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Pan L, Xu J, Xie H, Zhang Y, Jiang H, Yao Y, Wu W. Tyrosine kinase 2 inhibitors: Synthesis and applications in the treatment of autoimmune diseases. Eur J Med Chem 2025; 283:117114. [PMID: 39662285 DOI: 10.1016/j.ejmech.2024.117114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/11/2024] [Accepted: 11/27/2024] [Indexed: 12/13/2024]
Abstract
Janus kinase (JAK), a class of non-receptor tyrosine kinases, are essential in modulating the cytokine signaling cascade of cytokines associated with immune responses. Despite their potential in the treatment of autoimmune diseases, JAK inhibitors are associated with safety concerns, regarding cytokine suppression and significant side effects. Tyrosine kinase 2 (TYK2), a prominent member of the JAK family, is central to the signaling of interleukins (ILs) and interferons (IFNs), such as IL-12, IL-23 and IFNs. Targeted TYK2 inhibitors that specifically target the Janus Homology 1 (JH1) and pseudokinase (JH2) domains show enhanced specificity. JH1 acts as an ATP-competitive inhibitor, while JH2 acts as an allosteric regulator, contributing to reduced systemic side effects and improved therapeutic outcomes in clinical settings. This review summarizes the recent advances on the synthetic strategies of TYK2 inhibitors and their applications in the treatment of autoimmune diseases.
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Affiliation(s)
- Lin Pan
- Key Laboratory of Functional Molecular Engineering of Guangdong Province, State Key Laboratory of Luminescent Materials and Devices, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, China
| | - Juan Xu
- State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Company, Ltd., Dongguan, 523871, China
| | - Hongming Xie
- State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Company, Ltd., Dongguan, 523871, China
| | - Yingjun Zhang
- State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Company, Ltd., Dongguan, 523871, China
| | - Huanfeng Jiang
- Key Laboratory of Functional Molecular Engineering of Guangdong Province, State Key Laboratory of Luminescent Materials and Devices, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, China
| | - Yongqi Yao
- Food and Cosmetics Testing Institute, Guangzhou Customs Technology Center, 510623, Guangzhou, China
| | - Wanqing Wu
- Key Laboratory of Functional Molecular Engineering of Guangdong Province, State Key Laboratory of Luminescent Materials and Devices, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, China.
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Li Z, Zhang F, Jin X, Zhuang J. Elevated LIF and JAK-STAT activation drive severe COVID-19 in myeloma patients receiving the BCMA-CD3 bispecific antibody Elranatamab. J Transl Med 2025; 23:117. [PMID: 39865264 PMCID: PMC11765914 DOI: 10.1186/s12967-025-06140-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: 11/20/2024] [Accepted: 01/15/2025] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND Immunotherapy is a significant risk factor for severe COVID-19 in multiple myeloma (MM) patients. Understanding how immunotherapies lead to severe COVID-19 is crucial for improving patient outcomes. METHODS Human protein microarrays were used to examine the expression of 440 protein molecules in MM patients treated with bispecific T-cell engagers (BiTe) (n = 9), anti-CD38 monoclonal antibodies (mAbs) (n = 10), and proteasome inhibitor (PI)-based regimens (n = 10). Differentially expressed proteins (DEPs) were identified and analyzed using bioinformatics. RESULTS BiTe therapy was associated with a higher incidence of severe COVID-19. We identified 21 and 29 DEPs between BiTe and anti-CD38 mAbs group, and BiTe and PI-based group, respectively, along with 25 DEPs between the anti-CD38 and PI groups. Principal component analysis and clustering showed distinct protein expression profiles between the BiTe and PI groups. Gene Ontology (GO) analysis revealed that DEPs between the BiTe and PI groups were related to cytokine activity and leukocyte migration. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEPs were enriched in cytokine-cytokine receptor interaction and JAK-STAT signaling pathways. Leukemia inhibitory factor (LIF) is the most correlated with other DEPs and thus may play a key role in both enriched pathways, and the level of LIF protein was highest in the BiTe group. CONCLUSIONS BiTe therapy is linked to a higher risk of severe COVID-19 due to an inflammatory cytokine storm, with LIF and the JAK-STAT pathway playing key roles. Targeting LIF and JAK-STAT pathway may help reduce severe COVID-19 in MM patients treated with BiTe.
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Affiliation(s)
- Ziping Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China
| | - Fujing Zhang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China
| | - Xianghong Jin
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China
| | - Junling Zhuang
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China.
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Li J, Mao N, Wang Y, Deng S, Chen K. Novel insights into the ROCK-JAK-STAT signaling pathway in upper respiratory tract infections and neurodegenerative diseases. Mol Ther 2025; 33:32-50. [PMID: 39511889 PMCID: PMC11764622 DOI: 10.1016/j.ymthe.2024.11.011] [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: 08/12/2024] [Revised: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 11/15/2024] Open
Abstract
Acute upper respiratory tract infections are a major public health issue, with uncontrolled inflammation triggered by upper respiratory viruses being a significant cause of patient deterioration or death. This study focuses on the Janus kinase-signal transducer and activator of transcription Rho-associated coiled-coil containing protein kinase (JAK-STAT-ROCK) signaling pathway, providing an in-depth analysis of the interplay between uncontrolled inflammation after upper respiratory tract infections and the development of neurodegenerative diseases. It offers a conceptual framework for understanding the lung-brain-related immune responses and potential interactions. The relationship between the ROCK-JAK-STAT signaling pathway and inflammatory immunity is a complex and multi-layered research area and exploring potential common targets could open new avenues for the prevention and treatment of related inflammation.
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Affiliation(s)
- Jiaxuan Li
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Naihui Mao
- Department of Cardiac Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ying Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
| | - Shuli Deng
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
| | - Keda Chen
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China.
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Gawande MS, Zade N, Kumar P, Gundewar S, Weerarathna IN, Verma P. The role of artificial intelligence in pandemic responses: from epidemiological modeling to vaccine development. MOLECULAR BIOMEDICINE 2025; 6:1. [PMID: 39747786 PMCID: PMC11695538 DOI: 10.1186/s43556-024-00238-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 01/04/2025] Open
Abstract
Integrating Artificial Intelligence (AI) across numerous disciplines has transformed the worldwide landscape of pandemic response. This review investigates the multidimensional role of AI in the pandemic, which arises as a global health crisis, and its role in preparedness and responses, ranging from enhanced epidemiological modelling to the acceleration of vaccine development. The confluence of AI technologies has guided us in a new era of data-driven decision-making, revolutionizing our ability to anticipate, mitigate, and treat infectious illnesses. The review begins by discussing the impact of a pandemic on emerging countries worldwide, elaborating on the critical significance of AI in epidemiological modelling, bringing data-driven decision-making, and enabling forecasting, mitigation and response to the pandemic. In epidemiology, AI-driven epidemiological models like SIR (Susceptible-Infectious-Recovered) and SIS (Susceptible-Infectious-Susceptible) are applied to predict the spread of disease, preventing outbreaks and optimising vaccine distribution. The review also demonstrates how Machine Learning (ML) algorithms and predictive analytics improve our knowledge of disease propagation patterns. The collaborative aspect of AI in vaccine discovery and clinical trials of various vaccines is emphasised, focusing on constructing AI-powered surveillance networks. Conclusively, the review presents a comprehensive assessment of how AI impacts epidemiological modelling, builds AI-enabled dynamic models by collaborating ML and Deep Learning (DL) techniques, and develops and implements vaccines and clinical trials. The review also focuses on screening, forecasting, contact tracing and monitoring the virus-causing pandemic. It advocates for sustained research, real-world implications, ethical application and strategic integration of AI technologies to strengthen our collective ability to face and alleviate the effects of global health issues.
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Affiliation(s)
- Mayur Suresh Gawande
- Department of Artificial Intelligence and Data Science, Faculty of Engineering and Technology, Datta Meghe Institute of Higher Education and Research (Deemed to Be University), Sawangi (Meghe), Wardha, Maharashtra, 442001, India
| | - Nikita Zade
- Department of Artificial Intelligence and Data Science, Faculty of Engineering and Technology, Datta Meghe Institute of Higher Education and Research (Deemed to Be University), Sawangi (Meghe), Wardha, Maharashtra, 442001, India
| | - Praveen Kumar
- Department of Computer Science and Medical Engineering, Faculty of Engineering and Technology, Datta Meghe Institute of Higher Education and Research (Deemed to Be University), Sawangi (Meghe), Wardha, Maharashtra, 442001, India.
| | - Swapnil Gundewar
- Department of Artificial Intelligence and Machine Learning, Faculty of Engineering and Technology, Datta Meghe Institute of Higher Education and Research (Deemed to Be University), Wardha, Maharashtra, 442001, India
| | - Induni Nayodhara Weerarathna
- Department of Biomedical Sciences, School of Allied Health Sciences, Datta Meghe Institute of Higher Education and Research (Deemed to Be University), Wardha, Maharashtra, 442001, India
| | - Prateek Verma
- Department of Artificial Intelligence and Machine Learning, Faculty of Engineering and Technology, Datta Meghe Institute of Higher Education and Research (Deemed to Be University), Wardha, Maharashtra, 442001, India
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Wang Y, Li J, Chen R, Xu Q, Wang D, Mao C, Xiang Z, Wu G, Yu Y, Li J, Zheng Y, Chen K. Emerging concepts in mucosal immunity and oral microecological control of respiratory virus infection-related inflammatory diseases. Microbiol Res 2024; 289:127930. [PMID: 39427450 DOI: 10.1016/j.micres.2024.127930] [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: 01/08/2024] [Revised: 09/22/2024] [Accepted: 10/06/2024] [Indexed: 10/22/2024]
Abstract
Oral microecological imbalance is closely linked to oral mucosal inflammation and is implicated in the development of both local and systemic diseases, including those caused by viral infections. This review examines the critical role of the interleukin (IL)-17/helper T cell 17 (Th17) axis in regulating immune responses within the oral mucosa, focusing on both its protective and pathogenic roles during inflammation. We specifically highlight how the IL-17/Th17 pathway contributes to dysregulated inflammation in the context of respiratory viral infections. Furthermore, this review explores the potential interactions between respiratory viruses and the oral microbiota, emphasizing how alterations in the oral microbiome and increased production of proinflammatory factors may serve as early, non-invasive biomarkers for predicting the severity of respiratory viral infections. These findings provide insights into novel diagnostic approaches and therapeutic strategies aimed at mitigating respiratory disease severity through monitoring and modulating the oral microbiome.
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Affiliation(s)
- Ying Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China
| | - Jiaxuan Li
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Ruyi Chen
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Qiuyi Xu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Di Wang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Chenxi Mao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Ziyi Xiang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Guangshang Wu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China
| | - Ying Yu
- School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang 310063, China
| | - Jianhua Li
- Zhejiang Key Laboratory of Public Health Detection and Pathogenesis Research, Department of Microbiology, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China.
| | - Yuejuan Zheng
- The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Keda Chen
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, P.R. China.
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Chavda V, Dodiya P, Apostolopoulos V. Adverse drug reactions associated with COVID-19 management. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7353-7376. [PMID: 38743117 DOI: 10.1007/s00210-024-03137-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/30/2024] [Indexed: 05/16/2024]
Abstract
The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak, which causes COVID-19, had a devastating impact on both people's lives and the global economy. During the course of the pandemic, the lack of specific drugs or treatments tailored for COVID-19 led to extensive repurposing of existing drugs in the pursuit of effective treatments. Some drug molecules demonstrated efficacy, while others proved ineffective. In this context, the approach of drug repurposing emerged as a novel strategy for combating COVID-19. Repurposed drugs and biologics have shown effectiveness, leading to improved clinical outcomes among patients with COVID-19. Similarly, It is equally important to assess the risk-benefit ratio associated with drugs and biologics adapted for COVID-19 treatment. Herein, we primarily focus on evaluating adverse drug events linked to repurposed COVID-19 medications, repurposed biologics, and COVID-specific drug molecules.
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Affiliation(s)
- Vivek Chavda
- Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad, 380009, Gujarat, India.
| | - Payal Dodiya
- Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad, 380009, Gujarat, India
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
- Australian Institute for Musculoskeletal Science, Melbourne, VIC, Australia.
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Mao N, Xie X. Mechanisms of Tripterygium wilfordii Hook F on treating rheumatoid arthritis explored by network pharmacology analysis and molecular docking. Open Med (Wars) 2024; 19:20240967. [PMID: 38841174 PMCID: PMC11151399 DOI: 10.1515/med-2024-0967] [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: 01/14/2024] [Revised: 03/11/2024] [Accepted: 04/23/2024] [Indexed: 06/07/2024] Open
Abstract
Background Rheumatoid arthritis (RA) is a chronic inflammatory and disabling disease that imposes significant economic and social costs. Tripterygium wilfordii Hook F (TwHF) has a long history of use in traditional Chinese medicine for treating joint disorders, and it has been shown to be cost-effective in treating RA, but its exact mechanism is unknown. Objective The goal of the network pharmacology analysis and molecular docking was to investigate the potential active compounds and associated anti-RA mechanisms of TwHF. Methods TCMSP and UniProt databases were searched for active compounds and related targets of TwHF. PharmGKB, DrugBank, OMIM, TTD, and the Human Gene Databases were used to identify RA-related targets. The intersected RA and TwHF targets were entered into the STRING database to create a protein-protein interaction network. R software was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking technology was used to analyze the optimal effective components from TwHF for docking with the selected target gene. Results Following screening and duplicate removal, a total of 51 active compounds and 96 potential targets were chosen. The PPI network revealed that the target proteins are CXCL8, CXCL6, STAT3, STAT1, JUN, PPARG, TP53, IL14, MMP9, VEGFA, RELA, CASP3, PTGS2, IFNG, AKT1, FOS, ICAM1, and MAPK14. The results of the GO enrichment analysis focused primarily on the response to lipopolysaccharide, the response to molecules of bacterial origin, and the response to drugs. The KEGG results indicated that the mechanisms were closely related to lipid and atherosclerosis, chemical carcinogenesis-receptor activation, Kaposi sarcoma-associated, herpesvirus infection, hepatitis B, fluid shear stress and atherosclerosis, IL-17 signaling pathways, Th17-cell differentiation, and so on, all of which are involved in angiogenesis, immune cell chemotaxis, and inflammatory responses. Molecular docking results suggested that triptolide was the appropriate PTGS1, PTGS2, and TNF inhibitors. Conclusion Our findings provide an essential role and basis for further immune inflammatory studies into the molecular mechanisms of TwHF and PTGS1, PTGS2, and TNF inhibitor development in RA.
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Affiliation(s)
- Ni Mao
- Department of Rheumatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Clinical Medical Research Center for Systemic Autoimmune Diseases in Hunan Province, Changsha, Hunan, China
| | - Xi Xie
- Department of Rheumatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Clinical Medical Research Center for Systemic Autoimmune Diseases in Hunan Province, Changsha, Hunan, China
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Zhao R, Hu Z, Zhang X, Huang S, Yu G, Wu Z, Yu W, Lu J, Ruan B. The oncogenic mechanisms of the Janus kinase-signal transducer and activator of transcription pathway in digestive tract tumors. Cell Commun Signal 2024; 22:68. [PMID: 38273295 PMCID: PMC10809652 DOI: 10.1186/s12964-023-01421-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/03/2023] [Indexed: 01/27/2024] Open
Abstract
Digestive tract tumors are heterogeneous and involve the dysregulation of multiple signaling pathways. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway plays a notable role in the oncogenesis of digestive tract tumors. Typically activated by pro-inflammatory cytokines, it regulates important biological processes, such as cell growth, differentiation, apoptosis, immune responses, and inflammation. The aberrant activation of this pathway manifests in different forms, including mutations in JAKs, overexpression of cytokine receptors, and sustained STAT activation, and contributes to promoting the malignant characteristics of cancer cells, including uncontrolled proliferation, resistance to apoptosis, enhanced invasion and metastasis, angiogenesis, acquisition of stem-like properties, and drug resistance. Numerous studies have shown that aberrant activation of the JAK-STAT pathway is closely related to the development and progression of digestive tract tumors, contributing to tumor survival, angiogenesis, changes in the tumor microenvironment, and even immune escape processes. In addition, this signaling pathway also affects the sensitivity of digestive tract tumors to chemotherapy and targeted therapy. Therefore, it is crucial to comprehensively understand the oncogenic mechanisms underlying the JAK-STAT pathway in order to develop effective therapeutic strategies against digestive tract tumors. Currently, several JAK-STAT inhibitors are undergoing clinical and preclinical trials as potential treatments for various human diseases. However, further investigation is required to determine the role of this pathway, as well as the effectiveness and safety of its inhibitors, especially in the context of digestive tract tumors. In this review, we provide an overview of the structure, classic activation, and negative regulation of the JAK-STAT pathway. Furthermore, we discuss the pathogenic mechanisms of JAK-STAT signaling in different digestive tract tumors, with the aim of identifying potential novel therapeutic targets. Video Abstract.
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Affiliation(s)
- Ruihong Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Zhangmin Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Xiaoli Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Shujuan Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Guodong Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Zhe Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Wei Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
| | - Bing Ruan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
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Xiao C, Huang G, Cao X, Li X. Ganoderic acid A attenuated hepatic impairment by down-regulating the intracellular JAK2-STAT3 signaling pathway in induced mushroom poisoning. Am J Transl Res 2024; 16:295-303. [PMID: 38322557 PMCID: PMC10839386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/27/2023] [Indexed: 02/08/2024]
Abstract
BACKGROUND Mushroom poisoning is one of the most prominent public health problems. However, there is no special antidote so far. In the present study, we verified that Ganoderma lucidum may be an effective approach for treatment of acute mushroom poisoning. METHODS A retrospective study was performed within the past 20 years, we compiled information on the treatment of α-Amatoxin mushroom poisoning with Ganoderma lucidum by evaluating the mortality rate and liver function before and after treatment. Moreover, we explore the potential underlying mechanism of Ganoderma lucidum in the treatment of α-amanita poisoning in both in vivo animal experiments and in vitro cell experiments. RESULTS In our study, a total of 556 cases of mushroom poisoning were integrated over the past 20 years, the primary outcome was in-hospital mortality. Specificity, descriptive data of ALT, AST, BA and STB were evaluated for the effectiveness of protection to acute liver damage. From 1994 to 2002, there were 55 cases of mushroom poisoning in which 372 individuals were poisoned, 129 individuals died, with a mortality of 35%. Since 2002, after being treated with Ganoderma lucidum, surprisingly, the mortality decreased to 0%, and all the 184 patients were cured, the hepatic impairment improved significantly within 10 days. Based on a multivariate logistic regression analyses, after adjusting for age, gender and baseline clinical indicators, it was found that Ganoderma lucidum treatment was effective in reducing the morbidity (OR = 0.58), and Ganoderma lucidum treatment also showed an improvement in liver enzymes and in shortening the length of hospitalization significantly. Meanwhile, the main components of Ganoderma lucidum, Ganoderic acid A could significantly improve the survival rate and liver function in α-Amatoxin poisoned mice and may effectively inhibit the JAK2-STAT3 pathway, which could contribute to the detoxification in poisoned patients. CONCLUSION Ganoderma lucidum is very effective in treating mushroom poisoning by α-amanita and is worth promoting.
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Affiliation(s)
- Chenggen Xiao
- Department of Emergency Medicine, Xiangya Hospital, Central South UniversityChangsha 410000, Hunan, China
| | - Guoqing Huang
- Department of Emergency Medicine, Xiangya Hospital, Central South UniversityChangsha 410000, Hunan, China
| | - Xiaoxia Cao
- Clinical Nursing Teaching and Research Section, Xiangya Hospital, Central South UniversityChangsha 410000, Hunan, China
| | - Xiangmin Li
- Department of Emergency Medicine, Xiangya Hospital, Central South UniversityChangsha 410000, Hunan, China
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Alem F, Campos-Obando N, Narayanan A, Bailey CL, Macaya RF. Exogenous Klotho Extends Survival in COVID-19 Model Mice. Pathogens 2023; 12:1404. [PMID: 38133288 PMCID: PMC10746004 DOI: 10.3390/pathogens12121404] [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: 10/16/2023] [Revised: 11/18/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023] Open
Abstract
A striking feature of COVID-19 disease is the broad spectrum of risk factors associated with case severity, as well as the diversity of clinical manifestations. While no central agent has been able to explain the pathogenesis of SARS-CoV-2 infection, the factors that most robustly correlate with severity are risk factors linked to aging. Low serum levels of Klotho, an anti-aging protein, strongly correlate with the pathogenesis of the same risk factors and manifestations of conditions similar to those expressed in severe COVID-19 cases. The current manuscript presents original research on the effects of the exogenous application of Klotho, an anti-aging protein, in COVID-19 model mice. Klotho supplementation resulted in a statistically significant survival benefit in parametric and non-parametric models. Further research is required to elucidate the mechanistic role Klotho plays in COVID-19 pathogenesis as well as the possible modulation SARS-CoV-2 may have on the biological aging process.
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Affiliation(s)
- Farhang Alem
- Biomedical Research Laboratory, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA; (F.A.); (A.N.); (C.L.B.)
| | - Natalia Campos-Obando
- Formerly at Caja Costarricense de Seguro Social, San José P.O. Box 10105-1000, Costa Rica;
| | - Aarthi Narayanan
- Biomedical Research Laboratory, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA; (F.A.); (A.N.); (C.L.B.)
| | - Charles L. Bailey
- Biomedical Research Laboratory, George Mason University, 4400 University Dr., Fairfax, VA 22030, USA; (F.A.); (A.N.); (C.L.B.)
| | - Roman F. Macaya
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA
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11
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Li Y, Han L, Li P, Ge J, Xue Y, Chen L. Potential network markers and signaling pathways for B cells of COVID-19 based on single-cell condition-specific networks. BMC Genomics 2023; 24:619. [PMID: 37853311 PMCID: PMC10583333 DOI: 10.1186/s12864-023-09719-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
To explore the potential network markers and related signaling pathways of human B cells infected by COVID-19, we performed standardized integration and analysis of single-cell sequencing data to construct conditional cell-specific networks (CCSN) for each cell. Then the peripheral blood cells were clustered and annotated based on the conditional network degree matrix (CNDM) and gene expression matrix (GEM), respectively, and B cells were selected for further analysis. Besides, based on the CNDM of B cells, the hub genes and 'dark' genes (a gene has a significant difference between case and control samples not in a gene expression level but in a conditional network degree level) closely related to COVID-19 were revealed. Interestingly, some of the 'dark' genes and differential degree genes (DDGs) encoded key proteins in the JAK-STAT pathway, which had antiviral effects. The protein p21 encoded by the 'dark' gene CDKN1A was a key regulator for the COVID-19 infection-related signaling pathway. Elevated levels of proteins encoded by some DDGs were directly related to disease severity of patients with COVID-19. In short, the proteins encoded by 'dark' genes complement some missing links in COVID-19 and these signaling pathways played an important role in the growth and activation of B cells.
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Affiliation(s)
- Ying Li
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang, 471023, China
- Longmen Laboratory, Luoyang, 471003, Henan, China
| | - Liqin Han
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang, 471023, China
- Longmen Laboratory, Luoyang, 471003, Henan, China
| | - Peiluan Li
- School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang, 471023, China.
- Longmen Laboratory, Luoyang, 471003, Henan, China.
| | - Jing Ge
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Yun Xue
- College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, 471023, China
| | - Luonan Chen
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 201100, China.
- Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201100, China.
- West China Biomedical Big Data Center, Med-X Center for Informatics, West China Hospital, Sichuan University, Chengdu, 610041, China.
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12
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Mahjoor M, Mahmoudvand G, Farokhi S, Shadab A, Kashfi M, Afkhami H. Double-edged sword of JAK/STAT signaling pathway in viral infections: novel insights into virotherapy. Cell Commun Signal 2023; 21:272. [PMID: 37784164 PMCID: PMC10544547 DOI: 10.1186/s12964-023-01240-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/19/2023] [Indexed: 10/04/2023] Open
Abstract
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) is an intricate signaling cascade composed of various cytokines, interferons (IFN, growth factors, and other molecules. This pathway provides a delicate mechanism through which extracellular factors adjust gene expression, thereby acting as a substantial basis for environmental signals to influence cell growth and differentiation. The interactions between the JAK/STAT cascade and antiviral IFNs are critical to the host's immune response against viral microorganisms. Recently, with the emergence of therapeutic classes that target JAKs, the significance of this cascade has been recognized in an unprecedented way. Despite the functions of the JAK/STAT pathway in adjusting immune responses against viral pathogens, a vast body of evidence proposes the role of this cascade in the replication and pathogenesis of viral pathogens. In this article, we review the structure of the JAK/STAT signaling cascade and its role in immuno-inflammatory responses. We also highlight the paradoxical effects of this pathway in the pathogenesis of viral infections. Video Abstract.
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Affiliation(s)
- Mohamad Mahjoor
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Simin Farokhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Alireza Shadab
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
- Iran University of Medical Sciences, Deputy of Health, Tehran, Iran
| | - Mojtaba Kashfi
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
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13
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Hammersen J, Birndt S, Döhner K, Reuken P, Stallmach A, Sauerbrey P, La Rosée F, Pfirrmann M, Fabisch C, Weiss M, Träger K, Bremer H, Russo S, Illerhaus G, Drömann D, Schneider S, La Rosée P, Hochhaus A. The JAK1/2 inhibitor ruxolitinib in patients with COVID-19 triggered hyperinflammation: the RuxCoFlam trial. Leukemia 2023; 37:1879-1886. [PMID: 37507425 PMCID: PMC10457200 DOI: 10.1038/s41375-023-01979-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/12/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023]
Abstract
Dysregulated hyperinflammatory response is key in the pathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2-31). On day 7, median CIS declined to 6 (range, 1-13); 71% of patients (CI 64-77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3-5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.
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Affiliation(s)
- J Hammersen
- Universitätsklinikum Jena, Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Jena, Germany
| | - S Birndt
- Universitätsklinikum Jena, Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Jena, Germany
| | - K Döhner
- Universitätsklinikum Ulm, Klinik für Innere Medizin III, Hämatologie, Onkologie, Palliativmedizin, Rheumatologie und Infektionskrankheiten, Ulm, Germany
| | - P Reuken
- Universitätsklinikum Jena, Klinik für Innere Medizin IV, Gastroenterologie, Hepatologie, Infektiologie, Interdisziplinäre Endoskopie, Jena, Germany
| | - A Stallmach
- Universitätsklinikum Jena, Klinik für Innere Medizin IV, Gastroenterologie, Hepatologie, Infektiologie, Interdisziplinäre Endoskopie, Jena, Germany
| | - P Sauerbrey
- Universitätsklinikum Jena, Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Jena, Germany
| | - F La Rosée
- Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - M Pfirrmann
- Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), Medizinische Fakultät, Ludwig-Maximilians-Universität München, München, Germany
| | - C Fabisch
- Universitätsklinikum Jena, Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Jena, Germany
| | - M Weiss
- Universitätsklinikum Ulm, Klinik für Anästhesiologie und Intensivmedizin, Ulm, Germany
| | - K Träger
- Universitätsklinikum Ulm, Klinik für Anästhesiologie und Intensivmedizin, Ulm, Germany
| | - H Bremer
- Schwarzwald-Baar Klinikum, Lungenzentrum Donaueschingen, Donaueschingen, Germany
| | - S Russo
- Schwarzwald-Baar Klinikum, Klinik für Anästhesiologie, Intensiv-, Notfall- und Schmerzmedizin, Villingen-Schwenningen, Germany
| | - G Illerhaus
- Klinikum Stuttgart, Klinik für Hämatologie, Onkologie, Stammzelltransplantation und Palliativmedizin, Stuttgart, Germany
| | - D Drömann
- Universitätsklinikum Schleswig-Holstein, Medizinische Klinik III, Pulmologie, Lübeck, Germany
| | - S Schneider
- SRH Klinikum Gera, Klinik für Pneumologie/Infektiologie, Hämatologie/Onkologie, Rheumatologie, Gera, Germany
| | - P La Rosée
- Schwarzwald-Baar Klinikum, Klinik für Innere Medizin II, Hämatologie, Onkologie, Immunologie, Infektiologie und Palliativmedizin, Villingen-Schwenningen, Germany
| | - A Hochhaus
- Universitätsklinikum Jena, Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie, Jena, Germany.
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14
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Chen S, Zhang C, Chen D, Dong L, Chang T, Tang ZH. Advances in attractive therapeutic approach for macrophage activation syndrome in COVID-19. Front Immunol 2023; 14:1200289. [PMID: 37483597 PMCID: PMC10358730 DOI: 10.3389/fimmu.2023.1200289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/12/2023] [Indexed: 07/25/2023] Open
Abstract
Nowadays, people have relaxed their vigilance against COVID-19 due to its declining infection numbers and attenuated virulence. However, COVID-19 still needs to be concern due to its emerging variants, the relaxation of restrictions as well as breakthrough infections. During the period of the COVID-19 infection, the imbalanced and hyper-responsive immune system plays a critical role in its pathogenesis. Macrophage Activation Syndrome (MAS) is a fatal complication of immune system disease, which is caused by the excessive activation and proliferation of macrophages and cytotoxic T cells (CTL). COVID-19-related hyperinflammation shares common clinical features with the above MAS symptoms, such as hypercytokinemia, hyperferritinemia, and coagulopathy. In MAS, immune exhaustion or defective anti-viral responses leads to the inadequate cytolytic capacity of CTL which contributes to prolonged interaction between CTL, APCs and macrophages. It is possible that the same process also occurred in COVID-19 patients, and further led to a cytokine storm confined to the lungs. It is associated with the poor prognosis of severe patients such as multiple organ failure and even death. The main difference of cytokine storm is that in COVID-19 pneumonia is mainly the specific damage of the lung, while in MAS is easy to develop into a systemic. The attractive therapeutic approach to prevent MAS in COVID-19 mainly includes antiviral, antibiotics, convalescent plasma (CP) therapy and hemadsorption, extensive immunosuppressive agents, and cytokine-targeted therapies. Here, we discuss the role of the therapeutic approaches mentioned above in the two diseases. And we found that the treatment effect of the same therapeutic approach is different.
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Affiliation(s)
- Shunyao Chen
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Zhang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Deng Chen
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liming Dong
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Teding Chang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhao-Hui Tang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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15
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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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16
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Zielińska A, Eder P, Karczewski J, Szalata M, Hryhorowicz S, Wielgus K, Szalata M, Dobrowolska A, Atanasov AG, Słomski R, Souto EB. Tocilizumab-coated solid lipid nanoparticles loaded with cannabidiol as a novel drug delivery strategy for treating COVID-19: A review. Front Immunol 2023; 14:1147991. [PMID: 37033914 PMCID: PMC10073701 DOI: 10.3389/fimmu.2023.1147991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 03/06/2023] [Indexed: 04/11/2023] Open
Abstract
Commonly used clinical strategies against coronavirus disease 19 (COVID-19), including the potential role of monoclonal antibodies for site-specific targeted drug delivery, are discussed here. Solid lipid nanoparticles (SLN) tailored with tocilizumab (TCZ) and loading cannabidiol (CBD) are proposed for the treatment of COVID-19 by oral route. TCZ, as a humanized IgG1 monoclonal antibody and an interleukin-6 (IL-6) receptor agonist, can attenuate cytokine storm in patients infected with SARS-CoV-2. CBD (an anti-inflammatory cannabinoid and TCZ agonist) alleviates anxiety, schizophrenia, and depression. CBD, obtained from Cannabis sativa L., is known to modulate gene expression and inflammation and also shows anti-cancer and anti-inflammatory properties. It has also been recognized to modulate angiotensin-converting enzyme II (ACE2) expression in SARS-CoV-2 target tissues. It has already been proven that immunosuppressive drugs targeting the IL-6 receptor may ameliorate lethal inflammatory responses in COVID-19 patients. TCZ, as an immunosuppressive drug, is mainly used to treat rheumatoid arthritis, although several attempts have been made to use it in the active hyperinflammatory phase of COVID-19, with promising outcomes. TCZ is currently administered intravenously. It this review, we discuss the potential advances on the use of SLN for oral administration of TCZ-tailored CBD-loaded SLN, as an innovative platform for managing SARS-CoV-2 and related infections.
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Affiliation(s)
| | - Piotr Eder
- Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Jacek Karczewski
- Department of Environmental Medicine/Department of Gastroenterology, Human Nutrition and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Marlena Szalata
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznań, Poland
| | - Szymon Hryhorowicz
- Institute of Human Genetics, Polish Academy of Sciences Poznan, Poznan, Poland
| | - Karolina Wielgus
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Milena Szalata
- Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants National Research Institute, Poznan, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Atanas G. Atanasov
- Institute of Genetics and Animal Biotechnology, Magdalenka, Poland
- Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
- Department of Pharmacognosy, University of Vienna, Vienna, Austria
| | - Ryszard Słomski
- Institute of Human Genetics, Polish Academy of Sciences Poznan, Poznan, Poland
| | - Eliana B. Souto
- UCIBIO – Applied Molecular Biosciences Unit, MEDTECH, Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal
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17
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Baricitinib Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice by Inhibiting TGF-β1 Signaling Pathway. Molecules 2023; 28:molecules28052195. [PMID: 36903446 PMCID: PMC10004526 DOI: 10.3390/molecules28052195] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 03/03/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with unknown etiology, high mortality and limited treatment options. It is characterized by myofibroblast proliferation and extensive deposition of extracellular matrix (ECM), which will lead to fibrous proliferation and the destruction of lung structure. Transforming growth factor-β1 (TGF-β1) is widely recognized as a central pathway of pulmonary fibrosis, and the suppression of TGF-β1 or the TGF-β1-regulated signaling pathway may thus offer potential antifibrotic therapies. JAK-STAT is a downstream signaling pathway regulated by TGF-β1. JAK1/2 inhibitor baricitinib is a marketed drug for the treatment of rheumatoid arthritis, but its role in pulmonary fibrosis has not been reported. This study explored the potential effect and mechanism of baricitinib on pulmonary fibrosis in vivo and in vitro. The in vivo studies have shown that baricitinib can effectively attenuate bleomycin (BLM)-induced pulmonary fibrosis, and in vitro studies showed that baricitinib attenuates TGF-β1-induced fibroblast activation and epithelial cell injury by inhibiting TGF-β1/non-Smad and TGF-β1/JAK/STAT signaling pathways, respectively. In conclusion, baricitinib, a JAK1/2 inhibitor, impedes myofibroblast activation and epithelial injury via targeting the TGF-β1 signaling pathway and reduces BLM-induced pulmonary fibrosis in mice.
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18
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Huq AKMM, Roney M, Imran S, Khan SU, Uddin MN, Htar TT, Baig AA, Bhuiyan MA, Zakaria ZA, Aluwi MFFM, Tajuddin SN. Virtual screening of bioactive anti-SARS-CoV natural products and identification of 3β,12-diacetoxyabieta-6,8,11,13-tetraene as a potential inhibitor of SARS-CoV-2 virus and its infection related pathways by MD simulation and network pharmacology. J Biomol Struct Dyn 2023; 41:13923-13936. [PMID: 36786766 DOI: 10.1080/07391102.2023.2176926] [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: 11/02/2022] [Accepted: 01/28/2023] [Indexed: 02/15/2023]
Abstract
Since the first prevalence of COVID-19 in 2019, it still remains the most devastating pandemic throughout the world. The current research aimed to find potential natural products to inhibit the novel coronavirus and associated infection by MD simulation and network pharmacology approach. Molecular docking was performed for 39 natural products having potent anti-SARS-CoV activity. Five natural products showed high binding interaction with the viral main protease for the SARS-CoV-2 virus, where 3β,12-diacetoxyabieta-6,8,11,13 tetraene showed stable binding in MD simulation until 100 ns. Both 3β,12-diacetoxyabieta-6,8,11,13 tetraene and tomentin A targeted 11 common genes that are related to COVID-19 and interact with each other. Gene ontology development analysis further showed that all these 11 genes are attached to various biological processes. The KEGG pathway analysis also showed that the proteins that are targeted by 3β,12-diacetoxyabieta-6,8,11,13 tetraene and tomentin A are associated with multiple pathways related to COVID-19 infection. Furthermore, the ADMET and MDS studies reveals 3β,12-diacetoxyabieta-6,8,11,13 as the best-suited compound for oral drug delivery.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- A K M Moyeenul Huq
- Bio Aromatic Research Centre, Universiti Malaysia Pahang, Kuantan, Pahang, Malaysia
- School of Medicine, Department of Pharmacy, University of Asia Pacific, Dhaka, Bangladesh
| | - Miah Roney
- Bio Aromatic Research Centre, Universiti Malaysia Pahang, Kuantan, Pahang, Malaysia
- Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Kuantan, Pahang, Malaysia
| | - Syahrul Imran
- Atta-ur-Rahman Institute for Natural Product Discovery (AuRIns), Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Puncak Alam, Selangor, Malaysia
- Faculty of Applied Science, Universiti Teknologi MARA (UiTM), Shah Alam, Selangor, Malaysia
| | - Shafi Ullah Khan
- Product & Process Innovation Department, Qarshi Brands (Pvt) Ltd, Haripur, KPK, Pakistan
| | - Md Nazim Uddin
- Institute of Food Science and Technology, Bangladesh Council of Scientific and Industrial Research, Dhaka, Bangladesh
| | - Thet Thet Htar
- School of Pharmacy, Monash University Malaysia, Subang Jaya, Selangor, Malaysia
| | - Atif Amin Baig
- Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Terengannu, Malaysia
| | | | - Zainul Amiruddin Zakaria
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Jalan UMS, Kota Kinabalu, Sabah, Malaysia
| | - Mohd Fadhlizil Fasihi Mohd Aluwi
- Bio Aromatic Research Centre, Universiti Malaysia Pahang, Kuantan, Pahang, Malaysia
- Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Kuantan, Pahang, Malaysia
| | - Saiful Nizam Tajuddin
- Bio Aromatic Research Centre, Universiti Malaysia Pahang, Kuantan, Pahang, Malaysia
- Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Kuantan, Pahang, Malaysia
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19
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Huang HC, Wang SH, Fang GC, Chou WC, Liao CC, Sun CP, Jan JT, Ma HH, Ko HY, Ko YA, Chiang MT, Liang JJ, Kuo CT, Lee TA, Morales-Scheihing D, Shen CY, Chen SY, McCullough LD, Cui L, Wernig G, Tao MH, Lin YL, Chang YM, Wang SP, Lai YJ, Li CW. Upregulation of PD-L1 by SARS-CoV-2 promotes immune evasion. J Med Virol 2023; 95:e28478. [PMID: 36609964 PMCID: PMC10107526 DOI: 10.1002/jmv.28478] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/15/2022] [Accepted: 01/03/2023] [Indexed: 01/08/2023]
Abstract
Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T-cell sequestration, cytokine storm, and mortality. However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated nuclear factor-κB (NF-κB) and interferon regulatory factor 1 (IRF1) pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross-referencing our transcriptomic and epigenomic data sets revealed that coupling NF-κB and IRF1 pathways mediate programmed death ligand-1 (PD-L1) immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an early stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.
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Affiliation(s)
- Hsiang-Chi Huang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Shih-Han Wang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Guo-Chen Fang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Wen-Cheng Chou
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chun-Che Liao
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Cheng-Pu Sun
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jia-Tsrong Jan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hsiu-Hua Ma
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hui-Ying Ko
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yi-An Ko
- Biomedical Translational Research Center, Academia Sinica, Taipei, Taiwan
| | - Ming-Tsai Chiang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jian-Jong Liang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chun-Tse Kuo
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Te-An Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Diego Morales-Scheihing
- Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Chen-Yang Shen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Shih-Yu Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Louise D McCullough
- Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Lu Cui
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford University Medical Center, Stanford, California, USA
| | - Gerlinde Wernig
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford University Medical Center, Stanford, California, USA
| | - Mi-Hua Tao
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Biomedical Translational Research Center, Academia Sinica, Taipei, Taiwan
| | - Yi-Ling Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Biomedical Translational Research Center, Academia Sinica, Taipei, Taiwan
| | - Yao-Ming Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Shu-Ping Wang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yun-Ju Lai
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Solomont School of Nursing, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, USA
| | - Chia-Wei Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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20
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Purohit M, Gupta G, Afzal O, Altamimi ASA, Alzarea SI, Kazmi I, Almalki WH, Gulati M, Kaur IP, Singh SK, Dua K. Janus kinase/signal transducers and activator of transcription (JAK/STAT) and its role in Lung inflammatory disease. Chem Biol Interact 2023; 371:110334. [PMID: 36610610 DOI: 10.1016/j.cbi.2023.110334] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/23/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023]
Abstract
A key signaling channel for the signal transduction of several crucial cytokines implicated in sepsis is the JAK/STAT system. Once cytokines attach to the proper receptors, JAK kinases linked to them are activated and can selectively phosphorylate STATs. Activated STATs subsequently go to the nucleus, where they play a key role in the transcription of the target genes. Various biological activities use the JAK/STAT pathway, including hematopoiesis, immunological modulation, cell differentiation, and apoptosis. Inflammatory lung illnesses affect people worldwide and are a serious public health concern. Numerous common respiratory conditions, such as asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome, are strongly influenced by inflammation. Microorganism infections or the destruction or demise of host cells are the causes of inflammation and the factors that perpetuate it. This review discusses the main elements of severe lung inflammation and how the JAK/STAT signaling pathway is essential for lung inflammation.
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Affiliation(s)
- Manish Purohit
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, 302017, Mahal Road, Jaipur, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, 302017, Mahal Road, Jaipur, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj, 11942, Saudi Arabia
| | | | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, NSW, Australia
| | - Indu Pal Kaur
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, NSW, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, 2007, NSW, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW, 2007, Australia.
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21
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Karagaiah P, Schwartz RA, Lotti T, Wollina U, Grabbe S, Goldust M. Biologic and targeted therapeutics in vitiligo. J Cosmet Dermatol 2023; 22:64-73. [PMID: 35029034 DOI: 10.1111/jocd.14770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 01/03/2022] [Accepted: 01/10/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND Vitiligo is a long-standing progressive autoimmune disease with depigmented macules/patches with significant psychological morbidity to the patients. From being one of the most poorly understood diseases in the past, there has been a rampant advance in determining the molecular and genetic factors influencing the disease process. More light has been shed on the complex intracellular environment and interplay between innate and adaptive immunity. Numerous cytokines and signaling pathways have been associated with disease pathogenesis in the recent past. OBJECTIVE The aim of this review the efficacy of biologic and targeted therapeutics in vitiligo. METHODS A detailed literature search was conducted on databases like PubMed, COCHRANE Central, EMBASE and Google Scholar using keywords-"biologics," "vitiligo," "treatment," "repigmentation," "JAK inhibitors,", "TNF-ꭤ inhibitors," and "IL17/23 inhibitors," Relevant studies and review articles in English were analyzed in detail and report was written. This article aimed at a comprehensive review of all the biologicals and newer targeted therapeutics tried in vitiligo and their efficacy with an insight into the potential complications arising as a result of the therapy. RESULTS Most conventional vitiligo treatment modalities are restricted to generalized nonspecific immunosuppressants like topical and oral corticosteroids, calcineurin inhibitors, phototherapy, and surgical modalities. There have been reports and studies on the usage of biologicals in treating vitiligo. JAK inhibitors have shown good efficacy in vitiligo; however, it lacks substantial evidence in the form of randomized control trials. Similarly, the use of targeted therapeutics in treating vitiligo is substantiated by limited evidence and requires more randomized trials for further evidence. CONCLUSION JAK inhibitors have shown promising results and good tolerability; Adjuvant phototherapy can achieve a superior response compared to monotherapy. Though TNF-ꭤ has been tried in a few cases, it is best used if vitiligo is present in association with other chronic autoimmune diseases for which it is indicated. More in vitro studies and clinical research are required to understand the pathogenesis clearly, and therapy has to be targeted at specific pathways for a better approach toward vitiligo. Treatment aimed at induction and differentiation of melanocytes may be added to achieve faster repigmentation.
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Affiliation(s)
- Priyanka Karagaiah
- Department of Dermatology, Bangalore Medical College and Research Institute, Bangalore, India
| | - Robert A Schwartz
- Department of Dermatology, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - Torello Lotti
- Department of Dermatology, University of Studies Guglielmo Marconi, Rome, Italy.,Department of Dermatology and Communicable Diseases, First Medical State University of Moscow I. M. Sechenev Ministry of Health, Moscow, Russia
| | - Uwe Wollina
- Department of Dermatology and Allergology, Städtisches Klinikum Dresden, Academic Teaching Hospital of the Technical University of Dresden, Dresden, Germany
| | - Stephan Grabbe
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Mohamad Goldust
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
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22
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Wang L, Zhang X, Huang B, Hou Y, Liu X, Jiao H. Ruxolitinib as an Effective Treatment for Hemophagocytic Lymphohistiocytosis Secondary to SARS-Cov-2 Infection: A Case Report. Infect Drug Resist 2023; 16:2467-2473. [PMID: 37131454 PMCID: PMC10149062 DOI: 10.2147/idr.s384035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/20/2023] [Indexed: 05/04/2023] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. SARS-CoV-2 infection can induce secondary HLH, as described in previous case reports, but diagnosis and treatment are challenging. Case Study We described an older male patient diagnosed with HLH related to previous SARS-CoV-2 infection. Fever was the only clinical manifestation initially but deterioration in clinical condition and laboratory parameters was observed during hospitalization. He responded poorly to classical therapy but was successfully treated with ruxolitinib. Conclusion Clinicians should be aware of the possibility of HLH secondary to mild SARS-CoV-2 infection and take timely therapeutic measures to inhibit an inflammatory factor storm. Ruxolitinib is a potential choice for COVID-19 related HLH.
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Affiliation(s)
- Lina Wang
- Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China
| | - Xiaolin Zhang
- Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China
| | - Bo Huang
- Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China
| | - Yue Hou
- Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China
| | - Xinmin Liu
- Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China
| | - Hongmei Jiao
- Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China
- Correspondence: Hongmei Jiao, Department of Geriatrics, Peking University First Hospital, Beijing, 100034, People’s Republic of China, Email
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23
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Lei S, Chen X, Wu J, Duan X, Men K. Small molecules in the treatment of COVID-19. Signal Transduct Target Ther 2022; 7:387. [PMID: 36464706 PMCID: PMC9719906 DOI: 10.1038/s41392-022-01249-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 12/11/2022] Open
Abstract
The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and Mpro, interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.
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Affiliation(s)
- Sibei Lei
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Xiaohua Chen
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Jieping Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Xingmei Duan
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Ke Men
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
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24
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Ruxolitinib enhances cytotoxic and apoptotic effects of temozolomide on glioblastoma cells by regulating WNT signaling pathway-related genes. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:37. [PMID: 36460932 DOI: 10.1007/s12032-022-01897-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 11/07/2022] [Indexed: 12/04/2022]
Abstract
Although temozolomide is the primary chemotherapeutic agent in glioblastoma, current studies have focused on its combinational applications to overcome resistance by targeting multiple pathways. JAK/STAT and WNT are among the essential cancer-related signaling pathways. Ruxolitinib, the first approved JAK1/2 inhibitor, has promise in glioblastoma with its blood-brain barrier (BBB) crossing ability. The mentioned study aims to evaluate the anti-cancer potential of ruxolitinib individually and in combination with temozolomide on glioblastoma cells, brain cancer stem cells (BCSCs), and BBB-forming healthy cells. It also intends to determine the effects of JAK inhibitor treatment in combination with temozolomide on WNT signaling, which is known to cross-talk with the JAK/STAT pathway. The U87MG, BCSC, and HBMEC cell lines were the in vitro models. The cytotoxic and apoptotic effects of ruxolitinib and the combination were determined by the WST-1 test and Annexin V assay, respectively. The expression level changes of WNT signaling pathway genes caused by ruxolitinib and the combination treatments were defined by the qRT-PCR method. Network analysis of significantly upregulated and downregulated genes was performed via the GO KEGG pathway enrichment module of the String V11.5 database. The IC50 value of the ruxolitinib on U87MG glioblastoma cells was determined as 94.07 µM at 24th h. The combination of temozolomide and ruxolitinib had a synergistic effect on U87MG cells at 24th h. The combination index (CI) was determined as 0.796, and ED60 values of ruxolitinib and temozolomide were determined as 89.75 and 391.48 µM, respectively. Ruxolitinib improves the apoptotic effect of temozolomide on glioblastoma cells and brain cancer stem cells. Ruxolitinib regulates the WNT signaling pathway both individually and in combination with temozolomide. Our study indicates the potential of ruxolitinib to increase the cytotoxic and apoptotic activity of temozolomide in glioblastoma cells, also considering CSCs and healthy BBB-forming cells. As supported by gene expression and network analyses, the BBB-crossing agent ruxolitinib promises the potential to increase the efficacy of temozolomide in glioblastoma by affecting multiple signaling pathways in both cancer cells and CSCs.
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25
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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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26
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Malekinejad Z, Baghbanzadeh A, Nakhlband A, Baradaran B, Jafari S, Bagheri Y, Raei F, Montazersaheb S, Farahzadi R. Recent clinical findings on the role of kinase inhibitors in COVID-19 management. Life Sci 2022; 306:120809. [PMID: 35841979 PMCID: PMC9278000 DOI: 10.1016/j.lfs.2022.120809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 11/25/2022]
Abstract
The highly pathogenic, novel coronavirus disease (COVID-19) outbreak has emerged as a once-in-a-century pandemic with poor consequences, urgently calling for new therapeutics, cures, and supportive interventions. It has already affected over 250 million people worldwide; thereby, there is a need for novel therapies to alleviate the related complications. There is a paradigm shift in developing drugs and clinical practices to combat COVID-19. Several clinical trials have been performed or are testing diverse pharmacological interventions to alleviate viral load and complications such as cytokine release storm (CRS). Kinase-inhibitors have appeared as potential antiviral agents for COVID-19 patients due to their efficacy against CRS. Combination of kinase inhibitors with other therapies can achieve more efficacy against COVID-19. Based on the pre-clinical trials, kinase inhibitors such as Janus kinase-signal transducer and activator of transcription (JAK/STAT) inhibitors, Brutton's tyrosin kinase (BTK) inhibitors, p38 mitogen-activated protein kinases (p38 MAPK) inhibitors, Glycogen synthase kinase 3 (GSK-3) inhibitors can be a promising strategy against COVID-19. Kinase inhibitors possess crucial pharmacological properties for a successful re-purposing in terms of dual anti-inflammatory and anti-viral effects. This review will address the current clinical evidence and the newest discovery regarding the application of kinase inhibitors in COVID-19. An outlook on ongoing clinical trials (clinicaltrials.gov) and unpublished data is also presented here. Besides, Kinase inhibitors' function on COVID-19-mediated CRS is discussed.
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Affiliation(s)
- Zahra Malekinejad
- Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ailar Nakhlband
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sevda Jafari
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yasin Bagheri
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Raei
- Departement of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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27
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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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28
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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: 4] [Impact Index Per Article: 1.3] [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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Rasmi Y, Hatamkhani S, Naderi R, Shokati A, Nayeb Zadeh V, Hosseinzadeh F, Farnamian Y, Jalali L. Molecular signaling pathways, pathophysiological features in various organs, and treatment strategies in SARS-CoV2 infection. Acta Histochem 2022; 124:151908. [PMID: 35662001 PMCID: PMC9130726 DOI: 10.1016/j.acthis.2022.151908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 05/19/2022] [Indexed: 01/08/2023]
Abstract
Cytokine storms and extra-activated cytokine signaling pathways can lead to severe tissue damage and patient death. Activation of inflammatory signaling pathways during Cytokine storms are an important factor in the development of acute respiratory syndrome (SARS-CoV-2), which is the major health problem today, causing systemic and local inflammation. Cytokine storms attract many inflammatory cells that attack the lungs and other organs and cause tissue damage. Angiotensin-converting enzyme 2 (ACE2) are expressed in a different type of tissues. inhibition of ACE2 activity impairs renin-angiotensin (RAS) function, which is related to the severity of symptoms and mortality rate in COVID-19 patients. Different signaling cascades are activated, affecting various organs during SARS-CoV-2 infection. Nowadays, there is no specific treatment for COVID-19, but scientists have recognized and proposed several treatment alternatives, including applying cytokine inhibitors, immunomodulators, and plasma therapy. Herein, we have provided the detailed mechanism of SARS-CoV-2 induced cytokine signaling and its connection with pathophysiological features in different organs. Possible treatment options to cope with the severe clinical manifestations of COVID-19 are also discussed.
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Affiliation(s)
- Yousef Rasmi
- Cellular and Molecular Research Center,Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Shima Hatamkhani
- Experimental and Applied Pharmaceutical Sciences Research Center, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Pharmacy, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Roya Naderi
- Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Physiology, school of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ameneh Shokati
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | | | - Faezeh Hosseinzadeh
- Department of Tissue Engineering, Qom University of Medical Sciences, Qom, Iran
| | - Yeganeh Farnamian
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Ladan Jalali
- Cellular and Molecular Research Center,Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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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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Hasanvand A. COVID-19 and the role of cytokines in this disease. Inflammopharmacology 2022; 30:789-798. [PMID: 35505267 PMCID: PMC9064717 DOI: 10.1007/s10787-022-00992-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 12/13/2022]
Abstract
Studies have shown that SARS-CoV-2 has the ability to activate and mature proinflammatory cytokines in the body. Cytokine markers are a group of polypeptide signalling molecules that can induce and regulate many cellular biological processes by stimulating cell receptors at the surface. SARS-CoV-2 has been shown to be associated with activation of innate immunity, and an increase in neutrophils, mononuclear phagocytes, and natural killer cells has been observed, as well as a decrease in T cells including CD4+ and CD8. It is noteworthy that during the SARS-CoV-2 infection, an increase in the secretion or production of IL-6 and IL-8 is seen in COVID-19 patients along with a decrease in CD4+ and CD8+ and T cells in general. SARS-CoV-2 has been shown to significantly increase Th2, Th1/Th17 cells and antibody production in the body of patients with COVID-19. Specific immune profiles of SARS-CoV-2 infection can lead to secondary infections and dysfunction of various organs in the body. It has been shown that Interleukins (such as IL-1, IL-4, IL-6, IL-7, IL-10, IL-12, IL-17, and IL-18), IFN-γ, TNF-α,TGF-β and NF-κB play major roles in the body's inflammatory response to SARS-CoV-2 infection. The most important goal of this review is to study the role of inflammatory cytokines in COVID-19.
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Affiliation(s)
- Amin Hasanvand
- Department of Physiology and Pharmacology, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.
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32
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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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Han MK, Antila M, Ficker JH, Gordeev I, Guerreros A, Bernus AL, Roquilly A, Sifuentes-Osornio J, Tabak F, Teijeiro R, Bandelli L, Bonagura DS, Shu X, Felser JM, Knorr B, Cao W, Langmuir P, Lehmann T, Levine M, Savic S. Ruxolitinib in addition to standard of care for the treatment of patients admitted to hospital with COVID-19 (RUXCOVID): a randomised, double-blind, placebo-controlled, phase 3 trial. THE LANCET. RHEUMATOLOGY 2022; 4:e351-e361. [PMID: 35368384 PMCID: PMC8963773 DOI: 10.1016/s2665-9913(22)00044-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background COVID-19 is associated with acute respiratory distress and cytokine release syndrome. The Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib reduces inflammatory cytokine concentrations in disorders characterised by cytokine dysregulation, including graft-versus-host disease, myelofibrosis, and secondary hemophagocytic lymphohistiocytosis. We assessed whether treatment with the JAK1/JAK2 inhibitor ruxolitinib would be beneficial in patients with COVID-19 admitted to hospital. Methods RUXCOVID was an international, randomised, double-blind, phase 3 trial of ruxolitinib plus standard of care versus placebo plus standard of care in patients with COVID-19. Patients who were hospitalised but not on mechanical ventilation or in the intensive care unit [ICU] were randomly assigned (2:1) to oral ruxolitinib 5 mg twice per day or placebo for 14 days (14 additional days were allowed if no improvement). The primary endpoint was a composite of death, respiratory failure (invasive ventilation), or ICU care by day 29, analysed by logistic regression including region, treatment, baseline clinical status, age, and sex as covariates. This trial is registered with ClinicalTrials.gov, NCT04362137. Findings Between May 4 and Sept 19, 2020, 432 patients were randomly assigned to ruxolitinib (n=287) or placebo (n=145) plus standard of care; the mean age was 56·5 years (SD 13·3), 197 (46%) were female, and 235 (54%) were male. The primary objective was not met: the composite endpoint occurred in 34 (12%) of 284 ruxolitinib-treated patients versus 17 (12%) of 144 placebo-treated patients (odds ratio 0·91, 95% CI 0·48-1·73; p=0·77). By day 29, nine (3%) of 286 ruxolitinib-treated patients had died compared with three (2%) of 145 placebo-treated patients; 22 (8%) of 286 ruxolitinib-treated patients had received invasive ventilation compared with ten (7%) of 145 placebo-treated patients; and 30 (11%) of 284 ruxolitinib-treated patients had received ICU care compared with 17 (12%) of 144 placebo-treated patients. In an exploratory analysis, median time to recovery was 1 day faster with ruxolitinib versus placebo (8 days vs 9 days; hazard ratio 1·10, 95% CI 0·89-1·36). Adverse events included headache (23 [8%] of 281 on ruxolitinib vs 11 [8%] of 143 on placebo) and diarrhoea (21 [7%] vs 12 [8%]). Interpretation Ruxolitinib 5 mg twice per day showed no benefit in the overall study population. A larger sample is required to determine the clinical importance of trends for increased efficacy in patient subgroups. Funding Novartis and Incyte.
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Affiliation(s)
- MeiLan K Han
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Martti Antila
- Department of Medicine, Clínica de Alergia Martti Antila, Sorocaba, Brazil
| | - Joachim H Ficker
- Department of Respiratory Medicine, Paracelsus Medical University, Nuernberg General Hospital, Nuremberg, Germany
| | - Ivan Gordeev
- Department of Healthcare, City Clinical Hospital n.a. O M Filatov, Moscow, Russia
| | | | - Amparo Lopez Bernus
- Department of Internal Medicine, University Hospital of Salamanca, University of Salamanca, CIETUS, IBSAL, Salamanca, Spain
| | - Antoine Roquilly
- Université de Nantes, CHU Nantes, EA3826 Thérapeutiques Anti-Infectieuses, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, France
| | - José Sifuentes-Osornio
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Fehmi Tabak
- Department of Infectious Disease and Clinical Microbiology, Medical School of Cerrahpasa, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Ricardo Teijeiro
- Department of Medicine, Hospital General de Agudos Dr Ignacio Pirovano, CABA, Argentina
| | | | - Diane S Bonagura
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Xu Shu
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - James M Felser
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Barbara Knorr
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Weihua Cao
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | | | | | - Michael Levine
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Sinisa Savic
- Department of Immunology and Allergy, Leeds Teaching Hospitals NHS Trust and National Institute for Health Research-Leeds Biomedical Research Centre, Leeds, UK
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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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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: 29] [Impact Index Per Article: 9.7] [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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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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The Promising Mechanisms of Low Molecular Weight Compounds of Panax Ginseng C.A. Meyer in Alleviating COVID-19: A Network Pharmacology Analysis. Processes (Basel) 2022. [DOI: 10.3390/pr10020333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Panax Ginseng C.A. Meyer (PGCAM) is a well-known phytomedicine, but most of its compounds, such as ginsenoside derivatives, have poor absorption and bioavailability profile due to high molecular weight (≥500 Daltons), which is the major hurdle for their clinical application. Hence, this research explored the efficiency of low molecular weight compounds (LMWCs) (<500 Daltons) screened from PGCAM and their anti-COVID-19 mechanisms through network pharmacology. Molecular compounds from PGCAM were identified using public databases and filtered out by the drug-likeness evaluation. Genes interacted with these filtered compounds, and COVID-19-related genes were extracted from public databases. In addition, overlapping genes between compounds and interactive genes were identified using the Venn diagram. In parallel, the networking between compounds and overlapping genes was analyzed by RStudio. The pathway enrichment analysis of overlapping genes was determined by STRING. Finally, the key bioactive compounds were documented through virtual screening. The bubble chart suggested that the mechanisms of PGCAM against COVID-19 were related to 28 signaling pathways. The key molecular anti-COVID-19 mechanisms might be the anti-inflammation, anti-permeability, and pro-apoptosis by inactivating the PI3K-Akt signaling pathway. The six key genes and the five compounds related to the PI3K-Akt signaling pathway were RELA-paeonol, NFKB1-frutinone A, IL6-nepetin, MCL1-ramalic acid, VEGFA-trifolirhizin, and IL2-trifolirhizin. The docking between these key genes and compounds demonstrated promising binding affinity with a good binding score. Overall, our proposed LMWCs from PGCAM provide a fundamental basis with noteworthy pharmacological evidence to support the therapeutic efficacy of PGCAM in relieving the main symptoms of COVID-19.
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Mahboubi Mehrabani M, Karvandi MS, Maafi P, Doroudian M. Neurological complications associated with Covid-19; molecular mechanisms and therapeutic approaches. Rev Med Virol 2022; 32:e2334. [PMID: 35138001 PMCID: PMC9111040 DOI: 10.1002/rmv.2334] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/06/2022] [Accepted: 01/19/2022] [Indexed: 12/15/2022]
Abstract
With the progression of investigations on the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), neurological complications have emerged as a critical aspect of the ongoing coronavirus disease 2019 (Covid‐19) pandemic. Besides the well‐known respiratory symptoms, many neurological manifestations such as anosmia/ageusia, headaches, dizziness, seizures, and strokes have been documented in hospitalised patients. The neurotropism background of coronaviruses has led to speculation that the neurological complications are caused by the direct invasion of SARS‐CoV‐2 into the nervous system. This invasion is proposed to occur through the infection of peripheral nerves or via systemic blood circulation, termed neuronal and haematogenous routes of invasion, respectively. On the other hand, aberrant immune responses and respiratory insufficiency associated with Covid‐19 are suggested to affect the nervous system indirectly. Deleterious roles of cytokine storm and hypoxic conditions in blood‐brain barrier disruption, coagulation abnormalities, and autoimmune neuropathies are well investigated in coronavirus infections, as well as Covid‐19. Here, we review the latest discoveries focussing on possible molecular mechanisms of direct and indirect impacts of SARS‐CoV‐2 on the nervous system and try to elucidate the link between some potential therapeutic strategies and the molecular pathways.
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Affiliation(s)
- Mohammad Mahboubi Mehrabani
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Sobhan Karvandi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Pedram Maafi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
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Su C, Rousseau S, Emad A. Identification of transcriptional regulatory network associated with response of host epithelial cells to SARS-CoV-2. Sci Rep 2021; 11:23928. [PMID: 34907210 PMCID: PMC8671548 DOI: 10.1038/s41598-021-03309-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 12/01/2021] [Indexed: 12/15/2022] Open
Abstract
Identification of transcriptional regulatory mechanisms and signaling networks involved in the response of host cells to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable the identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, our goal was to identify a transcriptional regulatory network that is associated with gene expression changes between samples infected by SARS-CoV-2 and those that are infected by other respiratory viruses to narrow the results on those enriched or specific to SARS-CoV-2. We combined a series of recently developed computational tools to identify transcriptional regulatory mechanisms involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus when compared to other viruses. In addition, using network-guided analyses, we identified kinases associated with this network. The results identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory network identified herein reflects a combination of known hits and novel candidate pathways supporting the novel computational pipeline presented herein to quickly narrow down promising avenues of investigation when facing an emerging and novel disease such as COVID-19.
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Affiliation(s)
- Chen Su
- Department of Electrical and Computer Engineering, McGill University, 755, McConnell Engineering Building, 3480 University Street, Montreal, QC, H3A 0E9, Canada
| | - Simon Rousseau
- The Meakins-Christie Laboratories at the Research Institute of McGill University Heath Centre (RI-MUHC), McGill University, E M3.2244, 1001 Décarie, Montreal, QC, H4A 3J1, Canada.
- Department of Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada.
| | - Amin Emad
- Department of Electrical and Computer Engineering, McGill University, 755, McConnell Engineering Building, 3480 University Street, Montreal, QC, H3A 0E9, Canada.
- The Meakins-Christie Laboratories at the Research Institute of McGill University Heath Centre (RI-MUHC), McGill University, E M3.2244, 1001 Décarie, Montreal, QC, H4A 3J1, Canada.
- Mila, Quebec AI Institute, Montreal, QC, Canada.
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40
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Thapa K, Verma N, Singh TG, Kaur Grewal A, Kanojia N, Rani L. COVID-19-Associated acute respiratory distress syndrome (CARDS): Mechanistic insights on therapeutic intervention and emerging trends. Int Immunopharmacol 2021; 101:108328. [PMID: 34768236 PMCID: PMC8563344 DOI: 10.1016/j.intimp.2021.108328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 02/07/2023]
Abstract
AIMS The novel Coronavirus disease 2019 (COVID-19) has caused great distress worldwide. Acute respiratory distress syndrome (ARDS) is well familiar but when it happens as part of COVID-19 it has discrete features which are unmanageable. Numerous pharmacological treatments have been evaluated in clinical trials to control the clinical effects of CARDS, but there is no assurance of their effectiveness. MATERIALS AND METHODS A systematic review of the literature of the Medline, Scopus, Bentham, PubMed, and EMBASE (Elsevier) databases was examined to understand the novel therapeutic approaches used in COVID-19-Associated Acute Respiratory Distress Syndrome and their outcomes. KEY FINDINGS Current therapeutic options may not be enough to manage COVID-19-associated ARDS complications in group of patients and therefore, the current review has discussed the pathophysiological mechanism of COVID-19-associated ARDS, potential pharmacological treatment and the emerging molecular drug targets. SIGNIFICANCE The rationale of this review is to talk about the pathophysiology of CARDS, potential pharmacological treatment and the emerging molecular drug targets. Currently accessible treatment focuses on modulating immune responses, rendering antiviral effects, anti-thrombosis or anti-coagulant effects. It is expected that considerable number of studies conducting globally may help to discover effective therapies to decrease mortality and morbidity occurring due to CARDS. Attention should be also given on molecular drug targets that possibly will help to develop efficient cure for COVID-19-associated ARDS.
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Affiliation(s)
- Komal Thapa
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India; Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Nitin Verma
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | | | | | - Neha Kanojia
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Lata Rani
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, India
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41
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Lin Z, Niu J, Xu Y, Qin L, Ding J, Zhou L. Clinical efficacy and adverse events of baricitinib treatment for coronavirus disease-2019 (COVID-19): A systematic review and meta-analysis. J Med Virol 2021; 94:1523-1534. [PMID: 34846766 PMCID: PMC9015594 DOI: 10.1002/jmv.27482] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/08/2021] [Accepted: 11/24/2021] [Indexed: 12/16/2022]
Abstract
The benefits of baricitinib in coronavirus disease-2019 are inadequately defined. We performed a systematic review and meta-analysis of studies of baricitinib to determine its clinical efficacy and adverse events in patients with COVID-19. Databases were searched from their inception to September 5, 2021. The primary outcome was the coefficient of mortality. We also compared secondary indicators and adverse events between baricitinib treatment and placebo or other treatments. Twelve studies of 3564 patients were included and assessed qualitatively (modified Jadad and Newcastle-Ottawa Scale scores). Baricitinib effectively improved the mortality rate (relative risk of mortality = 0.56; 95% confidence interval: 0.46-0.69; p < 0.001; I2 = 2%), and this result was unchanged by subgroup analysis. Baricitinib improved intensive care unit admission, the requirement for invasive mechanical ventilation, and improved the oxygenation index. Data from these studies also showed that baricitinib slightly reduced the risk of adverse events. Regarding the choice of the drug dosage of baricitinib, the high-dose group appeared to have additional benefits for clinical efficacy. Our study shows that baricitinib may be a promising, safe, and effective anti-severe acute respiratory syndrome-coronavirus-2 drug candidate, with the advantages of low cost, easy production, and convenient storage.
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Affiliation(s)
- Zhiwei Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jianyi Niu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yifan Xu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lijie Qin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiabin Ding
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Luqian Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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42
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Hu S, Jiang S, Qi X, Bai R, Ye XY, Xie T. Races of small molecule clinical trials for the treatment of COVID-19: An up-to-date comprehensive review. Drug Dev Res 2021; 83:16-54. [PMID: 34762760 PMCID: PMC8653368 DOI: 10.1002/ddr.21895] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/18/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022]
Abstract
The coronavirus disease‐19 (COVID‐19) pandemic has become a global threat since its first outbreak at the end of 2019. Several review articles have been published recently, focusing on the aspects of target biology, drug repurposing, and mechanisms of action (MOAs) for potential treatment. This review gathers all small molecules currently in active clinical trials, categorizes them into six sub‐classes, and summarizes their clinical progress. The aim is to provide the researchers from both pharmaceutical industries and academic institutes with the handful information and dataset to accelerate their research programs in searching effective small molecule therapy for treatment of COVID‐19.
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Affiliation(s)
- Suwen Hu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, Hangzhou Normal Umiversity, Hangzhou, China.,Hangzhou Huadong Medicine Group, Pharmaceutical Research Institute Co. Ltd., Hangzhou, China.,Department of Chemistry and Biochemistry Los Angeles, University of California, Los Angeles, California, USA
| | - Songwei Jiang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, Hangzhou Normal Umiversity, Hangzhou, China
| | - Xiang Qi
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, Hangzhou Normal Umiversity, Hangzhou, China
| | - Renren Bai
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, Hangzhou Normal Umiversity, Hangzhou, China
| | - Xiang-Yang Ye
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, Hangzhou Normal Umiversity, Hangzhou, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou Normal University, Hangzhou, China.,Collaborative Innovation Center of Chinese Medicines from Zhejiang Province, Hangzhou Normal Umiversity, Hangzhou, China
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43
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Wang X, Wang Y, Li X, Yu Z, Song C, Du Y. Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies. RSC Med Chem 2021; 12:1650-1671. [PMID: 34778767 PMCID: PMC8528211 DOI: 10.1039/d1md00131k] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 06/27/2021] [Indexed: 12/12/2022] Open
Abstract
The nitrile group is an important functional group widely found in both pharmaceutical agents and natural products. More than 30 nitrile-containing pharmaceuticals have been approved by the FDA for the management of a broad range of clinical conditions in the last few decades. Incorporation of a nitrile group into lead compounds has gradually become a promising strategy in rational drug design as it can bring additional benefits including enhanced binding affinity to the target, improved pharmacokinetic profile of parent drugs, and reduced drug resistance. This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages.
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Affiliation(s)
- Xi Wang
- School of Pharmaceutical Science and Technology, Tianjin University Tianjin 300072 China
| | - Yuanxun Wang
- National Institution of Biological Sciences, Beijing No. 7 Science Park Road, Zhongguancun Life Science Park Beijing 102206 China
| | - Xuemin Li
- School of Pharmaceutical Science and Technology, Tianjin University Tianjin 300072 China
| | - Zhenyang Yu
- School of Pharmaceutical Science and Technology, Tianjin University Tianjin 300072 China
| | - Chun Song
- State Key Laboratory of Microbial Technology, Shandong University Qingdao City Shandong Province 266237 China
| | - Yunfei Du
- School of Pharmaceutical Science and Technology, Tianjin University Tianjin 300072 China
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44
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Li Y, Zhao W, Liu J, Chen Z, Lv Q, Zhang Z. Immunotherapy Summary for Cytokine Storm in COVID-19. Front Pharmacol 2021; 12:731847. [PMID: 34603047 PMCID: PMC8484328 DOI: 10.3389/fphar.2021.731847] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 09/06/2021] [Indexed: 01/08/2023] Open
Abstract
COVID-19 pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has ravaged the world, resulting in an alarming number of infections and deaths, and the number continues to increase. The pathogenesis caused by the novel coronavirus was found to be a disruption of the pro-inflammatory/anti-inflammatory response. Due to the lack of effective treatments, different strategies and treatment methods are still being researched, with the use of vaccines to make the body immune becoming the most effective means of prevention. Antiviral drugs and respiratory support are often used clinically as needed, but are not yet sufficient to alleviate the cytokine storm (CS) and systemic inflammatory response syndrome. How to neutralize the cytokine storm and inhibit excessive immune cell activation becomes the key to treating neocoronavirus pneumonia. Immunotherapy through the application of hormones and monoclonal antibodies can alleviate the immune imbalance, but the clinical effectiveness and side effects remain controversial. This article reviews the pathogenesis of neocoronavirus pneumonia and discusses the immunomodulatory therapies currently applied to COVID-19. We aim to give some conceptual thought to the prevention and immunotherapy of neocoronavirus pneumonia.
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Affiliation(s)
- Yaqun Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.,College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenjie Zhao
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jinhua Liu
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.,College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zichao Chen
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.,Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qingtao Lv
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhen Zhang
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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45
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Shi R, Feng Z, Zhang X. Integrative Multi-omics Landscape of Non-structural Protein 3 of Severe Acute Respiratory Syndrome Coronaviruses. GENOMICS, PROTEOMICS & BIOINFORMATICS 2021; 19:707-726. [PMID: 34774773 PMCID: PMC8578027 DOI: 10.1016/j.gpb.2021.09.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 08/26/2021] [Accepted: 09/14/2021] [Indexed: 11/30/2022]
Abstract
The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is currently a global pandemic. Extensive investigations have been performed to study the clinical and cellular effects of SARS-CoV-2 infection. Mass spectrometry-based proteomics studies have revealed the cellular changes due to the infection and identified a plethora of interactors for all SARS-CoV-2 components, except for the longest non-structural protein 3 (NSP3). Here, we expressed the full-length NSP3 proteins of SARS-CoV and SARS-CoV-2 to investigate their unique and shared functions using multi-omics methods. We conducted interactome, phosphoproteome, ubiquitylome, transcriptome, and proteome analyses of NSP3-expressing cells. We found that NSP3 plays essential roles in cellular functions such as RNA metabolism and immune response (e.g., NF-κB signal transduction). Interestingly, we showed that SARS-CoV-2 NSP3 has both endoplasmic reticulum and mitochondrial localizations. In addition, SARS-CoV-2 NSP3 is more closely related to mitochondrial ribosomal proteins, whereas SARS-CoV NSP3 is related to the cytosolic ribosomal proteins. In summary, our integrative multi-omics study of NSP3 improves the understanding of the functions of NSP3 and offers potential targets for the development of anti-SARS strategies.
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Affiliation(s)
- Ruona Shi
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhenhuan Feng
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaofei Zhang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Center for Cell Lineage and Atlas, Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510530, China.
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46
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Fang J, Wu Q, Ye F, Cai C, Xu L, Gu Y, Wang Q, Liu AL, Tan W, Du GH. Network-Based Identification and Experimental Validation of Drug Candidates Toward SARS-CoV-2 via Targeting Virus-Host Interactome. Front Genet 2021; 12:728960. [PMID: 34539756 PMCID: PMC8440948 DOI: 10.3389/fgene.2021.728960] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Despite that several therapeutic agents have exhibited promising prevention or treatment on Coronavirus disease-2019 (COVID-19), there is no specific drug discovered for this pandemic. Targeting virus-host interactome provides a more effective strategy for antivirus drug discovery compared with targeting virus proteins. In this study, we developed a network-based infrastructure to prioritize promising drug candidates from natural products and approved drugs via targeting host proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We firstly measured the network distances between drug targets and COVID-19 disease module utilizing the network proximity approach, and identified 229 approved drugs as well as 432 natural products had significant associations with SARS-CoV-2. After searching for previous literature evidence, we found that 60.7% (139/229) of approved drugs and 39.6% (171/432) of natural products were confirmed with antivirus or anti-inflammation. We further integrated our network-based predictions and validated anti-SARS-CoV-2 activities of some compounds. Four drug candidates, including hesperidin, isorhapontigenin, salmeterol, and gallocatechin-7-gallate, have exhibited activity on SARS-COV-2 virus-infected Vero cells. Finally, we showcased the mechanism of actions of isorhapontigenin and salmeterol via network analysis. Overall, this study offers forceful approaches for in silico identification of drug candidates on COVID-19, which may facilitate the discovery of antiviral drug therapies.
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Affiliation(s)
- Jiansong Fang
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qihui Wu
- Clinical Research Center, Hainan Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Haikou, China
| | - Fei Ye
- MHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Beijing, China
| | - Chuipu Cai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lvjie Xu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Gu
- Clinical Research Center, Hainan Provincial Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Haikou, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ai-lin Liu
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenjie Tan
- MHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Beijing, China
| | - Guan-hua Du
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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47
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Felicetti L, Femminella M, Reali G. A Molecular Communications System for the Detection of Inflammatory Levels Related to COVID-19 Disease. IEEE TRANSACTIONS ON MOLECULAR, BIOLOGICAL AND MULTI-SCALE COMMUNICATIONS 2021; 7:165-174. [PMID: 35782715 PMCID: PMC8544947 DOI: 10.1109/tmbmc.2021.3071788] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 01/27/2021] [Accepted: 03/15/2021] [Indexed: 12/29/2022]
Abstract
A recent and extensive research activity highlighted the process behind the attack and spread of COVID-19 in the human body. What emerged is that the SARS-CoV-2 virus makes use of both the ACE2 receptor, expressed by pneumocytes in the ephitelial alveolar lining, and by the endothelium to spread the disease and to replicate itself. Since the endothelium is an extended tissue lying in the circulatory system, this may lead to a large state of diffuse endothelial inflammation with serious clinical consequences. This situation may be further compromised by the immune system, that may generate pro-inflammatory cytokines (IL-6) as a consequence of the infection. In this paper we propose and analyze a molecular communication system, designed for the detection of excessive IL-6 level, that allows monitoring its evolution in the blood vessels. The proposed analysis was performed by using the BiNS2 simulator, which is suitable for the numerical analysis of flow-based molecular communications in blood vessels, as well as Markov models of the endothelium.
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Affiliation(s)
- Luca Felicetti
- Department of EngineeringUniversity of Perugia 06123 Perugia Italy
- Consorzio Nazionale Interuniversitario per le TelecomunicazioniUniversity of Perugia 06123 Perugia Italy
| | - Mauro Femminella
- Department of EngineeringUniversity of Perugia 06123 Perugia Italy
- Consorzio Nazionale Interuniversitario per le TelecomunicazioniUniversity of Perugia 06123 Perugia Italy
| | - Gianluca Reali
- Department of EngineeringUniversity of Perugia 06123 Perugia Italy
- Consorzio Nazionale Interuniversitario per le TelecomunicazioniUniversity of Perugia 06123 Perugia Italy
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48
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Palasiewicz K, Umar S, Romay B, Zomorrodi RK, Shahrara S. Tofacitinib therapy intercepts macrophage metabolic reprogramming instigated by SARS-CoV-2 Spike protein. Eur J Immunol 2021; 51:2330-2340. [PMID: 34107055 PMCID: PMC8237023 DOI: 10.1002/eji.202049159] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/14/2021] [Accepted: 06/07/2021] [Indexed: 12/27/2022]
Abstract
The molecular mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein was characterized to identify novel therapies. The impact of tofacitinib, IL-6R Ab, or TNFi therapy was determined on Spike protein or LPS/IFN-γ-induced signaling, inflammation, and metabolic reprogramming in MΦs and/or rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS). ACE2 frequency was markedly expanded in MΦs compared to T cells and RA FLS. Tofacitinib suppresses Spike protein potentiated STAT1 signaling, whereas this function was unchanged by TNFi. Tofacitinib impairs IL-6/IFN/LPS-induced STAT1 and STAT3 phosphorylation in RA MΦs and FLS. Interestingly, tofacitinib had a broader inhibitory effect on the monokines, glycolytic regulators, or oxidative metabolites compared to IL-6R Ab and TNFi in Spike-protein-activated MΦs. In contrast, all three therapies disrupted IFN-α and IFN-β secretion in response to Spike protein; nonetheless, the IFN-γ was only curtailed by tofacitinib or IL-6R Ab. While tofacitinib counteracted MΦ metabolic rewiring instigated by Spike protein, it was inconsequential on the glycolysis expansion mediated via HK2 and/or LDHA in the activated RA MΦ and FLS. Nevertheless, the potentiated inflammatory response and the diminished oxidative phosphorylation modulated by Spike protein and/or LPS/IFN-γ stimulation in MΦs or RA FLS were reversed by tofacitinib. In conclusion, tofacitinib suppresses MΦ inflammation and immunometabolism triggered by Spike protein and may provide a promising strategy for COVID-19 patients.
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Affiliation(s)
- Karol Palasiewicz
- Jesse Brown VA Medical CenterChicagoILUSA
- Division of RheumatologyDepartment of Medicine, The University of Illinois at ChicagoChicagoILUSA
| | - Sadiq Umar
- Jesse Brown VA Medical CenterChicagoILUSA
- Division of RheumatologyDepartment of Medicine, The University of Illinois at ChicagoChicagoILUSA
| | - Bianca Romay
- Division of RheumatologyDepartment of Medicine, The University of Illinois at ChicagoChicagoILUSA
| | - Ryan K. Zomorrodi
- Division of RheumatologyDepartment of Medicine, The University of Illinois at ChicagoChicagoILUSA
| | - Shiva Shahrara
- Jesse Brown VA Medical CenterChicagoILUSA
- Division of RheumatologyDepartment of Medicine, The University of Illinois at ChicagoChicagoILUSA
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Hasselbalch HC, Skov V, Kjær L, Ellervik C, Poulsen A, Poulsen TD, Nielsen CH. COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon. Cytokine Growth Factor Rev 2021; 60:28-45. [PMID: 33992887 PMCID: PMC8045432 DOI: 10.1016/j.cytogfr.2021.03.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/26/2021] [Accepted: 03/27/2021] [Indexed: 02/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state, which aggravates the type I interferon deficiency and slow IFN responses, which associate with e.g. aging and obesity. Additionally, SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression and ultimately the urgent need of ventilator support. Based upon several reports, it has been argued that early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. Similarly, preliminary studies have shown that JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm, which - in addition to the virus itself - also contributes to multi-organ thrombosis and multi-organ failure. Herein, we describe the rationale for treatment with IFNs (alpha2 or beta) and ruxolitinib emphasizing the urgent need to explore these agents in the treatment of SARS-CoV-2 - both as monotherapies and in combination. In this context, we take advantage of several safety and efficacy studies in patients with the chronic myeloproliferative blood cancers (essential thrombocythemia, polycythemia vera and myelofibrosis) (MPNs), in whom IFN-alpha2 and ruxolitinib have been used successfully for the last 10 (ruxolitinib) to 30 years (IFN) as monotherapies and most recently in combination as well. In the context of these agents being highly immunomodulating (IFN boosting immune cells and JAK1/2 inhibitors being highly immunosuppressive and anti-inflammatory), we also discuss if statins and hydroxyurea, both agents possessing anti-inflammatory, antithrombotic and antiviral potentials, might be inexpensive agents to be repurposed in the treatment of SARS-CoV-2.
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Affiliation(s)
- H C Hasselbalch
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
| | - V Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - L Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - C Ellervik
- Department of Research, Production, Innovation, Region Zealand, Denmark; Department of Pathology, Harvard Medical School, Boston, MA, United States; Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA, United States
| | - A Poulsen
- Department of Anestesiology and Intensive Care Unit, Zealand University Hospital, Roskilde, Denmark
| | - T D Poulsen
- Department of Anestesiology and Intensive Care Unit, Zealand University Hospital, Roskilde, Denmark
| | - C H Nielsen
- Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
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50
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Pfeifer ND, Lo A, Bourdet DL, Colley K, Singh D. Phase I study in healthy participants to evaluate safety, tolerability, and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID-19. Clin Transl Sci 2021; 14:2556-2565. [PMID: 34318597 PMCID: PMC8444931 DOI: 10.1111/cts.13123] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/29/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Nezulcitinib (TD‐0903), a lung‐selective pan–Janus‐associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID‐19). This two‐part, double‐blind, randomized, placebo‐controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment‐emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration‐time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose‐proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung‐selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well‐tolerated in healthy participants, with dose‐proportional PK supporting once‐daily administration.
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Affiliation(s)
- Nathan D Pfeifer
- Theravance Biopharma US, Inc., South San Francisco, California, USA
| | - Arthur Lo
- Theravance Biopharma US, Inc., South San Francisco, California, USA
| | - David L Bourdet
- Theravance Biopharma US, Inc., South San Francisco, California, USA
| | - Kenneth Colley
- Theravance Biopharma US, Inc., South San Francisco, California, USA
| | - Dave Singh
- Medicines Evaluation Unit, University of Manchester, Manchester University, Manchester, UK
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