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Background: Janus kinase (JAK) activation is suggested to have a pathological role in alopecia areata (AA). CTP-543, a deuterated compound that selectively inhibits JAK1 and JAK2, is being developed as an oral treatment for AA.Objective: To assess the safety and efficacy of a 24-week regimen of CTP-543 in patients with chronic, moderate-to-severe AA.Methods: In this phase 2, randomized, double-blind, placebo-controlled, sequential-design trial, patients were randomized to receive CTP-543 (4 mg, 8 mg, or 12 mg) or placebo every 12 hours for 24 weeks.Results: A dose-related increase was observed in the percentage of patients with ≥50% relative reduction in Severity of Alopecia Tool scores from baseline at week 24 (9% placebo, 21% 4 mg twice daily, 47% 8 mg twice daily, and 58% 12 mg twice daily), with statistical significance versus placebo (P < .001) observed for the 8-mg twice daily and 12-mg twice daily groups, with differences from placebo noted as early as 12 weeks after the initiation of treatment. Safety results were consistent with the known safety profiles of JAK inhibitors.Limitations: These initial findings are from a relatively small controlled trial, and additional studies are needed to fully characterize the safety and efficacy of CTP-543 in adult patients with AA.Conclusions: Patients treated with CTP-543 (8 or 12 mg, twice daily) had a significant reduction in the severity of AA. [ABSTRACT FROM AUTHOR]

Decreasing efficacy over time and initial suboptimal response to Janus kinase (JAK) inhibitors such as ruxolitinib in a subset of patients are critical clinical challenges associated with myeloproliferative neoplasms (MPNs), primarily myelofibrosis. The role of phosphatidylinositol-3 kinase (PI3K) in MPN disease progression and treatment resistance and as a potential therapeutic target in patients who experience loss of response to JAK inhibition is discussed. Understanding the complex signaling networks involved in the pathogenesis of MPNs has identified potentially novel therapeutic targets and treatment strategies, such as inhibiting other signaling pathways in addition to the JAK/signal transducer and activator of transcription (STAT) pathway. PI3K plays a crucial role downstream of JAK signaling in rescuing tumor cell proliferation, with PI3Kδ being particularly important in hematologic malignancies. Concurrent targeting of both PI3K and JAK/STAT pathways may offer an innovative therapeutic strategy to maximize efficacy. Based on our understanding of the underlying mechanisms and the role of PI3K pathway signaling in the loss of response or resistance to JAK inhibitor treatment and initial results from clinical studies, the combination of parsaclisib (PI3Kδ inhibitor) and ruxolitinib holds great clinical potential. If confirmed in larger clinical trials, parsaclisib may provide more treatment options and improve clinical outcomes for patients with MPNs. [ABSTRACT FROM AUTHOR]

Neurokinin 2 receptor (NK2R), a G protein‐coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. However, the precise role and regulation of NK2R expression in cancer cells have not been fully elucidated. In this study, we found that high NK2R gene expression was correlated with the poor survival of colorectal cancer patients, and Interferon (IFN‐α/β) stimulation significantly enhanced NK2R gene expression level of colon cancer cells in a Janus kinas 1/2 (JAK 1/2)‐dependent manner. NKA stimulation augmented viability/proliferation and phosphorylation of Extracellular‐signal‐regulated kinase 1/2 (ERK1/2) levels of IFN‐α/β‐treated colon cancer cells and NK2R blockade by using a selective antagonist reduced the proliferation in vitro. Administration of an NK2R antagonist alone or combined with polyinosinic‐polycytidylic acid, a synthetic analog of double‐stranded RNA, to CT26‐bearing mice significantly suppressed tumorigenesis. NK2R‐overexpressing CT26 cells showed enhanced tumorigenesis and metastatic colonization in both lung and liver after the inoculation into mice. These findings indicate that IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells, suggesting that NK2R blockade may be a promising strategy for colon cancers. [ABSTRACT FROM AUTHOR]

Background: Upadacitinib, a janus kinase 1 (JAK1) inhibitor, is effective for moderate-to-severe atopic dermatitis (AD). Upadacitinib treatment may be discontinued in some patients, however, the effectiveness and safety of retreatment after its withdrawal have not been precisely examined in real-world practice., Objectives: To evaluate the effectiveness and safety of upadacitinib retreatment after withdrawal in real-world clinical practice for Japanese AD patients., Methods: This retrospective study included 62 Japanese patients with moderate-to-severe AD treated with upadacitinib 15 mg (n = 38) or 30 mg (n = 24). Effectiveness was assessed using eczema area severity index (EASI) and peak pruritus numerical rating scale (PP-NRS) before treatment (baseline), at time-periods of discontinuation, retreatment, and week 12 after retreatment of upadacitinib. Safety was evaluated through the incidence of treatment-emergent adverse events (TEAE)., Results: EASI and PP-NRS scores significantly decreased at week 12 after retreatment of upadacitinib compared to baseline in both 15 mg and 30 mg groups. Achievement rates of EASI 75, EASI 90, and EASI 100 at week 12 after retreatment were 83.8%, 56.8%, and 18.9% in 15 mg group, and 87.0%, 56.5%, and 17.4% in 30 mg group, respectively. TEAEs were mild or moderate, and no serious adverse events or deaths were reported., Conclusions: Retreatment of upadacitinib after withdrawal effectively improved clinical signs and pruritus in patients with AD, with a manageable safety profile, supporting its use for long-term management of AD., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Lenvatinib resistance presents a significant challenge in the clinical management of advanced hepatocellular carcinoma (HCC). To address this issue, we established lenvatinib resistant HCC cells and performed high-throughput screening using FDA-approved anti-cancer drug library. Through quantitative selective drug sensitivity scoring (sDSS), pacritinib, a well-known JAK inhibitor, emerged as the top candidate, displaying the highest sDSS score among 219 compounds. We further demonstrated that pacritinib reduced the viability of a panel of HCC cell lines in a dose-dependent manner, while exhibiting minimal effects on normal liver cells. Interestingly, pacritinib, but not other JAK inhibitors such as ruxolitinib, upadacitinib, or filgotinib, acted synergistically with lenvatinib in HCC cells. In lenvatinib-resistant HCC cells, pacritinib significantly decreased proliferation and induced apoptosis. Rescue studies using IL-1 receptor-associated kinase 1 (IRAK1) overexpression and knockdown revealed that pacritinib's effects are mediated through IRAK1, with minimal impact on normal liver cells. In a xenograft model of lenvatinib-resistant HCC, oral administration of pacritinib significantly reduced tumor size without affecting body weight. Immunohistochemical analysis of tumor sections revealed that pacritinib reduced Ki67 staining and phosphorylated IRAK1. Our findings suggest that pacritinib may be a promising therapeutic option for the treatment of advanced HCC, particularly in patients who have developed resistance to lenvatinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Participating in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, TYK2 emerges as a promising therapy target in controlling various autoimmune diseases, including psoriasis and multiple sclerosis. Deucravacitinib (DEU) is a novel oral TYK2-specific inhibitor approved in 2022 that is clinically effective in moderate to severe psoriasis trials. Upon the AlphaFold2 predicted TYK2 pseudokinase domain (JH2) and kinase domain (JH1), we explored the details of the underlined allosteric inhibition mechanism on TYK2 JH2-JH1 with the aid of molecular dynamics simulation. Our results suggest that the allosteric inhibition of DEU on TYK2 is accomplished by affecting the JH2-JH1 interface and hampering the state transition and ATP binding in JH1. Particularly, DEU binding stabilized the autoinhibitory interface between JH2 and JH1 while disrupting the formation of the activation interface. As a result, the negative regulation of JH2 on JH1 was greatly enhanced. These findings offer additional details on the pseudokinase-dependent autoinhibition of the JAK kinase domain and provide theoretical support for the JH2-targeted drug discovery in JAK members., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Uveitis remains one of the leading causes of blindness worldwide, with different etiologies requiring separate approaches to treatment. For over a decade, oral, topical, and local injection of corticosteroids as well as systemic conventional disease-modifying antirheumatic drugs (DMARDs) have remained the most effective treatment for noninfectious uveitis (NIU). Systemic administration of antitumor necrosis factor-α and other biological DMARDs have been used for treating cases that responded inadequately to conventional treatments. Unfortunately, some refractory patients still suffer from frequent attacks despite the combination of multiple treatments. Recently, there has been promising evidence for Janus kinase (JAK) inhibitors as the next-generation therapy for NIU. The JAK/signal transducers and activators of the transcription (STAT) signaling pathway mediate the downstream events involved in immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis by binding various ligands, such as cytokines, growth hormones, and growth factors. The mutation or loss of JAK/STAT components is implicated in autoimmune diseases, thus inhibition of such pathways has been an important area of research in therapeutic development. 1 In this review, we provide a comprehensive overview of the efficacy and safety of JAK inhibitors for the management of NIU, with evidence from current trials and case reports.

Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization., Competing Interests: Competing interests The authors declare no competing interests.

Introduction: Alopecia Areata (AA), characterized by non-scarring hair loss due to the dysregulation of the JAK/STAT pathway, has long lacked effective treatment. In 2023, Ritlecitinib, a novel Janus kinase (JAK) 3 and tyrosine kinase family inhibitor, received its first approval from the US FDA to treat AA, followed by approvals in Japan, Europe, China, and the UK. This development aims to address the challenges faced by millions of individuals affected by this condition globally., Areas Covered: This review offers an overview of Ritlecitinib's pharmacological properties, biological targets, and development strategies. It examines its mechanism of action, pharmacokinetics, pharmacodynamics, and clinical trial insights. Additionally, it covers the drug's chemical synthesis, contraindications, drug interactions, and potential adverse effects, with special attention to its use in adolescents, pregnant women, and the elderly., Expert Opinion: Ritlecitinib represents a significant advancement in treating AA, offering a targeted approach with promising efficacy and a favorable safety profile. While long-term safety data and real-world effectiveness studies are needed, its oral administration and efficacy in both adults and adolescents position it as a potentially transformative therapy. Ongoing research should focus on optimizing treatment strategies, identifying predictive biomarkers, and assessing cost-effectiveness to fully realize Ritlecitinib's potential in improving outcomes.

Cardiac development requires precise gene expression programs at each developmental stage guided by multiple signaling pathways and transcription factors (TFs). MESP1 is transiently expressed in mesoderm, and is essential for subsequent cardiac development, while the precise mechanism regulating its own transcription and mesoderm cell fate is not fully understood. Therefore, we developed a high content screen assay to identify regulators of MESP1 expression in mesodermal cells differentiated from human pluripotent stem cells (hPSCs). The screen identified CYT387, a JAK1/JAK2 kinase inhibitor, as a potent activator of MESP1 expression, which was also found to promote cardiomyocyte differentiation in vitro. Mechanistic studies found that JAK inhibition promotes MESP1 expression by reducing cytoplasmic calcium concentration and subsequently activating canonical WNT signaling. Our study identified a role of JAK signaling in early mesodermal cells, and sheds light on the connection between the JAK-STAT pathway and transcriptional regulation of MESP1, which expands our understanding of mesoderm and cardiac development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Abstract Background Lineage plasticity in prostate cancer (PCa) has emerged as an important mechanism leading to the onset of therapy‐ and castration‐resistant PCa (t‐CRPC), which is closely associated with cancer stem cell (CSC) activity. This study is to identify critical driver(s) with mechanism of action and explore new targeting strategy. Methods Various PCa cell lines with different genetic manipulations were subjected to in vitro prostasphere assay, cell viability assay and in vivo stemness potential. In addition, bioinformatic analyses such as Ingenuity pathway and Gene Set Enrichment Analysis were carried out to determine clinical relevance. The in vivo anti‐tumour activity of JAK or STAT1 inhibitors was examined in clinically relevant t‐CRPC model. Results We demonstrated the role of interferon‐related signalling pathway in promoting PCa stemness, which correlated with significant elevation of interferon related DNA damage resistance signature genes in metastatic PCa. Inhibition of JAK‐STAT1 signalling suppresses the in vitro and in vivo CSC capabilities. Mechanistically, IFIT5, a unique downstream effector of JAK‐STAT1 pathway, can facilitate the acquisition of stemness properties in PCa by accelerating the turnover of specific microRNAs (such as miR‐128 and ‐101) that can target several CSC genes (such as BMI1, NANOG, and SOX2). Consistently, knocking down IFIT5 in t‐CRPC cell can significantly reduce in vitro prostasphere formation as well as decrease in vivo tumour initiating capability. Conclusions This study provides a critical role of STAT1‐IFIT5 in the acquisition of PCSC and highlights clinical translation of JAK or STAT1 inhibitors to prevent the outgrowth of t‐CRPC.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 (TCL1) overexpression and ATM loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between TCL1 family members and ATM is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.

Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn’s disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials.

Summary: Fedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109/l, based on outcomes from the phase 3, placebo‐controlled JAKARTA trial in JAK‐inhibitor‐naïve MF, and the phase 2, single‐arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109/l ("Low‐Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low‐Platelets cohort and patients with baseline platelet counts ≥100 × 109/l ("High‐Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low‐ and High‐Platelets cohorts. Fedratinib was generally well‐tolerated in both platelet‐count cohorts. New or worsening thrombocytopaenia was more frequent in the Low‐Platelets (44%) versus the High‐Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low‐Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients. [ABSTRACT FROM AUTHOR]

Oclacitinib maleate (Apoquel®, Zoetis Inc.) is commonly used around the world for the control/treatment of pruritus associated with allergic dermatitis and the control/treatment of atopic dermatitis in dogs at least 12 months of age. A new flavored chewable formulation of oclacitinib has been developed where more than 90% of doses offered to dogs were freely accepted when tested in clinical trials. The objective of this study was to determine whether the new chewable formulation of oclacitinib has a similar onset of anti‐pruritic activity as the original oclacitinib film‐coated tablets (FCT). Twenty‐one laboratory beagle dogs were randomized to treatment and received placebo, 0.4–0.6 mg/kg oclacitinib FCT or 0.4–0.6 mg/kg flavored chewable oclacitinib tablet (n = 7/group). Efficacy was measured by assessing reduction in pruritus 1–3 h post‐administration of treatments. Pruritus was induced by injecting canine IL‐31, intravenously (2.5 μg/kg), approximately 15 min prior to the pruritus observation window. Results from this study demonstrated both oclacitinib FCT and the flavored chewable oclacitinib tablet significantly reduced IL‐31‐induced pruritus within 1–3 h post‐dosing compared to placebo (p =.0069 and.0113, respectively), suggesting the new formulation of oclacitinib chewable tablets works as quickly to reduce pruritus in dogs as the oclacitinib FCT. [ABSTRACT FROM AUTHOR]

When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Introduction: Human glioma is known as the most frequent and primary malignant tumour of the central nervous system with high aggression and poor prognosis. Runx1 is essential for haematopoiesis and is associated with tumour progression in several types of cancers. Therefore, this study aimed to investigate the effect and the possible regulatory mechanisms of Runx1 in glioma.Material and methods: The expression of Runx1 in human glioma tissues was determined by qRT-PCR and immunohistochemistry (IHC). Subsequently, the effect of Runx1 on the glioma cell viability, migration, invasion and the protein level of p21, cyclin D1, MMP2, and MMP4 were detected by MTT, wound healing, transwell assays, and western blot, respectively, in U-138MG and U-251MG cell lines. We then explored the role of Runx1 in vivo by establishing a tumour-bearing mouse model.Results: The expression of Runx1 was significantly up-regulated in human glioma tissues and closely associated with tumour grade. Glioma patients with high Runx1 expression had decreased survival rate compared to those with low Runx1 level. Runx1 knockdown inhibited glioma cell viability, migration, invasion, and clone formation, while STAT3 suppressed these inhibitions. Moreover, Runx1 inhibited the activation of SOCS3/SOCS4 promoter, which in turn activated JAK/STAT3 signalling pathway. The tumour volume and weight of the siRunx1 group were lower than in the control group and the tumour mass grow more slowly as well.Conclusions: Runx1 promotes the development of glioma cells via JAK/STAT signalling pathway by inhibiting the activation of SOCS3/SOCS4 promoter. [ABSTRACT FROM AUTHOR]

• Identification of a pyrrolo[2,3- d ]pyrimidine derivative (IH-9) as a non-selective inhibitor against the kinases JAK3, SYK and GSK3β. • Design and synthesis of 13 compounds based on IH-9 structure for dual inhibition of JAK3 and SYK. • Experimental validation and SAR study of compound 6e as a dual inhibitor against JAK3 and SYK. Janus kinase (JAK) and spleen tyrosine kinase (SYK) are two crucial tyrosine kinases implicated in the immune modulation and represent launched therapeutic targets for immunological disorders. Nevertheless, the monotherapy targeting a single kinase encounters challenges related to drug resistance and inadequate efficacy. In this case, the exploration of inhibitors targeting both JAK and SYK has emerged as a promising therapeutic strategy. In this study, a series of novel pyrrolo[2,3- d ]pyrimidine derivatives were designed and synthesized to selectively inhibit both JAK3 and SYK. The lead compound, 6e , demonstrated an IC 50 value of 2.14 μM against JAK3 and 7.10 μM against SYK, while exhibiting negligible activity against GSK3β (IC 50 > 50 μM), providing a hit scaffold for the development of selective JAK/SYK dual inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]

TNF-α-inhibitors are known to induce skin adverseeffects including psoriasis and alopecia areata. Here, wedescribe a unique pattern of hair loss that has psoriaticand alopecia areata-like features. Diagnosis requiresclinical-pathologic correlation and is supportedby increased catagen/telogen hairs, psoriasiformepidermal hyperplasia, perifollicular lymphocyticinfiltrate, and the presence of eosinophils and plasmacells. Although there are no treatment consensusguidelines, management options include stoppingtherapy, switching to a different TNF-α inhibitor orustekinumab (in severe cases), or continuing TNF-αinhibitor therapy with addition of topical, intralesional,or systemic immunosuppressants.

Summary: Background: To date, only dexamethasone and tocilizumab have been shown to reduce mortality in patients with COVID-19. Baricitinib is a Janus kinase 1/2 inhibitor with known anti-inflammatory and anti-viral properties. We performed a meta-analysis of RCTs assessing the role of baricitinib in hospitalised patients with COVID-19. Methods: Electronic databases such as MEDLINE, EMBASE, and Cochrane Central were searched up until March 31, 2022, for RCTs evaluating the efficacy of baricitinib in hospitalised patients with COVID-19. The outcomes assessed were 28-day mortality, progression to invasive mechanical ventilation (IMV) or ECMO, progression to respiratory failure needing positive pressure ventilation, IMV or death, duration of hospitalisation and time to discharge. The meta-analysis was registered in the PROSPERO database (CRD42022314579). Findings: Four studies (with 10,815 patients) were included in the analysis. Pooled analysis using random-effects model showed a statistically significant reduction in 28-day mortality (OR 0.69, 95% CI 0.50-0.94; p=0.04, I2=65%) and composite outcome of progression to severe disease needing positive pressure ventilation, IMV or death (OR 0.89, 95% CI 0.80-0.99, p= 0.03, I2=0%). There was a favorable trend towards reduced progression to IMV or ECMO (OR 0.76, 95% CI 0.58-1.01; p=0.06, I2=49%) in the baricitinib arm compared to standard therapy, even though it was not statistically significant. Statistical significance was achieved for all outcomes with fixed-effects model analysis. Interpretation: In hospitalised patients with COVID-19, baricitinib was associated with reduced 28-day mortality although there was not a statistically significant reduction in progression to IMV or ECMO. Baricitinib used in conjunction with standard of care treatments is associated with improved mortality in hospitalised patients with COVID-19 disease. Funding: None.

When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers.

Myeloproliferative neoplasms (MPNs) are caused by genetic abnormalities in the stem cells and manifest with various systemic symptoms. Here, we describe a case of MPN complicated by alopecia areata. A 51-year-old woman visited our hematology department for further evaluation of a slight platelet elevation. Her recent medical history included 3 years of concurrent severe alopecia, mild fatigue, and hot flashes but no fever and weight loss. Physical examination revealed unilateral hair loss on the entire body but no hepatosplenomegaly. Laboratory analysis revealed a normal hemoglobin level, normal white blood cell count, and platelet count of 377,000/μL. Genetic testing confirmed the presence of the JAK2 V617F mutation. Bone marrow examination revealed no morphologic dysplasia in any stem cell lineage and no fibrotic change. Skin biopsy revealed lymphocyte infiltration around the hair follicles. We diagnosed MPN, unclassifiable, which was believed to be the cause of alopecia. About 6 months after treatment with ruxolitinib began, the patient's hair growth dramatically improved. The differential diagnosis of MPNs should include hematological diseases when affected patients have alopecia areata.

C/EBPβ is a member of the CCAAT/enhancer‐binding protein (C/EBP) family, which consists of a number of b‐ZIP transcription factors. Although C/EBPβ has been implicated in the development of certain cancers, including breast cancer, it remains unknown whether dysregulation of C/EBPβ in breast cancer is subtype‐specific. Moreover, the underlying mechanisms by which C/EBPβ regulates breast cancer carcinogenesis are not fully understood. Here, we present evidence that C/EBPβ is specifically overexpressed in human TNBC samples, but not in non‐TNBC samples. C/EBPβ depletion dramatically suppressed TNBC cell growth, migration, invasion, and colony formation ability. A subsequent mechanistic study revealed that the JAK/STAT signaling pathway was upregulated in C/EBPβ_high TNBC samples compared with C/EBPβ_low TNBC samples. C/EBPβ ChIP‐seq and qPCR were performed to demonstrate that C/EBPβ directly binds to and regulates JAK/STAT signaling pathway genes in TNBC. Taken together, our data indicate the oncogenic role of C/EBPβ in human TNBC and reveal a novel mechanism by which C/EBPβ promotes TNBC carcinogenesis.

The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been reported. To help design selective JAK inhibitors, in this paper, we used five model proteins to study the subtype selectivity of and the mutational effects on inhibitor binding. We also compared the Covalent Dock programs from the Schrodinger software suite and the MOE software suite to determine which method to use for the drug design of covalent inhibitors. Our results showed that the docking affinity from 4Z16 (JAK3 wild-type model), 4E4N (JAK1), 4D1S (JAK2), and 7UYT (TYK2) from the Schrödinger software suite agreed well with the experimentally derived binding free energies with small predicted mean errors. However, the data from the mutant 5TTV model using the Schrödinger software suite yielded relatively large mean errors, whereas the MOE Covalent Dock program gave small mean errors in both the wild-type and mutant models for our model proteins. The docking data revealed that Leu905 of JAK3 and the hydrophobic residue at the same position in different subtypes (Leu959 of JAK1, Leu932 of JAK2, and Val981 of TYK2) is important for ligand binding to the JAK proteins. Arg911 and Asp912 of JAK3, Asp939 of JAK2, and Asp988 of TYK2 can be used for selective binding over JAK1, which contains Lys965 and Glu966 at the respective positions. Asp1021, Asp1039, and Asp1042 can be utilized for JAK1-selective ligand design, whereas Arg901 and Val981 may help guide TYK2-selective molecule design.

To explore the metabolic mechanism of differential plasma interleukin (IL)-6 expression in patients with rheumatoid arthritis (RA). A total of 240 RA patients were enrolled in the non-target metabolomics study cohort and 69 healthy volunteers were included as healthy controls (HCs). Plasma IL-6 levels were detected by electrochemiluminescence assay. Plasma metabolites were detected by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Patients with active RA (n = 20) and remissive RA (n = 20) and 20 HCs were enrolled in the targeted validation cohort. Metabolites identified by non-target metabolomics were quantitatively analyzed by ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry. Effects of 1-oleoyl- sn -glycero-3-phosphocholine (OGPC) associated with IL-6 on MH7A cells were assessed. After 24-h or 48-h induction by TNF-α, the supernatants were collected for IL-6 quantification by enzyme-linked immunosorbent assay. Furthermore, Western blot was performed to investigate the relative JAK2 and p -JAK2 expressions. With an increasing IL-6 level, OGPC shown to be related to the glycerophospholipid metabolism pathway by Kyoto Encyclopedia of Genes and Genomes analysis displayed a significant decrease. In the validating RA cohort, the OGPC concentrations in remissive RA group and active RA group decreased compared with HC group. OGPC down-regulated IL-6 secretion and p -JAK2 expression in TNF-α-induced MH7A cells in vitro. In conclusion, glycerophospholipid metabolism is the main metabolic pathway associated with the differential IL-6 expression in RA patients. The down-regulated OGPC is a promoting factor for the increased IL-6 plasma level in RA patients, which further affects the downstream JAK signaling pathway. • Abnormal glycerophospholipid metabolism occurs in patients with rheumatoid arthritis. • OGPC negatively correlated with IL-6 in patients with rheumatoid arthritis. • OGPC had an inhibitory effect on MH7A cells through the IL-6/JAK signaling pathway. [ABSTRACT FROM AUTHOR]

Several Janus kinase (JAK) inhibitors (jakinibs) have recently been approved to treat inflammatory, autoimmune and hematological conditions. Despite emerging roles for JAKs and downstream signal transducer and activator of transcription (STAT) proteins in platelets, it remains unknown whether jakinibs affect platelet function. Here, we profile platelet biochemical and physiological responses in vitro in the presence of five different clinically relevant jakinibs, including ruxolitinib, upadacitinib, oclacitinib, baricitinib and tofacitinib. Flow cytometry, microscopy and other assays found that potent JAK1/2 inhibitors baricitinib and ruxolitinib reduced platelet adhesion to collagen, as well as platelet aggregation, secretion and integrin αIIbβ3 activation in response to the glycoprotein VI (GPVI) agonist collagen-related peptide (CRP-XL). Western blot analysis demonstrated that jakinibs reduced Akt phosphorylation and activation following GPVI activation, where ruxolitinib and baricitinib prevented DAPP1 phosphorylation. In contrast, jakinibs had no effects on platelet responses to thrombin. Inhibitors of GPVI and JAK signaling also abrogated platelet STAT5 phosphorylation following CRP-XL stimulation. Additional pharmacologic experiments supported roles for STAT5 in platelet secretion, integrin activation and cytoskeletal responses. Together, our results demonstrate that ruxolitinib and baricitinib have inhibitory effects on platelet function in vitro and support roles for JAK/STAT5 pathways in GPVI/ITAM mediated platelet function. [ABSTRACT FROM AUTHOR]

JAK inhibition is a new strategy for treating autoimmune and inflammatory diseases. Previous studies have shown the immunoregulatory and anti-inflammatory effects of Salvia miltiorrhiza and Cynara scolymus and suggest that the bioactivity of their phenolic acids involves the JAK-STAT pathway, but it is unclear whether these effects occur through JAK inhibition. The JAK binding affinities obtained by docking Rosmarinic acid (RosA), Salvianolic acid A (SalA), Salvianolic acid C (SalC), Lithospermic acid, Salvianolic acid B and Cynarin (CY) to JAK (PDB: 6DBN) with AutoDock Vina are −8.8, −9.8, −10.7, −10.0, −10.3 and −9.7 kcal/mol, respectively. Their predicted configurations enable hydrogen bonding with the hinge region and N- and C-terminal lobes of the JAK kinase domain. The benzofuran core of SalC, the compound with the greatest binding affinity, sits near Leu959, such as Tofacitinib's pyrrolopyrimidine. A SalC derivative with a binding affinity of −12.2 kcal/mol was designed while maintaining this relationship. The docking results show follow-up studies of these phenolic acids as JAK inhibitors may be indicated. Furthermore, derivatives of SalC, RosA, CY and SalA can yield better binding affinity or bioavailability scores, indicating that their structures may be suitable as scaffolds for the design of new JAK inhibitors. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) inhibitors have shown encouraging results in the treatment of alopecia areata (AA), an autoimmune form of hair loss, in small, uncontrolled studies and case reports. We conducted a biopsy substudy during the randomized, double-blind, placebo-controlled first 24 weeks of a phase 2a clinical trial that evaluated the efficacy and safety of ritlecitinib, an inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and brepocitinib, an inhibitor of tyrosine kinase 2 (TYK2)/JAK1 in the treatment of AA. Change in biomarkers in lesional scalp biopsy samples between baseline and weeks 12 and 24 was an exploratory end point, and 46 patients participated from the ritlecitinib (n = 18), brepocitinib (n = 16), and placebo (n = 12) groups. Correlations of biomarkers with hair regrowth, measured using the Severity of Alopecia Tool (SALT) score, were also evaluated. Clinical Trial Registration: NCT02974868. At week 24, both ritlecitinib and brepocitinib demonstrated improvement exceeding 100% in the lesional scalp transcriptome toward a nonlesional profile. At week 12, the improvements in scalp tissue were greater with brepocitinib than ritlecitinib; however, at week 24, the improvements were greater with ritlecitinib. For both ritlecitinib and brepocitinib, improvement in the SALT scores was positively associated with expression of T H 1 markers and negatively associated with expression of hair keratins. Larger, long-term clinical trials are warranted. [ABSTRACT FROM AUTHOR]

The effect of resistance training and a herbal supplement on muscular signaling pathways are limited. We investigated the expression of IL-6, Gp130, JAK and STAT after resistance training, and Spirulina platensis supplementation in animal muscle. Thirty-two male Sprague Dawley rats (weight: 290 ± 20 g, and 9 weeks of age) were divided into four groups: control (CO; n = 8), Spirulina platensis supplementation (SP; n = 8), resistance exercise (RE; n = 8), and Spirulina platensis + resistance exercise (SP + RE; n = 8). The resistance exercise group trained five sessions each week for eight weeks. Spirulina 200 mg kg-1 d-1 was used in the SP and SP + RE groups. Gene expression was measured by real-time PCR following the last training session. One-way ANOVA test with Tukey's post-hoc test were used for analysis of data (SPSS, version, 21). Data analysis revealed that the expression of IL-6 (P = 0.001), Gp130 (P = 0.001), JAK (P = 0.0001) and STAT (P = 0.004) increased significantly in the RE group. The expression of IL-6 (P = 0.018), JAK (P = 0.001) and STAT (P = 0.001) in SP + RE group also increased significantly (P ≤ 0.05). SP showed a significant increase in Gp130 (P = 0.001) and STAT (P = 0.001). Supplementation by Spirulina platensis may enhance muscle accretion during resistance training. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD. [ABSTRACT FROM AUTHOR]

Three main inflammatory signaling pathways include nuclear factor‐κB (NF‐κB), Janus kinases/Signal transducer and activator of transcriptions (JAKs/STATs), and mitogen‐activated protein kinases (MAPKs) play crucial roles in inducing, promoting, and regulating inflammatory responses in the immune system. Importantly, the breakdown of mechanisms that tightly regulate inflammatory signaling pathways can be the underlying cause of uncontrolled inflammatory responses and be associated with the generation and development of several inflammatory diseases. Hence, therapeutic strategies targeting inflammatory signaling pathways and their downstream components may promise to treat inflammatory diseases. Studies over the past two decades have provided important information on the polytrophic pharmacological and biochemical properties of berberine (BBR) as a naturally occurring compound, such as antioxidant, antitumor, antimicrobial, and antiinflammatory activates. Interestingly, the modulatory effects of BBR on inflammatory signaling cascades, which lead to the inhibition of inflammation, have been widely investigated in several in vitro and in vivo studies. For the first time, herein, this comprehensive review attempts to put together these studies and provide important insight into the modulatory effects of BBR on NF‐κB, JAKs/STATs, and MAPKs signaling pathways in vitro in various types of immune cells and in vivo in several experimental inflammatory diseases. As the second achievement of this review, we also explore the therapeutic efficacy and antiinflammatory effects of BBR regarding its modulatory action. [ABSTRACT FROM AUTHOR]

Ankylosing spondylitis, also known as radiographic axial spondyloarthritis, is a complex, immune-mediated inflammatory disorder most commonly involving the spine including the sacroiliac joints. Complex pathogenesis of axial spondyloarthritis involving genetic, environmental, and both innate and adaptive immune systems. Treatment options for ankylosing spondylitis. Pharmacologic properties, efficacy, and safety of tofacitinib, a JAK inhibitor. Data regarding efficacy of approved JAK inhibitors in the treatment of ankylosing spondylitis, including tofacitinib, upadacitinib, and filgotinib. Current treatment options of ankylosing spondylitis include NSAIDs, TNFi, and IL-17i. JAK inhibitors present a new class of therapy that has shown efficacy in the treatment of active ankylosing spondylitis in adults. While it has not been directly compared to alternative therapies, tofacitinib has been shown to be effective in both phase II and phase III trials for the treatment of ankylosing spondylitis. While these trials did not show any significant difference from placebo in terms of safety, the ORAL Surveillance study showed tofacitinib to be inferior to TNFi when comparing adverse events. Thus, tofacitinib presents a viable treatment option for the management of AS, however shared decision-making regarding risks and benefits will be important. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important “omics” tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual’s metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in “omics”-based biomarkers in AD.

A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[ d ][1, 3 ]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5- a ]pyridin-2-yl)amino)methyl)- N -hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC 50 values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.

Summary: NLRP3 inflammasome hyperactivation contributes to neuroinflammation in autoimmune disorders, but the underlying regulatory mechanism remains to be elucidated. We demonstrate that compared with wild-type (WT) mice, mice lacking thymic stromal lymphopoietin (TSLP) receptor (TSLPR) (Tslpr−/− mice) exhibit a significantly decreased experimental autoimmune encephalomyelitis (EAE) score, reduced CD4+ T cell infiltration, and restored myelin basic protein (MBP) expression in the brain after EAE induction by myelin oligodendrocyte glycoprotein35–55 (MOG35–55). TSLPR signals through Janus kinase (JAK)2, but not JAK1 or JAK3, to induce NLRP3 expression, and Tslpr−/− mice with EAE show decreased JAK2 phosphorylation and NLRP3 expression in the brain. JAK2 inhibition by ruxolitinib mimicked loss of TSLPR function in vivo and further decreased TSLP expression in the EAE mouse brain. The NLRP3 inhibitor MCC950 decreased CD4+ T cell infiltration, restored MBP expression, and decreased IL-1β and TSLP levels, verifying the pro-inflammatory role of NLRP3. In vitro experiments using BV-2 murine microglia revealed that TSLP directly induced NLRP3 expression, phosphorylation of JAK2 but not JAK1orJAK3, and IL-1β release, which were markedly inhibited by ruxolitinib. Furthermore, EAE induction led to an increase in the Th17 cell number, a decrease in the regulatory T (Treg) cell number in the blood, and an increase in the expression of the cytokine IL-17A in the WT mouse brain, which was drastically reversed in Tslpr−/− mice. In addition, ruxolitinib suppressed the increase in IL-17A expression in the EAE mouse brain. These findings identify TSLP as a prospective target for treating JAK2-NLRP3 axis-associated autoimmune inflammatory disorders. Thymic stromal lymphopoietin (TSLP)-mediated activation of inflammasome might be involved in experimental animal encephalitis. Janus kinase (JAK)2-directed NLRP3 inflammasome hyperactivation might play a critical role in the neuroinflammation. Ruxolitinib might be effective to alleviate NLRP3 inflammasome-mediated autoimmune inflammation in autoimmune encephalitis by inhibition of JAK2 signalling. [ABSTRACT FROM AUTHOR]

Major depressive disorder is a chronic psychiatric disease with a high prevalence. Brain mechanisms for depression at cellular and molecular levels are far from clear. Increasing evidence from clinical and preclinical studies reveals critical roles of the non-receptor tyrosine kinase (nRTK) superfamily in the pathophysiology, symptomatology, and therapy of depression. To date, several nRTK members from three nRTK subfamilies, i.e., the Src family kinase (SFK), the Janus tyrosine kinase (JAK) and the focal adhesion kinase (FAK) subfamilies, may connect to the intracellular, intranuclear, and synaptic signaling network linking chronic stress to depression- and anxiety-like behavior. These SFK/JAK/FAK nRTKs are abundantly expressed in the prefrontal cortex and hippocampus, two core limbic regions implicated in depression, and are enriched at synaptic sites. In various acute or chronic animal models of depression, the nRTKs were significantly altered (up- or downregulated) in their phosphorylation, expression, subcellular/subsynaptic distribution, and/or function. Stress that precipitates depressive behavior also influenced the interaction of nRTKs with other signaling molecules and downstream substrates, including ionotropic and metabotropic glutamate receptors. The commonly-used antidepressants showed the ability to alter nRTK activity. In sum, the limbic SFK/JAK/FAK nRTKs are sensitive to stress and undergo drastic adaptations in response to chronic depression. These long-lasting adaptations contribute to the remodeling of signaling network or synaptic plasticity critical for the vulnerability to depression and the therapeutic efficacy of antidepressants. [ABSTRACT FROM AUTHOR]

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STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes, notably including blood and immune cell development and function. Classically, STAT proteins have been viewed as inducible activators of transcription that mediate cellular responses to extracellular signals, particularly cytokines. In this 'canonical' paradigm, latent STAT proteins become tyrosine phosphorylated following receptor activation, typically via downstream JAK proteins, facilitating their dimerization and translocation into the nucleus where they bind to specific sequences in the regulatory region of target genes to activate transcription. However, growing evidence has challenged this paradigm and identified alternate 'non-canonical' functions, such as transcriptional repression and roles outside the nucleus, with both phosphorylated and unphosphorylated STATs involved. This review provides a revised framework for understanding the diverse kaleidoscope of STAT protein functional modalities. It further discusses the implications of this framework for our understanding of STAT proteins in normal blood and immune cell biology and diseases such as cancer, and also provides an evolutionary context to place the origins of these alternative functional modalities. [ABSTRACT FROM AUTHOR]

Bronchial asthma is a heterogeneous chronic inflammatory disease of airways. The studies of molecular and cellular mechanisms of bronchial asthma have established that a wide range of immune (T and B cells, eosinophils, neutrophils, macrophages, etc.) and structural (epithelial and endothelial) cells are involved in its pathogenesis. These cells are activated in response to external stimuli (bacteria, viruses, allergens, and other pollutants) and produce pro-inflammatory factors (cytokines, chemokines, metalloproteinases, etc.), which ultimately leads to the initiation of pathological processes in the lungs. Genes encoding transcription factors of the STAT family (signal transducer and activator of transcription), that includes seven representatives, are involved in the cell activation. Recent studies have shown that the transcription factor STAT3 plays an important role in the activation of the abovementioned cells, thus contributing to the development of asthma. In animal studies, selective inhibition of STAT3 significantly reduces the severity of lung inflammation, which indicates its potential as a therapeutic target. In this review, we describe the mechanisms of STAT3 activation and its role in polarization of Th2/Th17 cells and M2 macrophages, as well as in the dysfunction of endothelial cells, which ultimately leads to development of bronchial asthma symptoms, such as infiltration of neutrophils and eosinophils into the lungs, bronchial hyperreactivity, and the respiratory tract remodeling. [ABSTRACT FROM AUTHOR]

Abstract Vitiligo is a chronic inflammatory skin disease leading to the loss of epidermal melanocytes. To date, treatment options for vitiligo patients are limited, lack sustained efficacy, and are mainly based on off-label use of immunosuppressive agents, such as systemic or topical steroids or topical calcineurin inhibitors, in association with the use of ultraviolet light. However, recent insights into the understanding of the immune pathogenesis of the disease have led to the identification of several therapeutic targets and the development of targeted therapies that are now being tested in clinical trials. In this review, based on the physiopathology of the disease, we summarize emerging targets that could be developed for the treatment of vitiligo and discuss recent and ongoing developments of drugs for the management of the disease.

Purpose: Vitiligo is a T cell-mediated skin depigmentation disease. Though treatments arresting disease progression and inducing repigmentation are available, the efficacy of these options is often limited and poorly sustained. How stromal signals contribute to the interferon-γ-dominant skin niches is unclear. This study aims to determine how fibroblasts participate in the IFN-γ-dominant vitiligo niche. Patients and methods: Mouse vitiligo models were established. Fibroblasts from control and vitiligo mice were extracted for RNA sequencing. In vitro IFN-γ stimulation was performed to verify the JAK-STAT pathway by qPCR and Western blot. T cell polarization with chemokines was measured by flow cytometry. Protein levels in tissues were also examined by IHC. Results: The vitiligo mouse model recapitulates the human CD8-IFN-γ pathway. RNA sequencing revealed elevated chemokine CCL2 and CCL8 in vitiligo fibroblast, which may be regulated by the JAK-STAT signaling. Such phenomenon is verified by JAK inhibitor peficitinib in vitro. Moreover, CCL2 addition into the naïve T polarization system promoted type 2 cytokines secretion, which represents a hallmark of vitiligo lesions. Conclusion: Dermal fibroblasts, a principal constituent of skin structure, respond to IFN-γ by skewing T cells towards a type 2 cytokine profile via CCL2 and CCL8, which can be abrogated by JAK inhibitor peficitinib.

Background: The advent of JAK inhibitors (JAKi) has significantly modernised the treatment of atopic dermatitis (AD), offering a novel approach to treating this recalcitrant dermatological condition. Although topical treatment is shown to be effective, oral formulations are yet to be widely utilised in the treatment of AD. Objectives: To review the efficacy, safety, and tolerability of JAKi in the treatment of AD. Methods: A PRISMA systematic review of several databases was conducted: Cochrane Skin Specialised Register, Cochrane Central Register of Controlled Trials, Ovid Medline and Embase, LILACS, and Global Resource of EczemA Trials. Five clinical trial archives were also consulted. The following resources were manually searched: conference proceedings of the American Academy of Dermatology (AAD), FDA.gov, the European Medicines Agency (EMA), and Epistemonikos. Results: Of the 34 articles meeting inclusion criteria, 6 were chosen for final qualitative review. A total of 827 patients were pooled from 5 randomised controlled trials and 1 cohort study. Improvements in objective and subjective scoring indices were observed in patients receiving topical or oral JAKi. Overall safety and tolerability were satisfactory in JAKi treatment. Limitations: Due to the scarcity of randomised controlled trials and the small sample sets in the studies, a meta-analysis was not conducted. Conclusions: Preliminary investigations show promising results for patients with AD treated with oral or topical JAKi. However, existing gaps should be addressed with more extensive and long-term trials before JAKi become a standard treatment for AD.