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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 -
Expert Review of Clinical Immunology Mar 2022
Topics: Antirheumatic Agents; Humans; Janus Kinase Inhibitors; Janus Kinases
PubMed: 35254191
DOI: 10.1080/1744666X.2022.2050596 -
Journal of Immunology (Baltimore, Md. :... Apr 2020The discovery of JAKs and STATs and their roles in cytokine and IFN action represented a significant basic advance and a new paradigm in cell signaling. This was quickly... (Review)
Review
The discovery of JAKs and STATs and their roles in cytokine and IFN action represented a significant basic advance and a new paradigm in cell signaling. This was quickly followed by discoveries pointing to their essential functions, including identification of mutations as a cause of SCID. This and other findings predicted the use of therapeutically targeting JAKs as a new strategy for treating immune and inflammatory diseases. This now is a reality with seven approved jakinibs being used to treat multiple forms of arthritis, inflammatory bowel disease and myeloproliferative neoplasms, and numerous ongoing clinical trials in other settings. This story provides interesting insights into the process of translating basic discoveries and also reveals the need to return to basic work to fill gaps that now become apparent.
Topics: Animals; Humans; Inflammation; Janus Kinases; Protein Kinase Inhibitors
PubMed: 32253269
DOI: 10.4049/jimmunol.1901477 -
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 -
Clinical and Experimental Dermatology Sep 2023Janus kinase (JAK) refers to a family of tyrosine kinases that are involved in the production of proinflammatory mediators in response to various extracellular signals.... (Review)
Review
Janus kinase (JAK) refers to a family of tyrosine kinases that are involved in the production of proinflammatory mediators in response to various extracellular signals. The JAK-signal transducer and activator of transcription (STAT) pathway is an appealing target in many inflammatory illnesses as this pathway modulates immune cell activation and T-cell-mediated inflammation in response to several cytokines. The practical considerations of prescription for topical and oral JAK inhibitors (JAKis) in atopic dermatitis, vitiligo and psoriasis have been covered in prior publications. Currently, the US Food and Drug Administration has approved the topical JAKi ruxolitinib for atopic dermatitis and nonsegmental vitiligo. None of the remaining first- or second-generation topical JAKis have been approved for topical application in any dermatological indications so far. For this review, the PubMed database was searched using 'topical' and 'JAK inhibitor' or 'Janus kinase inhibitor' or the names of individual drug molecules as the keyword in the title with no date limits. The description of topical JAKi usage in dermatology from the literature was evaluated in each abstract. The current review concentrates on emphasizing the rising use of topical JAKis in both approved and off-label dermatological applications for both old and novel conditions.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Vitiligo; Psoriasis; Janus Kinases
PubMed: 37235767
DOI: 10.1093/ced/llad188 -
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 -
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