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The Journal of Allergy and Clinical... Oct 2021Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways... (Review)
Review
Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways implicated in asthma involve cytokines and growth factors that activate Janus kinases (JAKs). The discovery of the JAK/signal transducer and activator of transcription (STAT) signaling pathway was a major breakthrough that revolutionized our understanding of cell growth and differentiation. JAK inhibitors are under active investigation for immune and inflammatory diseases, and they have demonstrated clinical efficacy in diseases such as rheumatoid arthritis and atopic dermatitis. Substantial preclinical data support the idea that inhibiting JAKs will ameliorate airway inflammation and hyperreactivity in asthma. Here, we review the rationale for use of JAK inhibitors in different asthma endotypes as well as the preclinical and early clinical evidence supporting such use. We review preclinical data from the use of systemic and inhaled JAK inhibitors in animal models of asthma and safety data based on the use of JAK inhibitors in other diseases. We conclude that JAK inhibitors have the potential to usher in a new era of anti-inflammatory treatment for asthma.
Topics: Animals; Asthma; Drug Administration Routes; Humans; Janus Kinase Inhibitors; Janus Kinases; STAT Transcription Factors
PubMed: 34625142
DOI: 10.1016/j.jaci.2021.08.013 -
Journal of Translational Medicine Feb 2023Inadequate immunity caused by poor immune surveillance leads to tumorigenesis, while excessive immunity due to breakdown of immune tolerance causes autoimmune genesis....
BACKGROUND
Inadequate immunity caused by poor immune surveillance leads to tumorigenesis, while excessive immunity due to breakdown of immune tolerance causes autoimmune genesis. Although the function of immunity during the onset of these two processes appears to be distinct, the underlying mechanism is shared. To date, gene expression data for large bodies of clinical samples are available, but the resemblances of tumorigenesis and autoimmune genesis in terms of immune responses remains to be summed up.
METHODS
Considering the high disease prevalence, we chose invasive ductal carcinoma (IDC) and systemic lupus erythematosus (SLE) to study the potential commonalities of immune responses. We obtained gene expression data of IDC/SLE patients and normal controls from five IDC databases (GSE29044, GSE21422, GSE22840, GSE15852, and GSE9309) and five SLE databases (GSE154851, GSE99967, GSE61635, GSE50635, and GSE17755). We intended to identify genes differentially expressed in both IDC and SLE by using three bioinformatics tools including GEO2R, the limma R package, and Weighted Gene Co-expression Network Analysis (WGCNA) to perform function enrichment, protein-protein network, and signaling pathway analyses.
RESULTS
The mRNA levels of signal transducer and activator of transcription 1 (STAT1), 2'-5'-oligoadenylate synthetase 1 (OAS1), 2'-5'-oligoadenylate synthetase like (OASL), and PML nuclear body scaffold (PML) were found to be differentially expressed in both IDC and SLE by using three different bioinformatics tools of GEO2R, the limma R package and WGCNA. From the combined databases in this study, the mRNA levels of STAT1 and OAS1 were increased in IDC while reduced in SLE. And the mRNA levels of OASL and PML were elevated in both IDC and SLE. Based on Kyoto Encyclopedia of Genes and Genomes pathway analysis and QIAGEN Ingenuity Pathway Analysis, both IDC and SLE were correlated with the changes of multiple components involved in the Interferon (IFN)-Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway.
CONCLUSION
The expression levels of STAT1 and OAS1 manifest the opposite expression tendency across cancer and autoimmune disease. They are components in the IFN-JAK-STAT signaling pathway related to both tumorigenesis and autoimmune genesis. STAT1 and OAS1-associated IFN-JAK-STAT signaling could explain the commonalities during tumorigenesis and autoimmune genesis and render significant information for more precise treatment from the point of immune homeostasis.
Topics: Humans; Lupus Erythematosus, Systemic; Janus Kinases; Neoplasms; Carcinogenesis; Computational Biology; RNA, Messenger
PubMed: 36765396
DOI: 10.1186/s12967-023-03943-9 -
Current Treatment Options in Oncology Jan 2021JAK (janus kinase) inhibitors are becoming increasingly prescribed for various conditions from dermatologic diseases to graft versus host disease in bone marrow... (Review)
Review
JAK (janus kinase) inhibitors are becoming increasingly prescribed for various conditions from dermatologic diseases to graft versus host disease in bone marrow transplant recipients. This class of drugs has been found to be truly life-changing for many, though they are not without potential adverse effects. While JAK inhibitors have not been shown to significantly increase the risk of non-melanoma skin cancer (NMSC) in large scale clinical trials, NMSC is one of the most concerning possible adverse events, and there have been several reported cases of aggressive squamous cell carcinomas, especially in our already immunosuppressed patient populations. In these patients, it is incredibly important that patients are on the lowest possible dosage of the JAK inhibitor. In addition, these patients must be routinely screened by a dermatologist with a comprehensive skin exam to ensure early detection if skin cancer was to develop. For those patients diagnosed with skin cancer, early intervention is key to optimize outcomes, and at times, multi-disciplinary care coordination is needed. In the future, large-scale studies with longer follow-up of patients would help determine whether JAK inhibitors significantly increase the risk of NMSC.
Topics: Biomarkers; Clinical Trials as Topic; Disease Susceptibility; Drug Development; Humans; Janus Kinase Inhibitors; Janus Kinases; Molecular Targeted Therapy; Prognosis; STAT Transcription Factors; Signal Transduction; Skin Neoplasms; Treatment Outcome
PubMed: 33423161
DOI: 10.1007/s11864-020-00815-y -
Biochemical Pharmacology Oct 2022Non-infectious uveitis (NIU) refers to various intraocular inflammatory disorders responsible for severe visual loss. Cytokines participate in the regulation of ocular... (Review)
Review
Non-infectious uveitis (NIU) refers to various intraocular inflammatory disorders responsible for severe visual loss. Cytokines participate in the regulation of ocular homeostasis and NIU pathological processes. Cytokine receptors transmit signals by activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. Increasing evidence from human NIU and experimental models reveals the involvement of the JAK-STAT signaling pathway in NIU pathogenesis. Several small-molecule drugs that potentially inhibit multiple cytokine-dependent pathways are under investigation for treating autoimmune diseases, implicating possible applications for NIU treatment. This review summarizes the current understanding of the diverse roles of the JAK-STAT signaling pathway in ocular homeostasis and NIU pathology, providing a rationale for targeting JAKs and STATs for NIU treatment. Moreover, available evidence for the safety and efficacy of JAK inhibitors for refractory uveitis and potential approaches for treatment optimization are discussed.
Topics: Cytokines; Humans; Janus Kinase Inhibitors; Janus Kinases; Receptors, Cytokine; STAT Transcription Factors; Signal Transduction; Uveitis
PubMed: 36041544
DOI: 10.1016/j.bcp.2022.115236 -
Molecular Cancer Jan 2024Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT)... (Review)
Review
Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.
Topics: Humans; Janus Kinases; STAT Transcription Factors; Myeloproliferative Disorders; Leukemia; Signal Transduction
PubMed: 38273387
DOI: 10.1186/s12943-023-01929-1 -
International Review of Cell and... 2021The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary... (Review)
Review
The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.
Topics: Animals; Clinical Trials as Topic; Humans; Intestines; Janus Kinases; Neoplasms; STAT Transcription Factors; Signal Transduction
PubMed: 34074491
DOI: 10.1016/bs.ircmb.2021.02.001 -
Journal of Dermatological Science Mar 2024Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids and tacrolimus have been used as... (Review)
Review
Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids and tacrolimus have been used as topical treatments. Recently, novel topical agents targeting Janus kinase (JAK), a family of tyrosine kinases that regulates cytokine signaling, have emerged. Ruxolitinib is the first approved in vitiligo therapy. Furthermore, ritlecitinib is currently under clinical trials for oral treatment of active vitiligo. In this review, we discuss the possibility of topical JAK inhibitors as promising options for the treatment of vitiligo with regard to their mechanism of action, efficacy and safety.
Topics: Humans; Janus Kinase Inhibitors; Vitiligo; Protein Kinase Inhibitors; Janus Kinases; Administration, Topical
PubMed: 38326166
DOI: 10.1016/j.jdermsci.2023.12.008 -
European Journal of Immunology Jul 2021The European Journal of Immunology was launched 50 years ago, coinciding with the discovery of many cytokines and growth factors and the emergence of an entirely new... (Review)
Review
The European Journal of Immunology was launched 50 years ago, coinciding with the discovery of many cytokines and growth factors and the emergence of an entirely new field of research. Ultimately, our knowledge about the biological activity of these factors allowed us to better understand how the immune system functions in the context of inflammatory and autoimmune diseases leading to the development of targeted biologic therapies. The study of cytokine signal transduction led to the discovery of Janus kinases (JAK), and the consideration of therapeutically targeting JAKs to treat immune and inflammatory diseases. This year also marks the tenth anniversary of the approval of the first JAK inhibitor (jakinib) and now there are a total of nine approved jakinibs for treatment of rheumatologic, dermatologic, gastrointestinal, and neoplastic indications and most recently COVID-19. Here, we summarized the discoveries that led to development of first-generation jakinibs, discussed some of the newer, possibly more selective jakinibs, as well as jakinibs that also target other kinases. We also illustrated the rationale behind the application of these drugs in the treatment of COVID-19 cytokine storm. In this review, we will discuss the clinical success of jakinibs, the gaps in our understanding of their biological activities as well as challenges in regard to their clinical application.
Topics: Autoimmune Diseases; Cytokine Release Syndrome; Cytokines; Humans; Hypersensitivity; Janus Kinase Inhibitors; Janus Kinases; SARS-CoV-2; Signal Transduction; COVID-19 Drug Treatment
PubMed: 33930196
DOI: 10.1002/eji.202048922 -
Science (New York, N.Y.) Jun 2024Janus kinase (JAK) inhibitors improve antitumor responses.
Janus kinase (JAK) inhibitors improve antitumor responses.
Topics: Humans; Neoplasms; Janus Kinases; Janus Kinase Inhibitors; Animals; Mice
PubMed: 38900897
DOI: 10.1126/science.adq1717 -
Advances in Experimental Medicine and... 2021Cell signaling is an important part of the complex system of molecular communication that governs basic cellular activities and coordinates cell cycle machinery.... (Review)
Review
Cell signaling is an important part of the complex system of molecular communication that governs basic cellular activities and coordinates cell cycle machinery. Pathological alterations in the cellular information processing may be responsible for the diseases such as cancer. Numerous diseases may be treated effectively via the pharmacological management of cellular signaling. Protein kinases (PK) have significantly important roles in the cell signal transduction process. Protein kinases phosphorylate serine, threonine, tyrosine and histidine amino acids in a wide variety of molecular networks. Two main PK groups are distinguished; serine/threonine kinase and tyrosine kinases. MAPK (mitogen-activated protein kinases), ERK, EGFR (epidermal growth factor receptor), src, abl, FAK (focal adesion kinase), and JAK (janus family kinase) are considered as the main PK molecular networks. Protein kinases are closely related to the pathobiology of hematologic neoplastic disorders. For instance; JAKV617F point mutation-causing polycythemia vera and essential thrombocytosis occur at the position 617 in the JH2 domain of the JAK2 gene. The protein kinase inhibitor drugs targeting specific kinase molecules have already been developed and widely used in the field of Clinical Hematology. The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Local BM RAS is important in hematopoietic stem cell biology and microenvironment. There are interactions among the local BM RAS and PK. For example, ACE2-ang(1-7)-Mas axis inhibits p38 MAPK/NF-КB signaling pathway. The Local BM RAS may have a role in the effect on PK in this biological spectrum. The aim of this review is to outline the functions of PKs in the pathobiology of hematologic neoplastic disorders.
Topics: Hematopoietic Stem Cells; Janus Kinases; Phosphorylation; Renin-Angiotensin System; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 33539024
DOI: 10.1007/978-3-030-49844-3_15