57
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The JAK/STAT signaling pathway: from bench to clinic

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

          Related collections

          Most cited references596

          • Record: found
          • Abstract: found
          • Article: not found

          Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

          Abstract Background Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. Methods We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. Results A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P=0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3; P=0.03), as were new infections (5.9% vs. 11.2%; difference, −5.3 percentage points; 95% CI, −8.7 to −1.9; P=0.003). Conclusions Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.)
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Regulation of type I interferon responses.

            Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

              Given the scale and rapid spread of the 2019 novel coronavirus (2019-nCoV) acute respiratory disease, there is an immediate need for medicines that can help before a vaccine can be produced. Results of rapid sequencing of 2019-nCoV, coupled with molecular modelling based on the genomes of related virus proteins, 1 have suggested a few compounds that are likely to be effective, including the anti-HIV lopinavir plus ritonavir combination. BenevolentAI's knowledge graph is a large repository of structured medical information, including numerous connections extracted from scientific literature by machine learning. 2 Together with customisations bespoke to 2019-nCoV, we used BenevolentAI to search for approved drugs that could help, focusing on those that might block the viral infection process. We identified baricitinib, which is predicted to reduce the ability of the virus to infect lung cells. Most viruses enter cells through receptor-mediated endocytosis. The receptor that 2019-nCoV uses to infect lung cells might be ACE2, a cell-surface protein on cells in the kidney, blood vessels, heart, and, importantly, lung AT2 alveolar epithelial cells (figure ). These AT2 cells are particularly prone to viral infection. 3 One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles. 4 Figure The BenevolentAI knowledge graph The BenevolentAI knowledge graph integrates biomedical data from structured and unstructured sources. It is queried by a fleet of algorithms to identify new relationships to suggest new ways of tackling disease. 2019-nCoV=2019 novel coronavirus. AAK1=AP-2 associated kinase 1. GAK=cyclin g-associated kinase. JAK1/2=janus kinase 1/2. Of 378 AAK1 inhibitors in the knowledge graph, 47 have been approved for medical use and six inhibited AAK1 with high affinity. These included a number of oncology drugs such as sunitinib and erlotinib, both of which have been shown to inhibit viral infection of cells through the inhibition of AAK1. 5 However, these compounds bring serious side-effects, and our data infer high doses to inhibit AAK1 effectively. We do not consider these drugs would be a safe therapy for a population of sick and infected people. By contrast, one of the six high-affinity AAK1-binding drugs was the janus kinase inhibitor baricitinib, which also binds the cyclin G-associated kinase, another regulator of endocytosis. Because the plasma concentration of baricitinib on therapeutic dosing (either as 2 mg or 4 mg once daily) is sufficient to inhibit AAK1, we suggest it could be trialled, using an appropriate patient population with 2019-nCoV acute respiratory disease, to reduce both the viral entry and the inflammation in patients, using endpoints such as the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. 7
                Bookmark

                Author and article information

                Contributors
                xia-zhao@126.com
                weiwang@scu.edu.cn
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                26 November 2021
                26 November 2021
                2021
                : 6
                : 402
                Affiliations
                [1 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, , Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu, ; 610041 Sichuan, P. R. China
                [2 ]GRID grid.412901.f, ISNI 0000 0004 1770 1022, Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, , West China Second Hospital, Sichuan University, ; 610041 Chengdu, P. R. China
                Author information
                http://orcid.org/0000-0002-2786-4234
                http://orcid.org/0000-0001-7788-1895
                Article
                791
                10.1038/s41392-021-00791-1
                8617206
                34824210
                32ed6a93-ab69-4713-98cc-30b4914fdc18
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 12 April 2021
                : 9 September 2021
                : 21 September 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100002855, Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology);
                Award ID: 2020YFC860200
                Award ID: 2020YFC860200
                Award ID: 2020YFC860200
                Award ID: 2020YFC860200
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004829, Department of Science and Technology of Sichuan Province (Sichuan Provincial Department of Science and Technology);
                Award ID: 2020YFS0008
                Award Recipient :
                Funded by: Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology)
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: No. 81902662
                Award ID: No. 81902662
                Award Recipient :
                Funded by: Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology)
                Funded by: Ministry of Science and Technology of the People’s Republic of China (Chinese Ministry of Science and Technology)
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2021

                immunopathogenesis,molecular medicine,cancer,molecular biology

                Comments

                Comment on this article