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Expert Review of Gastroenterology &... Sep 2020Janus kinases inhibitors (JAKi) are new small molecules recently introduced in the armamentarium of treatments for Inflammatory Bowel Disease (IBD). Janus Kinases (JAK)... (Review)
Review
INTRODUCTION
Janus kinases inhibitors (JAKi) are new small molecules recently introduced in the armamentarium of treatments for Inflammatory Bowel Disease (IBD). Janus Kinases (JAK) are tyrosine kinases that act by linkage with different intracellular receptors, regulating cytokines gene transcription implicated in the inflammatory burden seen in IBD patients.
AREAS COVERED
A comprehensive literature search was performed to retrieve studies on JAKi and IBD to discuss the latest developments and how the selectivity of these drugs is changing the natural course of IBD.
EXPERT OPINION
Available data on efficacy and safety of JAKi in IBD are highly encouraging and because of their selectivity, these drugs might become among the foremost options in the treatment algorithm.
Topics: Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinase Inhibitors; Naphthyridines; Nitriles; Piperidines; Pyridines; Pyrimidines; Signal Transduction; TYK2 Kinase; Triazoles
PubMed: 32520647
DOI: 10.1080/17474124.2020.1780120 -
Frontiers in Immunology 2024Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). For many years,... (Review)
Review
Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). For many years, corticosteroids have been the mainstay treatment for GVHD, but cases of steroid-refractory GVHD and the severe adverse effects of high-dose corticosteroids have increased the need for preventative and therapeutic strategies for GVHD. Due to the nature of alloreactive T cells, GVHD is inherently linked to the graft-versus-leukemia (GVL) effect, the therapeutic driving force behind stem cell transplantation. A considerable clinical challenge is to preserve GVL while suppressing GVHD. The field of GVHD research has greatly expanded over the past decades, including advancements in T cell modulation and depletion, antibody therapies, chemotherapeutics, cellular therapies, and Janus kinase inhibition. In this review, we discuss current approaches and advances in the prophylaxis and treatment of GVHD with a focus on new emerging advancements in Janus kinase inhibitor therapy.
Topics: Humans; Janus Kinases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Adrenal Cortex Hormones; Transplantation, Homologous
PubMed: 38380328
DOI: 10.3389/fimmu.2024.1304065 -
Inflammopharmacology Oct 2023Curcumin (diferuloylmethane) is a herbal remedy which possesses numerous biological attributes including anti-inflammatory, anti-oxidant and anti-cancer properties.... (Review)
Review
Curcumin (diferuloylmethane) is a herbal remedy which possesses numerous biological attributes including anti-inflammatory, anti-oxidant and anti-cancer properties. Curcumin has been shown to impact a number of signaling pathways including nuclear factor kappa B (NF-KB), reactive oxygen species (ROS), Wingless/Integrated (Wnt), Janus kinase-signal transducer and activator of mitogen-activated protein kinase (MAPK) and transcription (JAK/STAT). P38 belongs to the MAPKs, is known as a stress-activated MAPK and is involved in diverse biological responses. P38 is activated in various signaling cascades. P38 plays a role in inflammation, cell differentiation, proliferation, motility and survival. This cascade can serve as a therapeutic target in many disorders. Extensive evidence confirms that curcumin impacts the P38 MAPK signaling pathway, through which it exerts anti-inflammatory, neuroprotective, and apoptotic effects. Hence, curcumin can positively affect inflammatory disorders and cancers, as well as to increase glucose uptake in cells. This review discusses the pharmacological and therapeutic effects of curcumin as effected through p38 MAPK.
Topics: Curcumin; p38 Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Signal Transduction; NF-kappa B; Janus Kinases; MAP Kinase Signaling System
PubMed: 37498375
DOI: 10.1007/s10787-023-01265-2 -
Expert Opinion on Investigational Drugs May 2023Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting about one-third of subjects with psoriasis. Several treatment modalities targeting Janus Kinase... (Review)
Review
INTRODUCTION
Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting about one-third of subjects with psoriasis. Several treatment modalities targeting Janus Kinase pathways and intracellular inflammatory cascade are now available and under clinical investigation to treat this disease.
AREAS COVERED
This review describes ongoing and recently completed phase 2 and 3 randomized clinical trials (RCTs) evaluating the efficacy and safety of approved JAK (Tofacitinib and Upadacitinib) and investigational JAK inhibitors (JAK1 inhibitors: Filgotinib and Ivarmacitinib (SHR0302); TYK2 inhibitors: Brepocitinib (PF-06700841) Deucravacitinib (BMS-986165), and NDI-034858) in PsA through February 2023.
EXPERT OPINION
Current standard of care has significantly improved the quality of life in PsA. Recently approved JAK inhibitors for PsA have addressed many of the unmet needs of PsA, particularly of those with severe phenotypes. Preliminary results from several RCTs have reported good and fast efficacy and an acceptable safety profile of investigational JAK inhibitors in PsA. Additional clinical trials and long-term outcome data on these agents are necessary for increasing available therapeutic options for PsA.
Topics: Humans; Arthritis, Psoriatic; Janus Kinase Inhibitors; Psoriasis; Janus Kinases; Antirheumatic Agents
PubMed: 37096862
DOI: 10.1080/13543784.2023.2207737 -
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 -
International Immunopharmacology Aug 2023Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which can regulate the signaling of multiple pro-inflammatory cytokines, including IL12, IL23 and... (Review)
Review
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which can regulate the signaling of multiple pro-inflammatory cytokines, including IL12, IL23 and type I interferon (IFNα/β), and its inhibitors can treat autoimmune diseases caused by the abnormal expression of IL12 and IL23. Interest in TYK2 JH2 inhibitors has increased as a result of safety concerns with JAK inhibitors. This overview introduces TYK2 JH2 inhibitors that are already on the market, including Deucravactinib (BMS-986165), as well as those currently in clinical trials, such as BMS-986202, NDI-034858, and ESK-001.
Topics: TYK2 Kinase; Janus Kinases; Janus Kinase Inhibitors; Signal Transduction; Interleukin-12
PubMed: 37315371
DOI: 10.1016/j.intimp.2023.110434 -
Cells Jan 2022Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this... (Review)
Review
Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the disease, perturbations in platelets, endothelial cells, and the coagulation system are key in triggering systemic coagulopathy, involving both the macro- and microvasculatures of different organs. Of the several mechanisms that might contribute to dysregulation of these cells following SARS-CoV-2 infection, the current review focuses on the role of activated Janus kinase (JAK) signaling in augmenting thrombotic processes and organ dysfunction. The review concludes with presenting the current understanding and emerging controversies concerning the potential therapeutic applications of JAK inhibitors for ameliorating the inflammation-thrombosis phenotype in COVID-19 patients.
Topics: COVID-19; Cytokine Release Syndrome; Endothelial Cells; Humans; Janus Kinases; SARS-CoV-2; Signal Transduction; Thrombosis
PubMed: 35053424
DOI: 10.3390/cells11020306 -
Clinical Reviews in Allergy & Immunology Dec 2020The dysregulation of the JAK-STAT pathway is associated with various immune disorders. Four JAK inhibitors have been approved for rheumatoid arthritis (RA), and numerous... (Review)
Review
The dysregulation of the JAK-STAT pathway is associated with various immune disorders. Four JAK inhibitors have been approved for rheumatoid arthritis (RA), and numerous JAK inhibitors are currently being tested in phase II and III trials for the treatment of various autoimmune inflammatory diseases. In this narrative review, we elucidate the involvement of the JAK-STAT signaling pathway in the pathogenesis of connective tissue diseases (CTDs). We also discuss the efficacy of the first- and second-generation JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib, filgotinib, upadacitinib, solcitinib, itacitinib, decernotinib, R333, and pf-06651600) for CTDs including RA, systemic lupus erythematosus, dermatomyositis, systemic sclerosis, Sjögren's syndrome, and vasculitis, based on laboratory and clinical research findings. JAK inhibitors have great potential for the treatment of various CTDs by reducing multiple cytokine production and suppressing inflammation, with the advantages of rapid onset in an oral formulation and decreased corticosteroid dependence and the associated adverse events, especially in refractory cases. We also highlight the safety of novel JAK inhibitors, which can cause opportunistic infections, especially viral infections. Being a very recent therapeutic option, information regarding the safety of JAK inhibitors during pregnancy and for pediatric use is limited. However, it is recommended that JAK inhibitors should be avoided in pregnant and breastfeeding women. More clinical data, especially on highly selective inhibitors, are required to judge the efficacy and safety of JAK inhibition in CTDs.
Topics: Animals; Biomarkers; Clinical Trials as Topic; Connective Tissue Diseases; Diagnosis, Differential; Disease Management; Disease Susceptibility; Drug Development; Humans; Janus Kinase Inhibitors; Janus Kinases; STAT Transcription Factors; Signal Transduction; Treatment Outcome
PubMed: 32222877
DOI: 10.1007/s12016-020-08786-6 -
Journal of Cellular Physiology Sep 2020Many cytokines are crucial drivers of cancers and autoimmune conditions. These proteins bind to receptors and signal their responses through Janus kinase (JAK) and... (Review)
Review
Many cytokines are crucial drivers of cancers and autoimmune conditions. These proteins bind to receptors and signal their responses through Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Genetic variations in the JAK-STAT pathway are correlated with the increased risk of cancers, autoimmunity as well as inflammatory diseases. Targeting JAKs and STATs can be a safe and efficacious strategy for treating these diseases. Tofacitinib, as the first JAK inhibitor, is approved for rheumatoid arthritis therapy. Also, many other JAK inhibitors have been proven or are in various phases of clinical trials for various diseases. At present, small-molecule JAK inhibitors are considered as a novel category of drugs in the treatment of cancer and immune-mediated diseases.
Topics: Autoimmune Diseases; Humans; Janus Kinase Inhibitors; Janus Kinases; Neoplasms; Protein Kinase Inhibitors; STAT Transcription Factors; Signal Transduction
PubMed: 32072644
DOI: 10.1002/jcp.29593 -
Annales de Dermatologie Et de... Dec 2022Alopecia areata is an acquired, chronic, non-scarring hair disorder of the skin affecting 0.5-2% of the general population worldwide. Multiple mechanisms are involved in... (Review)
Review
Alopecia areata is an acquired, chronic, non-scarring hair disorder of the skin affecting 0.5-2% of the general population worldwide. Multiple mechanisms are involved in the disease, namely genetic predisposition, environmental triggers, impaired hair growth, and altered inflammatory and immune responses. Recent progress in the understanding of immune pathophysiological mechanisms has opened interesting perspectives for innovative treatment strategies. Several strategies have been tested, with debated results. However, proof of concept in humans of targeting of the Interferon (IFN)γ/Th1 pathway and of the Janus Kinase (JAK) signaling pathway has led to the development of several topical and oral JAK inhibitors in this disease with high unmet needs. Our review covers novel immune mechanisms of the disease and promising therapeutic approaches already tested in clinical trials and/or under development.
Topics: Humans; Alopecia Areata; Alopecia; Janus Kinase Inhibitors; Janus Kinases; Hair
PubMed: 35752494
DOI: 10.1016/j.annder.2022.03.006