape in SARS-CoV-2-induced PAACG. The expression of 92 inflammation-related proteins in 19 aqueous humor samples from PAACGs or cataract patients was detected using the Olink Target 96 Inflammation Panel based on a highly sensitive and specific proximity extension assay technology. The results showed that 76 proteins were significantly more abundant in the PAACG group than in the cataract group. Notably, the top eight differentially expressed proteins were IL-8, MCP-1, TNFRSF9, DNER, CCL4, Flt3L, CXCL10, and CD40. Generally, immune markers are related to inflammation, macrophage activation, and viral infection, revealing the crucial role of macrophages in the occurrence of PAACGs caused by SARS-CoV-2.
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Affiliation(s)
- Qiaoyun Gong
- Department
of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
- National
Clinical Research Center for Eye Diseases, Shanghai 200080, China
- Shanghai
Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai
Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai
Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai 200080, China
| | - Mingshui Fu
- Department
of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
- National
Clinical Research Center for Eye Diseases, Shanghai 200080, China
- Shanghai
Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai
Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai
Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai 200080, China
| | - Jingyi Wang
- Department
of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
- National
Clinical Research Center for Eye Diseases, Shanghai 200080, China
- Shanghai
Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai
Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai
Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai 200080, China
| | - Shuzhi Zhao
- Department
of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
- National
Clinical Research Center for Eye Diseases, Shanghai 200080, China
- Shanghai
Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai
Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai
Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai 200080, China
| | - Haiyan Wang
- Department
of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
- National
Clinical Research Center for Eye Diseases, Shanghai 200080, China
- Shanghai
Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China
- Shanghai
Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China
- Shanghai
Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai 200080, China
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16
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Wicik Z, Eyileten C, Nowak A, Keshwani D, Simões SN, Martins DC, Klos K, Wlodarczyk W, Assinger A, Soldacki D, Chcialowski A, Siller-Matula JM, Postula M. Alteration of circulating ACE2-network related microRNAs in patients with COVID-19. Sci Rep 2024; 14:13573. [PMID: 38866792 PMCID: PMC11169442 DOI: 10.1038/s41598-024-58037-3] [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: 10/17/2023] [Accepted: 03/25/2024] [Indexed: 06/14/2024] Open
Abstract
Angiotensin converting enzyme 2 (ACE2) serves as the primary receptor for the SARS-CoV-2 virus and has implications for the functioning of the cardiovascular system. Based on our previously published bioinformatic analysis, in this study we aimed to analyze the diagnostic and predictive utility of miRNAs (miR-10b-5p, miR-124-3p, miR-200b-3p, miR-26b-5p, miR-302c-5p) identified as top regulators of ACE2 network with potential to affect cardiomyocytes and cardiovascular system in patients with COVID-19. The expression of miRNAs was determined through qRT-PCR in a cohort of 79 hospitalized COVID-19 patients as well as 32 healthy volunteers. Blood samples and clinical data of COVID-19 patients were collected at admission, 7-days and 21-days after admission. We also performed SHAP analysis of clinical data and miRNAs target predictions and advanced enrichment analyses. Low expression of miR-200b-3p at the seventh day of admission is indicative of predictive value in determining the length of hospital stay and/or the likelihood of mortality, as shown in ROC curve analysis with an AUC of 0.730 and a p-value of 0.002. MiR-26b-5p expression levels in COVID-19 patients were lower at the baseline, 7 and 21-days of admission compared to the healthy controls (P < 0.0001). Similarly, miR-10b-5p expression levels were lower at the baseline and 21-days post admission (P = 0.001). The opposite situation was observed in miR-124-3p and miR-302c-5p. Enrichment analysis showed influence of analyzed miRNAs on IL-2 signaling pathway and multiple cardiovascular diseases through COVID-19-related targets. Moreover, the COVID-19-related genes regulated by miR-200b-3p were linked to T cell protein tyrosine phosphatase and the HIF-1 transcriptional activity in hypoxia. Analysis focused on COVID-19 associated genes showed that all analyzed miRNAs are strongly affecting disease pathways related to CVDs which could be explained by their strong interaction with the ACE2 network.
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Affiliation(s)
- Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
- Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9 Street, 02-957, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Anna Nowak
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, 02-091, Warsaw, Poland
- Department of Diabetology and Internal Medicine, University Clinical Centre, Medical University of Warsaw, Warsaw, Poland
| | - Disha Keshwani
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
| | - Sérgio N Simões
- Federal Institute of Education, Science and Technology of Espírito Santo, Serra, Espírito Santo, 29056-264, Brazil
| | - David C Martins
- Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, Santo Andre, 09606-045, Brazil
| | - Krzysztof Klos
- Department of Infectious Diseases and Allergology - Military Institute of Medicine, Warsaw, Poland
| | - Wojciech Wlodarczyk
- Department of Infectious Diseases and Allergology - Military Institute of Medicine, Warsaw, Poland
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Dariusz Soldacki
- Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Andrzej Chcialowski
- Department of Infectious Diseases and Allergology - Military Institute of Medicine, Warsaw, Poland
| | - Jolanta M Siller-Matula
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090, Vienna, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland.
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17
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Li S, Zhang F, Lin R, Sun Q, Qu L, Zhong L. Shared Immune Associations Between COVID-19 and Inflammatory Bowel Disease: A Cross-Sectional Observational Study in Shanghai, China. J Inflamm Res 2024; 17:1929-1940. [PMID: 38558943 PMCID: PMC10981870 DOI: 10.2147/jir.s449746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 03/20/2024] [Indexed: 04/04/2024] Open
Abstract
Purpose The rapid global spread of the SARS-CoV-2 Omicron variant introduces a novel complication: the emergence of IBD (inflammatory bowel disease)-like ulcers in certain patients. This research delves into this new challenge by juxtaposing the clinical manifestations and genetic expression patterns of individuals affected by the Omicron variant of COVID-19 with those diagnosed with IBD. It aims to decode the link between these conditions, potentially shedding light on previously unexplored facets of COVID-19 pathophysiology. This investigation emphasizes gene expression analysis as a key tool to identify wider disease correlations and innovative therapeutic avenues. Patients and Methods From March to December 2022, patients with SARS-CoV-2 Omicron infection and inflammatory bowel disease and healthy controls were recruited in Shanghai East Hospital, Shanghai, China. The epidemiological and clinical characteristics of the patients were compared. Four RNA sequencing datasets (GSE205244, GSE201530, GSE174159, and GSE186507) were extracted from the Gene Expression Omnibus database to detect mutually differentially expressed genes and common pathways in patients with SARS-CoV-2 infection and inflammatory bowel disease. Results Compared to patients with active inflammatory bowel disease, patients with SARS-CoV-2 infection were more likely to have elevated interferon-α levels and an increased lymphocyte count and less likely to have high interleukin-6, tumor necrosis factor-α, and C-reactive protein levels and an elevated neutrophil count. A total of 51 common differentially expressed genes were identified in the four RNA-sequencing datasets. Enrichment analysis suggested that these genes were related to inflammation and the immune response, especially the innate immune response and nucleotide oligomerization domain-like receptor signaling pathway. Conclusion The inflammation and immune-response pathways in COVID-19 and inflammatory bowel disease have several similarities and some differences. The study identifies the NLR signaling pathway's key role in both COVID-19 and IBD, suggesting its potential as a target for therapeutic intervention and vaccine development.
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Affiliation(s)
- Shan Li
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Fengdi Zhang
- Department of Infectious Diseases, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Ritian Lin
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Qinjuan Sun
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Lihong Qu
- Department of Infectious Diseases, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Lan Zhong
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
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18
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Bektaş M, Ay M, Hamdi Uyar M, İkbal Kılıç M. Combination therapy of high-dose intravenous anakinra and baricitinib in patients with critical COVID-19: Promising results from retrospective observational study. Int Immunopharmacol 2024; 129:111586. [PMID: 38309091 DOI: 10.1016/j.intimp.2024.111586] [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: 11/18/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/05/2024]
Abstract
INTRODUCTION In this study, we aimed to evaluate the safety and efficacy of combination treatment of high-dose intravenous anakinra and baricitinib in patients with critically ill COVID-19. MATERIAL AND METHODS This retrospective observational study was conducted in a tertiary center with diagnosis of COVID-19 patients.Study population consisted of patients with positive polymerase chain reaction and computer tomography findings compatible with COVID-19 as well as critical illness. RESULTS Data of 15 patients in combination group and 43 patients in control group were evaluated and included into the study. Overall mortality was 46.7 % (n = 7) in combination arm and 69.8 % (n = 30) in control group although it was not statistically significant (p = 0.1). Similarly, need of intubation was also lower in combination arm (46.7 %) compared to control group (69.8 %), it was not significantly different (p = 0.1). ICU admission was significantly lower in combination (46.7 %, n = 7) arm than control group (76.7 %, n = 33) (p = 0.03, Odds ratio [OR]:4.7). Development of severe infection (20 %, n = 3 vs 25 %, n = 9/36), pulmonary embolism (6.7 %, n = 1 vs 0), myocardial infarction (6.7 %, n = 1 vs 2.6 %, n = 1/38) and pneumothorax (13.3 %, n = 2 vs 2.6 %, n = 1/38) were not different between two groups (p = 0.7, p = 0.3, p = 0.5 and p = 0.2). In multivariable analysis only cHIS score was associated with high mortality (p = 0.018, OR:2.8, [95 % confidence interval: 1.2-6.6]). In survival analysis, mortality rate was significantly lower in combination arm than control group (Log-Rank:p = 0.04). CONCLUSION Combination therapy of high-dose anakinra and baricitinib may be an adequate treatment option in patients with COVID-19 who had critical disease and has acceptable safety profile.
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Affiliation(s)
- Murat Bektaş
- Division of Rheumatology, Department of Internal Medicine, Istanbul Aydın University, Istanbul, Turkey; Division of Rheumatology, Department of Internal Medicine, Aksaray Training and Research Hospital, Aksaray, Turkey.
| | - Mustafa Ay
- Department of Emergency Medicine, Aksaray Training and Research Hospital, Aksaray, Turkey
| | - Muhammed Hamdi Uyar
- Department of Emergency Medicine, Aksaray Training and Research Hospital, Aksaray, Turkey
| | - Muhammed İkbal Kılıç
- Department of Internal Medicine, Aksaray Training and Research Hospital, Aksaray, Turkey
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19
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Suriya U, Mahalapbutr P, Geronikaki A, Kartsev V, Zubenko A, Divaeva L, Chekrisheva V, Petrou A, Oopkaew L, Somngam P, Choowongkomon K, Rungrotmongkol T. Discovery of furopyridine-based compounds as novel inhibitors of Janus kinase 2: In silico and in vitro studies. Int J Biol Macromol 2024; 260:129308. [PMID: 38218283 DOI: 10.1016/j.ijbiomac.2024.129308] [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: 09/01/2023] [Revised: 12/29/2023] [Accepted: 01/05/2024] [Indexed: 01/15/2024]
Abstract
Janus kinase 2 (JAK2), one of the JAK isoforms participating in a JAK/STAT signaling cascade, has been considered a potential clinical target owing to its critical role in physiological processes involved in cell growth, survival, development, and differentiation of various cell types, especially immune and hematopoietic cells. Substantial studies have proven that the inhibition of this target could disrupt the JAK/STAT pathway and provide therapeutic outcomes for cancer, immune disorders, inflammation, and COVID-19. Herein, we performed docking-based virtual screening of 63 in-house furopyridine-based compounds and verified the first-round screened compounds by in vitro enzyme- and cell-based assays. By shedding light on the integration of both in silico and in vitro methods, we could elucidate two promising compounds. PD19 showed cytotoxic effects on human erythroblast cell lines (TF-1 and HEL) with IC50 values of 57.27 and 27.28 μM, respectively, while PD12 exhibited a cytotoxic effect on TF-1 with an IC50 value of 83.47 μM by suppressing JAK2/STAT5 autophosphorylation. In addition, all screened compounds were predicted to meet drug-like criteria based on Lipinski's rule of five, and none of the extreme toxicity features were found. Molecular dynamic simulations revealed that PD12 and PD19 could form stable complexes with JAK2 in an aqueous environment, and the van der Waals interactions were the main force driving the complex formation. Besides, all compounds sufficiently interacted with surrounding amino acids in all crucial regions, including glycine, catalytic, and activation loops. Altogether, PD12 and PD19 identified here could potentially be developed as novel therapeutic inhibitors disrupting the JAK/STAT pathway.
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Affiliation(s)
- Utid Suriya
- Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Panupong Mahalapbutr
- Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khan Kaen 40002, Thailand.
| | - Athina Geronikaki
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Greece
| | | | - Alexsander Zubenko
- North-Caucasian Zonal Research Veterinary Institute, 346406 Novocherkassk, Russia
| | - Liudmila Divaeva
- Institute of Physical and Organic Chemistry, Southern Federal University, Rostov-on-Don, 344090, Russia
| | - Victoria Chekrisheva
- North-Caucasian Zonal Research Veterinary Institute, 346406 Novocherkassk, Russia
| | - Anthi Petrou
- Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Greece
| | - Lipika Oopkaew
- Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Phitchakorn Somngam
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
| | - Thanyada Rungrotmongkol
- Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Chulalongkorn University, Bangkok 10330, Thailand; Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
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Mansour HM. The interference between SARS-COV-2 and Alzheimer's disease: Potential immunological and neurobiological crosstalk from a kinase perspective reveals a delayed pandemic. Ageing Res Rev 2024; 94:102195. [PMID: 38244862 DOI: 10.1016/j.arr.2024.102195] [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: 11/14/2022] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 01/22/2024]
Abstract
Coronavirus disease 2019 (COVID-19) has infected over 700 million people, with up to 30% developing neurological manifestations, including dementias. However, there is a lack of understanding of common molecular brain markers causing Alzheimer's disease (AD). COVID-19 has etiological cofactors with AD, making patients with AD a vulnerable population at high risk of experiencing more severe symptoms and worse consequences. Both AD and COVID-19 have upregulated several shared kinases, leading to the repositioning of kinase inhibitors (KIs) for the treatment of both diseases. This review provides an overview of the interactions between the immune system and the nervous system in relation to receptor tyrosine kinases, including epidermal growth factor receptors, vascular growth factor receptors, and non-receptor tyrosine kinases such as Bruton tyrosine kinase, spleen tyrosine kinase, c-ABL, and JAK/STAT. We will discuss the promising results of kinase inhibitors in pre-clinical and clinical studies for both COVID-19 and Alzheimer's disease (AD), as well as the challenges in repositioning KIs for these diseases. Understanding the shared kinases between AD and COVID-19 could help in developing therapeutic approaches for both.
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Affiliation(s)
- Heba M Mansour
- General Administration of Innovative Products, Central Administration of Biological, Innovative Products, and Clinical Studies (Bio-INN), Egyptian Drug Authority (EDA), Giza, Egypt.
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21
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Aliska G, Putra AE, Anggrainy F, Lailani M. The exploration of glucocorticoid pathway based on disease severity in COVID-19 patients. Heliyon 2024; 10:e23579. [PMID: 38187222 PMCID: PMC10770556 DOI: 10.1016/j.heliyon.2023.e23579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Systemic inflammation is a hallmark of Coronavirus Disease 2019 (COVID-19) and is the key to the pathophysiology of its severe cases with host cytokine involvement. Glucocorticoids can moderate this inflammatory effect due to receptor binding (NRC31-the gene encoded), influencing the expression of effector genes and pro-inflammatory cytokines. Another important pathway in the processes of the immune and inflammatory responses is nuclear factor-κB (NF-κB) signaling (NFKBIA-the gene encoded). We aimed to explore the expression of genes in the glucocorticoid pathway in mild and severe COVID-19. We performed a cross-sectional, observational study on COVID-19 cases, assessing the expression of RNA in white blood cells. The Illumina® platform was used for RNA sequencing, and FASTQ data were quality-checked with Multiqc. The raw data were analyzed using CLC Genomics Workbench®. Our study included 23 patients with severe COVID-19 and 21 patients with mild COVID-19 with an average age of 49.9 ± 18.2 years old. The NR3C1 and NFKBIA expressions did not show a significantly significant difference between groups (log2 fold change 0.5, p = 0.1; 0.82, p = 0.09). However, the expressions of TSC22D3, DUSP-1, JAK-1 and MAPK-1 were significantly higher in mild cases (log2 fold change 1.3, p < 0.001; 2.6, p < 0.001; 0.9, p < 0.001; 1.48, p-value<0.001; respectively). Furthermore, the TNF, IL-1β, and IL-6 expressions were significantly lower in mild cases (log2 fold change 4.05, p < 0.001; 3.33, p < 0.001; 6.86, p < 0.001; respectively). In conclusion, our results showed that although the NRC31 and NFKBIA expressions did not show a statistically significant difference between groups, the expression of TSC22D3 was higher in mild cases. These results highlight the importance of effector genes, specifically TSC22D3, in combatting systemic inflammation. Our recent findings have the potential to lead to the identification of novel pharmacological targets that could prove to be vital in the fight against diseases associated with inflammation.
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Affiliation(s)
- Gestina Aliska
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Andalas, Padang, 25176, Indonesia
- Centre for Diagnostic and Research on Infectious Disease (PDRPI), Faculty of Medicine, Universitas Andalas, Padang, Indonesia
- Department of Clinical Pharmacology, Dr. M. Djamil General Hospital, Padang, Indonesia
| | - Andani Eka Putra
- Centre for Diagnostic and Research on Infectious Disease (PDRPI), Faculty of Medicine, Universitas Andalas, Padang, Indonesia
- Department of Microbiology, Faculty of Medicine, Universitas Andalas, Padang, 2517, Indonesia
| | - Fenty Anggrainy
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Andalas, Padang, 2517, Indonesia
| | - Mutia Lailani
- Centre for Diagnostic and Research on Infectious Disease (PDRPI), Faculty of Medicine, Universitas Andalas, Padang, Indonesia
- Department of Physiology, Faculty of Medicine, Universitas Andalas, Padang, 2517, Indonesia
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22
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Yang S, Fan Z, Lu X, Liu H, Zhou Z, Qi H, Zeng J, Zheng M, Zou X, Fang S, Zhang G. Response of Human Retinal Microvascular Endothelial Cells to Influenza A (H1N1) Infection and the Underlying Molecular Mechanism. Invest Ophthalmol Vis Sci 2024; 65:38. [PMID: 38252524 PMCID: PMC10810132 DOI: 10.1167/iovs.65.1.38] [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: 10/07/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Purpose Whether H1N1 infection-associated ocular manifestations result from direct viral infections or systemic complications remains unclear. This study aimed to comprehensively elucidate the underlying causes and mechanism. Method TCID50 assays was performed at 24, 48, and 72 hours to verify the infection of H1N1 in human retinal microvascular endothelial cells (HRMECs). The changes in gene expression profiles of HRMECs at 24, 48, and 72 hours were characterized using RNA sequencing technology. Differentially expressed genes (DEGs) were validated using real-time quantitative polymerase chain reaction and Western blotting. CCK-8 assay and scratch assay were performed to evaluate whether there was a potential improvement of proliferation and migration in H1N1-infected cells after oseltamivir intervention. Results H1N1 can infect and replicate within HRMECs, leading to cell rounding and detachment. After H1N1 infection of HRMECs, 2562 DEGs were identified, including 1748 upregulated ones and 814 downregulated ones. These DEGs primarily involved in processes such as inflammation and immune response, cytokine-cytokine receptor interaction, signal transduction regulation, and cell adhesion. The elevated expression levels of CXCL10, CXCL11, CCL5, TLR3, C3, IFNB1, IFNG, STAT1, HLA, and TNFSF10 after H1N1 infection were reduced by oseltamivir intervention, reaching levels comparable to those in the uninfected group. The impaired cell proliferation and migration after H1N1 infection was improved by oseltamivir intervention. Conclusions This study confirmed that H1N1 can infect HRMECs, leading to the upregulation of chemokines, which may cause inflammation and destruction of the blood-retina barrier. Moreover, early oseltamivir administration may reduce retinal inflammation and hemorrhage in patients infected with H1N1.
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Affiliation(s)
- Shuo Yang
- Jinzhou Medical University, Jinzhou, Liaoning, China
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Zixin Fan
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Xiaofeng Lu
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Hui Liu
- Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
| | - Ziying Zhou
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Hui Qi
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Jian Zeng
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Mianying Zheng
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
| | - Xuan Zou
- Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
| | - Shisong Fang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
| | - Guoming Zhang
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, Guangdong, China
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23
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Yazdanpanah N, Sedikides C, Ochs HD, Camargo CA, Darmstadt GL, Cerda A, Cauda V, Peters GJ, Sellke F, Wong ND, Comini E, Jimeno AR, Glover V, Hatziargyriou N, Vincenot CE, Bordas SPA, Rao IM, Abolhassani H, Gharehpetian GB, Weiskirchen R, Gupta M, Chandel SS, Olusanya BO, Cheson B, Pomponio A, Tanzer M, Myles PS, Ma WX, Bella F, Ghavami S, Moein Moghimi S, Pratico D, Hernandez AM, Martinez-Urbistondo M, Urbistondo DM, Fereshtehnejad SM, Ali I, Kimura S, Wallace Hayes A, Cai W, Ernest CKJ, Thomas S, Rahimi K, Sorooshian A, Schreiber M, Kato K, Luong JHT, Pluchino S, Lozano AM, Seymour JF, Kosik KS, Hofmann SG, McIntyre RS, Perc M, Leemans A, Klein RS, Ogino S, Wlezien C, Perry G, Nieto JJ, Levin L, Klionsky DJ, Mobasher B, Dorigo T, Rezaei N. Global Challenges After a Global Challenge: Lessons Learned from the COVID-19 Pandemic. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1457:1-31. [PMID: 39283418 DOI: 10.1007/978-3-031-61939-7_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Coronavirus disease 2019 (COVID-19) has affected not only individual lives but also the world and global systems, both natural and human-made. Besides millions of deaths and environmental challenges, the rapid spread of the infection and its very high socioeconomic impact have affected healthcare, economic status and wealth, and mental health across the globe. To better appreciate the pandemic's influence, multidisciplinary and interdisciplinary approaches are needed. In this chapter, world-leading scientists from different backgrounds share collectively their views about the pandemic's footprint and discuss challenges that face the international community.
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Affiliation(s)
- Niloufar Yazdanpanah
- , Houston, USA
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hans D Ochs
- , Houston, USA
- Department of Pediatrics, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA, USA
| | - Carlos A Camargo
- , Houston, USA
- Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Gary L Darmstadt
- , Houston, USA
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Artemi Cerda
- , Houston, USA
- Soil Erosion and Degradation Research Group, Department of Geography, Valencia University, Blasco Ibàñez, Valencia, Spain
| | - Valentina Cauda
- , Houston, USA
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi, Turin, Italy
| | - Godefridus J Peters
- , Houston, USA
- Laboratory Medical Oncology, Amsterdam University Medical Centers, Location VUMC, Amsterdam, the Netherlands
- Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland
| | - Frank Sellke
- , Houston, USA
- Warren Alpert Medical School, Brown University, Providence, RI, USA
- Division of Cardiothoracic Surgery, Rhode Island Hospital, Providence, RI, USA
| | - Nathan D Wong
- , Houston, USA
- Heart Disease Prevention Program, Division of Cardiology, University of California Irvine, C-240 Medical Sciences, Irvine, CA, USA
| | - Elisabetta Comini
- , Houston, USA
- SENSOR Laboratory, University of Brescia, Brescia, Italy
| | - Alberto Ruiz Jimeno
- , Houston, USA
- Instituto de Física de Cantabria (IFCA), CSIC-Universidad de Cantabria, Santander, Spain
| | - Vivette Glover
- , Houston, USA
- Department of Metabolism, Digestion and Reproduction Hammersmith Hospital Campus, Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
| | - Nikos Hatziargyriou
- , Houston, USA
- School of Electrical and Computer Engineering, National Technical University of Athens (NTUA), Athens, Greece
| | - Christian E Vincenot
- , Houston, USA
- Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, Esch-sur-Alzette, Grand Duchy of Luxembourg
| | - Stéphane P A Bordas
- , Houston, USA
- Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, Esch-sur-Alzette, Grand Duchy of Luxembourg
| | - Idupulapati M Rao
- , Houston, USA
- Alliance of Bioversity International, International Center for Tropical Agriculture, Cali, Colombia
- International Centre of Insect Physiology and Ecology (ICIPE), Nairobi, Kenya
| | - Hassan Abolhassani
- , Houston, USA
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | | | - Ralf Weiskirchen
- , Houston, USA
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Manoj Gupta
- , Houston, USA
- Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore
| | - Shyam Singh Chandel
- , Houston, USA
- Photovoltaics Research Group, Centre of Excellence in Energy Science and Technology, Shoolini University, Solan, Himachal Pradesh, 173212, India
| | | | - Bruce Cheson
- , Houston, USA
- Center for Cancer and Blood Disorders, Bethesda, MD, USA
| | - Alessio Pomponio
- , Houston, USA
- Dipartimento di Meccanica, Matematica e Management, Politecnico di Bari, Bari, Italy
| | - Michael Tanzer
- , Houston, USA
- Division of Orthopedic Surgery, McGill University, Montreal, QC, Canada
| | - Paul S Myles
- , Houston, USA
- Alfred Hospital and Monash University, Melbourne, Australia
| | - Wen-Xiu Ma
- , Houston, USA
- Department of Mathematics and Statistics, University of South Florida, Tampa, FL, USA
- Department of Mathematics, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Material Science Innovation and Modelling, North-West University, Mafikeng Campus, Mmabatho, 2735, South Africa
| | - Federico Bella
- , Houston, USA
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi, Turin, Italy
| | - Saeid Ghavami
- , Houston, USA
- Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada
| | - S Moein Moghimi
- , Houston, USA
- School of Pharmacy, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
- Faculty of Health and Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
- Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Domenico Pratico
- , Houston, USA
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Alfredo M Hernandez
- , Houston, USA
- Medicine and Endocrinology Department, Universidad de Valladolid and IMDEA, Madrid, Spain
| | | | | | - Seyed-Mohammad Fereshtehnejad
- , Houston, USA
- Division of Neurology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Division of Clinical Geriatrics, NVS Department, Karolinska Institutet, Stockholm, Sweden
| | - Imran Ali
- , Houston, USA
- Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi, India
| | - Shinya Kimura
- , Houston, USA
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - A Wallace Hayes
- , Houston, USA
- Center for Environmental/Occupational Risk Analysis and Management, College of Public Health, University of South Florida, Tampa, FL, 33612, USA
- Michigan State University, East Lansing, MI, USA
| | - Wenju Cai
- , Houston, USA
- CSIRO Environment, Hobart, TAS, Australia
| | - Chua K J Ernest
- , Houston, USA
- Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore
| | - Sabu Thomas
- , Houston, USA
- School of Energy Materials, Mahatma Gandhi University, Kottayam, Kerala, India
| | - Kazem Rahimi
- , Houston, USA
- Deep Medicine, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | - Armin Sorooshian
- , Houston, USA
- Department of Chemical and Environmental Engineering, University of Arizona, Tucson, AZ, USA
| | - Michael Schreiber
- , Houston, USA
- Institut für Physik, Technische Universität Chemnitz, 09107, Chemnitz, Germany
| | - Koichi Kato
- , Houston, USA
- Exploratory Research Center on Life and Living Systems (ExCELLS) and Institute for Molecular Science (IMS), National Institutes of Natural Sciences, Okazaki, Aichi, Japan
| | - John H T Luong
- , Houston, USA
- School of Chemistry, University College Cork, Cork, T12 YN60, Ireland
| | - Stefano Pluchino
- , Houston, USA
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Andres M Lozano
- , Houston, USA
- Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
- Krembil Research Institute, Toronto, ON, Canada
| | - John F Seymour
- , Houston, USA
- Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - Kenneth S Kosik
- , Houston, USA
- Department of Molecular Cellular Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, CA, USA
| | - Stefan G Hofmann
- , Houston, USA
- Department of Psychology, Philipps-University Marburg, Marburg, Germany
| | - Roger S McIntyre
- , Houston, USA
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Matjaz Perc
- , Houston, USA
- Faculty of Natural Sciences and Mathematics, University of Maribor, Koroška cesta 160, Maribor, Slovenia
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404332, Taiwan
- Alma Mater Europaea, Slovenska ulica 17, 2000, Maribor, Slovenia
- Complexity Science Hub Vienna, Josefstädterstraße 39, 1080, Vienna, Austria
- Department of Physics, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Republic of Korea
| | - Alexander Leemans
- , Houston, USA
- Image Sciences Institute, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Robyn S Klein
- , Houston, USA
- Center for Neuroimmunology and Neuroinfectious Diseases, St. Louis, MO, USA
- Departments of Medicine, Pathology and Immunology, and Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
| | - Shuji Ogino
- , Houston, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Christopher Wlezien
- , Houston, USA
- Department of Government, University of Texas at Austin, Austin, TX, USA
| | - George Perry
- , Houston, USA
- Department of Neuroscience, Developmental and Regenerative Biology, University of Texas at San Antonio, San Antonio, TX, USA
| | - Juan J Nieto
- , Houston, USA
- CITMAga, University of Santiago de Compostela, A Coruña, Spain
| | - Lisa Levin
- , Houston, USA
- Center for Marine Biodiversity and Conservation, Integrative Oceanography Division, Scripps Institution of Oceanography, University of California, San Diego, San Diego, CA, USA
| | - Daniel J Klionsky
- , Houston, USA
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Bahram Mobasher
- , Houston, USA
- Department of Physics and Astronomy, University of California, Riverside, CA, USA
| | - Tommaso Dorigo
- , Houston, USA
- Lulea University of Technology, Laboratorievagen 14, Lulea, Sweden
- Istituto Nazionale di Fisica Nucleare (INFN), Via Francesco Marzolo, Sezione di Padova, Italy
| | - Nima Rezaei
- , Houston, USA.
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
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24
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Huang H, Chen R, Xu Y, Fang N, Shao C, Xu K, Wang M. The Clinical Analysis of Checkpoint Inhibitor Pneumonitis with Different Severities in Lung Cancer Patients: A Retrospective Study. J Clin Med 2024; 13:255. [PMID: 38202262 PMCID: PMC10779509 DOI: 10.3390/jcm13010255] [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: 11/15/2023] [Revised: 12/17/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Immune-related adverse events (irAEs) of immunotherapy would lead to the temporary or permanent discontinuation of immune checkpoint inhibitors (ICIs). Among them, checkpoint inhibitor pneumonitis (CIP) is a potentially life-threatening irAE. This study aimed to identify the differences between patients with low-grade CIPs (grades 1-2) and high-grade CIPs (grades 3-5) and to explore the prognostic factors. We retrospectively reviewed the medical records of 916 lung cancer patients who were treated with ICIs. Patients with CIPs were identified after multidisciplinary discussion, and their clinical, laboratory, radiological, and follow-up data were analyzed. Among the 74 enrolled CIP patients, there were 31 low-grade CIPs and 43 high-grade CIPs. Compared with low-grade CIP patients, patients with high-grade CIPs were older (65.8 years vs. 61.5 years) and had lower serum albumin (35.2 g/L vs. 37.9 g/L), higher D-dimer (5.1 mg/L vs. 1.7 mg/L), and more pulmonary infectious diseases (32.6% vs. 6.5%) during follow-up. In addition, complication with pulmonary infectious diseases, management with intravenous immunoglobulin, tocilizumab, and longer duration of large dosage corticosteroids might be associated with worse outcomes for patients with CIPs. This study highlights potential risk factors for high-grade CIP and poor prognosis among lung cancer patients who were treated with anti-cancer ICIs.
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Affiliation(s)
- Hui Huang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (H.H.); (R.C.)
| | - Ruxuan Chen
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (H.H.); (R.C.)
| | - Yan Xu
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (H.H.); (R.C.)
| | - Nan Fang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Chi Shao
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (H.H.); (R.C.)
| | - Kai Xu
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Mengzhao Wang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (H.H.); (R.C.)
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25
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Mostafa N, Elsherbiny Badr M, Shaker OG, Elsaid G, Shemies RS, Khedr D, Abuelfadl HG, Elsherbeny ME. The association of Sirtuin1 (SIRT1) polymorphism and downregulation of STAT4 gene expression with increased susceptibility to COVID-19 infection. EGYPTIAN JOURNAL OF BASIC AND APPLIED SCIENCES 2023; 10:711-721. [DOI: 10.1080/2314808x.2023.2254507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/23/2023] [Indexed: 01/02/2025]
Affiliation(s)
- Nora Mostafa
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - May Elsherbiny Badr
- Anesthesiology, Surgical ICU and Pain Management Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Olfat G. Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ghada Elsaid
- Internal Medicine and Nephrology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rasha Samir Shemies
- Mansoura Nephrology and Dialysis Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Doaa Khedr
- Diagnostic Radiology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hend Gamal Abuelfadl
- Diagnostic Radiology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mona Elhelaly Elsherbeny
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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26
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Wang X, Wei Y, He Z, Wang D, Zhang L, Du J, Zhang M, Jiang M, Chen N, Deng M, Li B, Song C, Chen D, Liu H, Xiao J, Liang H, Zhao H, Kong Y. CD70-induced differentiation of proinflammatory Th1/17/22/GM lymphocytes associated with disease progression and immune reconstitution during HIV infection. Emerg Microbes Infect 2023; 12:2271068. [PMID: 37824079 PMCID: PMC10606822 DOI: 10.1080/22221751.2023.2271068] [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: 05/17/2023] [Accepted: 10/11/2023] [Indexed: 10/13/2023]
Abstract
Immune overactivation is a hallmark of chronic HIV infection, which is critical to HIV pathogenesis and disease progression. The imbalance of helper T cell (Th) differentiation and subsequent cytokine dysregulation are generally considered to be the major drivers of excessive activation and inflammatory disorders in HIV infection. However, the accurate factors driving HIV-associated Th changes remained to be established. CD70, which was a costimulatory molecule, was found to increase on CD4+ T cells during HIV infection. Overexpression of CD70 on CD4+ T cells was recently reported to associate with highly pathogenic proinflammatory Th1/Th17 polarization in multiple sclerosis. Thus, the role of CD70 in the imbalance of Th polarization and immune overactivation during HIV infection needs to be investigated. Here, we found that the elevated frequency of CD70 + CD4+ T cells was negatively correlated with CD4 count and positively associated with immune activation in treatment-naïve people living with HIV (PLWH). More importantly, CD70 expression defined a population of proinflammatory Th1/17/22/GM subsets in PLWH. Blocking CD70 decreased the mRNA expression of subset-specific markers during Th1/17/22/GM polarization. Furthermore, we demonstrated that CD70 influenced the differentiation of these Th cells through STAT pathway. Finally, it was revealed that patients with a high baseline level of CD70 on CD4+ T cells exhibited a greater risk of poor immune reconstitution after antiretroviral therapy (ART) than those with low CD70. In general, our data highlighted the role of CD70 in Th1/17/22/GM differentiation during HIV infection and provided evidence for CD70 as a potential biomarker for predicting immune recovery.
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Affiliation(s)
- Xinyue Wang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Yuqing Wei
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Zhijiao He
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Di Wang
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Leidan Zhang
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Juan Du
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Mengyuan Zhang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Meiqing Jiang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Na Chen
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Meiju Deng
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Bei Li
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Chuan Song
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Danying Chen
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Huan Liu
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
| | - Jiang Xiao
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Hongyuan Liang
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Hongxin Zhao
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Yaxian Kong
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Institute of Infectious Diseases, Beijing, People’s Republic of China
- National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing, People’s Republic of China
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27
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Ghosh MK, Tabassum S, Basu M. COVID‐19 and cancer: Dichotomy of the menacing dilemma. MEDCOMM – ONCOLOGY 2023; 2. [DOI: 10.1002/mog2.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/26/2023] [Indexed: 01/05/2025]
Abstract
AbstractThe coronavirus disease 2019 (COVID‐19) pandemic brought about unprecedented challenges to global healthcare systems. Among the most vulnerable populations are cancer patients, who face dilemmas due to their compromised immune systems and the intricate interplay with the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus. This comprehensive review delves into the multifaceted relationship between COVID‐19 and cancer. Through an analysis of existing literature and clinical data, this review unravels the structural intricacies of the virus and examines its profound implications for cancer patients, thereby bridging the knowledge gap between virology and oncology. The review commences with an introduction regarding the COVID‐19 pandemic and cancer. It then transitions into a detailed examination of the SARS‐CoV‐2 virus and its variants such as Alpha (PANGO lineage B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529 lineage). Subsequently, an insightful analysis of the impact of COVID‐19 on major cancer types (viz., Lung, Colon, Brain, and gastrointestinal cancer) is elaborated. Finally, the therapeutic avenues, oncological care, and management are discussed. The nexus between COVID‐19 and cancer adds a layer of complexity to patient care, emphasizing the importance of tailored approaches for those grappling with both conditions. Amid the landscape defined by the evolving viral strains, this review navigates through the multifaceted implications of COVID‐19 on cancer patients and underscores the significance of integrating virology and oncology.
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Affiliation(s)
- Mrinal K. Ghosh
- Cancer Biology and Inflammatory Disorder Division Council of Scientific and Industrial Research‐Indian Institute of Chemical Biology (CSIR‐IICB) Kolkata West Bengal India
| | - Shaheda Tabassum
- Cancer Biology and Inflammatory Disorder Division Council of Scientific and Industrial Research‐Indian Institute of Chemical Biology (CSIR‐IICB) Kolkata West Bengal India
| | - Malini Basu
- Department of Microbiology Dhruba Chand Halder College Dakshin Barasat West Bengal India
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28
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Kaur H, Singh M. Functional foods as immunomodulators: Tackling the SARS-CoV-2 related cytokine storm–A review. FOOD CHEMISTRY ADVANCES 2023; 3:100407. [DOI: 10.1016/j.focha.2023.100407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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29
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Li Y, Han L, Li P, Ge J, Xue Y, Chen L. Potential network markers and signaling pathways for B cells of COVID-19 based on single-cell condition-specific networks. BMC Genomics 2023; 24:619. [PMID: 37853311 PMCID: PMC10583333 DOI: 10.1186/s12864-023-09719-1] [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: 02/27/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
To explore the potential network markers and related signaling pathways of human B cells infected by COVID-19, we performed standardized integration and analysis of single-cell sequencing data to construct conditional cell-specific networks (CCSN) for each cell. Then the peripheral blood cells were clustered and annotated based on the conditional network degree matrix (CNDM) and gene expression matrix (GEM), respectively, and B cells were selected for further analysis. Besides, based on the CNDM of B cells, the hub genes and 'dark' genes (a gene has a significant difference between case and control samples not in a gene expression level but in a conditional network degree level) closely related to COVID-19 were revealed. Interestingly, some of the 'dark' genes and differential degree genes (DDGs) encoded key proteins in the JAK-STAT pathway, which had antiviral effects. The protein p21 encoded by the 'dark' gene CDKN1A was a key regulator for the COVID-19 infection-related signaling pathway. Elevated levels of proteins encoded by some DDGs were directly related to disease severity of patients with COVID-19. In short, the proteins encoded by 'dark' genes complement some missing links in COVID-19 and these signaling pathways played an important role in the growth and activation of B cells.
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Affiliation(s)
- Ying Li
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang, 471023, China
- Longmen Laboratory, Luoyang, 471003, Henan, China
| | - Liqin Han
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang, 471023, China
- Longmen Laboratory, Luoyang, 471003, Henan, China
| | - Peiluan Li
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang, 471023, China.
- Longmen Laboratory, Luoyang, 471003, Henan, China.
| | - Jing Ge
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Yun Xue
- College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, 471023, China
| | - Luonan Chen
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 201100, China.
- Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201100, China.
- West China Biomedical Big Data Center, Med-X Center for Informatics, West China Hospital, Sichuan University, Chengdu, 610041, China.
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30
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Hashemian SMR, Farhadi T. A narrative review on tofacitinib: The properties, function, and usefulness to treat coronavirus disease 2019. Int J Crit Illn Inj Sci 2023; 13:192-198. [PMID: 38292399 PMCID: PMC10824201 DOI: 10.4103/ijciis.ijciis_27_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/10/2023] [Accepted: 08/20/2023] [Indexed: 02/01/2024] Open
Abstract
In coronavirus disease 2019 (COVID-19), the formation of cytokine storm may have a role in worsening of the disease. By attaching the cytokines like interleukin-6 to the cytokine receptors on a cell surface, Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway will be activated in the cytoplasm lead to hyperinflammatory conditions and acute respiratory distress syndrome. Inhibition of JAK/STAT pathway may be useful to prevent the formation of cytokine storm. Tofacitinib is a pan inhibitor of JAKs. In this review, the main characteristics of tofacitinib and its usefulness against COVID-19 pneumonia were reviewed. Tofacitinib may be a hopeful therapeutic candidate against COVID-19 respiratory injury since it inhibits a range of inflammatory pathways. Hence, the agent may be considered a potential therapeutic against the post-COVID-19 respiratory damage. Compared to other JAK inhibitors (JAKi), the administration of tofacitinib in COVID-19 patients may be safer and more effective. Other JAKi such as baricitinib are related to severe adverse events such as thrombotic events compared to more common side effects of tofacitinib.
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Affiliation(s)
- Seyed Mohammad Reza Hashemian
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Disease, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayebeh Farhadi
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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31
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Kartchner D, McCoy K, Dubey J, Zhang D, Zheng K, Umrani R, Kim JJ, Mitchell CS. Literature-Based Discovery to Elucidate the Biological Links between Resistant Hypertension and COVID-19. BIOLOGY 2023; 12:1269. [PMID: 37759668 PMCID: PMC10526006 DOI: 10.3390/biology12091269] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/11/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023]
Abstract
Multiple studies have reported new or exacerbated persistent or resistant hypertension in patients previously infected with COVID-19. We used literature-based discovery to identify and prioritize multi-scalar explanatory biology that relates resistant hypertension to COVID-19. Cross-domain text mining of 33+ million PubMed articles within a comprehensive knowledge graph was performed using SemNet 2.0. Unsupervised rank aggregation determined which concepts were most relevant utilizing the normalized HeteSim score. A series of simulations identified concepts directly related to COVID-19 and resistant hypertension or connected via one of three renin-angiotensin-aldosterone system hub nodes (mineralocorticoid receptor, epithelial sodium channel, angiotensin I receptor). The top-ranking concepts relating COVID-19 to resistant hypertension included: cGMP-dependent protein kinase II, MAP3K1, haspin, ral guanine nucleotide exchange factor, N-(3-Oxododecanoyl)-L-homoserine lactone, aspartic endopeptidases, metabotropic glutamate receptors, choline-phosphate cytidylyltransferase, protein tyrosine phosphatase, tat genes, MAP3K10, uridine kinase, dicer enzyme, CMD1B, USP17L2, FLNA, exportin 5, somatotropin releasing hormone, beta-melanocyte stimulating hormone, pegylated leptin, beta-lipoprotein, corticotropin, growth hormone-releasing peptide 2, pro-opiomelanocortin, alpha-melanocyte stimulating hormone, prolactin, thyroid hormone, poly-beta-hydroxybutyrate depolymerase, CR 1392, BCR-ABL fusion gene, high density lipoprotein sphingomyelin, pregnancy-associated murine protein 1, recQ4 helicase, immunoglobulin heavy chain variable domain, aglycotransferrin, host cell factor C1, ATP6V0D1, imipramine demethylase, TRIM40, H3C2 gene, COL1A1+COL1A2 gene, QARS gene, VPS54, TPM2, MPST, EXOSC2, ribosomal protein S10, TAP-144, gonadotropins, human gonadotropin releasing hormone 1, beta-lipotropin, octreotide, salmon calcitonin, des-n-octanoyl ghrelin, liraglutide, gastrins. Concepts were mapped to six physiological themes: altered endocrine function, 23.1%; inflammation or cytokine storm, 21.3%; lipid metabolism and atherosclerosis, 17.6%; sympathetic input to blood pressure regulation, 16.7%; altered entry of COVID-19 virus, 14.8%; and unknown, 6.5%.
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Affiliation(s)
- David Kartchner
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Kevin McCoy
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Janhvi Dubey
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Dongyu Zhang
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Kevin Zheng
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Rushda Umrani
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- College of Computing, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - James J. Kim
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
| | - Cassie S. Mitchell
- Laboratory for Pathology Dynamics, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
- Center for Machine Learning at Georgia Tech, Georgia Institute of Technology, Atlanta, GA 30332, USA
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32
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Gonzaga A, Andreu E, Hernández-Blasco LM, Meseguer R, Al-Akioui-Sanz K, Soria-Juan B, Sanjuan-Gimenez JC, Ferreras C, Tejedo JR, Lopez-Lluch G, Goterris R, Maciá L, Sempere-Ortells JM, Hmadcha A, Borobia A, Vicario JL, Bonora A, Aguilar-Gallardo C, Poveda JL, Arbona C, Alenda C, Tarín F, Marco FM, Merino E, Jaime F, Ferreres J, Figueira JC, Cañada-Illana C, Querol S, Guerreiro M, Eguizabal C, Martín-Quirós A, Robles-Marhuenda Á, Pérez-Martínez A, Solano C, Soria B. Rationale for combined therapies in severe-to-critical COVID-19 patients. Front Immunol 2023; 14:1232472. [PMID: 37767093 PMCID: PMC10520558 DOI: 10.3389/fimmu.2023.1232472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.
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Affiliation(s)
- Aitor Gonzaga
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Institute of Bioengineering, Miguel Hernández University, Elche, Spain
| | - Etelvina Andreu
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Applied Physics Department, Miguel Hernández University, Elche, Spain
| | | | - Rut Meseguer
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Clinic University Hospital, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA) Health Research Institute, Valencia, Spain
| | - Karima Al-Akioui-Sanz
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
| | - Bárbara Soria-Juan
- Réseau Hospitalier Neuchâtelois, Hôpital Pourtalès, Neuchâtel, Switzerland
| | | | - Cristina Ferreras
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
| | - Juan R. Tejedo
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Seville, Spain
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) of the Carlos III Health Institute (ISCIII), Madrid, Spain
| | - Guillermo Lopez-Lluch
- University Pablo de Olavide, Centro Andaluz de Biología del Desarrollo - Consejo Superior de Investigaciones Científicas (CABD-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Sevilla, Spain
| | - Rosa Goterris
- Clinic University Hospital, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA) Health Research Institute, Valencia, Spain
| | - Loreto Maciá
- Nursing Department, University of Alicante, Alicante, Spain
| | - Jose M. Sempere-Ortells
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Biotechnology Department, University of Alicante, Alicante, Spain
| | - Abdelkrim Hmadcha
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Seville, Spain
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), Valencia, Spain
| | - Alberto Borobia
- Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAz, Madrid, Spain
| | - Jose L. Vicario
- Transfusion Center of the Autonomous Community of Madrid, Madrid, Spain
| | - Ana Bonora
- Health Research Institute Hospital La Fe, Valencia, Spain
| | | | - Jose L. Poveda
- Health Research Institute Hospital La Fe, Valencia, Spain
| | - Cristina Arbona
- Valencian Community Blood Transfusion Center, Valencia, Spain
| | - Cristina Alenda
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Fabian Tarín
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Francisco M. Marco
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Immunology Department, Dr. Balmis General University Hospital, Alicante, Spain
| | - Esperanza Merino
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Department of Clinical Medicine, Miguel Hernández University, Elche, Spain
- Infectious Diseases Unit, Dr. Balmis General University Hospital, Alicante, Spain
| | - Francisco Jaime
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - José Ferreres
- Intensive Care Service, Hospital Clinico Universitario, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Valencia, Spain
| | | | | | | | - Manuel Guerreiro
- Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Cristina Eguizabal
- Research Unit, Basque Center for Blood Transfusion and Human Tissues, Galdakao, Spain
- Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | | | | | - Antonio Pérez-Martínez
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Carlos Solano
- Hematology Service, Hospital Clínico Universitario, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Valencia, Spain
| | - Bernat Soria
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Institute of Bioengineering, Miguel Hernández University, Elche, Spain
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) of the Carlos III Health Institute (ISCIII), Madrid, Spain
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Almasi S, Rashidi A, Kachuee MA, Shirazi BM, Izadi S, Ghaffarpour S, Azimi M, Naghizadeh MM, Makiani MJ, Ranjbar M, Goudarzi M, Rahimian N, Ghazanfari T. Effect of tofacitinib on clinical and laboratory findings in severe and resistant patients with COVID-19. Int Immunopharmacol 2023; 122:110565. [PMID: 37454635 DOI: 10.1016/j.intimp.2023.110565] [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: 03/04/2023] [Revised: 06/12/2023] [Accepted: 06/23/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND The efficacy and safety of a strong Janus kinase inhibitor, tofacitinib, in individuals suffering from severe coronavirus disease 2019 (Covid-19) pneumonia are not definite well. METHODS In this non-randomized and non-blinded trial, a total of 52 Iranian patients with severe COVID-19 associated with decreased oxygen saturation, elevated C-reactive protein, and/or persistent fever were included. A total of 52 patients were included in this study. Tofacitinib was administered to 29 patients (55.8%) in addition to the standard care treatments, whereas 23 patients (44.2%) were treated with the standard of care alone (mostly antiviral agents and corticosteroids). Tofacitinib was administered at a dose of 5 mg twice daily for up to 10 days. The primary outcomes were mortality rate, oxygen saturation level, CT findings, rate of breath, heart rate, and level of consciousness. Inflammatory cytokines and blood biomarkers were considered as the secondary outcomes. RESULTS Death from any cause through day 14 occurred in 51.7% of the tofacitinib group and 65.2% of the control group. There was no significant difference in lung radiographic findings between the intervention and control groups at the first day of the study and after the study period. However, a significant decrease was observed in the extent of lung tissue involvement in the intervention group after administration of tofacitinib. Regarding cell and blood biomarkers, a significant decrease in the CPK levels in the intervention group and Hct and ACE levels in the control group was observed after fourteen days of the study. Moreover, a significant increase in SGOT and ferritin values was detected in the control group 14 days after the beginning tofacitinib administration. Comparing control and intervention groups, there was a significant difference in hemoglobin, SGOT, LDH, ferritin, and ACE values between groups before the intervention, while after fourteen days of the study, no significant difference was found. In case of DHEAS and TSH levels, a significant decrease was seen in the intervention group compared to the control after the study period. No other significant improvement was detected in other outcomes of the tofacitinib group compared to the control. CONCLUSIONS The administration of tofacitinib combined with corticosteroids, is not effective enough to treat severe COVID-19 patients and the use of this medication should be considered before the disease deterioration.
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Affiliation(s)
- Simin Almasi
- Department of Rheumatology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Azadeh Rashidi
- Immunoregulation Research Center, Shahed University, Tehran, Iran
| | - Manizhe Ataee Kachuee
- Department of Radiology, Firouzgar Hospital, Iran University of Medical Science, Tehran, Iran
| | | | - Shirin Izadi
- Department of Pulmonology, Firuzgar Hospital, Iran University of Medical Science, Tehran, Iran
| | - Sara Ghaffarpour
- Immunoregulation Research Center, Shahed University, Tehran, Iran
| | - Mehdi Azimi
- Department of Internal Medicine, School of Medicine, Firoozgar General Hospital, Iran University of Medical Science, Tehran, Iran
| | | | - Mahin Jamshidi Makiani
- Department of Infectious Disease, Antimicrobial Resistance Research Center, Institute of Immunology & Infectious Disease, School of Medicine Sciences, Tehran, Iran
| | - Mitra Ranjbar
- Department of Infectious Diseases, Iran University of Medical Science, Tehran, Iran
| | - Manizheh Goudarzi
- Department of Internal Medicine, School of Medicine, Firoozgar General Hospital, Iran University of Medical Science, Tehran, Iran
| | - Neda Rahimian
- Department of Internal Medicine, School of Medicine, Firoozgar General Hospital, Iran University of Medical Science, Tehran, Iran
| | - Tooba Ghazanfari
- Immunoregulation Research Center, Shahed University, Tehran, Iran; Department of Immunology, Faculty of Medicine, Shahed University, Tehran, Iran.
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Hu M, Liu R, Li J, Zhang L, Cao J, Yue M, Zhong D, Tang R. Clinical features and prognosis of pediatric acute lymphocytic leukemia with JAK-STAT pathway genetic abnormalities: a case series. Ann Hematol 2023; 102:2445-2457. [PMID: 37209119 PMCID: PMC10199427 DOI: 10.1007/s00277-023-05245-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: 01/28/2023] [Accepted: 04/20/2023] [Indexed: 05/22/2023]
Abstract
The objective of this study is to explore the clinical features and outcomes of pediatric patients with acute lymphoblastic leukemia (ALL) harboring JAK-STAT signaling pathway genetic abnormalities. This retrospective case series examined the clinical data of pediatric patients diagnosed with ALL harboring JAK-STAT pathway genetic abnormality at the Children's Hospital of the Capital Institute of Pediatrics between January 2016 and January 2022. Bone marrow next-generation sequencing was used to reveal the JAK pathway abnormalities. Descriptive statistics were used. From 432 children with ALL during the study period, eight had JAK-STAT pathway genetic abnormalities. Regarding immunotyping, there were four patients with common-B cell types and one with pre-B cell type. The three patients with T-ALL had early T-cell precursor(ETP) type, pre-T cell type, and T cell type. Gene mutations were more common than fusion genes. There was no central nervous system involvement in eight patients. All patients were considered at least at intermediate risk before treatments. Four patients underwent hematopoietic stem cell transplantation (HSCT). One child had a comprehensive relapse and died. The child had a severe infection and could not tolerate high-intensity chemotherapy. Another child relapsed 2 years after HSCT and died. Disease-free survival was achieved in six children. JAK-STAT pathway genetic abnormalities in pediatric Ph-like ALL are rare. Special attention should be paid to treatment-related complications, such as infection and combination therapy (chemotherapy, small molecule targeted drugs, immunotherapy, etc.) to reduce treatment-related death and improve long-term quality of life.
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Affiliation(s)
- Mengze Hu
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Rong Liu
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China.
| | - Juanjuan Li
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Lei Zhang
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Jing Cao
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Mei Yue
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Dixiao Zhong
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Ruihong Tang
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, Beijing, 100020, China
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Li J, Guo S, Tan Y, Zhang J, Wu Z, Stalin A, Zhang F, Huang Z, Wu C, Liu X, Huang J, Wu J. Integrated network pharmacology analysis and in vitro validation revealed the underlying mechanism of Xiyanping injection in treating coronavirus disease 2019. Medicine (Baltimore) 2023; 102:e34866. [PMID: 37653800 PMCID: PMC10470725 DOI: 10.1097/md.0000000000034866] [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: 03/20/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 09/02/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, leading to a pandemic. In China, Xiyanping injection (XYP) has been recommended as a drug for COVID-19 treatment in the Guideline on Diagnosis and Treatment of COVID-19 by the National Health Commission of the People Republic of China and National Administration of Traditional Chinese Medicine (Trial eighth Edition). However, the relevant mechanisms at the molecular-level need to be further elucidated. METHODS In this study, XYP related active ingredients, potential targets and COVID-19 related genes were searched in public databases. Protein-protein interaction network and module analyzes were used to screen for key targets. gene ontology and Kyoto encyclopedia of genes and genomes were performed to investigate the potentially relevant signaling pathways. Molecular docking was performed using Autodock Tools and Vina. For the validation of potential mechanism, PolyI:C was used to induce human lung epithelial cells for an inflammation model. Subsequently, CCK-8 assays, enzyme-linked immunosorbent assay, reverse transcription quantitative polymerase chain reaction and western blot were employed to determine the effect of XYP on the expression of key genes. RESULTS Seven effective active ingredients in XYP were searched for 123 targets in the relevant databases. Furthermore, 6446 COVID-19 disease targets were identified. Sodium 9-dehydro-17-hydro-andrographolide-19-yl sulfate was identified as the vital active compounds, and IL-6, TNF, IL-1β, CXCL8, STAT3, MAPK1, MAPK14, and MAPK8 were considered as the key targets. In addition, molecular docking revealed that the active compound and the targets showed good binding affinities. The enrichment analysis predicted that the XYP could regulate the IL-17, Toll-like receptor, PI3K-Akt and JAK-STAT signaling pathways. Consistently, further in vitro experiments demonstrated that XYP could slow down the cytokine storm in the lung tissue of COVID-19 patients by down-regulating IL-6, TNF-α, IL-1β, CXCL8, and p-STAT3. CONCLUSION Through effective network pharmacology analysis and molecular docking, this study suggests that XYP contains many effective compounds that may target COVID-19 related signaling pathways. Moreover, the in vitro experiment confirmed that XYP could inhibit the cytokine storm by regulating genes or proteins related to immune and inflammatory responses.
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Affiliation(s)
- Jialin Li
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- College of Pharmacy, Harbin Medical University-Daqing, Daqing, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yingying Tan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhishan Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Antony Stalin
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China
| | - Fanqin Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhihong Huang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Chao Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaqi Huang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Ghanbari Naeini L, Abbasi L, Karimi F, Kokabian P, Abdi Abyaneh F, Naderi D. The Important Role of Interleukin-2 in COVID-19. J Immunol Res 2023; 2023:7097329. [PMID: 37649897 PMCID: PMC10465260 DOI: 10.1155/2023/7097329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 06/04/2023] [Accepted: 07/13/2023] [Indexed: 09/01/2023] Open
Abstract
There is controversial literature about the effects of the interleukin-2 (IL-2) cytokine family in COVID-19 pathogenesis and immunity. So we aimed to identify the potential in the role of the IL-2 family in COVID-19. A narrative review search was done through online databases, including PubMed, Scopus, and Web of Science. The search deadline was up to December 2022. We applied no time limits for the searching strategy. After retrieving articles from the databases, the authors summarized the data into two data extraction tables. The first data extraction table described the changes in the IL-2 cytokine family in COVID-19 and the second table described the therapeutic interventions targeting IL-2 family cytokines. The results of the literature on the role of the IL-2 cytokine family do not show a singular rule. IL-2 cytokine family can change during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some studies suggest that IL-2 cytokine family rise during the infection and cause severe inflammatory response and cytokine storm. These cytokines are shown to be increased in immunocompromised patients and worsen their prognosis. In individuals without underlying disease, the upregulation of the IL-2 family shows the clinical outcome of the disease and rises with disease severity. However, some other studies show that these cytokines do not significantly change. IL-2 cytokine family is mostly upregulated in healthy individuals who had vaccination, but immunocompromised patients did not show significant changes after a single dose of vaccines, which shows that these patients need booster doses for efficient immunity. IL-2 cytokine family can also be used as immunotherapy agents in COVID-19.
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Affiliation(s)
| | - Laleh Abbasi
- Guilan University of Medical Sciences, Rasht, Iran
| | | | - Pajman Kokabian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Delaram Naderi
- Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
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Ashraf A, Liaquat A, Shabbir S, Bokhari SA, Tariq Z, Furrukh Z, Raja AA, Khan MJ. High level of lactate dehydrogenase and ischaemia-reperfusion injury regulate the multiple organ dysfunction in patients with COVID-19. Postgrad Med J 2023; 99:576-581. [PMID: 37319152 PMCID: PMC8960467 DOI: 10.1136/postgradmedj-2022-141573] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/11/2022] [Indexed: 01/02/2023]
Abstract
BACKGROUND Multiple organ damage has been observed in patients with COVID-19, but the exact pathway is not known. Vital organs of the human body may get affected after replication of SARS-CoV-2, including the lungs, heart, kidneys, liver and brain. It triggers severe inflammation and impairs the function of two or more organ systems. Ischaemia-reperfusion (IR) injury is a phenomenon that can have disastrous effects on the human body. METHODS In this study, we analysed the laboratory data of 7052 hospitalised patients with COVID-19 including lactate dehydrogenase (LDH). A total of 66.4% patients were men and 33.6% were women, which indicated gender difference as a prominent factor to be considered. RESULTS Our data showed high levels of inflammation and elevated markers of tissue injury from multiple organs C reactive protein, white blood cell count, alanine transaminase, aspartate aminotransferase and LDH. The number of red blood cells, haemoglobin concentration and haematocrit were lower than normal which indicated a reduction in oxygen supply and anaemia. CONCLUSION On the basis of these results, we proposed a model linking IR injury to multiple organ damage by SARS-CoV-2. COVID-19 may cause a reduction in oxygen towards an organ, which leads to IR injury.
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Affiliation(s)
- Aleena Ashraf
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Afrose Liaquat
- Department of Biochemistry, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Sana Shabbir
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | | | - Zainab Tariq
- Shifa International Hospitals, Islamabad, Pakistan
| | | | - Afraz Ahmad Raja
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Muhammad Jawad Khan
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
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Tukek T, Pehlivan S, Medetalibeyoglu A, Serin I, Oyacı Y, Arıcı H, Senkal N, Pehlivan M, Isoglu-Alkac U, Kose M. The suppressor of cytokine signaling-1 ( SOCS1) gene polymorphism and promoter methylation correlate with the course of COVID-19. Pathog Glob Health 2023; 117:392-400. [PMID: 36448222 PMCID: PMC10177741 DOI: 10.1080/20477724.2022.2151861] [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: 12/05/2022] Open
Abstract
The suppressor of the cytokine signaling-1 (SOCS1) gene is a short sequence located on chromosome 16 that functions to induce an appropriate immune response and is an essential physiological regulator of interferon (IFN) signaling. In addition to comparing the global DNA and SOCS1 gene promoter methylation status between our patients with coronavirus disease 2019 (COVID-19) and healthy controls, this study demonstrates the effect of the SOCS1 rs33989964 polymorphism on patients with COVID-19. The study group included 139 patients diagnosed with COVID-19 in our hospital's clinics between June and December 2020, and the control group included 78 healthy individuals. After comparing the initial gene polymorphisms of the patients with the healthy control group, three separate clinical subgroups were formed. The gene polymorphism distribution and the methylation status of SOCS1 were examined in these clinical subgroups. Hypomethylation of the SOCS1 gene was observed in the COVID-19 patient group compared to the healthy control group (p = 0.001). Between the patients divided into two separate clinical subgroups, those with severe and mild infections, the Del/Del genotype of the SOCS1 gene was more common in patients with severe infection than in patients with mild infection (p = 0.018). Patients with the CA/CA and CA/Del genotypes were 0.201 times more likely to have a severe infection (95% CI: 0.057-0.716, p = 0.007). Having a non-Del/Del genotype was a protective factor against severe infection. The effect of the SOCS1 rs33989964 polymorphism and methylation status of the SOCS1 gene throughout the COVID-19 pandemic could be significant contributions to the literature.
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Affiliation(s)
- Tufan Tukek
- Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sacide Pehlivan
- Department of Medical Biology, Faculty of Medicine, Institute of Health Sciences, Istanbul University, Istanbul, Turkey
| | - Alpay Medetalibeyoglu
- Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Istemi Serin
- Department of Hematology, Istanbul Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Yasemin Oyacı
- Department of Medical Biology, Faculty of Medicine, Institute of Health Sciences, Istanbul University, Istanbul, Turkey
| | - Huzeyfe Arıcı
- Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Naci Senkal
- Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mustafa Pehlivan
- Department of Hematology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Ummuhan Isoglu-Alkac
- Department of Physiology, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Murat Kose
- Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Xue Y, Mei H, Chen Y, Griffin JD, Liu Q, Weisberg E, Yang J. Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS-CoV-2. MedComm (Beijing) 2023; 4:e254. [PMID: 37193304 PMCID: PMC10183156 DOI: 10.1002/mco2.254] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/11/2023] [Accepted: 03/07/2023] [Indexed: 05/18/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time- and cost-effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID-19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID-19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS-CoV-2 variants.
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Affiliation(s)
- Yiying Xue
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Husheng Mei
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
- University of Science and Technology of ChinaHefeiAnhuiChina
| | - Yisa Chen
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - James D. Griffin
- Department of Medical Oncology, Dana‐Farber Cancer InstituteBostonMassachusettsUSA
- Department of Medicine, Harvard Medical SchoolBostonMassachusettsUSA
| | - Qingsong Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
- University of Science and Technology of ChinaHefeiAnhuiChina
- Hefei Cancer HospitalChinese Academy of SciencesHefeiChina
| | - Ellen Weisberg
- Department of Medical Oncology, Dana‐Farber Cancer InstituteBostonMassachusettsUSA
- Department of Medicine, Harvard Medical SchoolBostonMassachusettsUSA
| | - Jing Yang
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
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Kakavandi S, Zare I, VaezJalali M, Dadashi M, Azarian M, Akbari A, Ramezani Farani M, Zalpoor H, Hajikhani B. Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases. Cell Commun Signal 2023; 21:110. [PMID: 37189112 PMCID: PMC10183699 DOI: 10.1186/s12964-023-01104-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 03/15/2023] [Indexed: 05/17/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is caused by a new member of the Coronaviridae family known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are structural and non-structural proteins (NSPs) in the genome of this virus. S, M, H, and E proteins are structural proteins, and NSPs include accessory and replicase proteins. The structural and NSP components of SARS-CoV-2 play an important role in its infectivity, and some of them may be important in the pathogenesis of chronic diseases, including cancer, coagulation disorders, neurodegenerative disorders, and cardiovascular diseases. The SARS-CoV-2 proteins interact with targets such as angiotensin-converting enzyme 2 (ACE2) receptor. In addition, SARS-CoV-2 can stimulate pathological intracellular signaling pathways by triggering transcription factor hypoxia-inducible factor-1 (HIF-1), neuropilin-1 (NRP-1), CD147, and Eph receptors, which play important roles in the progression of neurodegenerative diseases like Alzheimer's disease, epilepsy, and multiple sclerosis, and multiple cancers such as glioblastoma, lung malignancies, and leukemias. Several compounds such as polyphenols, doxazosin, baricitinib, and ruxolitinib could inhibit these interactions. It has been demonstrated that the SARS-CoV-2 spike protein has a stronger affinity for human ACE2 than the spike protein of SARS-CoV, leading the current study to hypothesize that the newly produced variant Omicron receptor-binding domain (RBD) binds to human ACE2 more strongly than the primary strain. SARS and Middle East respiratory syndrome (MERS) viruses against structural and NSPs have become resistant to previous vaccines. Therefore, the review of recent studies and the performance of current vaccines and their effects on COVID-19 and related diseases has become a vital need to deal with the current conditions. This review examines the potential role of these SARS-CoV-2 proteins in the initiation of chronic diseases, and it is anticipated that these proteins could serve as components of an effective vaccine or treatment for COVID-19 and related diseases. Video Abstract.
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Affiliation(s)
- Sareh Kakavandi
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iman Zare
- Research and Development Department, Sina Medical Biochemistry Technologies Co. Ltd., Shiraz, 7178795844, Iran
| | - Maryam VaezJalali
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Dadashi
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Maryam Azarian
- Department of Radiology, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany
| | - Abdullatif Akbari
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Marzieh Ramezani Farani
- Department of Biological Sciences and Bioengineering, Nano Bio High-Tech Materials Research Center, Inha University, Incheon, 22212, Republic of Korea
| | - Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Bahareh Hajikhani
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Hashemi Sheikhshabani S, Amini-Farsani Z, Modarres P, Amini-Farsani Z, Khazaei Feyzabad S, Shaygan N, Hussen BM, Omrani MD, Ghafouri-Fard S. In silico identification of potential miRNAs -mRNA inflammatory networks implicated in the pathogenesis of COVID-19. HUMAN GENE (AMSTERDAM, NETHERLANDS) 2023; 36:201172. [PMID: 37520333 PMCID: PMC10085880 DOI: 10.1016/j.humgen.2023.201172] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 03/11/2023] [Accepted: 03/28/2023] [Indexed: 08/01/2023]
Abstract
COVID-19 has been found to affect the expression profile of several mRNAs and miRNAs, leading to dysregulation of a number of signaling pathways, particularly those related to inflammatory responses. In the current study, a systematic biology procedure was used for the analysis of high-throughput expression data from blood specimens of COVID-19 and healthy individuals. Differentially expressed miRNAs in blood specimens of COVID-19 vs. healthy specimens were then identified to construct and analyze miRNA-mRNA networks and predict key miRNAs and genes in inflammatory pathways. Our results showed that 171 miRNAs were expressed as outliers in box plot and located in the critical areas according to our statistical analysis. Among them, 8 miRNAs, namely miR-1275, miR-4429, miR-4489, miR-6721-5p, miR-5010-5p, miR-7110-5p, miR-6804-5p and miR-6881-3p were found to affect expression of key genes in NF-KB, JAK/STAT and MAPK signaling pathways implicated in COVID-19 pathogenesis. In addition, our results predicted that 25 genes involved in above-mentioned inflammatory pathways were targeted not only by these 8 miRNAs but also by other obtained miRNAs (163 miRNAs). The results of the current in silico study represent candidate targets for further studies in COVID-19.
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Affiliation(s)
- Somayeh Hashemi Sheikhshabani
- Student Research Committee, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Amini-Farsani
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parastoo Modarres
- Department of Cell and Molecular Biology and Microbiology, University of Isfahan, Isfahan, Iran
| | - Zahra Amini-Farsani
- Bayesian Imaging and Spatial Statistics Group, Institute of Statistics, Ludwig-Maximilian-Universität München, Ludwigstraße 33, 80539 Munich, Germany
| | - Sharareh Khazaei Feyzabad
- Department of Laboratory Sciences, School of Paramedical Sciences, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Nasibeh Shaygan
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Mir Davood Omrani
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Hufnagel K, Fathi A, Stroh N, Klein M, Skwirblies F, Girgis R, Dahlke C, Hoheisel JD, Lowy C, Schmidt R, Griesbeck A, Merle U, Addo MM, Schröder C. Discovery and systematic assessment of early biomarkers that predict progression to severe COVID-19 disease. COMMUNICATIONS MEDICINE 2023; 3:51. [PMID: 37041310 PMCID: PMC10089829 DOI: 10.1038/s43856-023-00283-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/31/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND The clinical course of COVID-19 patients ranges from asymptomatic infection, via mild and moderate illness, to severe disease and even fatal outcome. Biomarkers which enable an early prediction of the severity of COVID-19 progression, would be enormously beneficial to guide patient care and early intervention prior to hospitalization. METHODS Here we describe the identification of plasma protein biomarkers using an antibody microarray-based approach in order to predict a severe cause of a COVID-19 disease already in an early phase of SARS-CoV-2 infection. To this end, plasma samples from two independent cohorts were analyzed by antibody microarrays targeting up to 998 different proteins. RESULTS In total, we identified 11 promising protein biomarker candidates to predict disease severity during an early phase of COVID-19 infection coherently in both analyzed cohorts. A set of four (S100A8/A9, TSP1, FINC, IFNL1), and two sets of three proteins (S100A8/A9, TSP1, ERBB2 and S100A8/A9, TSP1, IFNL1) were selected using machine learning as multimarker panels with sufficient accuracy for the implementation in a prognostic test. CONCLUSIONS Using these biomarkers, patients at high risk of developing a severe or critical disease may be selected for treatment with specialized therapeutic options such as neutralizing antibodies or antivirals. Early therapy through early stratification may not only have a positive impact on the outcome of individual COVID-19 patients but could additionally prevent hospitals from being overwhelmed in potential future pandemic situations.
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Affiliation(s)
| | - Anahita Fathi
- University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany
- Bernhard-Nocht-Institute for Tropical Medicine, Department for Clinical Immunology of Infectious Diseases, Hamburg, Germany
- German Center for Infection Research, partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
- University Medical Center Hamburg-Eppendorf, First Department of Medicine, Division of Infectious Diseases, Hamburg, Germany
| | - Nadine Stroh
- Sciomics GmbH, Neckargemünd, Baden-Württemberg, Germany
| | - Marco Klein
- Sciomics GmbH, Neckargemünd, Baden-Württemberg, Germany
| | | | - Ramy Girgis
- Sciomics GmbH, Neckargemünd, Baden-Württemberg, Germany
| | - Christine Dahlke
- University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany
- Bernhard-Nocht-Institute for Tropical Medicine, Department for Clinical Immunology of Infectious Diseases, Hamburg, Germany
- German Center for Infection Research, partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany
| | - Camille Lowy
- Sciomics GmbH, Neckargemünd, Baden-Württemberg, Germany
| | - Ronny Schmidt
- Sciomics GmbH, Neckargemünd, Baden-Württemberg, Germany
| | | | - Uta Merle
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Marylyn M Addo
- University Medical Center Hamburg-Eppendorf, Institute for Infection Research and Vaccine Development (IIRVD), Hamburg, Germany
- Bernhard-Nocht-Institute for Tropical Medicine, Department for Clinical Immunology of Infectious Diseases, Hamburg, Germany
- German Center for Infection Research, partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
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Xu SW, Ilyas I, Weng JP. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin 2023; 44:695-709. [PMID: 36253560 PMCID: PMC9574180 DOI: 10.1038/s41401-022-00998-0] [Citation(s) in RCA: 185] [Impact Index Per Article: 92.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 09/11/2022] [Indexed: 12/15/2022]
Abstract
The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.
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Affiliation(s)
- Suo-Wen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China.
| | - Iqra Ilyas
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China
| | - Jian-Ping Weng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China.
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44
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Wang T, Zhai Y, Xue H, Zhou W, Ding Y, Nie H. Regulation of Epithelial Sodium Transport by SARS-CoV-2 Is Closely Related with Fibrinolytic System-Associated Proteins. Biomolecules 2023; 13:biom13040578. [PMID: 37189326 DOI: 10.3390/biom13040578] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/08/2023] [Accepted: 03/21/2023] [Indexed: 05/17/2023] Open
Abstract
Dyspnea and progressive hypoxemia are the main clinical features of patients with coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary pathology shows diffuse alveolar damage with edema, hemorrhage, and the deposition of fibrinogens in the alveolar space, which are consistent with the Berlin Acute Respiratory Distress Syndrome Criteria. The epithelial sodium channel (ENaC) is a key channel protein in alveolar ion transport and the rate-limiting step for pulmonary edema fluid clearance, the dysregulation of which is associated with acute lung injury/acute respiratory distress syndrome. The main protein of the fibrinolysis system, plasmin, can bind to the furin site of γ-ENaC and induce it to an activation state, facilitating pulmonary fluid reabsorption. Intriguingly, the unique feature of SARS-CoV-2 from other β-coronaviruses is that the spike protein of the former has the same furin site (RRAR) with ENaC, suggesting that a potential competition exists between SARS-CoV-2 and ENaC for the cleavage by plasmin. Extensive pulmonary microthrombosis caused by disorders of the coagulation and fibrinolysis system has also been seen in COVID-19 patients. To some extent, high plasmin (ogen) is a common risk factor for SARS-CoV-2 infection since an increased cleavage by plasmin accelerates virus invasion. This review elaborates on the closely related relationship between SARS-CoV-2 and ENaC for fibrinolysis system-related proteins, aiming to clarify the regulation of ENaC under SARS-CoV-2 infection and provide a novel reference for the treatment of COVID-19 from the view of sodium transport regulation in the lung epithelium.
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Affiliation(s)
- Tingyu Wang
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Yiman Zhai
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Hao Xue
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Wei Zhou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Yan Ding
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
| | - Hongguang Nie
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China
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Pan T, Cao G, Tang E, Zhao Y, Penaloza-MacMaster P, Fang Y, Huang J. A single-cell atlas reveals shared and distinct immune responses and metabolic profiles in SARS-CoV-2 and HIV-1 infections. Front Genet 2023; 14:1105673. [PMID: 36992700 PMCID: PMC10040851 DOI: 10.3389/fgene.2023.1105673] [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: 11/22/2022] [Accepted: 03/01/2023] [Indexed: 03/16/2023] Open
Abstract
Introduction: Within the inflammatory immune response to viral infection, the distribution and cell type-specific profiles of immune cell populations and the immune-mediated viral clearance pathways vary according to the specific virus. Uncovering the immunological similarities and differences between viral infections is critical to understanding disease progression and developing effective vaccines and therapies. Insight into COVID-19 disease progression has been bolstered by the integration of single-cell (sc)RNA-seq data from COVID-19 patients with data from related viruses to compare immune responses. Expanding this concept, we propose that a high-resolution, systematic comparison between immune cells from SARS-CoV-2 infection and an inflammatory infectious disease with a different pathophysiology will provide a more comprehensive picture of the viral clearance pathways that underscore immunological and clinical differences between infections. Methods: Using a novel consensus single-cell annotation method, we integrate previously published scRNA-seq data from 111,566 single PBMCs from 7 COVID-19, 10 HIV-1+, and 3 healthy patients into a unified cellular atlas. We compare in detail the phenotypic features and regulatory pathways in the major immune cell clusters. Results: While immune cells in both COVID-19 and HIV-1+ cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activity, and downregulated mitophagy. Discussion: Our results indicate that differential IFN-I signaling regulates the distinct immune responses in the two diseases, revealing insight into fundamental disease biology and potential therapeutic candidates.
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Affiliation(s)
- Tony Pan
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, United States
| | - Guoshuai Cao
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, United States
| | - Erting Tang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, United States
| | - Yu Zhao
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, United States
| | | | - Yun Fang
- Biological Sciences Division, University of Chicago, Chicago, IL, United States
| | - Jun Huang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, United States
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Obradović D, Popović M, Banjac M, Bulajić J, Đurović V, Urošević I, Milovančev A. Outcomes in COVID-19 Patients with Pneumonia Treated with High-Flow Oxygen Therapy and Baricitinib—Retrospective Single-Center Study. Life (Basel) 2023; 13:life13030755. [PMID: 36983910 PMCID: PMC10053916 DOI: 10.3390/life13030755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/07/2023] [Accepted: 03/08/2023] [Indexed: 03/14/2023] Open
Abstract
Background. The aim of the study was to assess the effect of baricitinib on 28-day all-cause mortality and the progression of respiratory failure in patients needing transfer to the intensive care unit (ICU) with COVID-19 pneumonia treated with high-flow oxygen therapy. Methods. This retrospective study included hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive ventilation receiving standard of care (SOC) or SOC in addition to baricitinib. Data on patients’ characteristics, pro-inflammatory markers, D dimer, and National Early Warning Score 2 (NEWS2) values were collected and compared between groups. The primary endpoint was 28-day all-cause in-hospital mortality and the secondary outcome was transfer to the ICU. Results. The study included 125 patients. The primary outcome was observed in 44.8% of them: 27% in the baricitinib group vs. 62% in the SOC group, p < 0.001. Transfer to the ICU ward was significantly lower in the baricitinib group: 29% vs. 81%, p < 0.001. A significant improvement was observed when the baricitinib group was compared to SOC in procalcitonin, CRP, D-dimer, neutrophil-to-lymphocyte ratio values, and NEWS2. Conclusion. Treatment with baricitinib in addition to SOC was associated with reduced mortality and a lower prevalence of transfer to the ICU in hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive therapy.
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Affiliation(s)
- Dušanka Obradović
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia
- Institute for Pulmonary Diseases of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Milica Popović
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia
- Clinic of Nephrology and Clinical Immunology, University Clinical Centre of Vojvodina, 21000 Novi Sad, Serbia
| | - Maja Banjac
- Institute for Pulmonary Diseases of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Jelena Bulajić
- Urgent Care Center, University Clinical Centre of Vojvodina, 21000 Novi Sad, Serbia
| | - Vladimir Đurović
- Clinic of Nephrology and Clinical Immunology, University Clinical Centre of Vojvodina, 21000 Novi Sad, Serbia
| | - Ivana Urošević
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia
- Clinic of Hematology, University Clinical Centre of Vojvodina, 21000 Novi Sad, Serbia
| | - Aleksandra Milovančev
- Faculty of Medicine Novi Sad, University of Novi Sad, 21000 Novi Sad, Serbia
- Institute for Cardiovascular Diseases of Vojvodina, 21204 Sremska Kamenica, Serbia
- Correspondence:
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Ferrarini A, Vacca A, Solimando AG, Tavio M, Acquaviva R, Rocchi M, Nitti C, Salvi A, Menditto V, Luchetti Gentiloni MM, Russo A, Moretti M, Pavani M, Giacometti A, Bonifazi M, Zuccatosta L, Romani L, Racanelli V, Moroncini G, Gabrielli A, Pomponio G. Early administration of tofacitinib in COVID-19 pneumonitis: An open randomised controlled trial. Eur J Clin Invest 2023; 53:e13898. [PMID: 36380693 DOI: 10.1111/eci.13898] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND Controversies on sub-populations most sensitive to therapy and the best timing of starting the treatment still surround the use of immunomodulatory drugs in COVID-19. OBJECTIVES We designed a multicentre open-label randomised controlled trial to test the effect of prompt adding of tofacitinib to standard therapy for hospitalised patients affected by mild/moderate COVID-19 pneumonitis. METHODS Patients admitted to three Italian hospitals affected by COVID-19 pneumonitis not requiring mechanical ventilation were randomised to receive standard treatment alone or tofacitinib (10 mg/bid) for 2 weeks, starting within the first 24 h from admission. RESULTS A total of 116 patients were randomised; 49 in the experimental arm completed the 14-day treatment period, 9 discontinued tofacitinib as the disease worsened and were included in the analysis, and 1 died of respiratory failure. All 58 control patients completed the study. Clinical and demographic characteristics were similar between the study groups. In the tofacitinib group, 9/58 (15.5%) patients progressed to noninvasive ventilation (CPAP) to maintain SO2 > 93%, invasive mechanical ventilation or death by day 14 was 15.5%, significantly less than in the control group (20/58, 34.4%, RR 0,45, RRR -55%, NNT 5; p = .018). No differences in severe adverse effect incidence had been observed across the groups. CONCLUSION High-dose tofacitinib therapy in patients with COVID pneumonitis is safe and may prevent deterioration to respiratory failure.
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Affiliation(s)
- Alessia Ferrarini
- Clinica Medica, Ospedali Riuniti di Ancona, Ancona, Italy.,Gastroenterologia ed Endoscopia Digestiva, Ospedali Riuniti Marche Nord, Fano, Italy
| | - Angelo Vacca
- Dipartimento di Scienze Biomediche e Oncologia Umana U.O.C, Medicina Interna Universitaria "G. Baccelli" A.O.U.C, Policlinico di Bari, Bari, Italy
| | - Antonio Giovanni Solimando
- Dipartimento di Scienze Biomediche e Oncologia Umana U.O.C, Medicina Interna Universitaria "G. Baccelli" A.O.U.C, Policlinico di Bari, Bari, Italy.,IRCCS Istituto Tumori "Giovanni Paolo II" Bari, Bari, Italy
| | - Marcello Tavio
- Malattie Infettive, Ospedali Riuniti di Ancona, Ancona, Italy
| | - Rossella Acquaviva
- Dipartimento di Scienze Biomediche e Oncologia Umana U.O.C, Medicina Interna Universitaria "G. Baccelli" A.O.U.C, Policlinico di Bari, Bari, Italy
| | - Marco Rocchi
- Statistica Medica, Dipartimento di Scienze Biomolecolari, Università di Urbino, Urbino, Italy
| | - Cinzia Nitti
- Medicina Interna e Sub Intensiva, Ospedali Riuniti di Ancona, Ancona, Italy
| | - Aldo Salvi
- Medicina Interna e Sub Intensiva, Ospedali Riuniti di Ancona, Ancona, Italy
| | - Vincenzo Menditto
- Medicina Interna e Sub Intensiva, Ospedali Riuniti di Ancona, Ancona, Italy
| | | | - Alessandro Russo
- Clinica di Malattie Infettive e Tropicali Dipartimento di Scienze Mediche e Chirurgiche Università "Magna Graecia" di Catanzaro, Catanzaro, Italy
| | - Marco Moretti
- SOD Medicina di Laboratorio Ospedali Riuniti di Ancona, Ancona, Italy
| | - Marianna Pavani
- SOD Medicina di Laboratorio Ospedali Riuniti di Ancona, Ancona, Italy
| | - Andrea Giacometti
- Clinica di Malattie Infettive, Ospedali Riuniti di Ancona, Ancona, Italy
| | | | | | - Laura Romani
- Clinica Medica, Ospedali Riuniti di Ancona, Ancona, Italy
| | - Vito Racanelli
- Dipartimento di Scienze Biomediche e Oncologia Umana U.O.C, Medicina Interna Universitaria "G. Baccelli" A.O.U.C, Policlinico di Bari, Bari, Italy
| | - Gianluca Moroncini
- Clinica Medica, Ospedali Riuniti di Ancona, Ancona, Italy.,Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
| | - Armando Gabrielli
- Clinica Medica, Ospedali Riuniti di Ancona, Ancona, Italy.,Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
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Purohit M, Gupta G, Afzal O, Altamimi ASA, Alzarea SI, Kazmi I, Almalki WH, Gulati M, Kaur IP, Singh SK, Dua K. Janus kinase/signal transducers and activator of transcription (JAK/STAT) and its role in Lung inflammatory disease. Chem Biol Interact 2023; 371:110334. [PMID: 36610610 DOI: 10.1016/j.cbi.2023.110334] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/23/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023]
Abstract
A key signaling channel for the signal transduction of several crucial cytokines implicated in sepsis is the JAK/STAT system. Once cytokines attach to the proper receptors, JAK kinases linked to them are activated and can selectively phosphorylate STATs. Activated STATs subsequently go to the nucleus, where they play a key role in the transcription of the target genes. Various biological activities use the JAK/STAT pathway, including hematopoiesis, immunological modulation, cell differentiation, and apoptosis. Inflammatory lung illnesses affect people worldwide and are a serious public health concern. Numerous common respiratory conditions, such as asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome, are strongly influenced by inflammation. Microorganism infections or the destruction or demise of host cells are the causes of inflammation and the factors that perpetuate it. This review discusses the main elements of severe lung inflammation and how the JAK/STAT signaling pathway is essential for lung inflammation.
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Affiliation(s)
- Manish Purohit
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, 302017, Mahal Road, Jaipur, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, 302017, Mahal Road, 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.
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, 11942, Saudi Arabia
| | | | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, NSW, Australia
| | - Indu Pal Kaur
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, NSW, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, NSW, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW, 2007, Australia.
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Wang R, Loscalzo J. Uncovering common pathobiological processes between COVID-19 and pulmonary arterial hypertension by integrating Omics data. Pulm Circ 2023; 13:e12191. [PMID: 36721384 PMCID: PMC9880519 DOI: 10.1002/pul2.12191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/15/2022] [Accepted: 01/01/2023] [Indexed: 01/19/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to the current pandemic. Many factors, including age and comorbidities, influence the severity and mortality of COVID-19. SARS-CoV-2 infection can cause pulmonary vascular dysfunction. The COVID-19 case-fatality rate in patients with pulmonary arterial hypertension (PAH) is higher in comparison with the general population. In this study, we aimed to identify pathobiological processes common to COVID-19 and PAH by utilizing the human protein-protein interactome and whole-genome transcription data from peripheral blood mononuclear cells (PBMCs) and from lung tissue. We found that there are significantly more interactions between SARS-CoV-2 targets and PAH disease proteins than expected by chance, suggesting that the PAH disease module is in the neighborhood of SARS-CoV-2 targets in the human interactome. In addition, SARS-CoV-2 infection-induced changes in gene expression significantly overlap with PAH-induced gene expression changes in both tissues, indicating SARS-CoV-2 and PAH may share common transcriptional regulators. We identified many upregulated genes and downregulated genes common to COVID-19 and PAH. Interestingly, we observed different co-regulation patterns and dysfunctional signaling pathways in PBMCs versus lung tissue. Endophenotype enrichment analysis revealed that genes regulating fibrosis, inflammation, hypoxia, oxidative stress, immune response, and thromboembolism are significantly enriched in the COVID-19-PAH co-expression modules. We examined the network proximity of the targets of repositioned drugs for COVID-19 to the co-expression modules in PBMCs and lung tissue, and identified 42 drugs that can be potentially used for COVID-19 patients with PAH as a comorbidity. The uncovered common pathobiological pathways are crucial for discovering therapeutic targets and designing tailored treatments for COVID-19 patients who also have PAH.
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Affiliation(s)
- Rui‐Sheng Wang
- Department of Medicine, Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Joseph Loscalzo
- Department of Medicine, Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
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Selvapandiyan A, Puri N, Kumar P, Alam A, Ehtesham NZ, Griffin G, Hasnain SE. Zooming in on common immune evasion mechanisms of pathogens in phagolysosomes: potential broad-spectrum therapeutic targets against infectious diseases. FEMS Microbiol Rev 2023; 47:6780197. [PMID: 36309472 DOI: 10.1093/femsre/fuac041] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 10/06/2022] [Accepted: 10/18/2022] [Indexed: 01/19/2023] Open
Abstract
The intracellular viral, bacterial, or parasitic pathogens evade the host immune challenges to propagate and cause fatal diseases. The microbes overpower host immunity at various levels including during entry into host cells, phagosome formation, phagosome maturation, phagosome-lysosome fusion forming phagolysosomes, acidification of phagolysosomes, and at times after escape into the cytosol. Phagolysosome is the final organelle in the phagocyte with sophisticated mechanisms to degrade the pathogens. The immune evasion strategies by the pathogens include the arrest of host cell apoptosis, decrease in reactive oxygen species, the elevation of Th2 anti-inflammatory response, avoidance of autophagy and antigen cross-presentation pathways, and escape from phagolysosomal killing. Since the phagolysosome organelle in relation to infection/cure is seldom discussed in the literature, we summarize here the common host as well as pathogen targets manipulated or utilized by the pathogens established in phagosomes and phagolysosomes, to hijack the host immune system for their benefit. These common molecules or pathways can be broad-spectrum therapeutic targets for drug development for intervention against infectious diseases caused by different intracellular pathogens.
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Affiliation(s)
| | - Niti Puri
- Cellular and Molecular Immunology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Pankaj Kumar
- Department of Biochemistry, Jamia Hamdard, New Delhi, 110062, India.,Centre for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, MD, 21218, United States
| | - Anwar Alam
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India.,Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology-Delhi, New Delhi, 110016, India
| | - Nasreen Zafar Ehtesham
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India
| | - George Griffin
- Department of Cellular and Molecular Medicine, St. George's University of London, London, SW17 0RE, United Kingdom
| | - Seyed Ehtesham Hasnain
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology-Delhi, New Delhi, 110016, India.,Department of Life Science, School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, 201310, India
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