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Haematologica Feb 2024
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Nitriles; Janus Kinase 2; Benzamides; Pyrazoles
PubMed: 37259556
DOI: 10.3324/haematol.2023.283106 -
International Journal of Clinical... Aug 2023Topical Janus kinase (JAK) inhibitors are being developed for the treatment of mild to moderate atopic dermatitis. However, comparative evidence on their safety profiles... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Topical Janus kinase (JAK) inhibitors are being developed for the treatment of mild to moderate atopic dermatitis. However, comparative evidence on their safety profiles is still limited.
AIM
This study aimed to compare the relative safety of topic JAK inhibitors in patients with atopic dermatitis.
METHOD
Phase 2 and 3 clinical trials (RCTs) evaluating the efficacy and safety of topical JAK inhibitors in atopic dermatitis were searched on Medline, EMBASE and clinicaltrials.gov. The following outcomes were considered: any adverse event (AE), serious AEs, AEs leading to treatment discontinuation, any infection, any application site reaction.
RESULTS
Ten RCTs were included in this network meta-analysis. Tofacitinib was associated with a reduced risk of any AE when compared with ruxolitinib (OR 0.18, 95% CrI 0.03-0.92). The analyses for the remaining outcomes did not identify other statistically significant risk differences between the topical JAK inhibitors.
CONCLUSION
Although tofacitinib seems to present a reduced risk of any adverse event compared with ruxolitinib, this was the only statistically significant result found between JAK inhibitors. Therefore, such findings should be interpreted with caution considering the scarce data available and the heterogeneity between the studies, and there is no robust evidence allowing pointing out clinically important differences between the safety profiles of the existing topical JAK inhibitors. Further pharmacovigilance activities are needed to confirm the safety profile of these drugs.
Topics: Humans; Dermatitis, Atopic; Janus Kinase Inhibitors; Network Meta-Analysis; Pyrazoles; Treatment Outcome
PubMed: 37074513
DOI: 10.1007/s11096-023-01569-x -
EBioMedicine Nov 2023JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders.... (Review)
Review
JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.
Topics: Humans; Janus Kinase Inhibitors; TYK2 Kinase; Autoimmune Diseases; Cytokines; Psoriasis; Janus Kinase 1
PubMed: 37863021
DOI: 10.1016/j.ebiom.2023.104840 -
Cell Reports May 2024Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and...
Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRAS-induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant downstream target of JAK1 signaling, which is upregulated in human PDAC. Reinstating the expression of C/EBPδ was sufficient to restore the growth of JAK1-deficient cancer cells as tumorspheres and in xenografted mice. Collectively, the findings of this study suggest that JAK1 executes important functions of inflammatory cytokines through C/EBPδ and may serve as a molecular target for PDAC prevention and treatment.
Topics: Animals; Janus Kinase 1; Pancreatic Neoplasms; Humans; Mice; Carcinoma, Pancreatic Ductal; STAT3 Transcription Factor; CCAAT-Enhancer-Binding Protein-delta; Disease Progression; Signal Transduction; Cell Line, Tumor; Mice, Knockout
PubMed: 38733583
DOI: 10.1016/j.celrep.2024.114202 -
Cell Death & Disease Nov 2023The role of METTL3-mediated N6-methyladenosine (mA) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal...
The role of METTL3-mediated N6-methyladenosine (mA) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal cancer exerted both methyltransferase activity-dependent and -independent functions in gene regulation. METTL3 deposited mA on the 3' untranslated region of the JAK1 transcript to promote JAK1 translation relying on YTHDF1 recognition. Besides, METTL3 was redistributed to the STAT3 promoter and worked in concert with NF-κB to facilitate STAT3 transcription, which was achieved independently on METTL3 methyltransferase activity. The increased JAK1 and STAT3 corporately contributed to the activation of the p-STAT3 signaling pathway and further upregulated downstream effectors expressions, including VEGFA and CCND1, which finally resulted in enhanced cancer cell proliferation and metastasis in vitro and in vivo. Collectively, our study revealed the unappreciated dual role of METTL3 as an mA writer and a transcription regulator, which worked together in the same signaling pathway to drive colorectal cancer malignancy.
Topics: Humans; Methyltransferases; Signal Transduction; Colorectal Neoplasms; Janus Kinase 1; STAT3 Transcription Factor
PubMed: 38001065
DOI: 10.1038/s41419-023-06287-w -
Aging and Disease Feb 2024Chronic pain is a notable health concern because of its prevalence, persistence, and associated mental stress. Drugs targeting chronic pain with potent abirritation, and... (Review)
Review
Chronic pain is a notable health concern because of its prevalence, persistence, and associated mental stress. Drugs targeting chronic pain with potent abirritation, and minimal side effects remain unidentified. Substantial evidence indicates that the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a distinct and critical role in different stages of chronic pain. Aberrant activation of the JAK2/STAT3 signaling pathway is evident in multiple chronic pain models. Moreover, an increasing number of studies have demonstrated that the downregulation of JAK2/STAT3 can attenuate chronic pain in different animal models. In this review, we investigated the mechanism and role of the JAK2/STAT3 signaling pathway in modulating chronic pain. The aberrant activation of JAK2/STAT3 can trigger chronic pain by interacting with microglia and astrocytes, releasing proinflammatory cytokines, inhibiting anti-inflammatory cytokines, and regulating synaptic plasticity. We also retrospectively reviewed current reports on JAK2/STAT3 pharmacological inhibitors that demonstrated their significant therapeutic potential in different types of chronic pain. In summary, our results provide strong evidence that the JAK2/STAT3 signaling pathway is a promising therapeutic target for chronic pain.
Topics: Animals; Janus Kinase 2; Chronic Pain; STAT3 Transcription Factor; Retrospective Studies; Signal Transduction; Cytokines
PubMed: 37307838
DOI: 10.14336/AD.2023.0515 -
Immunological Medicine Sep 2023Recent studies have demonstrated that Janus kinase (JAK) plays a crucial role in signal transduction by directly affecting various cytokine receptors involved in... (Review)
Review
Recent studies have demonstrated that Janus kinase (JAK) plays a crucial role in signal transduction by directly affecting various cytokine receptors involved in inflammatory diseases such as atopic dermatitis (AD). Large-scale clinical trials on AD utilizing JAK inhibitors and biologic reagents, such as dupilumab, which targets the IL-4Rα receptor subunit of the Th2 cytokines IL-4 and IL-13, have yielded highly favorable results in comparison to traditional therapies. This indicates that therapeutic strategies based on molecular biology are efficacious in clinical settings. However, in September 2021, the U.S. Food and Drug Administration (FDA) indicated that tofacitinib, a JAK inhibitor, may carry various risks, including severe heart disease. Similar concerns have been raised for other JAK inhibitors, and further safety evaluations are underway. Thus, human biology involving JAKs appeared more complicated than we expected. In this article, we provide an overview of the molecular mechanisms of AD and examine the molecular targeting drugs for AD from the perspective of JAK-related biology.
Topics: United States; Humans; Janus Kinases; Dermatitis, Atopic; Janus Kinase Inhibitors; Cytokines; Interleukin-13
PubMed: 37254967
DOI: 10.1080/25785826.2023.2214324 -
JAAD International Dec 2023
Comparison between dupilumab and oral Janus kinase inhibitors in the treatment of prurigo nodularis with or without atopic dermatitis in a tertiary care center in Singapore.
PubMed: 37575516
DOI: 10.1016/j.jdin.2023.06.005 -
Frontiers in Immunology 2024Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with... (Review)
Review
Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Psoriasis; Biological Products; Janus Kinases
PubMed: 38444845
DOI: 10.3389/fimmu.2024.1341632 -
Journal of Cellular and Molecular... Oct 2023Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic...
Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic targets are required. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) contributes to tumourigenesis and immune evasion in several cancers; however, its biological function in BC remains unknown. This study aimed to investigate the expression, prognostic value and protumoural function of MTHFD2 in BC and elucidate the mechanism of programmed death-ligand 1 (PD-L1) upregulation by MTHFD2. An analysis using publicly available databases revealed that a high MTHFD2 expression was correlated with clinical features and a poor prognosis in BC. Furthermore, MTHFD2 promoted the growth, migration, invasion and tumourigenicity and decreased the apoptosis of BC cells in vivo and in vitro. The results obtained from databases showed that MTHFD2 expression was correlated with immune infiltration levels, PD-L1 expression, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The expression of MTHFD2, PD-L1 and JAK/STAT signalling pathway-related proteins increased after interferon gamma treatment and decreased after MTHFD2 knockdown. Moreover, addition of a JAK/STAT pathway activator partially reduced the effect of MTHFD2 knockdown on BC cells. Collectively, our findings suggest that MTHFD2 promotes the expression of PD-L1 through the JAK/STAT signalling pathway in BC.
Topics: Humans; B7-H1 Antigen; Signal Transduction; Janus Kinases; STAT Transcription Factors; Urinary Bladder Neoplasms
PubMed: 37480214
DOI: 10.1111/jcmm.17863