JAK inhibitor

PURPOSE OF REVIEW: Topical therapies are a mainstay of treatment for mild psoriasis and may be a useful adjunct in treatment of moderate-to-severe psoriasis. This review summarizes recent advances in topical therapies for psoriasis and currently available treatments. RECENT FINDINGS: Topical aryl hydrocarbon receptor modulators (tapinarof) and topical phosphodiesterase-4 inhibitors (roflumilast) have been proven effective in randomized controlled trials for psoriasis...

Transcription control is a major determinant of cell fate decisions in somatic tissues. By contrast, early germline fate specification in numerous vertebrate and invertebrate species relies extensively on RNA-level regulation, exerted on asymmetrically inherited maternal supplies, with little-to-no zygotic transcription. However delayed, a maternal-to-zygotic transition is nevertheless poised to complete the deployment of pre-gametic programs in the germline. Here, we focus on early germline specification in the tunicate Ciona to study zygotic genome activation...

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib...

Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR-146a, a negative regulator of the NF-κB pathway, in the pathogenesis of MF; here we used miR-146a-/- (KO) mice, a MF-like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF-κB pathways may reverse the myelofibrotic phenotype of these mice...

Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by elevated platelet counts and fibrous tissues in the bone marrow. The JAK1/2 inhibitor (JAKi), ruxolitinib, has demonstrated efficacy in reducing splenic size, alleviating myelofibrosis-related symptoms, and improving overall survival. While an increased risk of lymphoproliferative disease (LPD) is suggested in patients with PMF, particularly those treated with JAKi, the involvement of Epstein-Barr virus (EBV) in such cases remains poorly documented...

Microglia, the resident immune cells of the brain, regulate neuroinflammation which can lead to secondary neuronal damage and cognitive impairment under pathological conditions. Two of the many molecules that can elicit an inflammatory response from microglia are lipopolysaccharide (LPS), a component of gram-negative bacteria, and interferon gamma (IFNγ), an endogenous pro-inflammatory cytokine. We thoroughly examined the concentration-dependent relationship between LPS from multiple bacterial species and IFNγ in cultured microglia and macrophages...

BACKGROUND: Vitiligo is a disease that affects people of all skin shades and can impact their quality of life. Reliable evidence on the effectiveness and adverse events associated with the recent use of Janus kinase (JAK) inhibitors to treat vitiligo is needed. This protocol for a systematic review and meta-analysis seeks to collect evidence from both randomized controlled trials (RCTs) and observational studies to determine the effectiveness and patient-centered outcomes concerning treatment with JAK inhibitors...

Somatic mutants of calreticulin (CRT) drive myeloproliferative neoplasms (MPNs) via binding to the thrombopoietin receptor (MPL) and aberrant activation of the JAK/STAT pathway. Compared with healthy donors, platelets from MPN patients with CRT mutations display low cell surface MPL. Additionally, co-expression of MPL with an MPN-linked CRT mutant (CRTDel52) reduces cell surface MPL, suggesting that CRTDel52 may induce MPL degradation. We show that lysosomal degradation is relevant to the turnover of CRTDel52 and MPL...

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth...

Coronavirus disease 2019 (COVID-19) induces respiratory dysfunction as well as kidney injury. Although the kidney is considered a target organ of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and affected by COVID-19-induced cytokine storm, the mechanisms of renal reaction in SARS-CoV-2 infection are unknown. In this study, a murine COVID-19 model was induced by nasal infection with mouse-adapted SARS-CoV-2 (MA10). MA10 infection induced body weight loss along with lung inflammation in mice four days after infection...

Indoleamine 2,3-dioxygenase 1 (IDO1), which catabolizes tryptophan, is a potential target to unlock the immunosuppressive tumor microenvironment. Correlations between IDO1 and immune checkpoint inhibitor (ICI) efficacy remain unclear. Herein, we investigated IDO1 transcript expression across cancers and clinical outcome correlations. High IDO1 transcripts were more frequent in uterine (54.2%) and ovarian cancer (37.2%) but varied between and within malignancies. High IDO1 RNA expression was associated with high expression of PD-L1 (immune checkpoint ligand), CXCL10 (an effector T cell recruitment chemokine), and STAT1 (a component of the JAK-STAT pathway) (all multivariable p  < 0...

BACKGROUND: Granuloma formation is an uncommon and persistent skin inflammatory condition caused by the injection of dermal fillers. The exact cause of this reaction is not well understood, but it may be associated with irritating components or abnormal immune function. Treating granulomas can be difficult. However, recent research has shown that Janus kinase (JAK) inhibitors hold promise as a potential therapy for refractory granulomatous diseases. OBJECTIVES: The aim was to evaluate the efficacy and safety of tofacitinib as a treatment for granulomas secondary to filler injection and the possible mechanisms were discussed and summarized...

PURPOSE OF REVIEW: Historically, systemic treatments for atopic dermatitis (AD) primarily consisted of immunosuppressive agents such as corticosteroids and Disease Modifying Antirheumatic Drugs (DMARDS), which provided symptomatic relief but often had long-term adverse effects. Newer treatments have shown significant efficacy with less side effects in clinical trials. This review discusses and compares conventional and newer systemic treatments for AD. RECENT FINDINGS: Newer medications for AD including dupilumab, tralokinumab, lebrikizumab, and oral JAK inhibitors have been shown to be safe and efficacious...

Erosive oral lichen planus (OLP) is a challenging disease. This T cell driven disorder frequently shows a treatment unresponsive course and strongly limits patients' quality of life. The disease lacks FDA or EMA approved drugs for its treatment and the efficacy of the commonly administered treatments (i.e. topical and systemic steroids, steroid sparing agents) is often only partial. Although the etiopathogenesis of the disease still needs to be fully elucidated, recent advances helped to identify interferon-ɣ (IFN-ɣ) as a pivotal cytokine in OLP pathogenesis, thus making the interference with its signalling a therapeutic target...

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B)...

Topical ruxolitinib 1.5% cream (Opzelura® ), a Janus kinase (JAK) inhibitor, is the first treatment to be approved in several countries for use in patients aged ≥ 12 years with non-segmental vitiligo. In the identical phase III TRuE-V1 and TRuE-V2 trials, significantly more ruxolitinib cream recipients were able to achieve statistically significant and clinically meaningful facial and total body repigmentation, as well as reductions in vitiligo noticeability, compared with vehicle recipients...

INTRODUCTION: Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation. AREAS COVERED: This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia...

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by a positive feedback loop between cytokine storm and macrophages and lymphocytes overactivation, which could serve as a valid therapeutic target for HLH treatment. In this study, the clinically extensively used JAK1/2 inhibitor ruxolitinib was encapsulated into macrophage membrane-coated nanoparticles (M@NP-R) with high drug-loading efficiency for targeted HLH treatment. In vitro and in vivo studies demonstrated that M@NP-R not only efficiently adsorbed extracellular proinflammation cytokines, like IFN-γ and IL-6 to alleviate the cytokine storm, but also effectively dampened macrophage activation and proliferation by intracellular JAK/STAT signaling pathway inhibition...

CONTEXT: SHP2 is a non-receptor protein tyrosine phosphatase to remove tyrosine phosphorylation. Functionally, SHP2 is an essential bridge to connect numerous oncogenic cell-signaling cascades including RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1 pathways. This study aims to discover novel and potent SHP2 inhibitors using a hierarchical structure-based virtual screening strategy that combines molecular docking and the fragment molecular orbital method (FMO) for calculating binding affinity (referred to as the Dock-FMO protocol)...

Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous lipids that act as agonists of the peroxisome proliferator-activated receptor α (PPARα). Recently, an interest in the role of these lipids in malignant tumors has emerged. Nevertheless, the effects of OEA and PEA on human neuroblastoma cells are still not documented. Type I interferons (IFNs) are immunomodulatory cytokines endowed with antiviral and anti-proliferative actions and are used in the treatment of various pathologies such as different cancer forms (i...