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Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.

Heme oxygenase-1 (HO-1) has several important roles in hepatocytes in terms of anti-inflammation, anti-apoptosis, and antioxidant properties. Interleukin-6 (IL-6) is a pleiotropic cytokine associated with liver regeneration and protection against injury. The aim of this study was to determine the potential crosstalk between HO-1 and IL-6, and to elucidate the signaling pathways involved in the induction of HO-1 by IL-6 in human hepatoma cells. Ectopic overexpression of HO-1 not only attenuated cell proliferation in vitro and in vivo, but also blocked the reactive oxygen species (ROS) induced by H2O2 and the pyocyanin in HepG2 or Hep3B cells. IL-6 expression was negatively regulated by HO-1, while IL-6 induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and HO-1 gene expression in HepG2 cells. The co-transfected HO-1 reporter vector and a protein inhibitor of the activated STAT3 (PIAS3) expression vector blocked the IL-6-induced HO-1 reporter activity. Both interferon γ and interleukin-1β treatments induced STAT1 but not STAT3 phosphorylation, which had no effects on the HO-1 expression. Treatments of AG490 and luteolin blocked the JAK/STAT3 signaling pathways which attenuated IL-6 activation on the HO-1 expression. Our results indicated that HO-1 is the antitumor gene induced by IL-6 through the IL-6/JAK/STAT3 pathways; moreover, a feedback circuit may exist between IL-6 and HO-1 in hepatoma cells.

The latest update of the EULAR recommendations for the treatment of RA maintain csDMARD (conventional systemic DMARDs) as the first line treatment, with methotrexate (MTX) still identified as the anchor drug, to which it is possible to add, in failure patients with negative prognostic factors, a biological drug or a tsDMARD (target synthetic DMARD), i.e JAK inhibitors.

BackgroundMutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection.CaseWe describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension.MethodsWhole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNβ and NF-κB activity in vitro.ResultsWGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro. The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease.ConclusionThis case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition.

The regulatory process of naïve-state induced pluripotent stem cell (iPSC) generation is not well understood. Leukemia inhibitory factor (LIF)-activated Janus kinase/signal transducer and activator of transcription 3 (Jak/Stat3) is the master regulator for naïve-state pluripotency achievement and maintenance. The estrogen-related receptor beta (Esrrb) serves as a naïve-state marker gene regulating self-renewal of embryonic stem cells (ESCs). However, the interconnection between Esrrb and LIF signaling for pluripotency establishment in reprogramming is unclear. We screened the marker genes critical for complete reprogramming during mouse iPSC generation, and identified genes including Esrrb that are responsive to LIF/Jak pathway signaling. Overexpression of Esrrb resumes the reprogramming halted by inhibition of Jak activity in partially reprogrammed cells (pre-iPSCs), and leads to the generation of pluripotent iPSCs. We further show that neither overexpression of Nanog nor stimulation of Wnt signaling, two upstream regulators of Esrrb in ESCs, stimulates the expression of Esrrb in reprogramming when LIF or Jak activity is blocked. Our study demonstrates that Esrrb is a specific reprogramming factor regulated downstream of the LIF/Jak signaling pathway. These results shed new light on the regulatory role of LIF pathway on complete pluripotency establishment during iPSC generation.

Tumor-associated macrophages (TAM) interact with cancer and stromal cells and are integral to sustaining many cancer-promoting features. Therapeutic manipulation of TAM could therefore improve clinical outcomes and synergize with immunotherapy and other cancer therapies. While different nanocarriers have been used to target TAM, a knowledge gap exists on which TAM pathways to target and what payloads to deliver for optimal antitumor effects. We hypothesized that a multipart combination involving the Janus tyrosine kinase (JAK), noncanonical nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and toll-like receptor (TLR) pathways could lead to a highly active myeloid therapy (HAMT). Thus, we devised a screen to determine drug combinations that yield maximum IL-12 production from myeloid cells to treat the otherwise highly immunosuppressive myeloid environments in tumors. Here we show the extraordinary efficacy of a triple small-molecule combination in a TAM-targeted nanoparticle for eradicating murine tumors, jumpstarting a highly efficient antitumor response by adopting a distinctive antitumor TAM phenotype and synergizing with other immunotherapies. The HAMT therapy represents a recently developed approach in immunotherapy and leads to durable responses in murine cancer models.

With multiple Janus Kinase (JAK) inhibitors approved or in late development for myelofibrosis, there is a logical desire in the field for comparative efficacy and safety data among these agents in order to inform treatment selection. However, due to the highly disparate nature of patient populations enrolled in different JAK inhibitor trials, as well as key differences in study design, any cross-study comparative analyses should be undertaken with a high degree of caution. Here, we show how differences in enrolled populations can impact both efficacy and safety conclusions and why quantitative comparisons of outcomes across studies is prone to spurious conclusions. We conclude by offering guidance on how to approach comparative analyses in the absence of direct head-to-head data based on a thorough understanding of how study design impacts outcomes. Ultimately there is enough room in the myelofibrosis treatment landscape for multiple JAK inhibitors, and sequencing of therapies should depend on how each agent was studied and where it showed the most benefit, both in trials and in real-world practice., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway is an essential final step in the signaling process of most interleukins with a critical role in the pathogenesis of atopic dermatitis. By achieving broad, intermittent inhibition of the activity of multiple cytokines, JAK inhibitors help modulate T helper 2 cell-mediated inflammation, epidermal barrier dysfunction, and itch signaling. This comprehensive blockade, however, can result in a wider range of adverse effects. We review a number of JAK inhibitors that have been recently approved for use in atopic dermatitis, such as baricitinib, upadacitinib, and abrocitinib, as well as others that are currently in the pipeline or under development, such as gusacitinib, delgocitinib, ruxolitinib, brepocitinib, tofacitinib, and cerdulatinib. The use of JAK inhibitors to block the signaling of numerous cytokines with a critical role in the pathogenesis of atopic dermatitis has revolutionized the treatment of this pathogenically complex, phenotypically heterogeneous skin disease., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

While the peripheral T-cell lymphomas (PTCL) remain a therapeutic challenge, and increasingly account for a disproportionate number of lymphoma-related deaths, improved understanding of disease pathogenesis and classification, and the development of novel therapeutic agents over the past decade, all provide reasons for a more optimistic outlook in the next. Despite their genetic and molecular heterogeneity, many PTCL are dependent upon signaling input provided by antigen, costimulatory, and cytokine receptors. While gain-of-function alterations effecting these pathways are recurrently observed in many PTCL, more often than not, signaling remains ligand-and tumor microenvironment (TME)-dependent. Consequently, the TME and its constituents are increasingly recognized as "on target". Utilizing a "3 signal" model, we will review new-and old-therapeutic targets that are relevant for the more common nodal PTCL subtypes., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract The physiopathology of rheumatoid arthritis (RA) is mediated by proinflammatory cytokines, some of which are regulated by the JAK/STAT pathway. Tofacitinib is a JAK inhibitor, but its role in the regulation of microRNAs (miRNAs) is unknown. There is also no information regarding the role of miRNAs in the clinical relapse/remission of RA. The present project aims to identify a signature profile of miRNA expression in a subgroup of RA patients who had to discontinue tofacitinib treatment (because of the ending of a 5-year open-label clinical trial) and to describe the expression of miRNAs during RA remission or flare-up. The relative expression of 61 miRNAs was determined in serum samples with the Firefly™ BioWorks assay. Statistical analysis was performed by means of Student's t -test and heatmap analysis was performed with Firefly™ Analysis Workbench software and in the software GraphPad® Prism v5.0. Target prediction and Gene Ontology analysis were carried out using bioinformatic tools. We found a distinctive signature of miRNA expression associated with relapse, featuring upregulated expression of hsa‑miR‑432‑5p ( p < 0.05). We also found upregulation of hsa‑miR‑194‑5p ( p < 0.05) in samples of patients with RA flare-up. Gene Ontology analysis of the target genes for hsa‑miR‑432‑5p was performed to identify relevant pathways associated with relapse; the implications of these pathways in the physiopathology of RA are discussed. Tofacitinib treatment does not have a direct effect on the expression of measured miRNAs. The changes in hsa‑miR‑432‑5p and hsa‑miR‑194‑5p are associated with the regulation of proinflammatory pathways and RA flare-up. Highlights • hsa‑miR‑432‑5p is downregulated in patients achieving clinical remission. • Treatment with Tofacitinib does not affect miRNA expression directly. • Patients with relapse have a specific miRNA signature as measured by Firefly Bioworks. • hsa‑miR‑194-5p is upregulated during RA flare-up patients suggesting that this miRNA could be used as a biomarker for relapse. [ABSTRACT FROM AUTHOR]

Background and Aims Janus kinase [JAK] inhibitors have shown efficacy in ulcerative colitis [UC]. We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. Methods In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25 mg once daily [o.d.], 75 mg o.d. 150 mg o.d. and 75 mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8, with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire [IBDQ], and normalisation of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose. Results A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75 mg o.d. achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalisation. Treatment-emergent adverse event [TEAE] rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than in the placebo group; patients receiving doses of ≥75 mg o.d. peficitinib reported TEAEs more frequently. Conclusions No dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, but evidence of efficacy was suggested at doses ≥75 mg o.d. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282. [ABSTRACT FROM AUTHOR]

Introduction: Cytokines represent the key pathophysiologic elements that govern the initiation, progression, and, in some circumstances, the resolution of the inflammation occurring in inflammatory bowel disease (IBD). Areas covered: In this review, we will focus on the main effector and anti-inflammatory cytokines produced in IBD and discuss the results of recent trials in which cytokine-based therapy has been used for treating IBD patients. Expert commentary: The possibility to sample mucosal biopsies from IBD patients and analyze which molecular pathways are prominent during the active phases of the disease and the easy access to various models of experimental colitis has largely advanced our understanding about the role of cytokines in IBD. These progresses have facilitated the development of several therapeutic compounds, which either target inflammatory cytokines or enhance the regulatory function of immunosuppressive cytokines. While some of such drugs are effective in the induction and maintenance of remission of the disease, other compounds are not useful for attenuating the ongoing mucosal inflammation, thus establishing a hierarchical scale of the relevance of cytokines in IBD. Further work is needed to identify biomarkers, which could help personalize cytokine-targeted therapy and minimize potential side effects. [ABSTRACT FROM AUTHOR]

The development and activity of our immune system are largely controlled by the action of pleiotropic cytokines and growth factors, small secreted proteins, which bind to receptors on the surface of immune cells to initiate an appropriate physiological response. Cytokine signalling is predominantly executed by intracellular proteins known as the Janus kinases (JAKs) and the signal transducers and activators of transcriptions (STATs). Although the 'nuts and bolts' of cytokine-activated pathways have been well established, the nuanced way in which distinct cellular outcomes are achieved and the precise molecular details of the proteins that regulate these pathways are still being elucidated. This is highlighted by the intricate role of the suppressor of cytokine signalling (SOCS) proteins. The SOCS proteins act as negative feedback inhibitors, dampening specific cytokine signals to prevent excessive cellular responses and returning the cell to a homeostatic state. A great deal of study has demonstrated their ability to inhibit these pathways at the receptor complex, either through direct inhibition of JAK activity or by targeting the receptor complex for proteasomal degradation. Detailed analysis of individual SOCS proteins is slowly revealing the complex and highly controlled manner by which they can achieve specificity for distinct substrates. However, for many of the SOCS, a level of detail is still lacking, including confident identification of the full suite of tyrosine phosphorylated targets of their SH2 domain. This review will highlight the general mechanisms which govern SOCS specificity of action and discuss the similarities and differences between selected SOCS proteins, focusing on CIS, SOCS1 and SOCS3. Because of the functional and sequence similarities within the SOCS family, we will also discuss the evidence for functional redundancy. [ABSTRACT FROM AUTHOR]

Background: Mutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection. Case: We describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension. Methods: Whole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNβ and NF-κB activity in vitro. Results: WGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro. The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease. Conclusion: This case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition. [ABSTRACT FROM AUTHOR]

Inhibitors of Janus kinases (JAK) are synthetic small molecules for oral use targeting intracellular signalling pathways of many mediators with the essential role in the pathogenesis of rheumatoid arthritis (RA). Tofacitinib inhibits JAK3, JAK1 and to a lesser extent JAK2, whilst baricitinib preferentially interferes with JAK1 and JAK2. Their clinical efficacy was proven in several phase III clinical trials in RA patients either treatment naive or with inadequate response to conventional and biological disease modifying antirheumatic drugs. The clinical response was shown shortly after treatment initiation and low disease activity remained throughout the study. Both tofacitinib and baricitinib reduced radiographic progression. Some results showed either superiority or non-inferiority to methotreaxte or adalimumab. Both clinical efficacy and favourable safety profile enabled approval of tofacitinib and baricitinib for use in adult patients with RA with inadequate response to methotrexate. Tofacitinib has also been approved for treatment of patients with psoriatic arthritis and ulcerative colitis. Ongoing clinical trials with these and other JAK inhibitors will show their efficacy and safety in patients with RA or other inflammatory conditions. [ABSTRACT FROM AUTHOR]

Background and Objective: Periodontitis is an increasingly prevalent complication of diabetes mellitus (known as diabetes mellitus‐associated periodontitis), and 25‐hydroxyvitamin D3 (25VD3) was recently found to be a critical regulator of innate immunity in this disease, but the underlying mechanisms remain poorly understood. T‐cell protein tyrosine phosphatase non‐receptor type 2 (PTPN2) is a potential downstream protein of the 25VD3/vitamin D receptor pathway. The aim of this study was to investigate the regulation of PTPN2 in periodontal inflammation in diabetes mellitus‐associated periodontitis. Material and Methods: Porphyromonas gingivalis‐infected db/db mice were treated with 25VD3. Their fasting blood glucose and body weight were monitored every other week, and the levels of alveolar bone loss and serum inflammatory cytokines (tumor necrosis factor‐α, interferon‐γ and interleukin‐6) were determined at the time of killing. The effect of PTPN2 on human OKF6‐TERT2 oral keratinocytes was examined through the knockout of PTPN2 using the CRISPR/Cas9 knockout plasmid. The expression levels of the PTPN2, vitamin D receptor and JAK1/STAT3 signaling proteins in the gingival epithelium and OKF6‐TERT2 cells were determined through western blot and immunohistochemical analyses. Results: After 25VD3 treatment, db/db mice exhibited alleviated serum inflammatory cytokines and alveolar bone loss, and 25VD3‐enhanced PTPN2 expression decreased the expression of the JAK1/STAT3 signaling proteins in the gingival epithelium. Analyses of human oral keratinocytes showed that 25VD3 increased the expression of PTPN2, which dephosphorylates protein substrates in the JAK1/STAT3 signaling pathway. Conclusion: PTPN2 contributed to a decrease in periodontal inflammation in type 2 diabetes mellitus via dephosphorylate protein substrates in the JAK1/STAT3 signaling pathway after 25VD3 treatment in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. A thorough understanding of PTPN2 and its involvement in inhibiting inflammation might provide alternative therapeutic approaches for the pathogenesis and treatment of diabetes mellitus‐associated periodontitis. [ABSTRACT FROM AUTHOR]

Vascular leakage is a hallmark of the inflammatory response. Acute changes in endothelial permeability are due to posttranslational changes in intercellular adhesion and cytoskeleton proteins. However, little is known about the mechanisms leading to long-term changes in vascular permeability. Here, we show that interleukin-6 (IL-6) promotes an increase in endothelial monolayer permeability that lasts over 24 h and demonstrate that activation of Src and MEK/ERK pathways is required only for short-term increases in permeability, being dispensable after 2 h. In contrast, Janus kinase (JAK)-mediated STAT3 phosphorylation at Y705 (but not S727) and de novo synthesis of RNA and proteins are required for the sustained permeability increases. Loss of junctional localization of VE-cadherin and ZO-1 is evident several hours after the maximal IL-6 response, thus suggesting that these events are a consequence of IL-6 signaling, but not a cause of the increased permeability. Understanding the mechanisms involved in sustaining vascular permeability may prove crucial to allow us to directly target vascular leakage and minimize tissue damage, thus reducing the rates of mortality and chronic sequelae of excessive edema. Targeting endothelial-specific mechanisms regulating barrier function could provide a new therapeutic strategy to prevent vascular leakage while maintaining the immune response and other beneficial aspects of the inflammatory response that are required for bacterial clearance and tissue repair. [ABSTRACT FROM AUTHOR]

We investigated the effects of dasatinib on natural killer (NK) cell-induced signaling protein and perforin expression as well as plasma cytokine levels by analyzing blood samples from patients with well-controlled chronic myeloid leukemia receiving tyrosine kinase inhibitor (TKI) therapy. Perforin expression and phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, Janus kinase (JAK) 1, and JAK2 in NK cells were evaluated by flow cytometry, and the levels of plasma cytokines, including interferon (IFN)-γ and interleukin (IL)-2, were determined by enzyme-linked immunosorbent assays in 40 patients (dasatinib, n = 23; imatinib, n = 11; and nilotinib, n = 6). Perforin levels in NK cells were higher in dasatinib-treated patients before TKI treatment; phospho (p)-STAT1 levels were closely correlated with pJAK1 and perforin levels, and pSTAT3 levels were correlated with pJAK2 and perforin levels. The correlation between pJAK1 and pSTAT1 was apparent in dasatinib-treated patients but not in other TKI-treated patients, and the correlation between pJAK2 and pSTAT3 was apparent in patients treated with other TKIs. Constitutive expression of IFN-γ was higher in patients treated with dasatinib or with other TKIs than in those who were in treatment-free remission (TFR). In contrast, constitutive expression of IL-2 was lower in patients treated with other TKIs than in those treated with dasatinib or in those who were in TFR. These results provided insights into the effects of dasatinib on JAK/STAT signaling in NK cells in vivo and the mechanisms underlying NK cell activation induced by dasatinib therapy. [ABSTRACT FROM AUTHOR]

Objective: We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, which are major regulators of energy homeostasis, on the RNA level. Methods: We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro, and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student's t-test for independent samples was applied, and effect sizes using Cohen's d with 95% confidence intervals were therefore calculated. Results: In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11 (-3.53, -2.70)), Irf9 (689Leu; d = 44.65 (-2.57, -2.26)), and Isg15 (150Arg; d = 20.35 (-2.19, -1.57))). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 (Cap1 (150Arg; d = 7.48 (-0.62, -0.24)), Mapk1 (343Met; d = -6.80 (0.17, 0.45)), and Sorbs1 (689Leu; d = 7.82 (-1.60, -0.64))). Conclusion: The increased expression of genes in the leptin (JAK/STAT or AKT) signaling pathway implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling. [ABSTRACT FROM AUTHOR]

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is one of the main pleiotropic cascades used to transmit information from extracellular receptors to the nucleus, which results in DNA transcription and expression of genes involved in immunity, proliferation, differentiation, migration, apoptosis, and cell survival. Members of JAK family and STAT family have been extensively studied in different mammalian species because of their important roles in innate and adaptive immune responses. However, they have not been systematically studied among teleost fish species. In this study, five JAK family members and eight STAT family members were identified and characterized from channel catfish. Phylogenetic analysis was conducted to properly annotate these genes. Syntenic analysis was also conducted to establish orthology, and confirm the results from phylogenetic analysis. Compared to mammals, more members of the JAK and STAT family were identified in channel catfish genome. Expression of JAK and STAT family members was detected in healthy catfish tissues, but was induced in gill, liver, and intestine after bacterial challenge. Notably, the significant upregulation of STAT1b gene in catfish liver, gill and intestine after Edwardsiella ictaluri infection supported the notion that high STAT1 expression are involved in defense against pathogens. Collectively, the increased expression of JAK and STAT members in tested tissues suggested their crucial function in defending the host against pathogen invasion. [ABSTRACT FROM AUTHOR]

The majority of Parkinson’s disease (PD) cases are sporadic with only about 10% of PD patients having a family history of the disease suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Both oxidative stress and neuroinflammation are thought to contribute to PD. Previously, we showed that the activation of interleukin 13 receptor alpha 1 (IL-13Rα1) increases the sensitivity of dopaminergic neurons to oxidative damage both in cultured cells and in animals. In this study, we investigated the pathways involved in the IL-13-mediated potentiation of oxidative stress-induced dopaminergic cell death using a combination of cell survival assays and Western blotting with appropriate antibodies. In addition, siRNA was used to examine the role of 4E-BP1 in this cell toxicity paradigm. We show that activation of both the Jak-Stat and PI3 kinase-mTOR pathways play key roles in the promotion of cell death by IL-13 in the presence of mild oxidative stress. The Jak 1/2 inhibitor ruxolitinib, the mTOR inhibitor rapamycin and the PI3 kinase inhibitor LY294002 all prevented the potentiation of cell death by IL-13. Moreover, 4E-BP1, a target of mTOR, appeared to mediate the protective effects of rapamycin. Together, these results indicate that multiple signaling pathways downstream of IL-13Rα1 activation play a role in the toxic effects of IL-13 in dopaminergic neurons in the presence of mild oxidative stress and suggest that any of these pathways might provide potential targets for the treatment of PD. [ABSTRACT FROM AUTHOR]

To investigate whether IL‐6 signaling affects the susceptibility of castration‐resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL‐6 levels) were developed by lentiviral transduction. While observing no secreted IL‐6 level in parental C4‐2 and CWR22Rv1 cells, we found the IL‐6 expression/secretion in these cells was induced after the transduction process and the IL‐6 level difference in C4‐2siIL‐6/sc and CWR22siIL‐6/sc cell CRPC cell sets could be detected. We then found that IL‐6‐knockdown cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD‐L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL‐6‐expressing cell‐derived tumors were more resistant to NK cell action than the tumors of IL‐6‐knockdown cells. Further, we discovered that JAK‐Stat3 is the most critical IL‐6 downstream signaling that modulates PD‐L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4‐2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD‐L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL‐6 signaling (or its downstream signaling) may enhance the NK cell‐mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat patients with CRPC. [ABSTRACT FROM AUTHOR]

Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point, ruxolitinib effects towards expression of main inflammatory cytokines were studied in human macrophages, which constitute a key-cell type implicated in inflammation. Analysis of mRNA expression of cytokines ( n = 84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus lipopolysaccharide (LPS) ( n = 44), 61.4% ( n = 27) were repressed by 5 μM ruxolitinib. The major inflammatory cytokines, interleukin (IL) 6 and tumor necrosis factor α, were notably down-regulated by ruxolitinib at both the mRNA and protein level. Other repressed cytokines included IL27 and the chemokines CCL2, CXCL9, CXCL10 and CXCL11, but not IL1β. The interferon (IFN) β/JAK/signal transducer and activator of transcription (STAT) pathway, well-activated by LPS in human macrophages as demonstrated by increased secretion of IFNβ, STAT1 phosphorylation, and up-regulation of reference IFNβ-responsive genes, was concomitantly blocked by the JAK inhibitor. Most of cytokines targeted by ruxolitinib were shown to be regulated by IFNβ in a JAK-sensitive manner. In addition, counteracting the IFNβ/JAK/STAT cascade using a blocking monoclonal antibody directed against IFNβ receptor resulted in a similar profile of cytokine repression to that observed in response to the JAK inhibitor. Overall, these data provide evidence for ruxolitinib-mediated repression of inflammatory cytokines in human macrophages through inhibition of the LPS/IFNβ/JAK/STAT signalling pathway, which probably contributes to the anti-inflammatory effects of the JAK inhibitor. [ABSTRACT FROM AUTHOR]

Janus kinases (JAKs) are non-receptor protein tyrosine kinases that are expressed in many tissues. Once the JAKs are activated, a cascade of further signaling events is triggered involving phosphorylation of selected receptor chain tyrosines, binding of signal transducer and activator of transcription (STAT) proteins and phosphorylation of these STATs. Due to their ability to selectively modulate immune function, targeted JAK inhibitors are promising candidates for some skin diseases such as psoriasis and atopic dermatitis. The aim of this study was to assess the level of JAK1 in both vitiligo and psoriasis patients before and after treatment with NB-UVB which is considered a gold standard therapy for both diseases. This study was conducted on 10 patients with psoriasis, 10 patients with vitiligo and 10 controls. JAK1 levels before and after treatment with NB-UVB 311 nm (36 sessions) were measured using Western blot assay. The level of JAK1 was significantly higher in vitiligo and psoriasis patients than controls. There was a decline in the level of JAK1 after treatment, which was statistically significant. VASI and PASI scores of patients decreased after treatment with NB-UVB. In psoriatic patients, the JAK1 level positively correlated with the female participants, disease duration and PASI change. It was concluded that JAK1 plays a role in the pathogenesis of both vitiligo and psoriasis based on its upregulated level before treatment and downregulated level after treatment. This raises the possibility of using the JAK1 inhibitors as targeted immunotherapy for vitiligo and psoriasis. [ABSTRACT FROM AUTHOR]

The role of JAK/STAT3-mediated signaling pathway in the realization of the growth potential of mesenchymal precursor cells was examined in vitro. The stimulating role of JAKs and STAT3 towards proliferating activity of progenitor cells and their different role in the regulation of differentiation of the progenitor elements were demonstrated. Inhibitors of JAKs and STAT3 reduced the yield of fibroblast CFU and their mitotic activity. Blockade of JAKs accelerated and selective inactivation of STAT3 decelerated differentiation of progenitor cells. [ABSTRACT FROM AUTHOR]

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is crucial for transducing signals from a variety of metabolically relevant hormones and cytokines including growth hormone, leptin, erythropoietin, IL4, IL6 and IFNγ. A growing body of evidence suggests that this pathway is dysregulated in the context of obesity and metabolic disease. Recent development of animal models has been instrumental in identifying the role of JAK/STAT signaling in the peripheral metabolic organs including adipose, liver, muscle, pancreas, and the immune system. In this review we summarize current knowledge about the function of JAK/STAT proteins in the regulation of metabolism, and highlight new potential therapeutic targets for the treatment of obesity and diabetes. [ABSTRACT FROM AUTHOR]

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is central to signaling by receptors of diverse cytokines, growth factors, and other related molecules. Many of these receptors transmit anti-apoptosis, proliferation, and differentiation signals that are critical for normal hematopoiesis and immune response. However, the JAK/STAT signaling pathway is deregulated in many hematologic malignancies, and as such is co-opted by malignant cells to promote their survival and proliferation. It has recently come to light that an alternative mechanism, wherein nuclear JAKs epigenetically modify the chromatin to increase gene expression independent of STATs, also plays an important role in the pathogenesis of many hematologic malignancies. In this review, we will focus on common genetic alterations of the JAK family members in leukemia and lymphoma, and provide examples in which JAKs regulate gene expression by targeting the cancer epigenome. [ABSTRACT FROM AUTHOR]

Background The cellular and molecular mechanisms implicated in age-associated changes in myocardial structure are of paramount importance since they cause profound alterations in the functional response and represent targets for alleviating age-related pathologies. One of these mechanisms is the JAK/STAT/SOCS signaling pathway. Aim of the study The present study is designed to elucidate age-dependent changes of the myocardium to provide morphological basis displaying the pathogenesis of myocardial hypertrophy, fibrosis and inflammation with aging. Material and methods Thirty male Sprague Dawley rats aged; 6, 30 and 36 months were used in this study. The animals were divided into three age groups, young adult, senile and very senile rats, respectively. The heart weight/body weight ratio was determined. The heart was subjected to gross morphologic examination, microscopic examination using H&E and Masson’s trichrome stains and immunohistochemical examination for detection of JAK, pSTAT3, α-SMA, β-MHC and CD45. Western blotting was also carried out to detect SOCS genes. Real-time PCR was used to detect the inflammatory markers TNFα and IL1β and the hypertrophy marker α-SKA. Biochemical analysis of cardiac troponin I and creatine kinase-MB was done. Quantitative histomorphometric estimations included estimation of cardiac myocyte cross sectional area, estimation of the area percent of collagen fibers in Masson's trichrome stained sections and determination of optical density in immunostained sections. Electron microscopic examination was done to determine capillary density. Results Jak and pSTAT3 were predominantly localized to the nuclei and exhibited progressive decline with aging, while SOCS3 activity displayed an age-related increase. The aged myocardium displayed profound age associated structural changes as well as myocardial hypertrophy, fibrosis and inflammation in senile and very senile rats. Conclusion The age-related modifications in the JAK/STAT/SOCS signaling as well as the age-associated pathological changes in myocardial structure are of particular interest as they provide further insight in age-associated heart pathologies and represent potential targets for cardioprotective and therapeutic approaches. [ABSTRACT FROM AUTHOR]

[Display omitted] Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2 – 4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC 50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis which is lethal in over 90% of cases despite the standard therapies. Mainly activated by Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) is a key transcription factor, capable of exerting the expression of multitude of genes involved in survival. Moreover, STAT3 activity is regulated by the interleukin 28 receptor α (IL28RA) and glutathione s-transferase mu-3 (GSTM3), up-regulation of both contributes to the invasiveness of pancreatic cancer cells. In this regard, STAT3 overactivity has an important pathogenic role in the development of PDAC as it is associated with enhanced cell proliferation, survival, angiogenesis, and metastasis. STAT3-associated expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 3 and 9 are implicated in the angiogenic and metastatic behavior of the PDAC. Multitude of evidence underline the protective role of STAT3 inhibition against PDAC both in cell cultures and in tumor grafts. However, specific inhibition of STAT3 was not feasible until recently, when a selective potent chemical STAT3 inhibitor, termed N4, were developed and it turned out to be highly effective against PDAC in vitro, as well as in vivo. This review aims to discuss the most recent advances in our understanding of STAT3 role in the pathogenesis of PDAC and its therapeutic applications. [ABSTRACT FROM AUTHOR]

The realisation that unregulated activation of the Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway is a key driver of a wide range of diseases has identified its components as targets for therapeutic intervention by small molecule inhibitors and biologicals. In this review, we discuss JAK-STAT signalling pathway inhibition by the inducible inhibitor “suppressor of cytokine signaling 3 (SOCS3), its role in diseases such as myeloproliferative disorders, and its function as part of a multi-subunit E3 ubiquitin ligase complex. In addition, we highlight potential applications of these insights into SOCS3-based therapeutic strategies for management of conditions such as vascular re-stenosis associated with acute vascular injury, where there is strong evidence that multiple processes involved in disease progression could be attenuated by localized potentiation of SOCS3 expression levels.

Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies.