-
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 -
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 -
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 -
Translational Neurodegeneration Oct 2023Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Janus Kinase Inhibitors; Neurodegenerative Diseases; Central Nervous System; Janus Kinases
PubMed: 37828541
DOI: 10.1186/s40035-023-00380-y -
Indian Journal of Dermatology,... 2023The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has been identified as a key player in the pathophysiology of alopecia areata... (Review)
Review
The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has been identified as a key player in the pathophysiology of alopecia areata and a potential target for therapy. Here, we give a narrative review of what is known about Janus kinase inhibitors in alopecia areata. Several clinical trials as well as smaller studies have demonstrated hair regrowth and remission with oral Janus kinase inhibitors therapy, even in patients who failed conventional treatment. Baricitinib is the only US FDA-approved treatment for alopecia areata but data for other oral Janus kinase inhibitors such as tofacitinib, ruxolitinib and ritlecitinib are also promising. Fewer clinical trials have investigated topical Janus kinase inhibitors for alopecia areata, with many of them terminated early due to unfavourable results. Overall, Janus kinase inhibitors are an efficacious addition to the therapeutic arsenal for treatment-refractory alopecia areata. Further work is needed to examine the effects of long-term usage of Janus kinase inhibitors, the efficacy of topical Janus kinase inhibitors, as well as to identify biomarkers that could predict differential therapeutic responses to the various Janus kinase inhibitors.
Topics: Humans; Alopecia Areata; Janus Kinase Inhibitors; Alopecia; Hair; Janus Kinases
PubMed: 37436019
DOI: 10.25259/IJDVL_1093_2022 -
Skin Therapy Letter May 2023As systemic administration of Janus kinase-inhibitors is associated with safety concerns, local alternatives, such as topical ruxolitinib, have been developed. This... (Review)
Review
As systemic administration of Janus kinase-inhibitors is associated with safety concerns, local alternatives, such as topical ruxolitinib, have been developed. This review summarizes utilization of topical ruxolitinib in dermatology. A literature search was performed of studies reporting topical use of ruxolitinib in dermatologic conditions. Twenty-four articles were included, representing 2618 patients. Results show improvement with topical ruxolitinib formulations in atopic dermatitis, vitiligo, psoriasis, and lichen planus. Results are conflicting in alopecia areata. Minimal bioavailability and low rates of mild-to-moderate treatment-related adverse events support a favorable safety profile and higher tolerability of topical ruxolitinib compared to oral Janus kinase-inhibitors.
Topics: Humans; Dermatology; Psoriasis; Janus Kinase Inhibitors; Vitiligo; Janus Kinases
PubMed: 37339609
DOI: No ID Found -
Molecules (Basel, Switzerland) Dec 2023Janus kinase inhibitors, also known as JAK inhibitors, JAKinibs or JAKi, are a new group of disease-modifying drugs. They work by inhibiting enzymes involved in the... (Review)
Review
Janus kinase inhibitors, also known as JAK inhibitors, JAKinibs or JAKi, are a new group of disease-modifying drugs. They work by inhibiting enzymes involved in the transmission of information from receptors located in the cell membrane to the cell interior, specifically to the cell nucleus, thus disrupting the JAK-STAT pathway. This pathway plays a role in key cellular processes such as the immune response and cell growth. This feature is used in the treatment of patients with rheumatological, gastroenterological and hematological diseases. Recently, it has been discovered that JAK-STAT pathway inhibitors also show therapeutic potential against dermatological diseases such as atopic dermatitis, psoriasis, alopecia areata and acquired vitiligo. Studies are underway to use them in the treatment of several other dermatoses. Janus kinase inhibitors represent a promising class of drugs for the treatment of skin diseases refractory to conventional therapy. The purpose of this review is to summarize the latest knowledge on the use of JAKi in dermatological treatment.
Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; Signal Transduction; STAT Transcription Factors; Vitiligo
PubMed: 38138551
DOI: 10.3390/molecules28248064 -
Current Neuropharmacology 2023Epilepsy is defined as spontaneous recurrent seizures in the brain. There is increasing evidence that inflammatory mediators and immune cells are involved in epileptic... (Review)
Review
Epilepsy is defined as spontaneous recurrent seizures in the brain. There is increasing evidence that inflammatory mediators and immune cells are involved in epileptic seizures. As more research is done on inflammatory factors and immune cells in epilepsy, new targets for the treatment of epilepsy will be revealed. The Janus kinase-signal transducer and transcriptional activator (JAKSTAT) signaling pathway is strongly associated with many immune and inflammatory diseases, At present, more and more studies have found that the JAK-STAT pathway is involved in the development and development of epilepsy, indicating the JAK-STAT pathway's potential promise as a target in epilepsy treatment. In this review, we discuss the composition, activation, and regulation of the JAK-STAT pathway and the relationship between the JAK-STAT pathway and epilepsy. In addition, we summarize the common clinical inhibitors of JAK and STAT that we would expect to be used in epilepsy treatment in the future.
Topics: Humans; Signal Transduction; STAT Transcription Factors; Janus Kinases; Epilepsy; Brain
PubMed: 36518035
DOI: 10.2174/1570159X21666221214170234 -
Antiviral Research Sep 2023Hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of...
Hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication. To this end, we evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E. Further, experiments with HEV (Kernow-C1 p6) were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. Upregulation of interferon-stimulated genes (ISG) was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. The obtained results suggest that therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, JAKi treatment and the occurrence of elevated liver enzymes requires a monitoring of potential HEV infections.
Topics: Humans; Hepatitis E; Hepatitis E virus; Janus Kinases; Interferons; Antiviral Agents; Virus Replication
PubMed: 37517633
DOI: 10.1016/j.antiviral.2023.105690 -
Indian Journal of Dermatology,... 2023For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect,... (Review)
Review
For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect, cytokines/chemokines are well-known inflammatory agents which play a critical role in signalling pathways by activating the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signalling proteins (Janus kinase-signal transducers and activators of transcription) which are a group of intracellular kinase molecules. Cytokines are a category of small proteins (∼5-25 kDa) that play a major role in cell signalling and are major drivers of an autoimmune response. Here we will discuss the role of Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative cascades of autoimmune disease and about the recent progress in the development of oral synthetic Janus kinase inhibitors (JAKi) and their therapeutic efficacies in dermatologic and systemic autoimmune diseases. Therapeutic efficacy of Janus kinase inhibitors is now well established in the treatment of array of autoimmune and inflammatory disease: spondylarthritis with a special focus on psoriatic arthritis (PsA) and its dermatologic manifestations (psoriasis) and ankylosing spondylitis (AS), atopic dermatitis (AD), alopecia areata (AA), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In addition to the first-generation Janus kinase inhibitors several new-generation Janus kinase inhibitors are currently being evaluated. It is expected that these Janus kinase inhibitors likely have higher potency and less adverse effects as compared to their predecessors. Here we have discussed: (1) the functional significance of the Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative processes of autoimmune diseases and its cellular/molecular mechanisms and (2) progress in the development of oral synthetic Janus kinase inhibitors and their therapeutic efficacies in several systemic and cutaneous autoimmune diseases.
Topics: Humans; Janus Kinase Inhibitors; Arthritis, Psoriatic; Janus Kinases; Autoimmune Diseases; Cytokines
PubMed: 37609730
DOI: 10.25259/IJDVL_1152_2022