JAK-signal Transducer Research Articles

Occupational exposure to arsenic and leukopenia risk: Toxicological alert.

Arsenic and its inorganic compounds affect numerous organs and systemic functions, such as the nervous and hematopoietic systems, liver, kidneys, and skin. Despite a large number of studies on arsenic toxicity, rare reports have investigated the leukopenia incidence in workers exposed to arsenic. In workplaces, the main source of workers' exposure is the contaminated air by the inorganic arsenic in mines, arsenic or copper smelter industries, and chemical factories. Erythropoiesis inhibition is one of the arsenic effects and it is related to regulatory factor GATA-1. This factor is necessary for the normal differentiation of early erythroid progenitors. JAK-STAT is an important intracellular signal transduction pathway responsible for the mediating normal functions of several cytokines related to cell proliferation and hematopoietic systems development and regulation. Arsenic inactivates JAK-STAT by inhibiting JAK tyrosine kinase and using the IFNγ pathway. The intravascular hemolysis starts after the absorption phase when arsenic binds to the globin of hemoglobin in erythrocytes and is transported into the body, which increases the oxidation of sulfhydryl groups in hemoglobin. So, this article intends to highlight the potential leukopenia risk via inhalation for workers exposed to arsenic and suggests a possible mechanism for this leukopenia through the JAK-signal transducer and activator of transcription (STAT) pathway inhibition.

Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease

The involvement of chronic inflammation in the pathogenesis of age-related macular degeneration (AMD) opens therapeutic possibilities to AMD management. To determine whether Janus kinase inhibitors (JAKis) are associated with a reduced risk of AMD development in patients with autoimmune diseases. This retrospective observational cohort study used administrative claims data from Merative MarketScan research databases (Commercial and Medicare Supplemental) and Optum Clinformatics Data Mart databases between January 1, 2010, and January 31, 2022. Patients with autoimmune diseases satisfying study eligibility criteria and who received JAKi treatment (9126 in MarketScan and 5667 in Optum) were propensity score matched (1:1) to identical numbers of study-eligible patients who received non-JAKi-based immunotherapy. Treatment duration of 6 months or longer. Incidence rates of AMD (exudative and nonexudative) over the first 6 to 18 months of treatment were determined, and bayesian Poisson regression models were used to estimate incidence rate ratios, 95% CIs, and posterior probabilities of AMD. After matching, female sex represented the majority of the patient population in both MarketScan and Optum (14 019/18 252 [76.6%] and 8563/3364 [75.2%], respectively in the JAKi patient population). More than 60% of the patient population was older than 55 years of age in both cohorts. Over the specified treatment period, a 49% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (10/9126 events; adjusted incidence rate ratio [AIRR], 0.51; 95% CI, 0.19-0.90) vs those who received non-JAKi therapy (43/9126 events; AIRR, 1 [reference]) in MarketScan, and a 73% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (3/5667 events; AIRR, 0.27; 95% CI, 0.03-0.74) vs those who received non-JAKi therapy (21/5667 events; AIRR, 1 [reference]) in Optum. The absolute percentage reductions were 0.36% (MarketScan) and 0.32% (Optum), favoring patients who received JAKi therapy. Posterior probabilities of the adjusted risk being less than unity were 97.6% (MarketScan) and 98.9% (Optum) for those who received JAKi therapy vs those who received non-JAKi therapy in MarketScan and Optum, respectively. JAKi use may be associated with a reduced risk of incident AMD in US adults with major autoimmune diseases. The absolute percentage reduction is consistent with a potential role for JAKi in this population. Future studies with long-term follow-up are recommended to investigate the association between JAKi use and incident AMD in other disease indications. Investigation into the role of systemic inflammation and JAK-signal transducers and activators of transcription signaling in AMD may improve understanding of the pathophysiology of AMD and lead to new treatment options.

Drug Repurposing Using Molecular Network Analysis Identifies Jak as Targetable Driver in Necrobiosis Lipoidica

Drug repurposing is an attractive strategy for therapy development, particularly in rare diseases where traditional drug development approaches may be challenging owing to high cost and small numbers of patients. In this study, we used a drug identification and repurposing pipeline to identify candidate targetable drivers of disease and corresponding therapies through application of causal reasoning using a combination of open-access resources and transcriptomics data. We optimized our approach on psoriasis as a disease model, demonstrating the ability to identify known and, to date, unrecognized molecular drivers of psoriasis and link them to current and emerging therapies. Application of our approach to a cohort of tissue samples of necrobiosis lipoidica (an unrelated; rare; and, to date, molecularly poorly characterized cutaneous inflammatory disorder) identified a unique set of upstream regulators, particularly highlighting the role of IFNG and the Jak-signal transducer and activator of transcription pathway as a likely driver of disease pathogenesis and linked it to Jak inhibitors as potential therapy. Analysis of an independent cohort of necrobiosis lipoidica samples validated these findings, with the overall agreement of drug-matched upstream regulators above 96%. These data highlight the utility of our approach in rare diseases and offer an opportunity for drug discovery in other rare diseases in dermatology and beyond.

Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons

BackgroundJanus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis.MethodsWe treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells.ResultsBoth baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1β and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia–astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells.ConclusionsOur findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.

P10 Janus kinase inhibitors to restore skin barrier function in a mouse model of Harlequin ichthyosis

Abstract Introduction and aims The autosomal recessive congenital ichthyoses (ARCIs) are a group of chronic conditions where there is unmet therapeutic need. Harlequin ichthyosis (HI) is the most severe form of ARCI with aberrant differentiation of the epidermis leading to a severe barrier defect. It is caused by mutations in ABCA12, a lipid transporter involved in transport of glucosylceramides from the lamellar body to the lipid lamellae. Several Janus kinase (JAK) inhibitors inhibiting the JAK-signal transducer and activator of transcription pathway are now licensed for atopic dermatitis. Previous work from our group in an HI in vitro model showed that tofacitinib, a pan-JAK inhibitor, had a restorative effect on the lipid barrier. Methods Further selective JAKis were tested in three dimensional skin equivalents using ABCA12 CRISPR-Cas9 knockout and wildtype keratinocytes to identify the most promising JAKi for use in an HI murine model (ABCA12tm1c: Het Cre+). JAKi-A (5 mg kg−1) and vehicle (10% dimethylsulfoxide in corn oil) were tested on male and female HI-inducible and wildtype mice (N = 4). All mice were initially treated with 4-OH-Tamoxifen to induce the HI phenotype and after 1 day JAKi-A was administered via oral gavage for 9 days. All mice were killed, and skin was collected and processed for haematoxylin and eosin, Nile Red, ABCA12, glucosylceramide and immune cell marker staining. Results JAKi-A had a positive effect on HI epidermal morphology, showing a significantly reduced epidermal thickness in treated HI mice compared with controls. JAKi-A also had a positive effect on the epidermal barrier, restoring neutral and polar lipids compared with vehicle-treated mice as observed using Nile Red and glucosylceramide staining. Further analysis on immune cell infiltrates is in progress. Conclusions These Results suggest that JAKi-A restores the skin barrier in vivo and may be a promising treatment for severe ichthyosis.

A novel approach to study multi-domain motions in JAK1's activation mechanism based on energy landscape.

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.

Romidepsin and Afatinib Abrogate Jak–Signal Transducer and Activator of Transcription Signaling and Elicit Synergistic Antitumor Effects in Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas (CTCL) are mature lymphoid neoplasias resulting from the malignant transformation of skin-resident T cells. A distinctive clinical feature of CTCL is their sensitivity to treatment with histone deacetylase (HDAC) inhibitors. However, responses to HDAC inhibitor therapy are universally transient and non-curative, highlighting the need for effective and durable drug combinations. Here we demonstrate that the combination of romidepsin, a selective class I HDAC inhibitor, with afatinib, an epidermal growth factor receptor (EGFR) family inhibitor, induces strongly synergistic antitumor effects in CTCL models in vitro and in vivo via abrogation of JAK-STAT signalling. These results support a previously unrecognized potential role for HDAC inhibitor plus afatinib combination in the treatment of CTCL.

Current Views on Pathophysiology and Potential Therapeutic Targets in Sjögren's Syndrome: A Review from the Perspective of Viral Infections, Toll-like Receptors, and Long-Noncoding RNAs.

Sjögren's syndrome (SS) is a rheumatic disease characterized by sicca and extraglandular symptoms, such as interstitial lung disease and renal tubular acidosis. SS potentially affects the prognosis of patients, especially in cases of complicated extraglandular symptoms; however, only symptomatic therapies against xerophthalmia and xerostomia are currently included in the practice guidelines as recommended therapies for SS. Considering that SS is presumed to be a multifactorial entity caused by genetic and environmental factors, a multidisciplinary approach is necessary to clarify the whole picture of its pathogenesis and to develop disease-specific therapies for SS. This review discusses past achievements and future prospects for pursuing the pathophysiology and therapeutic targets for SS, especially from the perspectives of viral infections, toll-like receptors (TLRs), long-noncoding RNAs (lncRNAs), and related signals. Based on the emerging roles of viral infections, TLRs, long-noncoding RNAs and related signals, antiviral therapy, hydroxychloroquine, and vitamin D may lower the risk of or mitigate SS. Janus-kinase (JAK) inhibitors are also potential novel therapeutic options for several rheumatic diseases involving the JAK-signal transducer and activator of transcription pathways, which are yet to be ascertained in a randomized controlled study targeting SS.

Current therapies for classic myeloproliferative neoplasms: A focus on pathophysiology and supportive care.

This article concisely evaluates current therapies that have received regulatory approval for the treatment of classic myeloproliferative neoplasms (MPNs). Pertinent pathophysiology and supportive care are discussed. Emerging therapies are also briefly described. MPNs are a heterogeneous group of diseases characterized by acquired abnormalities of hematopoietic stem cells (HSCs), resulting in the generation of transformed myeloid progenitor cells that overproduce mature and immature cells within the myeloid lineage. Mutations in JAK2 and other driver oncogenes are central to the genetic variability of these diseases. Cytoreductive therapies such as hydroxyurea, anagrelide, interferon, and therapeutic phlebotomy aim to lower the risk of thrombotic events without exposing patients to an increased risk of leukemic transformation. However, no comparisons can be made between these therapies, as reduction of thrombotic risk has not been used as an endpoint. On the other hand, Janus kinase (JAK) inhibitors such as ruxolitinib, fedratinib, pacritinib, and momelotinib (an investigational agent at the time of writing) directly target the constitutively activated JAK-signal transducer and activator of transcription (JAK-STAT) pathway of HSCs in the bone marrow. Mutations of genes in the JAK-STAT signaling pathway provide a unifying understanding of MPNs, spur therapeutic innovations, and represent opportunities for pharmacists to optimize mitigation strategies for both disease-related and treatment-related adverse effects. Treatment options for MPNs span a wide range of disease mechanisms. The growth of targeted therapies holds promise for expanding the treatment arsenal for these rare, yet complex diseases and creates opportunities to optimize supportive care for affected patients.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Efficacy of Baricitinib in Patients with Refractory Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is an idiopathic systemic inflammatory disease of unknown aetiology. Some patients exhibit resistance to conventional treatment during long-term therapy. Janus kinase inhibitors (JAKinibs) may contribute to the improvement in AOSD symptoms via the JAK-signal transducer and activator of transcription (STAT) pathway. We aimed to explore the efficacy and safety of baricitinib in patients with refractory AOSD. Patients were enrolled if they fulfilled the Yamaguchi AOSD classification criteria in China between 2020 and 2022. All patients were recognized as having refractory AOSD and were treated with oral baricitinib at a dosage of 4mg once daily. A systemic score and prednisone dosage were used to evaluate the efficacy of baricitinib at months 1, 3, and 6 and at the last follow-up visit. The safety profiles were recorded and analysed at every assessment. Seven female patients with refractory AOSD received baricitinib. The median age was 31 (IQR 10) years. Treatment was terminated in one patient due to progressive macrophage activation syndrome (MAS). Others continued baricitinib treatment until the last assessment. The systemic score decreased significantly at 3 months (p=0.0216), 6 months (p=0.0007), and the last follow-up visit (p=0.0007) compared with baseline. One month after the initiation of baricitinib, the rates of improvement in fever, rash, sore throat, and myalgia symptoms were 71.4% (5/7), 40% (2/5), 80% (4/5), and 66.7% (2/3), respectively. Five patients remained symptom-free at the last follow-up visit. In most patients, their laboratory values had returned to normal by the last follow-up visit. A significant reduction in the levels of C-reactive protein (CRP) (p=0.0165) and ferritin (p=0.0047) was observed at the last visit compared with baseline. The daily prednisolone dosage significantly decreased from 35.7± 15.1mg/day at baseline to 8.8± 4.4mg/day by month 6 (p=0.0256), and it was 5.8± 4.7mg/day at the last assessment (p=0.0030). Leukopenia due to MAS was noted in one patient. Except for mild abnormalities in lipid parameters, no other severe adverse events occurred during follow-up. Our findings suggest that baricitinib therapy could provide rapid and durable clinical and laboratory improvement in patients with refractory AOSD. Treatment seemed to be well tolerated by these patients. The long-term efficacy and safety of baricitinib therapy for AOSD should be assessed further in prospective controlled clinical trials in the future. Trial registration number (TRN): ChiCTR2200061599. Date of registration: 29 June 2022 (retrospectively registered).

Interactions between driver genes shape the signaling pathway landscape and direct hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that exhibit a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The sgTrp53+sgPten tumor upregulated mTOR and noncanonical NF-κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. JAK-STAT signaling was activated in the Ctnnb1mut +sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). MTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent anti-proliferative effects in the sgPten+KrasG12D tumor. JAK-STAT, MAPK, and cytoskeleton signaling were activated in the sgTrp53+KrasG12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC, who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor.

English version of Japanese guidance for the use of oral Janus kinase inhibitors (JAK1 and TYK2 inhibitors) in the treatments of psoriasis.

This is the English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors (JAK1 and tyrosine kinase 2 [TYK2] inhibitors) in the treatments of psoriasis. Several cytokines, such as interleukin (IL)-6, IL-7, IL-12, IL-21, IL-22, IL-23, interferon (IFN)-α, and IFN-γ, are involved in the pathogenesis of psoriasis (including psoriatic arthritis). As oral JAK inhibitors hinder the JAK-signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of psoriasis. JAK has four types: JAK1, JAK2, JAK3, and TYK2. Regarding the use of oral JAK inhibitors for the treatment of psoriasis in Japan, indications of the JAK1 inhibitor upadacitinib were extended also to psoriatic arthritis in 2021, and the use of the TYK2 inhibitor deucravacitinib for plaque-type psoriasis, pustular psoriasis, and erythrodermic psoriasis became covered by health insurance in 2022. This guidance was developed for board-certified dermatologists who specialize in the treatment of psoriasis and to promote the proper use of oral JAK inhibitors. In the package inserts and guides for appropriate use, upadacitinib and deucravacitinib are classified as a "JAK inhibitor" and a "TYK2 inhibitor", respectively, and it is possible that there may be differences in safety between the two drugs. The safety of these drugs will be evaluated for the future by the postmarketing surveillance for molecularly targeted drugs for psoriasis of the Japanese Dermatological Association.

English version of Japanese guidance for the use of oral Janus kinase (JAK) inhibitors in the treatments of atopic dermatitis.

This is the English version of guidance for the use of oral Janus kinase (JAK) inhibitors in the treatment of atopic dermatitis. Several cytokines, such as interleukin (IL)-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and interferon-γ, are involved in the pathogenesis of atopic dermatitis. As oral JAK inhibitors hinder the JAK-signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of atopic dermatitis. In Japan, as oral JAK inhibitors for atopic dermatitis, a JAK1/2 inhibitor, baricitinib, expanded its authorized indications for atopic dermatitis in 2020. Consequentially, a JAK1 inhibitor, upadacitinib, also expanded its indications to atopic dermatitis in 2021, followed by new approval of another JAK1 inhibitor, abrocitinib, for the use under the Japanese health insurance system. Physicians who intend to use them should sufficiently understand and comply with contents of guidelines prepared by the Japanese Ministry of Health, Labour and Welfare to promote optimal use of these drugs. In the treatment with oral JAK inhibitors, it is important to sufficiently consider disease factors, treatment factors and patient backgrounds, and share them with patients to choose treatment options. Points to be considered for drug selection include the efficacy and safety of drugs, age of patients, and dosage and administration of the drug. This guidance was developed for board certified dermatologists, who are specialized in the treatment of atopic dermatitis, and for promoting proper use of oral JAK inhibitors, taking into account a variety of factors in individual patients.

AIRE Deficiency Leads to the Development of Alopecia Areata‒Like Lesions in Mice

Alopecia areata (AA) is an autoimmune hair loss disorder with no cure. Patients with sequence variation in AIRE are 15 times more likely to develop AA than the general population, yet the roles of AIRE in AA pathogenesis are unknown. In this study, we report that 62% of C57BL/6J female Aire‒/‒ mice spontaneously developed persistent AA-like lesions that displayed several hallmarks of human AA. Lesional Aire‒/‒ skin exhibited hair follicle (HF) dystrophy as determined by a reduced number of anagen HFs, decreased anagen HF proliferation, hair pigmentary changes, and decreased hair width and length. Inflammatory infiltrate comprising CD8+ T cells, CD4+ T cells, CD68+ macrophages, and mast cells was prominent in lesional Aire‒/‒ HFs. From gene expression analyses, we found lesional Aire‒/‒ skin to have significantly increased expression of human AA signature genes, including H2-Ab1, Ifnγ, IFN-γ‒induced chemokines (Ccl5, Cxcl9‒11), γc family cytokine receptor Il2RA, and JAK‒signal transducer and activator of transcription (STAT) signaling components (Stat1, Stat2, Stat4). By immunostaining, lesional Aire‒/‒ HFs also show upregulated major histocompatibility complex class I and downregulated α-melanocyte-stimulating hormone, signifying immune privilege collapse, and increased STAT1 activation in HF keratinocytes. Our study highlights a role for AIRE in HF biology and shows that Aire‒/‒ mice may serve as a valuable model system to study AA pathogenesis.

Baricitinib Attenuates IFN-γ and Polyinosinic:polycytidylic Acid‒Induced Mitochondrial Damage and Inflammasome Activation in Human Keratinocytes

Alopecia areata (AA) is a common hair loss condition characterized by the acute onset of nonscarring hair loss (Shin et al., 2019). GWAS data have found several susceptibility loci involved in autoimmunity that have crucial roles in T-cell‒mediated pathways in AA pathogenesis (Betz et al., 2015; Petukhova et al., 2010). Especially, CD8+NKG2D+ T cells around the affected hair follicles contribute to the progression of inflammation, and the JAK‒signal transducer and activator of transcription (STAT) pathway plays an important role in mediating the CD8+NKG2D+T cell reaction.

Transcription Factor EGR1 Regulates the Expression of the Clock Gene PER2 under IL-4 Stimulation in Human Keratinocytes

PER2 is a core circadian clock gene that regulates circadian rhythms. IL-4 plays a critical role in the pathogenesis of skin inflammation, including atopic dermatitis. IL-4 enhances PER2 expression, suggesting a relationship between inflammation and the circadian clock. However, little is known about the molecular and cellular mechanisms regulating PER2 expression by inflammatory cytokines. This study showed that transcription factor EGR1 interacted with the PER2 promoter and promoted IL-4‒induced transcriptional activation of the PER2, as revealed by promoter‒reporter assay, electrophoretic mobility shift assay, DNA affinity precipitation assay, and chromatin immunoprecipitation analysis. We also found that IL-4 can use both MAPK and Jak signaling pathways to induce EGR1-mediated PER2 expression, and c-Jun N-terminal kinase 1/2 can augment IL-4‒induced activation of the Jak‒signal transducer and activator of transcription 3 pathway. Consistently, Per2 expression was reduced in dinitrochlorobenzene-induced atopic dermatitis‒like skin lesions in Egr1‒/‒ mice compared with that in Egr1+/+ mice. In addition, using a real-time bioluminescence assay, we observed that EGR1 is required for rhythmic oscillation of PER2 expression under IL-4 exposure. These findings provide further insight into the role of EGR1 in regulating PER2 expression in impaired circadian rhythm in skin inflammation.

Effects of Janus kinase (JAK) on hemocyte proliferation and disease resistance in Scylla paramamosain

Janus kinase (JAK), a nonreceptor tyrosine kinase, is the JAK-signal transducer and activator of transcription (STAT) signaling pathway. In this study, RNA interference technology was used to knockdown the expression of JAK to explore the immune function of JAK in Scylla paramamosain. JAK expression was relatively high in the intestine and relatively low in the heart and hemocytes of S. paramamosain. JAK was highly expressed in all examined tissues of S. paramamosain after infection with white spot syndrome virus (WSSV) or Vibrio alginolyticus. The expression levels of Astakine, STAT, CAP, TLR, proPO, and CTL were downregulated, while MCM7, Myosin and Relish expression was upregulated in hemocytes at 24 h after injection of JAK-dsRNA. Astakine expression was significantly downregulated within 72 h after injection of JAK-dsRNA. The total hemocyte count and hemocyte proliferation were significantly decreased after treatment with Astakine-dsRNA or JAK-dsRNA. The results showed that JAK may promote hemocyte proliferation, probably by regulating Astakine expression. The activities of phenoloxidase, superoxide dismutase, and lysozyme were decreased significantly, while production of reactive oxygen species was increased significantly in hemocytes after treatment with JAK-dsRNA. After JAK knockdown, the phagocytosis rate of WSSV or V. alginolyticus in hemocytes was increased. After WSSV challenge, the WSSV copy number in the JAK-dsRNA-treated group was higher than that in the WSSV group. After V. alginolyticus challenge, the apoptosis rate of hemocytes in the JAK-dsRNA group was higher than that in the V. alginolyticus group. The mortality rate of WSSV or V. alginolyticus-infected crabs after JAK knockdown was higher than that of the infection group. These results suggest that JAK can regulate the expression of some immune-related genes, such as Astakine, to influence the innate immune response of S. paramamosain against pathogens (WSSV or V. alginolyticus), mostly by regulating enzyme activities, hemocyte phagocytosis and apoptosis.

Therapeutic Effects of Tofacitinib on Pristane-Induced Murine Lupus.

Objectives This study aims to investigate the effectiveness of tofacitinib, a Janus kinase (JAK) 1/JAK3 inhibitor, in treating murine lupus, and also explore 12 related genes downstream of JAK-signal transducer and activator of transcription (STAT) signaling pathways to find the underlying mechanism.Materials and methods This study was conducted between July 2017 and January 2020. Fifty-seven female BALB/c mice (aging 8 to 10 weeks old; weighing 18 to 20 g) were assigned to a saline control (SC) group and a pristane-induced lupus group. The latter included four groups, namely, pristane control (PC), tofacitinib (T), methylprednisolone (MP), and tofacitinib plus methylprednisolone (T+MP). Animal models of lupus were induced with pristane, whereas SC mice were treated with normal saline. From the 22nd week after induction, each group was given the aforementioned corresponding intervention for 11 weeks. The following variables were tested: serum concentrations of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), interleukin 6 (IL-6), and interferon gamma (IFN-γ); number of regulatory T (Treg) cells; messenger ribonucleic acid levels of forkhead box P3 and 12 related genes downstream of JAK-STAT pathway; and renal impairment.Results Red swollen joints and proteinuria were first observed in PC after the 12th week. After treatment, T, MP, and T+MP showed relieved red swollen joints and splenomegaly, as well as decreased urine protein, anti-dsDNA, IL-6, IFN-γ, Treg cells, pathological scores, and hyperplasia of mesangial matrix in glomeruli compared with PC. The IFN regulatory factor 7 level was higher in T+MP (p0.05) and MP (p>0.05) than in PC after treatment. The expression of suppressor of cytokine signaling (SOCS) 1 was lower in T (p>0.05), T+MP (p0.05) than in PC. The SOCS3 level was higher in T (p>0.05) and T+MP (p0.05) than in PC.Conclusion Tofacitinib can ameliorate glomerulonephritis and arthritis in a pristane-induced murine model of lupus. SOCS3 gene may be involved in the therapeutic mechanism of tofacitinib.

YTHDC1-mediated VPS25 regulates cell cycle by targeting JAK-STAT signaling in human glioma cells

BackgroundGlioma is a common type of malignant brain tumor with a high mortality and relapse rate. The endosomal sorting complex required for transport (ESCRT) has been reported to be involved in tumorigenesis. However, the molecular mechanisms have not been clarified.MethodsBioinformatics was used to screen the ESCRT subunits highly expressed in glioma tissues from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The function of the ESCRT subunits in glioma cells was examined in vitro. Transcriptome sequencing analyzed the target genes and signaling pathways affected by the ESCRT subunit. Finally, the relationship between m6A (N6-methyladenosine) modification and high expression of the ESCRT subunit was studied.ResultsVPS25 was upregulated in glioma tissues, which was correlated with poor prognosis in glioma patients. Furthermore, VPS25 knockdown inhibited the proliferation, blocked the cell cycle, and promoted apoptosis in glioma cells. Meanwhile, VPS25 induced a G0/G1 phase arrest of the cell cycle in glioma cells by directly mediating p21, CDK2, and cyclin E expression, and JAK-signal transducer and activator of transcription (STAT) activation. Finally, YTHDC1 inhibited glioma proliferation by reducing the expression of VPS25.ConclusionThese results suggest that VPS25 is a promising prognostic indicator and a potential therapeutic target for glioma.