Atopic dermatitis is a chronic inflammatory dermatosis characterized by pruritic, scaly, erythematous lesions. Its incidence varies but is estimated to be approximately 20% in children and between 7 and 14% in adults, with variation amongst countries. It is a multifactorial condition, with a complex interplay between genetic, immunological, and environmental factors. Research into the inflammatory response has identified new therapeutic targets that work to reduce inflammation and subsequently reduce flares. This study explores existing therapeutic agents for atopic dermatitis as well as newer therapies such as biologics and small molecules, drawing upon each agent\'s mechanism of action, relevant landmark clinical trials, efficacy, and safety profile. Current therapies include emollients, corticosteroids, cyclosporine A, calcineurin inhibitors, phototherapy, and methotrexate. Biologics described include dupilumab, tralokinumab, lebrikizumab, nemolizumab, and rocatinlimab. Small molecules inhibitors include Janus kinase inhibitors, phosphodiesterase 4 inhibitors, transient receptor potential vanilloid subfamily V member 1 antagonist, and aryl hydrocarbon receptor antagonist.

Interferon-gamma (IFN-γ) plays a dual role in cancer; it is both a pro- and an antitumorigenic cytokine, depending on the type of cancer. The deregulation of the IFN-γ canonic pathway is associated with several disorders, including vulnerability to viral infections, inflammation, and cancer progression. In particular, the interplay between lung adenocarcinoma (LUAD) and viral infections appears to exist in association with the deregulation of IFN-γ signaling. In this mini-review, we investigated the status of the IFN-γ signaling pathway and the expression level of its components in LUAD. Interestingly, a reduction in IFNGR1 expression seems to be associated with LUAD progression, affecting defenses against viruses such as severe acute respiratory syndrome coronavirus 2. In addition, alterations in the expression of IFNGR1 may inhibit the antiproliferative action of IFN-γ signaling in LUAD.

The family of Janus Kinases (JAKs) associated with the JAK-signal transducers and activators of transcription signaling pathway plays a vital role in the regulation of various cellular processes. The conformational change of JAKs is the fundamental steps for activation, affecting multiple intracellular signaling pathways. However, the transitional process from inactive to active kinase is still a mystery. This study is aimed at investigating the electrostatic properties and transitional states of JAK1 to a fully activation to a catalytically active enzyme. To achieve this goal, structures of the inhibited/activated full-length JAK1 were modelled and the energies of JAK1 with Tyrosine Kinase (TK) domain at different positions were calculated, and Dijkstra\'s method was applied to find the energetically smoothest path. Through a comparison of the energetically smoothest paths of kinase inactivating P733L and S703I mutations, an evaluation of the reasons why these mutations lead to negative or positive regulation of JAK1 are provided. Our energy analysis suggests that activation of JAK1 is thermodynamically spontaneous, with the inhibition resulting from an energy barrier at the initial steps of activation, specifically the release of the TK domain from the inhibited Four-point-one, Ezrin, Radixin, Moesin-PK cavity. Overall, this work provides insights into the potential pathway for TK translocation and the activation mechanism of JAK1.

This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold (p = 0.037), 1.75-fold (p = 0.019), and 3.33-fold (p < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase (p = 0.002) and 1.58-fold increase (p = 5.5 × 10-4), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2high group of pbDMG patients = 2.88 (1.12-7.39); p = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 (p = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.

Acute myeloid leukemia (AML), characterized by the abnormal accumulation of immature marrow cells in the bone marrow, is a malignant tumor of the blood system. Currently, the pathogenesis of AML is not yet clear. Therefore, this study aims to explore the mechanisms underlying the development of AML. Firstly, we identified a competing endogenous RNA (ceRNA) SUCLG2-AS1-miR-17-5p-JAK1 axis through bioinformatics analysis. Overexpression of SUCLG2-AS1 inhibits proliferation, migration and invasion and promotes apoptosis of AML cells. Secondly, luciferase reporter assay and RIP assay validated that SUCLG2-AS1 functioned as ceRNA for sponging miR-17-5p, further leading to JAK1 underexpression. Additionally, the results of MeRIP-qPCR and m6A RNA methylation quantification indicted that SUCLG2-AS1(lncRNA) had higher levels of m6A RNA methylation compared with controls, and SUCLG2-AS1 is regulated by m6A modification of WTAP in AML cells. WTAP, one of the main regulatory components of m6A methyltransferase complexes, proved to be highly expressed in AML and elevated WTAP is associated with poor prognosis of AML patients. Taken together, the WTAP-SUCLG2-AS1-miR-17-5p-JAK1 axis played essential roles in the process of AML development, which provided a novel therapeutic target for AML.

MiR-494-5p expression has been suggested to be associated with colorectal cancer (CRC) and its metastases in our previous studies. However, functional investigations on the molecule-mediating actions of this miR in CRC are lacking. In silico analysis in the present study revealed a putative binding sequence within the 3\'UTR of JAK1. Overexpression of miR-494-5p in cultured CRC significantly reduced the luciferase activity of a reporter plasmid containing the wild-type JAK1-3\'UTR, which was abolished by seed sequence mutation. Furthermore, the overexpression of miR-494-5p in CRC cell lines led to a significant reduction in JAK1 expression, proliferation, in vitro migration, and invasion. These effects were abolished by co-transfection with a specific double-stranded RNA that inhibits endogenous miR-494-5p. Moreover, IL-4-induced migration, invasion, and phosphorylation of JAK1, STAT6, and AKT proteins were reduced after an overexpression of this miR, suggesting that this miR affects one of the most essential pathways in CRC. A Kaplan-Meier plotter analysis revealed that patients with high JAK1 expression show reduced survival. Together, these data suggest that miR-494-5p physically inhibits the expression of JAK1 at the translational level as well as in migration and invasion, supporting the hypothesis of miR-494-5p as an early tumor suppressor and inhibitor of early steps of metastasis in CRC.

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

OBJECTIVE: MicroRNA (miR)-22-3p is expressed in atherosclerosis (AS), but its function and regulatory mechanisms remain unclear. Therefore, the effects of miR-22-3p in AS were assessed in this study.
METHODS: MiR-22-3p expression was assessed in AS, and miR-22-3p target genes were predicted using sequencing transcriptomics. The effect of miR-22-3p agomir on atherosclerotic lesions in an AS mouse model were determined by Oil red O, Masson\'s, and sirius red staining, and by anti-smooth muscle actin and macrophage antigen-3 immunostaining. Gene expression in AS was evaluated by western blot and immunofluorescence.
RESULTS: MiR-22-3p was expressed in AS and control samples (32.5% and 33.9% levels, respectively, relative to total miRNA among six highly expressed miRNAs). In the mouse model of AS, miR-22-3p agomir significantly reduced lipid deposition, proliferation of aortic collagen fibres, and macrophage content. Additionally, inducible nitric oxide synthase, interleukin-6, and tumour necrosis factor-α levels were significantly reduced, and levels of arginase 1 and CD206 were significantly enhanced. MiR-22-3p was found to target janus kinase 1(JAK1), and significantly inhibited the activation of NLR family pyrin domain containing 3 (NLRP3) and JAK1 in mice.
CONCLUSIONS: MiR-22-3p appears to reduce the inflammatory response in AS, which might be achieved by inducing the M2 macrophage phenotype and suppressing NLRP3 activation via JAK1.

UNASSIGNED: JAK1 is a signaling molecule downstream of cytokine receptors, including IL-4 receptor α. Abrocitinib is an oral JAK1 inhibitor; it is a safe and effective US Food and Drug Administration-approved treatment for adults with moderate-to-severe atopic dermatitis.
UNASSIGNED: Our objective was to investigate the effect of abrocitinib on basophil activation and T-cell activation in patients with peanut allergy to determine the potential for use of JAK1 inhibitors as a monotherapy or an adjuvant to peanut oral immunotherapy.
UNASSIGNED: Basophil activation in whole blood was measured by detection of CD63 expression using flow cytometry. Activation of CD4+ effector and regulatory T cells was determined by the upregulation of CD154 and CD137, respectively, on anti-CD3/CD28- or peanut-stimulated PBMCs. For the quantification of peanut-induced cytokines, PBMCs were stimulated with peanut for 5 days before harvesting supernatant.
UNASSIGNED: Abrocitinib decreased the allergen-specific activation of basophils in response to peanut. We showed suppression of effector T-cell activation when stimulated by CD3/CD28 beads in the presence of 10 ng of abrocitinib, whereas activation of regulatory T-cell populations was preserved in the presence of abrocitinib. Abrocitinib induced statistically significant dose-dependent inhibition in IL-5, IL-13, IL-10, IL-9, and TNF-α in the presence of peanut stimulation.
UNASSIGNED: These results support our hypothesis that JAK1 inhibition decreases basophil activation and TH2 cytokine signaling, reducing in vitro allergic responses in subjects with peanut allergy. Abrocitinib may be an effective adjunctive immune modulator in conjunction with peanut oral immunotherapy or as a monotherapy for individuals with food allergy.

Dysregulation of vitamin D receptor (VDR) is implicated in chronic obstructive pulmonary disease. However, whether VDR dysregulation contributes to the development of pulmonary fibrosis remains largely unknown. Analysis of bulk and single-cell RNA profiling datasets revealed VDR upregulation in lung fibroblasts from patients with pulmonary fibrosis or fibrotic mice, which was validated in lung fibroblasts from bleomycin-exposed mice and bleomycin-treated fibroblasts. Stable VDR knockdown promoted, whereas the VDR agonist paricalcitol suppressed lung fibroblast proliferation and activation. Gene set enrichment analysis (GSEA) showed that the JAK/STAT pathway and unfolded protein response (UPR), a process related to endoplasmic reticulum (ER) stress, were enriched in lung fibroblasts of fibrotic lungs. Stable VDR knockdown stimulated, but paricalcitol suppressed ER stress and JAK1/STAT3 activation in lung fibroblasts. The STAT3 inhibitor blocked bleomycin- or stable VDR knockdown-induced ER stress. Paricalcitol inhibited the bleomycin-induced enrichment of STAT3 to the ATF6 promoter, thereby suppressing ATF6 expression in fibroblasts. Paricalcitol or intrapulmonary VDR overexpression inactivated JAK1/STAT3 and suppressed ER stress in bleomycin-treated mice, thus resulting in the inhibition of fibroblast proliferation and activation. Collectively, this study suggests that fibroblast VDR upregulation may be a self-protective response to limit fibroblast proliferation and activation during pulmonary fibrosis by suppressing the JAK1/STAT3/ER stress pathway.