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Nie J, Zhou L, Tian W, Liu X, Yang L, Yang X, Zhang Y, Wei S, Wang DW, Wei J. Deep insight into cytokine storm: from pathogenesis to treatment. Signal Transduct Target Ther 2025; 10:112. [PMID: 40234407 PMCID: PMC12000524 DOI: 10.1038/s41392-025-02178-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/22/2024] [Accepted: 02/12/2025] [Indexed: 04/17/2025] Open
Abstract
Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.
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Grants
- 82070217, 81873427 National Natural Science Foundation of China (National Science Foundation of China)
- 82100401 National Natural Science Foundation of China (National Science Foundation of China)
- 81772477, 81201848, 82473220 National Natural Science Foundation of China (National Science Foundation of China)
- 82330010，81630010，81790624 National Natural Science Foundation of China (National Science Foundation of China)
- National High Technology Research and Development Program of China, Grant number: 2021YFA1101500.
- The Hubei Provincial Natural Science Foundation (No.2024AFB050)
- Project of Shanxi Bethune Hospital, Grant Numbber: 2023xg02); Fundamental Research Program of Shanxi Province, Grant Numbber: 202303021211224
- The Key Scientific Research Project of COVID-19 Infection Emergency Treatment of Shanxi Bethune Hospital (2023xg01), 2023 COVID-19 Research Project of Shanxi Provincial Health Commission (No.2023XG001, No. 2023XG005), Four “Batches” Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province (2023XM003), Cancer special Fund research project of Shanxi Bethune Hospital (No. 2020-ZL04), and External Expert Workshop Fund Program of Shanxi Provincial Health Commission（Proteomics Shanxi studio for Huanghe professor）
- Fundamental Research Program of Shanxi Province(No.202303021221192); 2023 COVID-19 Emergency Project of Shanxi Health Commission (Nos.2023XG001,2023XG005)
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Affiliation(s)
- Jiali Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Ling Zhou
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China
| | - Weiwei Tian
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Xiansheng Liu
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Liping Yang
- Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- Sino-German Joint Oncological Research Laboratory, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Xingcheng Yang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yicheng Zhang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Wei
- Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan, China.
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
| | - Jia Wei
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Iacobucci I, Cipollone I, Cozzolino F, Iaconis D, Talarico C, Coppola G, Morasso S, Costanzi E, Malune P, Storici P, Tramontano E, Esposito F, Monti M. Cys44 of SARS-CoV-2 3CL pro affects its catalytic activity. Int J Biol Macromol 2025; 295:139590. [PMID: 39788258 DOI: 10.1016/j.ijbiomac.2025.139590] [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: 09/05/2024] [Revised: 12/18/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
SARS-CoV-2 encodes a 3C-like protease (3CLpro) that is essential for viral replication. This cysteine protease cleaves viral polyproteins to release functional nonstructural proteins, making it a prime target for antiviral drug development. We investigated the inhibitory effects of halicin, a known c-Jun N-terminal kinase inhibitor, on 3CLpro. Mass spectrometry and crystallographic analysis revealed that halicin covalently binds to several cysteine residues in 3CLpro. As expected, Cys145, the catalytic residue, was found to be the most targeted residue by halicin. Secondly, Cys44 was found to be modified, suggesting a potential inhibitory role of this residue. A mutant protease (Cys44Ala) was generated to further understand the function of Cys44. In silico and enzymatic assays showed that the mutation significantly reduced the stability and activity of 3CLpro, indicating the importance of Cys44 in maintaining the active conformation of the protease. Differential scanning fluorimetry assays confirmed this evidence, showing a reduced thermal stability of the mutant compared to the wild-type protease. Our results highlight the potential of halicin as a multi-target inhibitor of 3CLpro and underline the importance of Cys44 in the function of the protease. These findings contribute to the development of effective antiviral therapies against COVID-19 by targeting critical residues in 3CLpro.
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Affiliation(s)
- Ilaria Iacobucci
- Department of Chemical Sciences, University of Naples "Federico II", Via Cintia, 21, 80126 Napoli, Italy; CEINGE Advanced Biotechnologies s.c.a r.l. "Franco Salvatore", Via Gaetano Salvatore 486, 80131 Napoli, Italy
| | - Irene Cipollone
- Department of Chemical Sciences, University of Naples "Federico II", Via Cintia, 21, 80126 Napoli, Italy; CEINGE Advanced Biotechnologies s.c.a r.l. "Franco Salvatore", Via Gaetano Salvatore 486, 80131 Napoli, Italy; Dompé Farmaceutici SpA, EXSCALATE, Via Tommaso De Amicis, 95, I-80131 Napoli, Italy
| | - Flora Cozzolino
- Department of Chemical Sciences, University of Naples "Federico II", Via Cintia, 21, 80126 Napoli, Italy; CEINGE Advanced Biotechnologies s.c.a r.l. "Franco Salvatore", Via Gaetano Salvatore 486, 80131 Napoli, Italy
| | - Daniela Iaconis
- Dompé Farmaceutici SpA, EXSCALATE, Via Tommaso De Amicis, 95, I-80131 Napoli, Italy
| | - Carmine Talarico
- Dompé Farmaceutici SpA, EXSCALATE, Via Tommaso De Amicis, 95, I-80131 Napoli, Italy
| | - Gabriele Coppola
- Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR), 80145 Naples, Italy
| | - Stefano Morasso
- Elettra Sincrotrone Trieste, Structural Biology, Protein Targets for Drug Discovery Lab, SS 14 - km 163,5 in AREA Science Pack, Basovizza, 34149 Trieste, Italy
| | - Elisa Costanzi
- Elettra Sincrotrone Trieste, Structural Biology, Protein Targets for Drug Discovery Lab, SS 14 - km 163,5 in AREA Science Pack, Basovizza, 34149 Trieste, Italy
| | - Paolo Malune
- Department of Life and Environmental Sciences, University of Cagliari, S.P. 8 Monserrato, Sestu Km 0.700, I-09042 Monserrato, Italy
| | - Paola Storici
- Elettra Sincrotrone Trieste, Structural Biology, Protein Targets for Drug Discovery Lab, SS 14 - km 163,5 in AREA Science Pack, Basovizza, 34149 Trieste, Italy
| | - Enzo Tramontano
- Department of Life and Environmental Sciences, University of Cagliari, S.P. 8 Monserrato, Sestu Km 0.700, I-09042 Monserrato, Italy
| | - Francesca Esposito
- Department of Life and Environmental Sciences, University of Cagliari, S.P. 8 Monserrato, Sestu Km 0.700, I-09042 Monserrato, Italy
| | - Maria Monti
- Department of Chemical Sciences, University of Naples "Federico II", Via Cintia, 21, 80126 Napoli, Italy; CEINGE Advanced Biotechnologies s.c.a r.l. "Franco Salvatore", Via Gaetano Salvatore 486, 80131 Napoli, Italy.
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Chen Y, Jan J, Yang C, Yen T, Linh TTD, Annavajjula S, Satapathy MK, Tsao S, Hsieh C. Cognitive Sequelae of COVID-19: Mechanistic Insights and Therapeutic Approaches. CNS Neurosci Ther 2025; 31:e70348. [PMID: 40152069 PMCID: PMC11950837 DOI: 10.1111/cns.70348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 03/10/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND The COVID-19 pandemic has left an indelible mark on the world, with mounting evidence suggesting that it not only posed acute challenges to global healthcare systems but has also unveiled a complex array of long-term consequences, particularly cognitive impairment (CI). As the persistence of post-COVID-19 neurological syndrome could evolve into the next public health crisis, it is imperative to gain a better understanding of the intricate pathophysiology of CI in COVID-19 patients and viable treatment strategies. METHODS This comprehensive review explores the pathophysiology and management of cognitive impairment across the phases of COVID-19, from acute infection to Long-COVID, by synthesizing findings from clinical, preclinical, and mechanistic studies to identify key contributors to CI, as well as current therapeutic approaches. RESULTS Key mechanisms contributing to CI include persistent neuroinflammation, cerebrovascular complications, direct neuronal injury, activation of the kynurenine pathway, and psychological distress. Both pharmacological interventions, such as anti-inflammatory therapies and agents targeting neuroinflammatory pathways, and non-pharmacological strategies, including cognitive rehabilitation, show promise in addressing these challenges. Although much of the current evidence is derived from preclinical and animal studies, these findings provide foundational insights into potential treatment approaches. CONCLUSION By synthesizing current knowledge, this review highlights the importance of addressing COVID-19-related cognitive impairment and offers actionable insights for mitigation and recovery as the global community continues to grapple with the pandemic's long-term impact.
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Affiliation(s)
- Yu‐Hao Chen
- Section of Neurosurgery, Department of SurgeryDitmanson Medical Foundation, Chia‐Yi Christian HospitalChia‐Yi CityTaiwan
- Chung‐Jen Junior College of Nursing, Health Sciences and ManagementChia‐Yi CountryTaiwan
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Jing‐Shiun Jan
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Chih‐Hao Yang
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Ting‐Lin Yen
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
- Department of Medical ResearchCathay General HospitalTaipeiTaiwan
| | - Tran Thanh Duy Linh
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
- Family Medicine Training Center, University of Medicine and Pharmacy at Ho Chi Minh CityHo Chi Minh CityVietnam
| | - Saileela Annavajjula
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Mantosh Kumar Satapathy
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
| | - Shin‐Yi Tsao
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
- Division of Endocrinology and Metabolism, Department of Internal MedicineTaipeiTaiwan
| | - Cheng‐Ying Hsieh
- Department of PharmacologySchool of Medicine, College of Medicine, Taipei Medical UniversityTaipeiTaiwan
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Wilar G, Suhandi C, Fukunaga K, Kawahata I. Efficacy and safety of tofacitinib on COVID-19 patients: A systematic review and meta-analysis. Heliyon 2024; 10:e38229. [PMID: 39381111 PMCID: PMC11456853 DOI: 10.1016/j.heliyon.2024.e38229] [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: 07/03/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/10/2024] Open
Abstract
The use of drugs off-label for managing COVID-19 offers a potential approach. Among these potential drugs, tofacitinib, a JAK inhibitor, is strongly implicated in its ability to mitigate mortality by attenuating the cytokine storm syndrome. This study systematically reviewed and quantitatively assessed the effectiveness and safety profile of tofacitinib use through meta-analysis. Through searches of the PubMed, Scopus, and the Cochrane Library databases up to May 31, 2024, six articles meeting inclusion criteria were identified, encompassing 669 patients diagnosed with COVID-19. The review findings indicate that tofacitinib use demonstrates significant clinical efficacy, as evidenced by a reduced risk of mortality (P = 0.003), and a decreased need for invasive mechanical ventilation (P = 0.0002). Furthermore, tofacitinib use is not correlated with an increased risk of adverse drug reactions (P = 0.98), indicating a favorable safety profile. In conclusion, the evidence supports the clinical efficacy of tofacitinib for COVID-19 patients without concomitant risks of adverse effects. Further clinical studies, especially larger-scale randomized controlled trials, are necessary to validate the findings of this study.
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Affiliation(s)
- Gofarana Wilar
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia
| | - Cecep Suhandi
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia
| | - Kohji Fukunaga
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Ichiro Kawahata
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
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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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Yu Q, Zhou X, Kapini R, Arsecularatne A, Song W, Li C, Liu Y, Ren J, Münch G, Liu J, Chang D. Cytokine Storm in COVID-19: Insight into Pathological Mechanisms and Therapeutic Benefits of Chinese Herbal Medicines. MEDICINES (BASEL, SWITZERLAND) 2024; 11:14. [PMID: 39051370 PMCID: PMC11270433 DOI: 10.3390/medicines11070014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/20/2024] [Accepted: 06/26/2024] [Indexed: 07/27/2024]
Abstract
Cytokine storm (CS) is the main driver of SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) in severe coronavirus disease-19 (COVID-19). The pathological mechanisms of CS are quite complex and involve multiple critical molecular targets that turn self-limited and mild COVID-19 into a severe and life-threatening concern. At present, vaccines are strongly recommended as safe and effective treatments for preventing serious illness or death from COVID-19. However, effective treatment options are still lacking for people who are at the most risk or hospitalized with severe disease. Chinese herbal medicines have been shown to improve the clinical outcomes of mild to severe COVID-19 as an adjunct therapy, particular preventing the development of mild to severe ARDS. This review illustrates in detail the pathogenesis of CS-involved ARDS and its associated key molecular targets, cytokines and signalling pathways. The therapeutic targets were identified particularly in relation to the turning points of the development of COVID-19, from mild symptoms to severe ARDS. Preclinical and clinical studies were reviewed for the effects of Chinese herbal medicines together with conventional therapies in reducing ARDS symptoms and addressing critical therapeutic targets associated with CS. Multiple herbal formulations, herbal extracts and single bioactive phytochemicals with or without conventional therapies demonstrated strong anti-CS effects through multiple mechanisms. However, evidence from larger, well-designed clinical trials is lacking and their detailed mechanisms of action are yet to be well elucidated. More research is warranted to further evaluate the therapeutic value of Chinese herbal medicine for CS in COVID-19-induced ARDS.
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Affiliation(s)
- Qingyuan Yu
- Beijing Key Laboratory of Pharmacology of Chinese Materia Region, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Q.Y.); (W.S.); (J.R.)
- Xiyuan Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xian Zhou
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia; (X.Z.); (R.K.); (A.A.); (C.L.); (Y.L.); (G.M.)
| | - Rotina Kapini
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia; (X.Z.); (R.K.); (A.A.); (C.L.); (Y.L.); (G.M.)
- School of Science, Western Sydney University, Campbelltown, NSW 2560, Australia
| | - Anthony Arsecularatne
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia; (X.Z.); (R.K.); (A.A.); (C.L.); (Y.L.); (G.M.)
- Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia
| | - Wenting Song
- Beijing Key Laboratory of Pharmacology of Chinese Materia Region, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Q.Y.); (W.S.); (J.R.)
| | - Chunguang Li
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia; (X.Z.); (R.K.); (A.A.); (C.L.); (Y.L.); (G.M.)
| | - Yang Liu
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia; (X.Z.); (R.K.); (A.A.); (C.L.); (Y.L.); (G.M.)
| | - Junguo Ren
- Beijing Key Laboratory of Pharmacology of Chinese Materia Region, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Q.Y.); (W.S.); (J.R.)
| | - Gerald Münch
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia; (X.Z.); (R.K.); (A.A.); (C.L.); (Y.L.); (G.M.)
- Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia
| | - Jianxun Liu
- Beijing Key Laboratory of Pharmacology of Chinese Materia Region, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; (Q.Y.); (W.S.); (J.R.)
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Westmead, NSW 2145, Australia; (X.Z.); (R.K.); (A.A.); (C.L.); (Y.L.); (G.M.)
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Xie Y, Lv S, Luo S, Chen Y, Du M, Xu Y, Yang D. The correlation between corona virus disease 2019 and alopecia areata: a literature review. Front Immunol 2024; 15:1347311. [PMID: 39021569 PMCID: PMC11251897 DOI: 10.3389/fimmu.2024.1347311] [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: 11/30/2023] [Accepted: 05/01/2024] [Indexed: 07/20/2024] Open
Abstract
Corona virus disease 2019(COVID-19) is one of the most serious respiratory pandemic diseases threatening human health for centuries. Alopecia areata (AA) is a sudden patchy hair loss, an autoimmune disease, which seriously affects the image and mental health of patients. Evidence shows that the risk of autoimmune diseases significantly increases after COVID-19, and is positively correlated with the severity, with a significant increase in the risk of alopecia in those over 40 years old. The relationship between COVID-19 and AA has become a hot topic of current research. Strengthening the research on the correlation between COVID-19 and AA can help to identify and protect susceptible populations at an early stage. This article reviews the research progress on the epidemiological background of COVID-19 and AA, the situation and possible mechanisms of AA induced by COVID-19 or COVID-19 vaccination, and potential treatment methods.
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Affiliation(s)
- Ying Xie
- School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Shuying Lv
- School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Sha Luo
- Department of Dermatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yuxuan Chen
- School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Meijiao Du
- School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Yonglong Xu
- School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
| | - Dingquan Yang
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China
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Kow CS, Ramachandram DS, Hasan SS. Effect of JAK Inhibitors on the Risk of Death in Patients with Moderate to Severe COVID-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Can J Hosp Pharm 2024; 77:e3493. [PMID: 38868321 PMCID: PMC11146300 DOI: 10.4212/cjhp.3493] [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: 04/26/2023] [Accepted: 01/25/2024] [Indexed: 06/14/2024]
Abstract
Background The pathophysiology of COVID-19 involves a signalling pathway based on the Janus kinases (JAKs) and the signal transducer and activator of transcription (STAT) family of proteins. As such, there has been growing interest in exploring JAK inhibitors as potential therapeutic agents for this disease. Objective To provide a comprehensive summary of the efficacy of JAK inhibitors in the treatment of COVID-19 through a systematic review and meta-analysis. Data Sources A systematic literature search was conducted in multiple electronic databases (PubMed, Scopus, and the Cochrane Central Register of Controlled Trials) and preprint repositories, without language restrictions, to identify relevant studies published up to December 31, 2023. Study Selection and Data Extraction The primary outcome of interest was all-cause mortality. Randomized controlled trials (RCTs) investigating the administration of JAK inhibitors in patients with COVID-19 were included. Data Synthesis Through the systematic literature search, a total of 20 RCTs meeting the inclusion criteria were identified. A random-effects model was employed to estimate the pooled odds ratio for death with administration of a JAK inhibitor relative to non-administration of such an agent, with 95% confidence interval. Meta-analysis of these trials revealed a significant reduction in mortality among patients with COVID-19 who received JAK inhibitors relative to those who did not receive these agents (pooled odds ratio 0.70, 95% confidence interval 0.58-0.84). Conclusions The results of this systematic review and meta-analysis suggest that JAK inhibitors, specifically baricitinib, may address the urgent need for effective treatments in the ongoing COVID-19 pandemic by reducing the risk of death among affected patients. However, further research, including larger-scale RCTs, is needed to establish the efficacy and safety of other JAK inhibitors in the treatment of COVID-19 and to generate more robust evidence regarding their use in this specific patient population.
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Affiliation(s)
- Chia Siang Kow
- , MPharm, is with the School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia
| | | | - Syed Shahzad Hasan
- , PhD, is with the School of Applied Sciences, University of Huddersfield, Huddersfield, UK, and the School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan, Australia
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9
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Ghalehbaghi B, Aazami H, Khoshmirsafa M, Mohebbi A, Babaheidarian P, Rashidi N, Mokhtarian K, Ahmadi R, Kamali M, Ponour M, Sanaei A, Seif F, Jalessi M. Suppressor of Cytokine Signaling Proteins 3 and 5 Potentially Delineate Polarization of Th cells in Chronic Rhinosinusitis. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2024; 97:165-177. [PMID: 38947108 PMCID: PMC11202107 DOI: 10.59249/hzfn2950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Background: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Th cells manage inflammatory cells in CRS. Suppressor of Cytokine Signaling (SOCS) proteins regulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in Th cells by polarizing toward Th1, Th2, and Th17 cells. This study evaluated the levels of SOCS1,3,5 in CRS patients to find associations with Th cells. Methods: In this cross-sectional study, 20 CRSwNP patients, 12 CRSsNP patients, and 12 controls participated. The infiltration of CD4+ T cells was determined using immunohistochemistry. The expression of specific transcription factors and SOCS proteins was assessed using real-time PCR. Cytokine levels were evaluated using ELISA. SOCS protein levels were investigated using western blot analysis. Results: The expression of SOCS3 increased in the CRSwNP group compared to CRSsNP and control groups (p <0.001). SOCS3 protein levels increased in the CRSwNP group compared to CRSsNP (p <0.05) and control (p <0.001) groups. Although there was a significant difference in SOCS5 expression between CRSsNP and control groups, SOCS5 protein levels were significantly different between CRSsNP and control (p <0.001) and CRSwNP (p <0.05) groups. Conclusions: Targeted therapies may be suggested for CRS by modulating SOCS3 and SOCS5 proteins that are responsible for polarization of Th cells toward Th2 or Th1 cells, respectively. JAK-STAT pathway targeting, which encompasses numerous cells, can be limited to SOCS proteins to more effectively orchestrate Th cell differentiation.
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Affiliation(s)
- Babak Ghalehbaghi
- ENT and Head and Neck Research Center and Department,
Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran,
Iran
| | - Hossein Aazami
- Endocrinology and Metabolism Research Center,
Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of
Medical Sciences, Tehran, Iran
| | - Majid Khoshmirsafa
- Immunology Research Center, Institute of Immunology and
Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Mohebbi
- ENT and Head and Neck Research Center and Department,
Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran,
Iran
| | - Pegah Babaheidarian
- Department of Pathology, Rasoul Akram Medical Complex,
Iran University of Medical Sciences, Tehran, Iran
| | - Nesa Rashidi
- Immunology Research Center, Institute of Immunology and
Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Kobra Mokhtarian
- Cellular and Molecular Research Center, Basic Health
Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord,
Iran
| | - Reza Ahmadi
- Clinical Biochemistry Research Center, Basic Health
Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord,
Iran
| | - Monireh Kamali
- Rajaei Cardiovascular Medical and Research Center, Iran
University of Medical Sciences, Tehran, Iran
| | - Majid Ponour
- Department of Oncology, School of Medicine, University
of Maryland, Maryland, USA
| | - Ayda Sanaei
- Department of Photodynamic Therapy, Medical Laser
Research Center, Academic Center for Education, Culture, and Research (ACECR),
Tehran, Iran
| | - Farhad Seif
- Department of Photodynamic Therapy, Medical Laser
Research Center, Academic Center for Education, Culture, and Research (ACECR),
Tehran, Iran
- Department of Immunology and Allergy, Academic Center
for Education, Culture, and Research (ACECR), Tehran, Iran
| | - Maryam Jalessi
- ENT and Head and Neck Research Center and Department,
Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran,
Iran
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10
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Khalil B, Sharif-Askari NS, Hafezi S, Sharif-Askari FS, Al Anouti F, Hamid Q, Halwani R. Vitamin D regulates COVID-19 associated severity by suppressing the NLRP3 inflammasome pathway. PLoS One 2024; 19:e0302818. [PMID: 38748756 PMCID: PMC11095707 DOI: 10.1371/journal.pone.0302818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 04/14/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND The role of vitamin D3 (VitD3) in modulating innate and adaptive immunity has been reported in different disease contexts. Since the start of the coronavirus disease-2019 (COVID-19) pandemic, the role of VitD3 has been highlighted in many correlational and observational studies. However, the exact mechanisms of action are not well identified. One of the mechanisms via which VitD3 modulates innate immunity is by regulating the NLRP3-inflammasome pathway, being a main underlying cause of SARS-CoV-2-induced hyperinflammation. AIMS AND MAIN METHODS Blood specimens of severe COVID-19 patients with or without VitD3 treatment were collected during their stay in the intensive care unit and patients were followed up for 29 days. qPCR, western blot, and ELISA were done to investigate the mechanism of action of VitD3 on the NLRP3 inflammasome activation. KEY FINDINGS We here report the ability of VitD3 to downregulate the NLRP3-inflammsome pathway in severe COVID-19 patients. Lower inflammasome pathway activation was observed with significantly lower gene and protein expression of NLRP3, cleaved caspase-1, ASC and IL-1β among severe COVID-19 patients treated with VitD3. The reduction of the inflammasome pathway was associated with a reduction in disease severity markers and enhancement of type I IFN pathway. SIGNIFICANCE Our data reveals an important anti-inflammatory effect of VitD3 during SARS-CoV-2 infection. Further investigations are warranted to better characterize the ability of VitD3 to control disease pathogenesis and prevent progression to severe states. This will allow for a more efficient use of a low cost and accessible treatment like VitD3.
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Affiliation(s)
- Bariaa Khalil
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Narjes Saheb Sharif-Askari
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Shirin Hafezi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Fatemeh Saheb Sharif-Askari
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
| | - Fatme Al Anouti
- College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates
- ASPIRE Precision Medicine Research Institute, Abu Dhabi, United Arab Emirates
| | - Qutayba Hamid
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Rabih Halwani
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Prince Abdullah Ben Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
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11
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Riyaz Tramboo S, Elkhalifa AM, Quibtiya S, Ali SI, Nazir Shah N, Taifa S, Rakhshan R, Hussain Shah I, Ahmad Mir M, Malik M, Ramzan Z, Bashir N, Ahad S, Khursheed I, Bazie EA, Mohamed Ahmed E, Elderdery AY, Alenazy FO, Alanazi A, Alzahrani B, Alruwaili M, Manni E, E. Hussein S, Abdalhabib EK, Nabi SU. The critical impacts of cytokine storms in respiratory disorders. Heliyon 2024; 10:e29769. [PMID: 38694122 PMCID: PMC11058722 DOI: 10.1016/j.heliyon.2024.e29769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 05/03/2024] Open
Abstract
Cytokine storm (CS) refers to the spontaneous dysregulated and hyper-activated inflammatory reaction occurring in various clinical conditions, ranging from microbial infection to end-stage organ failure. Recently the novel coronavirus involved in COVID-19 (Coronavirus disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has been associated with the pathological phenomenon of CS in critically ill patients. Furthermore, critically ill patients suffering from CS are likely to have a grave prognosis and a higher case fatality rate. Pathologically CS is manifested as hyper-immune activation and is clinically manifested as multiple organ failure. An in-depth understanding of the etiology of CS will enable the discovery of not just disease risk factors of CS but also therapeutic approaches to modulate the immune response and improve outcomes in patients with respiratory diseases having CS in the pathogenic pathway. Owing to the grave consequences of CS in various diseases, this phenomenon has attracted the attention of researchers and clinicians throughout the globe. So in the present manuscript, we have attempted to discuss CS and its ramifications in COVID-19 and other respiratory diseases, as well as prospective treatment approaches and biomarkers of the cytokine storm. Furthermore, we have attempted to provide in-depth insight into CS from both a prophylactic and therapeutic point of view. In addition, we have included recent findings of CS in respiratory diseases reported from different parts of the world, which are based on expert opinion, clinical case-control research, experimental research, and a case-controlled cohort approach.
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Affiliation(s)
- Shahana Riyaz Tramboo
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Ahmed M.E. Elkhalifa
- Department of Public Health, College of Health Sciences, Saudi Electronic University, Riyadh, 11673, Saudi Arabia
- Department of Haematology, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Syed Quibtiya
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Medical College, Srinagar, 190011, Jammu & Kashmir, India
| | - Sofi Imtiyaz Ali
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Naveed Nazir Shah
- Department of Chest Medicine, Govt. Medical College, Srinagar, 191202, Jammu & Kashmir, India
| | - Syed Taifa
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Rabia Rakhshan
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu & Kashmir, 190006, India
| | - Iqra Hussain Shah
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Muzafar Ahmad Mir
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Masood Malik
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Zahid Ramzan
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Nusrat Bashir
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Shubeena Ahad
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Ibraq Khursheed
- Department of Zoology, Central University of Kashmir, 191201, Nunar, Ganderbal, Jammu & Kashmir, India
| | - Elsharif A. Bazie
- Pediatric Department, Faculty of Medicine, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Elsadig Mohamed Ahmed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, 61922, Saudi Arabia
- Department of Clinical Chemistry, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Abozer Y. Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Fawaz O. Alenazy
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Awadh Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Muharib Alruwaili
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Emad Manni
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Sanaa E. Hussein
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Ezeldine K. Abdalhabib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Showkat Ul Nabi
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
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12
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Curtis BE, Abdo Z, Graham B, LaVoy A, Evans SJM, Santangelo K, Dean GA. An Aptamer-Based Proteomic Analysis of Plasma from Cats ( Felis catus) with Clinical Feline Infectious Peritonitis. Viruses 2024; 16:141. [PMID: 38257841 PMCID: PMC10819688 DOI: 10.3390/v16010141] [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] [Revised: 01/13/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
Feline infectious peritonitis (FIP) is a systemic disease manifestation of feline coronavirus (FCoV) and is the most important cause of infectious disease-related deaths in domestic cats. FIP has a variable clinical manifestation but is most often characterized by widespread vasculitis with visceral involvement and/or neurological disease that is typically fatal in the absence of antiviral therapy. Using an aptamer-based proteomics assay, we analyzed the plasma protein profiles of cats who were naturally infected with FIP (n = 19) in comparison to the plasma protein profiles of cats who were clinically healthy and negative for FCoV (n = 17) and cats who were positive for the enteric form of FCoV (n = 9). We identified 442 proteins that were significantly differentiable; in total, 219 increased and 223 decreased in FIP plasma versus clinically healthy cat plasma. Pathway enrichment and associated analyses showed that differentiable proteins were related to immune system processes, including the innate immune response, cytokine signaling, and antigen presentation, as well as apoptosis and vascular integrity. The relevance of these findings is discussed in the context of previous studies. While these results have the potential to inform diagnostic, therapeutic, and preventative investigations, they represent only a first step, and will require further validation.
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Affiliation(s)
| | | | | | | | | | | | - Gregg A. Dean
- Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA; (B.E.C.); (A.L.); (S.J.M.E.); (K.S.)
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13
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Lotfi A, Hajian P, Abbasi L, Gargari MK, Fard NNG, Naderi D. A Review on Role of Inflammation in Coronavirus Disease. Endocr Metab Immune Disord Drug Targets 2024; 24:1488-1505. [PMID: 38303532 DOI: 10.2174/0118715303265274231204075802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/25/2023] [Accepted: 10/25/2023] [Indexed: 02/03/2024]
Abstract
The respiratory illness known as COVID-19 is caused by the novel coronavirus, SARS-CoV-2. While the precise pathogenic mechanism of COVID-19 remains unclear, the occurrence of a cytokine storm subsequent to viral infection plays a pivotal role in the initiation and advancement of the disease. The infection of SARS-CoV-2 induces a state of immune system hyperactivity, leading to an excessive production of inflammatory cytokines. Consequently, the identification of the various signaling pathways implicated in the inflammation induced by COVID-19 will enable researchers to investigate new targets for therapeutic intervention.
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Affiliation(s)
| | - Pouran Hajian
- Department of Anesthesiology, Besat Hospital, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Laleh Abbasi
- Guilan University of Medical Sciences, Rasht, Iran
| | | | - Najmeh Nameh Goshay Fard
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Delaram Naderi
- Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
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14
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Dasgupta A, Gangai S, Narayan R, Kapoor S. Mapping the Lipid Signatures in COVID-19 Infection: Diagnostic and Therapeutic Solutions. J Med Chem 2023; 66:14411-14433. [PMID: 37899546 DOI: 10.1021/acs.jmedchem.3c01238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
The COVID-19 pandemic ignited research centered around the identification of robust biomarkers and therapeutic targets. SARS-CoV-2, the virus responsible, hijacks the metabolic machinery of the host cells. It relies on lipids and lipoproteins of host cells for entry, trafficking, immune evasion, viral replication, and exocytosis. The infection causes host cell lipid metabolic remodelling. Targeting lipid-based processes is thus a promising strategy for countering COVID-19. Here, we review the role of lipids in the different steps of the SARS-CoV-2 pathogenesis and identify lipid-centric targetable avenues. We discuss lipidome changes in infected patients and their relevance as potential clinical diagnostic or prognostic biomarkers. We summarize the emerging direct and indirect therapeutic approaches for targeting COVID-19 using lipid-inspired approaches. Given that viral protein-targeted therapies may become less effective due to mutations in emerging SARS-CoV-2 variants, lipid-inspired interventions may provide additional and perhaps better means of combating this and future pandemics.
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Affiliation(s)
- Aishi Dasgupta
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
- IIT-Bombay Monash Academy, Indian Institute of Technology Bombay, Mumbai 400076, India
| | - Shon Gangai
- School of Chemical and Materials Sciences (SCMS), Institute of Technology Goa, Farmagudi, Ponda, Goa 403401, India
| | - Rishikesh Narayan
- School of Chemical and Materials Sciences (SCMS), Institute of Technology Goa, Farmagudi, Ponda, Goa 403401, India
- School of Interdisciplinary Life Sciences (SILS), Institute of Technology Goa, Farmagudi, Ponda, Goa 403401, India
| | - Shobhna Kapoor
- Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
- IIT-Bombay Monash Academy, Indian Institute of Technology Bombay, Mumbai 400076, India
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8528, Japan
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15
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Nakase H. Understanding the efficacy of individual Janus kinase inhibitors in the treatment of ulcerative colitis for future positioning in inflammatory bowel disease treatment. Immunol Med 2023; 46:121-130. [PMID: 37036140 DOI: 10.1080/25785826.2023.2195522] [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: 01/06/2023] [Accepted: 03/19/2023] [Indexed: 04/11/2023] Open
Abstract
Recent studies have gradually elucidated the pathogenesis of inflammatory bowel disease; thus, the Janus kinase (JAK)-signal transducers and activators of transcription pathway are strongly involved in the pathophysiology of inflammatory bowel disease. Generally, Janus kinase inhibitors are being used for the treatment of rheumatoid arthritis and other immunological diseases, with the therapeutic promising effects. Currently, in Japan, three Janus kinase inhibitors, namely tofacitinib, filgotinib, and upadacitinib, are available for the treatment of patients with active ulcerative colitis. Therefore, evaluating the efficacy and safety of each JAK inhibitor is essential for determining the role of JAK inhibitors in future therapeutic strategies for inflammatory bowel disease (IBD).
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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16
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Sampath A, Banerjee A, Atal S, Jhaj R. Use of baricitinib in treatment of COVID-19: a systematic review. Med Res Rev 2023; 43:1322-1345. [PMID: 36951224 DOI: 10.1002/med.21951] [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: 01/05/2022] [Revised: 08/30/2022] [Accepted: 02/28/2023] [Indexed: 03/24/2023]
Abstract
OBJECTIVE To assess the role of baricitinib alone or in combination with other therapies as a treatment for patients with COVID-19. METHODS Systematic literature search was conducted in the WHO COVID-19 coronavirus disease database to find clinical studies on use of baricitinib for treatment of COVID-19 between December 1, 2019 and September 30, 2021. Two independent set of reviewers identified the eligible studies fulfilling the inclusion criteria, relevant data was extracted and a qualitative synthesis of evidence performed. The risk of bias was evaluated with validated tools. RESULTS A total of 267 articles were found to be eligible after primary screening of titles and abstracts. Following assessment of full texts, 19 studies were finally included for this systematic review, out of which 16 are observational, and 3 are interventional studies. Collating the results from these observational and interventional studies, baricitinib used as add-on to standard therapy, either alone or in combination with other drugs, was found to have favorable outcomes in hospitalized patients with moderate to severe COVID-19. Furthermore, ongoing trials indicate that the drug is being extensively studied across the world for its safety and efficacy in COVID-19. CONCLUSION Baricitinib significantly improves clinical outcomes in hospitalized patients with COVID-19 pneumonia, and further evidence will establish the drug as a standard treatment among such patients.
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Affiliation(s)
- Ananyan Sampath
- Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Aditya Banerjee
- Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Shubham Atal
- Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Ratinder Jhaj
- Department of Pharmacology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
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17
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El Zahran T, Kalot N, Cheaito R, Khalifeh M, Estelly N, El Majzoub I. Predictors of intensive care unit admission in adult cancer patients presenting to the emergency department with COVID-19 infection: A retrospective study. PLoS One 2023; 18:e0287649. [PMID: 37643201 PMCID: PMC10464997 DOI: 10.1371/journal.pone.0287649] [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: 03/08/2023] [Accepted: 06/12/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Adult cancer patients with COVID-19 were shown to be at higher risk of Intensive Care Unit (ICU) admission. Previously published prediction models showed controversy and enforced the importance of heterogeneity among different populations studied. Therefore, this study aimed to identify predictors of ICU admission (demographic, clinical, and COVID-19 targeted medications) in cancer patients with active COVID-19 infection presenting to the Emergency Department (ED). METHODS This is a retrospective cohort study. It was conducted on adult cancer patients older than 18 years who presented to the American University of Beirut Medical Center ED from February 21, 2020, till February 21, 2021, and were found to have COVID-19 infection. Relevant data were extracted from electronic medical records. The association between different variables and ICU admission was tested. Logistic regression was done to adjust for confounding variables. A p-value less than 0.05 was considered significant. RESULTS Eighty-nine distinct patients were included. About 37% were admitted to the ICU (n = 33). Higher ICU admission was seen in patients who had received chemotherapy within one month, had a respiratory rate at triage above 22 breaths per minute, oxygen saturation less than 95%, and a higher c-reactive protein upon presentation to the ED. After adjusting for confounding variables, only recent chemotherapy and higher respiratory rate at triage were significantly associated with ICU admission. CONCLUSION Physicians need to be vigilant when taking care of COVID-19 infected cancer patients. Patients who are tachypneic at presentation and those who have had chemotherapy within one month are at high risk for ICU admission.
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Affiliation(s)
- Tharwat El Zahran
- Department of Emergency Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Nour Kalot
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rola Cheaito
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Malak Khalifeh
- Department of Emergency Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Natalie Estelly
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Imad El Majzoub
- Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
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18
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Ziaie N, Tabatabaie SMR, Ezoji K, Bijani A, Mouodi S. Correlation of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) with radiographic features of congestion in chest CT scan of patients with COVID-19. Egypt Heart J 2023; 75:59. [PMID: 37439968 DOI: 10.1186/s43044-023-00390-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 07/09/2023] [Indexed: 07/14/2023] Open
Abstract
BACKGROUND Given the importance of chest computed tomography (CT) to differentiate congestion from COVID-19 pneumonia, and considering the association of chest CT findings with cardiac biomarkers in patients with concomitant COVID-19 and heart failure, this study was conducted to identify the correlation between plasma NT-proBNP level and radiographic features of congestion in patients with COVID-19. This retrospective cohort research was carried out on adult hospitalized patients with COVID-19 and the plasma concentration of NT-proBNP was measured. The most important findings in chest CT have been considered to differentiate COVID-19 pneumonia from congestion. The study population was divided into two groups based on the presence of these imaging characteristics. RESULTS Totally, 180 patients with a mean age of 59.6 ± 14.6 years were included in the research. The radiographic findings related to congestion have been found in chest CT of 107 (59.4%) patients. Mean plasma concentration of NT-proBNP in patients with and without radiographic features of congestion was 9886.5 ± 12,676 and 2079.9 ± 4209.3 pg/mL, respectively (p < 0.001). The area under the curve of plasma levels of NT-proBNP for identification of patients with COVID-19 who had pulmonary vein enlargement in chest CT was 0.765 (95% CI 0.688-0.842) and 0.731 (95% CI 0.648-0.813) for the individuals who had interlobar fissure thickening (p < 0.001). CONCLUSIONS The diagnostic accuracy of plasma NT-proBNP and its positive correlation with radiographic features of congestion in chest CT scan of patients with COVID-19 can be helpful for administering appropriate medications to prevent blood volume overload.
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Affiliation(s)
- Naghmeh Ziaie
- Department of Cardiology, Babol University of Medical Sciences, Babol, Iran
| | | | - Khadijeh Ezoji
- Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Bijani
- Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Simin Mouodi
- Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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19
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Singh PK, Sharma VK, Lalwani LK, Chaudhry D, Govindagoudar MB, Sriram CP, Ahuja A. Role of Janus Kinase inhibitors in the management of pulmonary involvement due to Long COVID-19 disease: A case control study. Turk J Emerg Med 2023; 23:149-155. [PMID: 37529783 PMCID: PMC10389097 DOI: 10.4103/tjem.tjem_363_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 08/03/2023] Open
Abstract
OBJECTIVES Ongoing symptomatic coronavirus disease 2019 (OSC) is defined as persistent symptoms beyond 4 weeks of acute illness. OSC leads to prolonged hospitalization and oxygen dependence. We aimed to find the outcome of Janus kinase inhibitors (JAKi) as a steroid-sparing agent to treat OSC. METHODS In this single-center case-controlled study comparing JAKi and corticosteroids in OSC cases, data of 41 cases out of 86 were included - 21 in the JAKi group and 20 in the corticosteroid group from 4 weeks of acute illness to the next 4 weeks. Clinical parameters and inflammatory markers were recorded. The primary outcome was to compare the proportion of patients who were able to maintain oxygen saturation ≥95% with any oxygen supplementation in the two groups. RESULTS The baseline clinical and demographic characteristics were similar in the two groups. The age was 53.65 ± 9.8 years and 51.48 ± 14.0 years in the corticosteroid group and JAKi group, respectively. At the baseline, 85% of patients in the corticosteroid group and 85.8% in the JAKi group were on oxygen support. The most common symptom in both groups was breathlessness followed by cough. Twenty percent of patients in the JAKi group received baricitinib and the remaining were given tofacitinib. At the time of follow-up, the majority of cases had a significant reduction in C-reactive protein (CRP) and D-dimer; however, the change in CRP and D-dimer was similar in both groups. The number of patients off oxygen support at 4 weeks was higher in the JAKi group (85% in the corticosteroid group vs. 95.2% in the JAKi group, P = 0.269), and the median time to liberation from oxygen support was significantly lower in JAKi group (19 days in corticosteroid group vs. 9 days in JAKi group, P < 0.001). The frequency of any adverse event was also higher in the corticosteroid group (70% vs. 23.8%, P = 0.003). CONCLUSION JAKi can be used as immunomodulatory drugs in hypoxic OSC cases having evidence of ongoing inflammation.
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Affiliation(s)
- Pawan Kumar Singh
- Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Vinod Kumar Sharma
- Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Lokesh Kumar Lalwani
- Department of Respiratory Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Dhruva Chaudhry
- Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Manjunath B. Govindagoudar
- Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Chaudhari Pramod Sriram
- Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Aman Ahuja
- Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
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20
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Feng Y, Chen Z, Xu Y, Han Y, Jia X, Wang Z, Zhang N, Lv W. The central inflammatory regulator IκBζ: induction, regulation and physiological functions. Front Immunol 2023; 14:1188253. [PMID: 37377955 PMCID: PMC10291074 DOI: 10.3389/fimmu.2023.1188253] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
IκBζ (encoded by NFKBIZ) is the most recently identified IkappaB family protein. As an atypical member of the IkappaB protein family, NFKBIZ has been the focus of recent studies because of its role in inflammation. Specifically, it is a key gene in the regulation of a variety of inflammatory factors in the NF-KB pathway, thereby affecting the progression of related diseases. In recent years, investigations into NFKBIZ have led to greater understanding of this gene. In this review, we summarize the induction of NFKBIZ and then elucidate its transcription, translation, molecular mechanism and physiological function. Finally, the roles played by NFKBIZ in psoriasis, cancer, kidney injury, autoimmune diseases and other diseases are described. NFKBIZ functions are universal and bidirectional, and therefore, this gene may exert a great influence on the regulation of inflammation and inflammation-related diseases.
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Affiliation(s)
- Yanpeng Feng
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Zhiyuan Chen
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Yi Xu
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Yuxuan Han
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
| | - Xiujuan Jia
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zixuan Wang
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nannan Zhang
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenjing Lv
- Department of Neurosurgery & Pathophysiology, Institute of Neuroregeneration & Neurorehabilitation, Qingdao University, Qingdao, China
- Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, China
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21
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [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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22
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Iaconis D, Caccuri F, Manelfi C, Talarico C, Bugatti A, Filippini F, Zani A, Novelli R, Kuzikov M, Ellinger B, Gribbon P, Riecken K, Esposito F, Corona A, Tramontano E, Beccari AR, Caruso A, Allegretti M. DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action. Viruses 2023; 15:v15051128. [PMID: 37243214 DOI: 10.3390/v15051128] [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: 04/05/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 05/28/2023] Open
Abstract
During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.
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Affiliation(s)
- Daniela Iaconis
- EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, Italy
| | - Francesca Caccuri
- Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Candida Manelfi
- EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, Italy
| | - Carmine Talarico
- EXSCALATE, Dompé Farmaceutici SpA, Via Tommaso De Amicis, 95, 80131 Napoli, Italy
| | - Antonella Bugatti
- Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Federica Filippini
- Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Alberto Zani
- Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Rubina Novelli
- Dompè Famaceutici SpA, Via Campo di Pile snc, 67100 L'Aquila, Italy
| | - Maria Kuzikov
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany
- Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - Bernhard Ellinger
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany
- Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - Philip Gribbon
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany
- Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Francesca Esposito
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), Italy
| | - Angela Corona
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), Italy
| | - Enzo Tramontano
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042 Monserrato (CA), Italy
| | | | - Arnaldo Caruso
- Section of Microbiology Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
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23
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COVID-19 signalome: Potential therapeutic interventions. Cell Signal 2023; 103:110559. [PMID: 36521656 PMCID: PMC9744501 DOI: 10.1016/j.cellsig.2022.110559] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/21/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
The COVID-19 pandemic has triggered intensive research and development of drugs and vaccines against SARS-CoV-2 during the last two years. The major success was especially observed with development of vaccines based on viral vectors, nucleic acids and whole viral particles, which have received emergent authorization leading to global mass vaccinations. Although the vaccine programs have made a big impact on COVID-19 spread and severity, emerging novel variants have raised serious concerns about vaccine efficacy. Due to the urgent demand, drug development had originally to rely on repurposing of antiviral drugs developed against other infectious diseases. For both drug and vaccine development the focus has been mainly on SARS-CoV-2 surface proteins and host cell receptors involved in viral attachment and entry. In this review, we expand the spectrum of SARS-CoV-2 targets by investigating the COVID-19 signalome. In addition to the SARS-CoV-2 Spike protein, the envelope, membrane, and nucleoprotein targets have been subjected to research. Moreover, viral proteases have presented the possibility to develop different strategies for the inhibition of SARS-CoV-2 replication and spread. Several signaling pathways involving the renin-angiotensin system, angiotensin-converting enzymes, immune pathways, hypoxia, and calcium signaling have provided attractive alternative targets for more efficient drug development.
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24
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Hillary VE, Ceasar SA. An update on COVID-19: SARS-CoV-2 variants, antiviral drugs, and vaccines. Heliyon 2023; 9:e13952. [PMID: 36855648 PMCID: PMC9946785 DOI: 10.1016/j.heliyon.2023.e13952] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/07/2023] [Accepted: 02/15/2023] [Indexed: 02/25/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and pathogenic virus that first appeared in late December 2019. This SARS-CoV-2 causes an infection of an acute respiratory disease called "coronavirus infectious disease-2019 (COVID-19). The World Health Organization (WHO) declared this SARS-CoV-2 outbreak a great pandemic on March 11, 2020. As of January 31, 2023, SARS-CoV-2 recorded more than 67 million cases and over 6 million deaths. Recently, novel mutated variants of SARS-CoV are also creating a serious health concern worldwide, and the future novel variant is still mysterious. As infection cases of SARS-CoV-2 are increasing daily, scientists are trying to combat the disease using numerous antiviral drugs and vaccines against SARS-CoV-2. To our knowledge, this is the first comprehensive review that summarized the dynamic nature of SARS-CoV-2 transmission, SARS-CoV-2 variants (a variant of concern and variant of interest), antiviral drugs and vaccines utilized against SARS-CoV-2 at a glance. Hopefully, this review will enable the researcher to gain knowledge on SARS-CoV-2 variants and vaccines, which will also pave the way to identify efficient novel vaccines against forthcoming SARS-CoV-2 strains.
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Key Words
- ACE2, Angiotensin-converting enzyme 2
- Antiviral drugs
- COVID-19
- COVID-19, Coronavirus infectious disease-2019
- EUA, Emergency Use Authorization
- FDA, Food and Drug Administration
- NIH, National Institutes of Health
- RBD, Receptor-binding domain
- SARS-CoV-2
- SARS-CoV-2 variants
- SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2
- VOC, Variants of Concern
- VOI, Variants of Interests
- Vaccines
- WHO, World Health Organization
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Affiliation(s)
- Varghese Edwin Hillary
- Department of Biosciences, Rajagiri College of Social Sciences, Cochin, 683 104, Kerala, India
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25
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Bankole AA, Nwaonu J, Saeed J. Impact of SARS-CoV-2/COVID-19 on Provision of Medical Care to Patients With Systemic Autoimmune Rheumatic Disease and the Practice of Rheumatology. Cureus 2023; 15:e35402. [PMID: 36987476 PMCID: PMC10040147 DOI: 10.7759/cureus.35402] [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] [Accepted: 02/24/2023] [Indexed: 03/30/2023] Open
Abstract
The SARS-CoV-2 pandemic has had a significant impact on the healthcare field that resulted in changes to the way safe and effective medical care is delivered. The effects range from service disruption including ambulatory clinic closure due to both patient and provider concerns, to lack of capacity in hospital services. In rheumatology, there were other effects including viral infection-related autoantibody production, concerns about the use of systemic immunosuppression in the presence of an infectious pandemic and even concerns for viral infection-induced flares of rheumatic disease. Coronavirus disease 2019 (COVID-19) led to the rapid adoption of innovative technologies that permitted the introduction and increased use of telemedicine via a number of platforms. Rapid discoveries and innovations led to the development of diagnostic and therapeutic agents in the management of COVID-19. Scientific advancement and discoveries around COVID-19 infection, symptoms, autoantibody production, chronic sequela and the repurposing of rheumatic immunosuppressive agents led to improved survival and an expanded role for the rheumatologist. Rheumatologists may sometimes be involved in the diagnosis and management of the hospitalized COVID-19 patient. In the ambulatory clinic, a rheumatologist also helps to differentiate between symptoms of long COVID and those of systemic autoimmune rheumatic disease (SARD). Rheumatologists must also grapple with the concerns related to immunosuppressive therapy and the risk of COVID-19 infections. In addition, there are concerns around vaccine effectiveness in people with SARD and those on immunosuppressive medications. Although the SARS-CoV-2 pandemic and the effects on healthcare resulted in difficulties, both patients and providers have risen to the challenge. The long-term outcome of COVID-19 for the medical system and rheumatologists in particular is not yet fully understood and will need further study. This review concentrates on the changing role of the rheumatologists, improved understanding of rheumatic disease and immunosuppressive therapies in the wake of the pandemic and how this has led to an improvement in the care of patients with COVID-19.
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Affiliation(s)
| | - Jane Nwaonu
- Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, USA
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26
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Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives. Mol Ther Oncolytics 2023; 28:132-157. [PMID: 36816749 PMCID: PMC9922830 DOI: 10.1016/j.omto.2023.01.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The tumor microenvironment (TME) comprises a variety of immune cells, among which T cells exert a prominent axial role in tumor development or anti-tumor responses in patients with breast cancer (BC). High or low levels of anti-inflammatory cytokines, such as transforming growth factor β, in the absence or presence of proinflammatory cytokines, such as interleukin-6 (IL-6), delineate the fate of T cells toward either regulatory T (Treg) or T helper 17 (Th17) cells, respectively. The transitional state of RORγt+Foxp3+ Treg (IL-17-producing Treg) resides in the middle of this reciprocal polarization, which is known as Treg/IL-17-producing Treg/Th17 cell axis. TME secretome, including microRNAs, cytokines, and extracellular vesicles, can significantly affect this axis. Furthermore, immune checkpoint inhibitors may be used to reconstruct immune cells; however, some of these novel therapies may favor tumor development. Therefore, understanding secretory and cell-associated factors involved in their differentiation or polarization and functions may be targeted for BC management. This review discusses microRNAs, cytokines, and extracellular vesicles (as secretome), as well as transcription factors and immune checkpoints (as cell-associated factors), which influence the Treg/IL-17-producing Treg/Th17 cell axis in BC. Furthermore, approved or ongoing clinical trials related to the modulation of this axis in the TME of BC are described to broaden new horizons of promising therapeutic approaches.
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27
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Dissook S, Umsumarng S, Mapoung S, Semmarath W, Arjsri P, Srisawad K, Dejkriengkraikul P. Luteolin-rich fraction from Perilla frutescens seed meal inhibits spike glycoprotein S1 of SARS-CoV-2-induced NLRP3 inflammasome lung cell inflammation via regulation of JAK1/STAT3 pathway: A potential anti-inflammatory compound against inflammation-induced long-COVID. Front Med (Lausanne) 2023; 9:1072056. [PMID: 36698809 PMCID: PMC9870545 DOI: 10.3389/fmed.2022.1072056] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
Objective The multi-systemic inflammation as a result of COVID-19 can persevere long after the initial symptoms of the illness have subsided. These effects are referred to as Long-COVID. Our research focused on the contribution of the Spike protein S1 subunit of SARS-CoV-2 (Spike S1) on the lung inflammation mediated by NLRP3 inflammasome machinery and the cytokine releases, interleukin 6 (IL-6), IL-1beta, and IL-18, in lung epithelial cells. This study has attempted to identify the naturally- occurring agents that act against inflammation-related long-COVID. The seed meal of Perilla frutescens (P. frutescens), which contains two major dietary polyphenols (rosmarinic acid and luteolin), has been reported to exhibit anti-inflammation activities. Therefore, we have established the ethyl acetate fraction of P. frutescens seed meal (PFEA) and determined its anti-inflammatory effects on Spike S1 exposure in A549 lung cells. Methods PFEA was established using solvent-partitioned extraction. Rosmarinic acid (Ra) and luteolin (Lu) in PFEA were identified using the HPLC technique. The inhibitory effects of PFEA and its active compounds against Spike S1-induced inflammatory response in A549 cells were determined by RT-PCR and ELISA. The mechanistic study of anti-inflammatory properties of PFEA and Lu were determined using western blot technique. Results PFEA was found to contain Ra (388.70 ± 11.12 mg/g extract) and Lu (248.82 ± 12.34 mg/g extract) as its major polyphenols. Accordingly, A549 lung cells were pre-treated with PFEA (12.5-100 μg/mL) and its two major compounds (2.5-20 μg/mL) prior to the Spike S1 exposure at 100 ng/mL. PFEA dose-dependently exhibited anti-inflammatory properties upon Spike S1-exposed A549 cells through IL-6, IL-1β, IL-18, and NLRP3 gene suppressions, as well as IL-6, IL-1β, and IL-18 cytokine releases with statistical significance (p < 0.05). Importantly, Lu possesses superior anti-inflammatory properties when compared with Ra (p < 0.01). Mechanistically, PFEA and Lu effectively attenuated a Spike S1-induced inflammatory response through downregulation of the JAK1/STAT3-inflammasome-dependent inflammatory pathway as evidenced by the downregulation of NLRP3, ASC, and cleaved-caspase-1 of the NLRP3 inflammasome components and by modulating the phosphorylation of JAK1 and STAT3 proteins (p < 0.05). Conclusion The findings suggested that luteolin and PFEA can modulate the signaling cascades that regulate Spike S1-induced lung inflammation during the incidence of Long-COVID. Consequently, luteolin and P. frutescens may be introduced as potential candidates in the preventive therapeutic strategy for inflammation-related post-acute sequelae of COVID-19.
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Affiliation(s)
- Sivamoke Dissook
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
| | - Sonthaya Umsumarng
- Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand,Division of Veterinary Preclinical Sciences, Department of Veterinary Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Sariya Mapoung
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
| | - Warathit Semmarath
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand,Akkraratchkumari Veterinary College, Walailak University, Nakhon Si Thammarat, Thailand
| | - Punnida Arjsri
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
| | - Kamonwan Srisawad
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand,Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pornngarm Dejkriengkraikul
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand,Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand,*Correspondence: Pornngarm Dejkriengkraikul,
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Nazerian Y, Ghasemi M, Yassaghi Y, Nazerian A, Mahmoud Hashemi S. Role of SARS-CoV-2-induced Cytokine Storm in Multi-Organ Failure: Molecular Pathways and Potential Therapeutic Options. Int Immunopharmacol 2022; 113:109428. [PMID: 36379152 PMCID: PMC9637536 DOI: 10.1016/j.intimp.2022.109428] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/19/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
Abstract
Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called “cytokine storm” is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19.
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Affiliation(s)
- Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Ghasemi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Younes Yassaghi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Mahmoud Hashemi
- Medical nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Corresponding author at: Medical nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran / Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Nabati F, kamyabiamineh A, Kosari R, Ghasemi F, Seyedebrahimi S, Mohammadi S, Moradi M. Virtual screening based on the structure of more than 105 compounds against four key proteins of SARS-CoV-2: MPro, SRBD, RdRp, and PLpro. INFORMATICS IN MEDICINE UNLOCKED 2022; 35:101134. [PMID: 36406927 PMCID: PMC9652154 DOI: 10.1016/j.imu.2022.101134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/11/2022] [Accepted: 11/11/2022] [Indexed: 11/15/2022] Open
Abstract
Background SARS-CoV-2 initially originated in Wuhan (China) around December 2019, and spread all over the world. Currently, WHO (Word Health Organization) has licensed several vaccines for this viral infection. However, not everyone can be vaccinated. People with underlying health conditions that weaken their immune systems or those with severe allergies to some vaccine components, may not be able to be vaccinated. Moreover, no vaccination is 100% safe, and the emergence of new SARS-CoV-2 mutations may reduce the efficacy of immunizations. Therefore, it is urgent to develop effective drugs to protect people against this virus. Material and method We performed structure-based virtual screening (SBVS) of a library that was built from ChemDiv and PubChem databases against four SARS-CoV-2 target proteins: S-protein (spike), main protease (MPro), RNA-dependent RNA polymerase, and PLpro. A virtual screening study was performed using PyRx and AutoDock tools. Results Our results suggest that twenty-five top-ranked drugs with the highest energy binding as the potential inhibitors against four SARS-CoV-2 targets, relative to the reference molecules. Based on the energy binding, we suggest that these compounds could be used to produce effective anti-viral drugs against SARS-CoV-2. Conclusion The discovery of novel compounds for COVID-19 using computer-aided drug discovery tools requires knowledge of the structure of coronavirus and various target proteins of the virus. These compounds should be further assessed in experimental assays and clinical trials to validate their actual activity against the disease. These findings may contribute to the drug design studies against COVID-19.
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30
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Li X, Jiang W, Dong S, Li W, Zhu W, Zhou W. STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer. Biomolecules 2022; 12:1450. [PMID: 36291659 PMCID: PMC9599947 DOI: 10.3390/biom12101450] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/10/2022] [Accepted: 09/30/2022] [Indexed: 11/29/2022] Open
Abstract
The signal transducer and activator of transcription (STAT) is a family of intracellular cytoplasmic transcription factors involved in many biological functions in mammalian signal transduction. Among them, STAT3 is involved in cell proliferation, differentiation, apoptosis, and inflammatory responses. Despite the advances in the treatment of pancreatic cancer in the past decade, the prognosis for patients with pancreatic cancer remains poor. STAT3 has been shown to play a pro-cancer role in a variety of cancers, and inhibitors of STAT3 are used in pre-clinical and clinical studies. We reviewed the relationship between STAT3 and pancreatic cancer and the latest results on the use of STAT3 inhibitors in pancreatic cancer, with the aim of providing insights and ideas around STAT3 inhibitors for a new generation of chemotherapeutic modalities for pancreatic cancer.
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Affiliation(s)
- Xin Li
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Wenkai Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Shi Dong
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Wancheng Li
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Weixiong Zhu
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
| | - Wence Zhou
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou 730030, China
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Prameswari HS, Putra ICS, Raffaello WM, Nathaniel M, Suhendro AS, Khalid AF, Pranata R. Managing Covid-19 in patients with heart failure: current status and future prospects. Expert Rev Cardiovasc Ther 2022; 20:807-828. [PMID: 36185009 DOI: 10.1080/14779072.2022.2132230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
INTRODUCTION COVID-19 may contribute to decompensation of previously stable chronic HF or cause a de-novo heart failure, which may come from the hyperinflammatory response and subsequent increase in metabolic demand. AREAS COVERED Two independent investigators searched MEDLINE (via PubMed), Europe PMC, and ScienceDirect databases with the following search terms: COVID-19, heart failure, COVID-19 drugs, heart failure drugs, and device therapy. All of the included full-text articles were rigorously evaluated by both authors in case there was disagreement about whether research should be included or not. In total, 157 studies were included and underwent extensive reading by the authors. EXPERT OPINION The World Health Organization (WHO) and the National Institute of Health (NIH) have published COVID-19 drug recommendations, although recommendations for HF-specific drug choices in COVID-19 are still lacking. We hope that this review can answer the void of comprehensive research data regarding the management options of HF in the COVID-19 condition so that clinicians can at least choose a more beneficial therapy or avoid combination therapies that have a high burden of side effects on HF; thus, morbidity and mortality in COVID-19 patients with HF may be reduced.
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Affiliation(s)
- Hawani Sasmaya Prameswari
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Iwan Cahyo Santosa Putra
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | | | - Michael Nathaniel
- School of Medicine and Health Sciences Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Adrian Sebastian Suhendro
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Achmad Fitrah Khalid
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Raymond Pranata
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
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The Role of Natural Products as Inhibitors of JAK/STAT Signaling Pathways in Glioblastoma Treatment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7838583. [PMID: 36193062 PMCID: PMC9526628 DOI: 10.1155/2022/7838583] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/28/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022]
Abstract
The permeability of glioblastoma, as well as its escaping the immune system, makes them one of the most deadly human malignancies. By avoiding programmed cell death (apoptosis), unlimited cell growth and metastatic ability could dramatically affect the immune system. Genetic mutations, epigenetic changes, and overexpression of oncogenes can cause this process. On the other hand, the blood-brain barrier (BBB) and intratumor heterogeneity are important factors causing resistance to therapy. Several signaling pathways have been identified in this field, including the Janus tyrosine kinase (JAK) converter and signal transducer and activator of transcription (STAT) activator pathways, which are closely related. In addition, the JAK/STAT signaling pathway contributes to a wide array of tumorigenesis functions, including replication, anti-apoptosis, angiogenesis, and immune suppression. Introducing this pathway as the main tumorigenesis and treatment resistance center can give a better understanding of how it operates. In light of this, it is an important goal in treating many disorders, particularly cancer. The inhibition of this signaling pathway is being considered an approach to the treatment of glioblastoma. The use of natural products alternatively to conventional therapies is another area of research interest among researchers. Some natural products that originate from plants or natural sources can interfere with JAK/STAT signaling in human malignant cells, also by stopping the progression and phosphorylation of JAK/STAT, inducing apoptosis, and stopping the cell cycle. Natural products are a viable alternative to conventional chemotherapy because of their cost-effectiveness, wide availability, and almost no side effects.
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Jiang Y, Zhao T, Zhou X, Xiang Y, Gutierrez‐Castrellon P, Ma X. Inflammatory pathways in COVID-19: Mechanism and therapeutic interventions. MedComm (Beijing) 2022; 3:e154. [PMID: 35923762 PMCID: PMC9340488 DOI: 10.1002/mco2.154] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing an inflammatory cytokine storm in severe cases. Cytokine storm leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is an important cause of COVID-19 progression and even death. Among them, activation of inflammatory pathways is a major factor in generating cytokine storms and causing dysregulated immune responses, which is closely related to the severity of viral infection. Therefore, elucidation of the inflammatory signaling pathway of SARS-CoV-2 is important in providing otential therapeutic targets and treatment strategies against COVID-19. Here, we discuss the major inflammatory pathways in the pathogenesis of COVID-19, including induction, function, and downstream signaling, as well as existing and potential interventions targeting these cytokines or related signaling pathways. We believe that a comprehensive understanding of the regulatory pathways of COVID-19 immune dysregulation and inflammation will help develop better clinical therapy strategies to effectively control inflammatory diseases, such as COVID-19.
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Affiliation(s)
- Yujie Jiang
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Tingmei Zhao
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Xueyan Zhou
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Yu Xiang
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
| | - Pedro Gutierrez‐Castrellon
- Center for Translational Research on Health Science Hospital General Dr. Manuel Gea GonzalezMinistry of HealthMexico CityMexico
| | - Xuelei Ma
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
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Khaledi M, Sameni F, Yahyazade S, Radandish M, Owlia P, Bagheri N, Afkhami H, Mahjoor M, Esmaelpour Z, Kohansal M, Aghaei F. COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy. Front Med (Lausanne) 2022; 9:961027. [PMID: 36111104 PMCID: PMC9469902 DOI: 10.3389/fmed.2022.961027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Recent evidence proposed that the severity of the coronavirus disease 2019 (COVID-19) in patients is a consequence of cytokine storm, characterized by increased IL-1β, IL-6, IL-18, TNF-α, and IFN-γ. Hence, managing the cytokine storm by drugs has been suggested for the treatment of patients with severe COVID-19. Several of the proinflammatory cytokines involved in the pathogenesis of COVID-19 infection recruit a distinct intracellular signaling pathway mediated by JAKs. Consequently, JAK inhibitors, including baricitinib, pacritinib, ruxolitinib, and tofacitinib, may represent an effective therapeutic strategy for controlling the JAK to treat COVID-19. This study indicates the mechanism of cytokine storm and JAK/STAT pathway in COVID-19 as well as the medications used for JAK/STAT inhibitors.
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Affiliation(s)
- Mansoor Khaledi
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Fatemeh Sameni
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Sheida Yahyazade
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maedeh Radandish
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parviz Owlia
- Molecular Microbiology Research Center, Faculty of Medicine, Shahed University, Tehran, Iran
- *Correspondence: Parviz Owlia ;
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Nader Bagheri
| | | | - Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Esmaelpour
- Reference Laboratory for Bovine Tuberculosis, Razi Vaccine and Serum Research Institute, Karaj, Iran
| | - Maryam Kohansal
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzad Aghaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Khoshmirsafa M, Assarehzadegan MA, Fallahpour M, Azimi M, Faraji F, Riahi T, Minaeian S, Fassahat D, Divsalar F, Abbasi MA. Expression Pattern of Inflammatory and Anti-Inflammatory Cytokines and Key Differential Transcription Factors in Peripheral Blood Mononuclear Cells of Iranian Coronavirus Disease 2019 Patients with Different Disease Severity. Viral Immunol 2022; 35:474-482. [PMID: 35997599 DOI: 10.1089/vim.2021.0224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The purpose of this research was to investigate the gene expression levels of inflammatory cytokines interferon (IFN)γ, tumor necrosis factor (TNF)α, interleukin (IL)1β, IL2, IL6, IL8, and IL17, and anti-inflammatory cytokines IL4, IL10, IFNα, and IFNβ, as well as relevant key transcription factors (TFs), including GATA3, PU1, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), IRF3 (interferon regulatory factor 3), BCL6 (B cell lymphoma 6 protein), FOXP3 (forkhead box P3), RORγt, and T-bet (T-box expressed in T cell) in Iranian patients with moderate and severe coronavirus disease 2019 (COVID-19). Fifty-six patients with COVID-19, and 25 healthy controls (HCs) age and sex matched were investigated. Based on the interim guidance of COVID-19 from the World Health Organization, the patients were classified into 33 moderate and 23 severe patients with COVID-19. The gene expression levels of cytokines and relevant TFs were quantified in peripheral blood mononuclear cells by quantitative real-time polymerase chain reaction (qRT-PCR). The gene expression levels of TFs RoRγ (RAR-related orphan nuclear receptor γ), NF-κB, and T-bet were significantly higher in patients with COVID-19 compared with HCs. Furthermore, the gene expression levels of cytokines, including IL2, IFNγ, IL6, TNFα, IL1β, IL8, and IL17, were significantly higher in patients with COVID-19 than HCs. However, there was a significant increase for IL6, TNFα, and IL17 in severe compared with moderate patients with COVID-19. Finally, The Spearman correlation analysis revealed a significantly positive correlation for IL6 and TNFα, IL6 and IL2, IL6, IFNγ, and IL2 and IFNγ. These data suggest that expression of IL6, TNFα, and IL17 as well as the synergic effect of elevated values of IL2 and IFNγ should be considered in the treatment and management of patients with severe COVID-19.
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Affiliation(s)
- Majid Khoshmirsafa
- Immunology Research Center, Institute of Immunology and Infectious Diseases; Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine; Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad-Ali Assarehzadegan
- Immunology Research Center, Institute of Immunology and Infectious Diseases; Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine; Iran University of Medical Sciences, Tehran, Iran
| | - Morteza Fallahpour
- Allergy and Clinical Immunology Department, Rasool e Akram Hospital; Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Azimi
- Immunology Research Center, Institute of Immunology and Infectious Diseases; Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Faraji
- Immunology Research Center, Institute of Immunology and Infectious Diseases; Iran University of Medical Sciences, Tehran, Iran
| | - Taghi Riahi
- Rasoul-e-Akram Hospital; Iran University of Medical Sciences, Tehran, Iran
| | - Sara Minaeian
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases; Iran University of Medical Sciences, Tehran, Iran
| | - Davood Fassahat
- Firoozabadi Clinical Research Development (FCRDU); Iran University of Medical Sciences, Tehran, Iran
| | - Farshad Divsalar
- Firoozabadi Clinical Research Development (FCRDU); Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Abbasi
- Firoozabadi Clinical Research Development (FCRDU); Iran University of Medical Sciences, Tehran, Iran
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Tahsini Tekantapeh S, Ghojazadeh M, Ghamari AA, Mohammadi A, Soleimanpour H. Therapeutic and anti-inflammatory effects of baricitinib on mortality, ICU transfer, clinical improvement, and CRS-related laboratory parameters of hospitalized patients with moderate to severe COVID-19 pneumonia: a systematic review and meta-analysis. Expert Rev Respir Med 2022; 16:1109-1132. [PMID: 35981253 DOI: 10.1080/17476348.2022.2114899] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND Due to the high incidence and mortality of the worldwide COVID-19 pandemic, beneficial effects of effective antiviral and anti-inflammatory drugs used in other diseases, especially rheumatic diseases, were observed in the treatment of COVID-19. METHODS Clinical and laboratory parameters of eight included cohort studies and five Randomized Control Trials between the baricitinib group and the control group were analyzed on the first day of admission and days 7, 14, and 28 during hospitalization. RESULTS According to the meta-analysis result of eight included cohort studies with 2088 patients, the Pooled Risk Ratios were 0.46 (P<0.001) for mortality, 6.14 (P< 0.001) for hospital discharge, and the mean differences of 76.78 (P< 0.001) for PaO2/FiO2 ratio was -47.32 (P= 0.02) for CRP, in the baricitinib group vs. control group on the seventh or fourteenth day of the treatment compared to the first day. Based on the meta-analysis of five RCT studies with 11825 patients, the pooled RR was 0.84 (P= 0.001) for mortality and 1.07 (P= 0.014) for patients' recovery. The mean differences were -0.80 (P<0.001) for hospitalization days, -0.51(P= 0.33) for time to recovery in the baricitinib group vs. control group. CONCLUSIONS Baricitinib prescription is strongly recommended in moderate to severe COVID-19. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number: CRD42021254541.
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Affiliation(s)
| | - Morteza Ghojazadeh
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Ghamari
- Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aida Mohammadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Soleimanpour
- Road Traffic Injury research center, Tabriz university of medical sciences, Tabriz, Iran
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Zalpoor H, Nabi-Afjadi M, Forghaniesfidvajani R, Tavakol C, Farahighasreaboonasr F, Pakizeh F, Dana VG, Seif F. Quercetin as a JAK-STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases. Cell Mol Biol Lett 2022; 27:60. [PMID: 35883021 PMCID: PMC9327369 DOI: 10.1186/s11658-022-00355-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/22/2022] [Indexed: 02/08/2023] Open
Abstract
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in many immunological processes, including cell growth, proliferation, differentiation, apoptosis, and inflammatory responses. Some of these processes can contribute to cancer progression and neurodegeneration. Owing to the complexity of this pathway and its potential crosstalk with alternative pathways, monotherapy as targeted therapy has usually limited long-term efficacy. Currently, the majority of JAK-STAT-targeting drugs are still at preclinical stages. Meanwhile, a variety of plant polyphenols, especially quercetin, exert their inhibitory effects on the JAK-STAT pathway through known and unknown mechanisms. Quercetin has shown prominent inhibitory effects on the JAK-STAT pathway in terms of anti-inflammatory and antitumor activity, as well as control of neurodegenerative diseases. This review discusses the pharmacological effects of quercetin on the JAK-STAT signaling pathway in solid tumors and neurodegenerative diseases.
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Affiliation(s)
- Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Razieh Forghaniesfidvajani
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | | | | | - Farid Pakizeh
- Students Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Ghobadi Dana
- Department of Immunology and Allergy, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran
| | - Farhad Seif
- Department of Immunology and Allergy, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran
- Neuroscience Research Center, Iran University of Medical Sciences, Enghelab St., Aboureyhan St., Vahid Nazari Crossroad, P17, Tehran, Postal code: 1315795613 Iran
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Andaluz-Ojeda D, Vidal-Cortes P, Aparisi Sanz Á, Suberviola B, Del Río Carbajo L, Nogales Martín L, Prol Silva E, Nieto del Olmo J, Barberán J, Cusacovich I. Immunomodulatory therapy for the management of critically ill patients with COVID-19: A narrative review. World J Crit Care Med 2022; 11:269-297. [PMID: 36051937 PMCID: PMC9305685 DOI: 10.5492/wjccm.v11.i4.269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 12/01/2021] [Accepted: 05/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. AIM To describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of hyperinflammation and abnormal immune responses to disease progression together with a complete narrative review of the different immunoadjuvant treatments used so far in COVID-19 and their indication in severe and life-threatening subsets. METHODS A comprehensive literature search was developed. Authors reviewed the selected manuscripts following the PRISMA recommendations for systematic review and meta-analysis documents and selected the most appropriate. Finally, a recommendation of the use of each treatment was established based on the level of evidence of the articles and documents reviewed. This recommendation was made based on the consensus of all the authors. RESULTS A brief rationale on the SARS-CoV-2 pathogenesis, immune response, and inflammation was developed. The usefulness of 10 different families of treatments related to inflammation and immunopathogenesis of COVID-19 was reviewed and discussed. Finally, based on the level of scientific evidence, a recommendation was established for each of them. CONCLUSION Although several promising therapies exist, only the use of corticosteroids and tocilizumab (or sarilumab in absence of this) have demonstrated evidence enough to recommend its use in critically ill patients with COVID-19. Endotypes including both, clinical and biological characteristics can constitute specific targets for better select certain therapies based on an individualized approach to treatment.
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Affiliation(s)
- David Andaluz-Ojeda
- Department of Critical Care, Hospital Universitario HM Sanchinarro, Hospitales Madrid, Madrid 28050, Spain
| | - Pablo Vidal-Cortes
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | | | - Borja Suberviola
- Department of Intensive Care, Hospital Universitario Marqués de Valdecilla, Santander 39008, Spain
| | - Lorena Del Río Carbajo
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | - Leonor Nogales Martín
- Department of Intensive Care, Hospital Clínico Universitario de Valladolid, Valladolid 47005, Spain
| | - Estefanía Prol Silva
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | - Jorge Nieto del Olmo
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | - José Barberán
- Department of Internal Medicine, Hospital Universitario HM Montepríncipe, Hospitales Madrid, Boadilla del Monte 28860, Madrid, Spain
| | - Ivan Cusacovich
- Department of Internal Medicine, Hospital Clínico Universitario de Valladolid, Valladolid 47005, Spain
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39
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Huang J, Zhou C, Deng J, Zhou J. JAK Inhibition as a New Treatment Strategy for Patients with COVID-19. Biochem Pharmacol 2022; 202:115162. [PMID: 35787993 PMCID: PMC9250821 DOI: 10.1016/j.bcp.2022.115162] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 06/06/2022] [Accepted: 06/27/2022] [Indexed: 01/08/2023]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic continues to spread globally. The rapid dispersion of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 drives an urgent need for effective treatments, especially for patients who develop severe pneumonia. The excessive and uncontrolled release of pro-inflammatory cytokines has proved to be an essential factor in the rapidity of disease progression, and some cytokines are significantly associated with adverse outcomes. Most of the upregulated cytokines signal through the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway. Therefore, blocking the exaggerated release of cytokines, including IL-2, IL-6, TNF-α, and IFNα/β/γ, by inhibiting JAK/STAT signaling will, presumably, offer favorable pharmacodynamics and present an attractive prospect. JAK inhibitors (JAKi) can also inhibit members of the numb-associated kinase (NAK) family, including AP2-associated kinase 1 (AAK1) and cyclin G-associated kinase (GAK), which regulate the angiotensin-converting enzyme 2 (ACE-2) transmembrane protein and are involved in host viral endocytosis. According to the data released from current clinical trials, JAKi treatment can effectively control the dysregulated cytokine storm and improve clinical outcomes regarding mortality, ICU admission, and discharge. There are still some concerns surrounding thromboembolic events, opportunistic infection such as herpes zoster virus reactivation, and repression of the host's type-I IFN-dependent immune repair for both viral and bacterial infection. However, the current JAKi clinical trials of COVID-19 raised no new safety concerns except a slightly increased risk of herpes virus infection. In the updated WHO guideline, Baricitinb is strongly recommended as an alternative to IL-6 receptor blockers, particularly in combination with corticosteroids, in patients with severe or critical COVID-19. Future studies will explore the application of JAKi to COVID-19 treatment in greater detail, such as the optimal timing and course of JAKi treatment, individualized medication strategies based on pharmacogenomics, and the effect of combined medications.
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Affiliation(s)
- Jin Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
| | - Chi Zhou
- Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology 1095# Jiefang Ave., Wuhan 430030, People's Rep. of China
| | - Jinniu Deng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Jianfeng Zhou
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
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Eskandarian Boroujeni M, Sekrecka A, Antonczyk A, Hassani S, Sekrecki M, Nowicka H, Lopacinska N, Olya A, Kluzek K, Wesoly J, Bluyssen HAR. Dysregulated Interferon Response and Immune Hyperactivation in Severe COVID-19: Targeting STATs as a Novel Therapeutic Strategy. Front Immunol 2022; 13:888897. [PMID: 35663932 PMCID: PMC9156796 DOI: 10.3389/fimmu.2022.888897] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/13/2022] [Indexed: 01/08/2023] Open
Abstract
A disease outbreak in December 2019, caused by a novel coronavirus SARS-CoV-2, was named COVID-19. SARS-CoV-2 infects cells from the upper and lower respiratory tract system and is transmitted by inhalation or contact with infected droplets. Common clinical symptoms include fatigue, fever, and cough, but also shortness of breath and lung abnormalities. Still, some 5% of SARS-CoV-2 infections progress to severe pneumonia and acute respiratory distress syndrome (ARDS), with pulmonary edema, acute kidney injury, and/or multiple organ failure as important consequences, which can lead to death. The innate immune system recognizes viral RNAs and triggers the expression of interferons (IFN). IFNs activate anti-viral effectors and components of the adaptive immune system by activating members of the STAT and IRF families that induce the expression of IFN-stimulated genes (ISG)s. Among other coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, common strategies have been identified to antagonize IFN signaling. This typically coincides with hyperactive inflammatory host responses known as the “cytokine storm” that mediate severe lung damage. Likewise, SARS-CoV-2 infection combines a dysregulated IFN response with excessive production of inflammatory cytokines in the lungs. This excessive inflammatory response in the lungs is associated with the local recruitment of immune cells that create a pathogenic inflammatory loop. Together, it causes severe lung pathology, including ARDS, as well as damage to other vulnerable organs, like the heart, spleen, lymph nodes, and kidney, as well as the brain. This can rapidly progress to multiple organ exhaustion and correlates with a poor prognosis in COVID-19 patients. In this review, we focus on the crucial role of different types of IFN that underlies the progression of SARS-CoV-2 infection and leads to immune cell hyper-activation in the lungs, exuberant systemic inflammation, and multiple organ damage. Consequently, to protect from systemic inflammation, it will be critical to interfere with signaling cascades activated by IFNs and other inflammatory cytokines. Targeting members of the STAT family could therefore be proposed as a novel therapeutic strategy in patients with severe COVID-19.
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Affiliation(s)
- Mahdi Eskandarian Boroujeni
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Agata Sekrecka
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Aleksandra Antonczyk
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Sanaz Hassani
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Michal Sekrecki
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Hanna Nowicka
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Natalia Lopacinska
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Arta Olya
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Katarzyna Kluzek
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Joanna Wesoly
- Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Hans A R Bluyssen
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
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41
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Roncato R, Angelini J, Pani A, Talotta R. Lipid rafts as viral entry routes and immune platforms: A double-edged sword in SARS-CoV-2 infection? Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159140. [PMID: 35248801 PMCID: PMC8894694 DOI: 10.1016/j.bbalip.2022.159140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/13/2022] [Accepted: 02/25/2022] [Indexed: 12/15/2022]
Abstract
Lipid rafts are nanoscopic compartments of cell membranes that serve a variety of biological functions. They play a crucial role in viral infections, as enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exploit rafts to enter or quit target cells. On the other hand, lipid rafts contribute to the formation of immune synapses and their proper functioning is a prerequisite for adequate immune response and viral clearance. In this narrative review we dissect the panorama focusing on this singular aspect of cell biology in the context of SARS-CoV-2 infection and therapy. A lipid raft-mediated mechanism can be hypothesized for many drugs recommended or considered for the treatment of SARS-CoV-2 infection, such as glucocorticoids, antimalarials, immunosuppressants and antiviral agents. Furthermore, the additional use of lipid-lowering agents, like statins, may affect the lipid composition of membrane rafts and thus influence the processes occurring in these compartments. The combination of drugs acting on lipid rafts may be successful in the treatment of more severe forms of the disease and should be reserved for further investigation.
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Affiliation(s)
- Rossana Roncato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a carattere Scientifico (IRCCS), via Gallini, 33081 Aviano (PN), Italy
| | - Jacopo Angelini
- Clinical Pharmacology Institute, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), via Pozzuolo, 33100 Udine, Italy
| | - Arianna Pani
- Toxicology Department of Oncology and Hemato-Oncology, University of Milan, via Vanvitelli, 20133 Milan, Italy
| | - Rossella Talotta
- Department of Clinical and Experimental Medicine, Rheumatology Unit, AOU "Gaetano Martino", University of Messina, 98100 Messina, Italy
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42
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Jiménez D, Torres Arias M. Immunouniverse of SARS-CoV-2. Immunol Med 2022; 45:186-224. [PMID: 35502127 DOI: 10.1080/25785826.2022.2066251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
SARS-CoV-2 virus has become a global health problem that has caused millions of deaths worldwide. The infection can present with multiple clinical features ranging from asymptomatic or mildly symptomatic patients to patients with severe or critical illness that can even lead to death. Although the immune system plays an important role in pathogen control, SARS-CoV-2 can drive dysregulation of this response and trigger severe immunopathology. Exploring the mechanisms of the immune response involved in host defense against SARS-CoV-2 allows us to understand its immunopathogenesis and possibly detect features that can be used as potential therapies to eliminate the virus. The main objective of this review on SARS-CoV-2 is to highlight the interaction between the virus and the immune response. We explore the function and action of the immune system, the expression of molecules at the site of infection that cause hyperinflammation and hypercoagulation disorders, the factors leading to the development of pneumonia and subsequent severe acute respiratory distress syndrome which is the leading cause of death in patients with COVID-19.
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Affiliation(s)
- Dennis Jiménez
- Departamento de Ciencias de la Vida y Agricultura, Carrera de Ingeniería en Biotecnología, Universidad de las Fuerzas Armadas ESPE, Sangolquí, Pichincha, Ecuador
| | - Marbel Torres Arias
- Departamento de Ciencias de la Vida y Agricultura, Carrera de Ingeniería en Biotecnología, Universidad de las Fuerzas Armadas ESPE, Sangolquí, Pichincha, Ecuador.,Laboratorio de Inmunología y Virología, CENCINAT, GISAH, Universidad de las Fuerzas Armadas, Sangolquí, Pichincha, Ecuador
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43
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Farasati Far B, Bokov D, Widjaja G, Setia Budi H, Kamal Abdelbasset W, Javanshir S, Seif F, Pazoki-Toroudi H, Dey SK. Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12. J Biomol Struct Dyn 2022:1-19. [PMID: 35446232 DOI: 10.1080/07391102.2022.2064917] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
COVID-19 patients have shown overexpressed serum levels of several pro-inflammatory cytokines, leading to a high mortality rate due to numerous complications. Also, previous studies demonstrated that the metronidazole (MTZ) administration reduced pro-inflammatory cytokines and improved the treatment outcomes for inflammatory disorders. However, the effect and mechanism of action of MTZ on cytokines have not been studied yet. Thus, the current study aimed to identify anti-cytokine therapeutics for the treatment of COVID-19 patients with cytokine storm. The interaction of MTZ with key cytokines was investigated using molecular docking studies. MTZ-analogues, and its structurally similar FDA-approved drugs were also virtually screened against interleukin-12 (IL-12). Moreover, their mechanism of inhibition regarding IL-12 binding to IL-12 receptor was investigated by measuring the change in volume and area. IL-12-metronidazole complex is found to be more stable than all other cytokines under study. Our study also revealed that the active sites of IL-12 are inhibited from binding to its target, IL-12 receptor, by modifying the position of the methyl and hydroxyl functional groups in MTZ. Three MTZ analogues, metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5-nitroimidazol-2-yl]-N-methylmethanimine-oxide, and two FDA-approved drugs acyclovir (ACV), and tetrahydrobiopterin (THB) were also found to prevent binding of IL-12 to IL-12 receptor similar to MTZ by changing the surface and volume of IL-12 upon IL-12-drug/ligand complex formation. According to the RMSD results, after 100 ns MD simulations of human IL-12-MTZ/ACV/THB drug complexes, it was also observed that each complex was swinging within a few Å compared to their corresponding docking poses, indicating that the docking poses were reliable. The current study demonstrates that three FDA-approved drugs, namely, metronidazole, acyclovir and tetrahydrobiopterin, are potential repurposable treatment options for overexpressed serum cytokines found in COVID-19 patients. Similar approach is also useful to develop therapeutics against other human disorders.
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Affiliation(s)
- Bahareh Farasati Far
- Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Dmitry Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation.,Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russian Federation
| | - Gunawan Widjaja
- Faculty of Public Health, Universitas Indonesia, Depok, Indonesia
| | - Hendrik Setia Budi
- Department of Oral Biology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia.,Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Shahrzad Javanshir
- Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Farhad Seif
- Department of Immunology & Allergy, Academic Center for Education, Culture, and Research, Tehran, Iran
| | - Hamidreza Pazoki-Toroudi
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sanjay Kumar Dey
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
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Niedźwiedzka-Rystwej P, Majchrzak A, Kurkowska S, Małkowska P, Sierawska O, Hrynkiewicz R, Parczewski M. Immune Signature of COVID-19: In-Depth Reasons and Consequences of the Cytokine Storm. Int J Mol Sci 2022; 23:4545. [PMID: 35562935 PMCID: PMC9105989 DOI: 10.3390/ijms23094545] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/17/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023] Open
Abstract
In the beginning of the third year of the fight against COVID-19, the virus remains at least still one step ahead in the pandemic "war". The key reasons are evolving lineages and mutations, resulting in an increase of transmissibility and ability to evade immune system. However, from the immunologic point of view, the cytokine storm (CS) remains a poorly understood and difficult to combat culprit of the extended number of in-hospital admissions and deaths. It is not fully clear whether the cytokine release is a harmful result of suppression of the immune system or a positive reaction necessary to clear the virus. To develop methods of appropriate treatment and therefore decrease the mortality of the so-called COVID-19-CS, we need to look deeply inside its pathogenesis, which is the purpose of this review.
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Affiliation(s)
| | - Adam Majchrzak
- Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, 71-455 Szczecin, Poland; (A.M.); (M.P.)
| | - Sara Kurkowska
- Department of Nuclear Medicine, Pomeranian Medical University, 71-252 Szczecin, Poland;
| | - Paulina Małkowska
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (P.M.); (O.S.); (R.H.)
- Doctoral School, University of Szczecin, 71-412 Szczecin, Poland
| | - Olga Sierawska
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (P.M.); (O.S.); (R.H.)
- Doctoral School, University of Szczecin, 71-412 Szczecin, Poland
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (P.M.); (O.S.); (R.H.)
| | - Miłosz Parczewski
- Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, 71-455 Szczecin, Poland; (A.M.); (M.P.)
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45
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Naik RR, Shakya AK, Aladwan SM, El-Tanani M. Kinase Inhibitors as Potential Therapeutic Agents in the Treatment of COVID-19. Front Pharmacol 2022; 13:806568. [PMID: 35444538 PMCID: PMC9014181 DOI: 10.3389/fphar.2022.806568] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/17/2022] [Indexed: 12/12/2022] Open
Abstract
Corona virus is quickly spreading around the world. The goal of viral management is to disrupt the virus's life cycle, minimize lung damage, and alleviate severe symptoms. Numerous strategies have been used, including repurposing existing antivirals or drugs used in previous viral outbreaks. One such strategy is to repurpose FDA-approved kinase inhibitors that are potential chemotherapeutic agents and have demonstrated antiviral activity against a variety of viruses, including MERS, SARS-CoV-1, and others, by inhibiting the viral life cycle and the inflammatory response associated with COVID-19. The purpose of this article is to identify licensed kinase inhibitors that have the ability to reduce the virus's life cycle, from entrance through viral propagation from cell to cell. Several of these inhibitors, including imatinib, ruxolitinib, silmitasertib, and tofacitinib (alone and in conjunction with hydroxychloroquine), are now undergoing clinical studies to determine their efficacy as a possible treatment drug. The FDA approved baricitinib (a Janus kinase inhibitor) in combination with remdesivir for the treatment of COVID-19 patients receiving hospital care in November 2020. While in vitro trials with gilteritinib, fedratinib, and osimertinib are encouraging, further research is necessary before these inhibitors may be used to treat COVID-19 patients.
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Affiliation(s)
- Rajashri R. Naik
- Department of Biopharmaceutics and Clinical Pharmacy, Al-Ahliyya Amman University, Faculty of Pharmacy, Amman, Jordan
- Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan
| | - Ashok K. Shakya
- Faculty of Pharmacy, Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman, Jordan
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
| | - Safwan M. Aladwan
- Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan
| | - Mohamed El-Tanani
- Department of Biopharmaceutics and Clinical Pharmacy, Al-Ahliyya Amman University, Faculty of Pharmacy, Amman, Jordan
- Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan
- Faculty of Pharmacy, Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman, Jordan
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
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46
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Elahi R, Karami P, Heidary AH, Esmaeilzadeh A. An updated overview of recent advances, challenges, and clinical considerations of IL-6 signaling blockade in severe coronavirus disease 2019 (COVID-19). Int Immunopharmacol 2022; 105:108536. [PMID: 35074571 PMCID: PMC8747952 DOI: 10.1016/j.intimp.2022.108536] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/01/2022] [Accepted: 01/07/2022] [Indexed: 02/07/2023]
Abstract
Since 2019, COVID-19 has become the most important health dilemma around the world. The dysregulated immune response which results in ARDS and cytokine storm has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through induction of pro-inflammatory chemokines and cytokines, is the pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, IL-6 pathway blockade is considered an emerging approach with high efficacy to reduce lung damage in COVID-19. This article aims to review the pleiotropic roles of the IL-6 pathway in lung damage and ARDS in severe COVID-19, and the rationale for IL-6 signaling blockade at different levels, including IL-6 soluble and membrane receptor pathways, IL-6 downstream signaling (such as JAK-STAT) inhibition, and non-specific anti-inflammatory therapeutic approaches. Recent clinical data of each method, with specific concentration on tocilizumab, along with other new drugs, such as sarilumab and siltuximab, have been discussed. Challenges of IL-6 signaling inhibition, such as the risk of superinfection and hepatic injury, and possible solutions have also been explained. Moreover, to achieve the highest efficacy, ongoing clinical trials and special clinical considerations of using different IL-6 inhibitors have been discussed in detail. Special considerations, including the appropriate timing and dosage, monotherapy or combination therapy, and proper side effect managment must be noticed regarding the clinical administration of these drugs. Future studies are still necessary to improve the productivity and unknown aspects of IL-6 signaling blockade for personalized treatment of severe COVID-19.
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Affiliation(s)
- Reza Elahi
- Zanjan University of Medical Sciences, Zanjan, Iran
| | - Parsa Karami
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Abdolreza Esmaeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran; Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran.
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47
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Plens-Gałąska M, Woźniak T, Wesoły J, Bluyssen HAR. SINBAD, structural, experimental and clinical characterization of STAT inhibitors and their potential applications. Sci Data 2022; 9:139. [PMID: 35361787 PMCID: PMC8971479 DOI: 10.1038/s41597-022-01243-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/07/2022] [Indexed: 12/23/2022] Open
Abstract
The abnormal activation of signal transducer and activator of transcription (STAT) protein family is recognized as cause or driving force behind multiple diseases progression. Therefore, searching for potential treatment strategy is pursued by multiple scientific groups. We consider that providing comprehensive, integrated and unified dataset for STAT inhibitory compounds may serve as important tool for other researchers. We developed SINBAD (STAT INhbitor Biology And Drug-ability) in response to our experience with inhibitory compound research, knowing that gathering detailed information is crucial for effective experiment design and also for finding potential solutions in case of obtaining inconclusive results. SINBAD is a curated database of STAT inhibitors which have been published and described in scientific articles providing prove of their inhibitory properties. It is a tool allowing easy analysis of experimental conditions and provides detailed information about known STAT inhibitory compounds.
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Affiliation(s)
- Martyna Plens-Gałąska
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Tomasz Woźniak
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Joanna Wesoły
- Laboratory of High Throughput Technologies, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Hans A R Bluyssen
- Laboratory of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
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48
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Ziaie N, Ezoji K, Ziaei SG, Chehrazi M, Maleh PA, Pourkia R, Seyfi S. The relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and diastolic heart failure in patients with COVID-19. Int J Cardiovasc Imaging 2022; 38:1289-1296. [PMID: 37522074 PMCID: PMC8943789 DOI: 10.1007/s10554-021-02513-8] [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: 09/01/2021] [Accepted: 12/29/2021] [Indexed: 11/24/2022]
Abstract
Diastolic dysfunction has been reported in patients with COVID-19. Due to the role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of heart failure, this study investigated the relationship between serum NT-proBNP levels and diastolic heart failure in patients with COVID-19. This descriptive-analytical study was performed at Ayatollah Rouhani Hospital in Babol. Fifty-two patients with confirmed COVID-19 diagnosis, who were admitted to the ICU, were included in this study. The primary outcome was about the relationship and predictive role of NT-proBNP and diastolic heart failure in patients with severe SARS-CoV-2 infection. Patients with pro BNP > 125 pg/ml underwent echocardiography, and the relationship between echocardiographic indices and NT-proBNP was assessed as the secondary outcome. Our study showed that plasma NT-proBNP levels in patients with increased diastolic dysfunction were associated with disease severity. It was also found that the cut-off point of NT-proBNP = 799 pg/ml could be a predictor of diastolic dysfunction grades two and three. In this study, patients with a serum NT-proBNP level > 799 had 37 times higher chance of having diastolic dysfunction than those with a serum NT-proBNP < 799. Patients with NT-proBNP > 556 had RV_EA > 2 in echocardiography, indicating increased right-sided filling pressures. Despite the confounding factors in the interpretation of the NT-proBNP level in COVID-19, its level can be used to estimate the presence of high-grade diastolic heart failure on the left side and the right side of the heart and the presence of high filling pressures. Lower levels of NT-proBNP are associated with right-sided diastolic failure.
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Affiliation(s)
- Naghmeh Ziaie
- Department of Cardiology, Babol University of Medical Sciences, Babol, Iran
| | - Khadijeh Ezoji
- Social Determinants of Health Research Center, Health Research
Institute, Babol University of Medical Sciences, Babol, Iran
| | | | - Mohammad Chehrazi
- Department of Biostatistics and Epidemiology, School of
Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Parviz Amri Maleh
- Department of Anesthesiology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Roghayeh Pourkia
- Department of Cardiology, Babol University of Medical Sciences, Babol, Iran
| | - Shahram Seyfi
- Department of Anesthesiology, Clinical Research Development Unit of
Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
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49
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Optimal cut points of N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) in patients with COVID-19. Egypt Heart J 2022; 74:16. [PMID: 35294679 PMCID: PMC8924742 DOI: 10.1186/s43044-022-00253-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/03/2022] [Indexed: 12/23/2022] Open
Abstract
Background COVID19 patients may suffer from multiple cardiovascular complications. Recently, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) was a potentially independent risk factor for COVID-19 in-hospital death. The present study aimed to find new optimal cut points for NT-proBNP across censored survival failure time outcomes in hospitalized COVID-19 patients. Results This cohort study was conducted on 272 patients with COVID-19 whose initial records were recorded from March 2020 to July 2020. Demographic characteristics, clinical examinations, and laboratory measurements were collected at the beginning of the admission registered in the patient record system located in the hospital. We used the maximally selected rank statistics to determine the optimal cut points for NT-proBNP (the most significant split based on the standardized log-rank test). Survival time was defined as the days from hospital admission to discharge day. In this cohort study, two optimal cut points for NT-proBNP were 331 (pg/mL) and 11,126 (pg/mL) based on a survival model. The adjusted HR of NT-proBNP for in-hospital death was 3.41 (95% CI: 1.22–9.51, P = 0.02) for medium against low category, and 3.84 (95% CI: 1.30–11.57, P = 0.01) for high in comparison with low group. Conclusions We reported a dramatically increased concentration of NT-proBNP among COVID-19 patients without heart failure in both severe and non-severe cases. Moreover, our study showed that a high level of NT-proBNP was highly associated with the prolonged survival time of patients with COVID-19. NT-proBNP is a strong prognostic indicator of in-hospital death in the second week of admission.
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Barilli A, Visigalli R, Ferrari F, Bianchi MG, Dall’Asta V, Rotoli BM. Immune-Mediated Inflammatory Responses of Alveolar Epithelial Cells: Implications for COVID-19 Lung Pathology. Biomedicines 2022; 10:biomedicines10030618. [PMID: 35327420 PMCID: PMC8945544 DOI: 10.3390/biomedicines10030618] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/03/2022] [Accepted: 03/03/2022] [Indexed: 02/07/2023] Open
Abstract
Background. Clinical and experimental evidence point to a dysregulated immune response caused by SARS-CoV-2 as the primary mechanism of lung disease in COVID-19. However, the pathogenic mechanisms underlying COVID-19-associated ARDS (Acute Respiratory Distress Syndrome) remain incompletely understood. This study aims to explore the inflammatory responses of alveolar epithelial cells to either the spike S1 protein or to a mixture of cytokines secreted by S1-activated macrophages. Methods and Results. The exposure of alveolar A549 cells to supernatants from spike-activated macrophages caused a further release of inflammatory mediators, with IL-8 reaching massive concentrations. The investigation of the molecular pathways indicated that NF-kB is involved in the transcription of IP-10 and RANTES, while STATs drive the expression of all the cytokines/chemokines tested, with the exception of IL-8 which is regulated by AP-1. Cytokines/chemokines produced by spike-activated macrophages are also likely responsible for the observed dysfunction of barrier integrity in Human Alveolar Epithelial Lentivirus-immortalized cells (hAELVi), as demonstrated by an increased permeability of the monolayers to mannitol, a marked decrease of TEER and a disorganization of claudin-7 distribution. Conclusion. Upon exposure to supernatants from S1-activated macrophages, A549 cells act both as targets and sources of cytokines/chemokines, suggesting that alveolar epithelium along with activated macrophages may orchestrate lung inflammation and contribute to alveolar injury, a hallmark of ARDS.
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