Search Results (164)

Background and Objectives: Oral Janus kinase (JAK) inhibitors have become an important therapeutic class in dermatology, with approved indications including atopic dermatitis and alopecia areata. Owing to their broad immunomodulatory effects and rapid onset of action, these agents are increasingly used off label for a variety of inflammatory skin disorders that are often refractory to standard therapies. The objective of this review was to provide a comprehensive overview of the published literature on the off-label dermatologic use of oral JAK inhibitors, summarizing clinical outcomes, safety profiles and treatment durations reported in real-world settings. Materials and Methods: A literature search was conducted in PubMed to identify case reports and case series describing off-label dermatologic use of baricitinib, abrocitinib, upadacitinib, and ritlecitinib. Extracted data included authorship and year, article type, treatment regimen, treatment duration and follow-up, prior systemic therapies, clinical outcomes, and reported adverse events. Results: A total of 136 articles were included, comprising 45 articles on abrocitinib (63 patients), 55 on upadacitinib (94 patients), 35 on baricitinib (45 patients), and 2 on ritlecitinib (2 patients). Across a wide spectrum of dermatological conditions, oral JAK inhibitors showed consistent clinical efficacy. Responses were frequently rapid and disease control was often maintained over several months of treatment. In many cases, dose reduction or treatment discontinuation did not lead to immediate relapse. Overall tolerability was favorable, with adverse events reported in a minority of patients and predominantly described as mild and transient. Conclusions: Although our data is limited to case-based literature, this review highlights the broad off-label therapeutic potential of oral JAK inhibitors in dermatology. Their rapid onset of action, sustained clinical responses, frequent maintenance of remission after dose tapering or discontinuation and generally acceptable safety profile support their consideration as treatment options in selected patients. Full article

Background/Objective: Systematic reviews (SRs) with network meta-analysis (NMA) support evidence-based decision-making by enabling both direct and indirect comparisons across multiple interventions. Given the expanding use of Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA), the methodological rigor of SRs with NMA is essential for trustworthy conclusions. This study is aimed at evaluating the methodological quality of SRs with NMA assessing the efficacy and/or safety of JAK inhibitors in RA. Methods: PubMed and Embase were searched for full-text SRs with NMAs evaluating JAK inhibitors as a therapeutic class in RA. Eligible publications were English-language articles reporting efficacy and/or safety outcomes. Narrative reviews, letters, duplicates, reviews focused on a single JAK inhibitor, and reviews without quantitative synthesis were excluded. Three independent reviewers assessed methodological quality using AMSTAR 2. Descriptive statistics were used to summarize findings. Results: Of the 222 records identified, 18 SRs with NMA met the inclusion criteria: 5 focused on efficacy, 5 on safety, and 8 assessed both. The most consistently fulfilled AMSTAR 2 items were a clearly defined PICO question (100%), duplicate study selection (100%), and reporting of conflicts of interest (100%). Common shortcomings included lack of protocol registration (44%), incomplete reporting of the search strategy (39%), and absence of publication bias assessment (50%). Risk-of-bias assessment varied by review focus: all safety reviews complied (100%), compared with 20% of efficacy reviews and 37% of mixed reviews. Conclusions: Most SRs with NMA of JAK inhibitors in RA present relevant methodological limitations, particularly in protocol registration, search reporting, and risk-of-bias assessment. Methodological standards were generally higher in safety-focused reviews, underscoring the need for more consistent and rigorous conduct and reporting, especially in efficacy and mixed reviews, to strengthen confidence in NMA-derived conclusions. Full article

Janus kinase 2 (JAK2) is a key mediator of oncogenic signaling and a promising therapeutic target in cervical cancer. This study employed a combination of in silico and in vitro approach to discover sesquiterpene lactone (SL) derivatives with JAK2 inhibitory activity. Molecular docking of forty SL derivatives, followed by drug-likeness and toxicity prediction, led to the selection of six candidates for synthesis and biological evaluation. Among these, SL10 (12.7 nM) and SL35 (21.7 nM) demonstrated potent JAK2 inhibition and exhibited selective cytotoxicity toward HeLa cervical cancer cells, outperforming ruxolitinib. Flow cytometry confirmed apoptosis induction and ROS elevation, suggesting ROS-mediated cytotoxic mechanisms. The 1 µs MD simulations demonstrated that both hydrogen bonding and hydrophobic interactions are critical determinants in stabilizing potent SLs–JAK2 complexes. These findings support SL10 and SL35 as promising scaffolds for further development of JAK2-targeted therapies in cervical cancer. Full article

Astrocytes and microglia constitute nearly half of all central nervous system cells and are indispensable for its proper function. Both exhibit striking morphological and functional heterogeneity, adopting either neuroprotective (A2, M2) or proinflammatory (A1, M1) phenotypes in response to cytokines, pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), toll-like receptor 4 (TLR4) activation, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Crucially, many of these phenotypic transitions arise during the earliest stages of neurodegeneration, when glial dysfunction precedes overt neuronal loss and may act as a primary driver of disease onset. This review critically examines glial-centered hypotheses of neurodegeneration, with emphasis on their roles in early disease phases: (i) microglial polarization from an M2 neuroprotective state to an M1 proinflammatory state; (ii) NLRP3 inflammasome assembly via P2X purinergic receptor 7 (P2X7R)-mediated K⁺ efflux; (iii) a self-amplifying astrocyte–microglia–neuron inflammatory feedback loop; (iv) impaired microglial phagocytosis and extracellular-vesicle–mediated propagation of β-amyloid (Aβ) and tau; (v) astrocytic scar formation driven by aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), glial fibrillary acidic protein (GFAP)/vimentin, connexins, and janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling; (vi) cellular reprogramming of astrocytes and NG2 glia into functional neurons; and (vii) mitochondrial dysfunction in glia, including Dynamin-related protein 1/Mitochondrial fission protein 1 (Drp1/Fis1) fission imbalance and dysregulation of the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Sirt1/PGC-1α) axis. Promising therapeutic strategies target pattern-recognition receptors (TLR4, NLRP3/caspase-1), cytokine modulators (interleukin-4 (IL-4), interleukin-10 (IL-10)), signaling cascades (JAK2–STAT, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase–protein kinase B (PI3K–AKT), adenosine monophosphate-activated protein kinase (AMPK)), microglial receptors (triggering receptor expressed on myeloid cells 2 (TREM2)/spleen tyrosine kinase (SYK)/ DNAX-activating protein 10 (DAP10), siglec-3 (CD33), chemokine C-X3-C motif ligand 1/ CX3C motif chemokine receptor 1 (CX3CL1/CX3CR1), Cluster of Differentiation 200/ Cluster of Differentiation 200 receptor 1 (CD200/CD200R), P2X7R), and mitochondrial biogenesis pathways, with a focus on normalizing glial phenotypes rather than simply suppressing pathology. Interventions that restore neuroglial homeostasis at the earliest stages of disease may hold the greatest potential to delay or prevent progression. Given the complexity of glial phenotypes and molecular isoform diversity, a comprehensive, multitargeted approach is essential for mitigating Alzheimer’s disease and related neurodegenerative disorders. This review not only synthesizes pathogenesis but also highlights therapeutic opportunities, offering what we believe to be the first concise overview of the principal hypotheses implicating glial cells in neurodegeneration. Rather than focusing on isolated mechanisms, our goal is a holistic perspective—integrating diverse glial processes to enable comparison across interconnected pathological conditions. Full article

The absent in melanoma 2 (AIM2) inflammasome is a cytosolic DNA sensor that links genomic instability, mitochondrial dysfunction, and chronic inflammation. Unlike the nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome, AIM2 is activated directly by double-stranded Deoxyribonucleic Acid (dsDNA), including mitochondrial DNA (mtDNA) released under stress conditions. This positions AIM2 at the intersection of oxidative stress, impaired mitophagy, and innate immune dysregulation. Current therapies for ankylosis spondylitis (AS), such as anti-tumor necrosis factor (TNF), anti-interleukin 17 (IL-17), and Janus kinase (JAK) inhibitors, improve clinical outcomes; however, they do not address upstream mitochondrial dysfunction or DNA-driven inflammasome activation. By contrast, other inflammasomes, such as AIM2, remain comparatively less studied. Since autoimmune diseases, including AS, are frequently accompanied by uncontrolled innate immune responses to self-DNA, these findings provide a framework for comprehending the mechanisms of AIM2 activation and its interaction with inflammation, mitophagy, and oxidative stress. Here, we review the current evidence on AIM2 inflammasome involvement in AS pathogenesis and its potential as a therapeutic target. This approach offers new insight into disease control through re-establishing the balance between mitochondrial dysfunction and autoimmunity. Full article

Atopic dermatitis is the most prevalent chronic inflammatory skin disease, posing a significant individual and healthcare burden. Traditionally managed with topical agents and broad immunosuppressants, the treatment landscape has shifted significantly in recent years. This review explores the transition from immunopathogenic understanding to personalized treatment strategies through advanced systemic therapies. We provide a thorough description of the current therapeutic arsenal, including approved monoclonal antibodies and Janus kinase (JAK) inhibitors, as well as experimental agents under clinical investigation. Key cytokines and receptors implicated in type 2 inflammation are explored alongside relevant intracellular signaling pathways. Special attention has been given to literature published from 2015 onwards. By synthesizing the latest scientific and clinical knowledge, this review aims to provide clinicians with practical guidance for navigating the evolving landscape of atopic dermatitis management and improving patient outcomes. Full article

Background/Objectives: Janus kinase 2 (JAK2) is a pivotal signaling protein implicated in various hematological malignancies and inflammatory disorders, making it a compelling target for therapeutic intervention. Methods: In this study, we employed an integrative computational approach combining ligand-based screening, pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations, and MM/PBSA free energy calculations to identify JAK2 inhibitors from the ChEMBL database. A comprehensive virtual screening of over 1,900,000 compounds was conducted using Tanimoto similarity and a validated pharmacophore model, resulting in the identification of 39 structurally promising candidates. Docking analyses prioritized compounds with favorable interaction energies, while MD simulations over 100 ns assessed the dynamic behavior and binding stability of top hits. Results: Four compounds, CHEMBL4169802, CHEMBL4162254, CHEMBL4286867, and CHEMBL2208033, exhibited consistently superior performance, forming stable hydrogen bonds, favorable RMSD profiles (≤0.5 nm), and strong binding interactions, including salt bridges. Notably, the binding free energies revealed ΔG values as low as −29.91 kcal/mol, surpassing that of the reference inhibitor, momelotinib (−24.17 kcal/mol). Conclusions: Among these, CHEMBL4169802 emerged as the most promising candidate due to its synergistic electrostatic and hydrophobic interactions. Collectively, our results highlight these compounds as probable, JAK2-selective inhibitors with strong potential for further biological validation and optimization. Full article

Background: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder with limited treatment options. Emerging evidence reveals bidirectional crosstalk between gut and brain through inflammatory signaling, leading us to hypothesize that anti-neuroinflammatory agents may concurrently ameliorate intestinal inflammation. The scorpion venom-derived heat-resistant synthetic peptide (SVHRSP), a bioactive peptide initially identified in scorpion venom and subsequently synthesized by our laboratory, possesses neuroprotective, anti-inflammatory, and antioxidative activities. Its properties make SVHRSP a promising candidate for investigating the therapeutic potential of anti-neuroinflammatory strategies in mitigating intestinal inflammation. Methods: Using a chronic dextran sodium sulfate (DSS)-induced colitis model in wild-type and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice, along with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, we assessed SVHRSP’s effects on inflammation, histopathology, gut permeability, oxidative stress markers, and α7nAChR-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Results: SVHRSP treatment significantly ameliorated colitis symptoms in wild-type mice by reducing inflammation, repairing histological damage, restoring gut barrier function, and attenuating oxidative stress, with these effects abolished in α7nAChR knockout mice. Mechanistically, SVHRSP activated JAK2/STAT3 signaling through α7nAChR engagement, suppressing proinflammatory cytokine production in macrophages. Conclusion: These results demonstrated that SVHRSP alleviated intestinal inflammation via α7nAChR-dependent JAK2/STAT3 activation. Combined with its known neuroprotective properties, our findings support the repurposing of this neuroactive peptide, SVHRSP, for treating intestinal inflammatory disorders. Full article

(1) Background: This study aims to systematically identify key candidate genes and the regulatory networks governing ovarian development in sheep breeds with divergent fecundity. Focusing on elucidating the central regulatory roles of these factors during distinct ovarian developmental stages in highly prolific breeds, the research seeks to reveal the mechanism by which multilevel regulatory networks synergistically determine ewe reproductive capacity. (2) Methods: This study utilized the ovaries from the low-fecundity sheep breed Ujumqin sheep, the high-fecundity breed small-tailed Han sheep, and various developmental stages of small-tailed Han sheep as research subjects. Through whole-transcriptome sequencing analysis, differentially expressed mRNAs(DEGs) and non-coding RNAs (ncRNAs) were screened, and a ceRNA regulatory network was constructed and subjected to bioinformatic analysis. The dual-luciferase reporter gene detection system was employed to validate the targeting relationships within the obtained key circRNA-miRNA-mRNA networks. Finally, qRT-PCR was used to verify the accuracy of the sequencing results. (3) Results: Our analysis constructed two distinct ceRNA networks: one from different fecundity groups (116 DECs, 46 DEMs, 82 DEGs) and another from different ovarian stages (186 DECs, 143 DEMs, 338 DEGs). Functional enrichment revealed key reproduction-related pathways, including Mitogen-Activated Protein Kinase(MAPK), Janus Kinase-Signal Transducer and Activator of Transcription(JAK-STAT), and WNT signaling in the fecundity comparison, and MAPK, Ras, WNT, Hippo signaling in the developmental stage comparison. Integrated analysis identified a core circRNA-miRNA-mRNA network, pinpointing circRNA2058-miR-9226-5p-MET as a central regulatory axis. The dual-luciferase assay confirmed that circRNA2058 acts as a sponge for miR-9226-5p, thereby mediating MET expression. qRT-PCR validation of randomly selected RNAs confirmed the sequencing reliability. (4) Conclusions: this study deciphers a synergistic regulatory network and identifies, for the first time, the pivotal circRNA2058-miR-9226-5p-MET ceRNA axis as an potential critical molecular switch driving follicular dominance in sheep. This discovery provides a molecular foundation for targeting core regulators of ovine reproductive efficiency and offers significant insights for innovative strategies in enhancing sheep reproduction. Full article

Background/Objectives: Baricitinib, a selective Janus kinase (JAK) 1 and 2 inhibitor, has recently emerged as a therapeutic option for patients with severe alopecia areata (AA). The aim of this study was to identify clinical and biological predictors of early therapeutic response to baricitinib in patients with AA in real-world clinical practice. Methods: A retrospective cohort study was conducted including patients with AA initiating baricitinib between January 2022 and January 2025. Patients were stratified into early responders and non-early responders. Univariate and multivariate logistic regression analyses were performed to assess factors independently associated with early therapeutic response. Results: A total of 44 patients with AA treated with baricitinib were included, the majority being female (65.9%, 29/44), with a mean age of 37.3 years (SD 16.1). Early responders accounted for 34.1% (15/44) of the cohort. In multivariate analysis, early response to baricitinib was independently associated with a lower baseline Severity of Alopecia Tool (SALT) score, shorter disease duration, and elevated erythrocyte sedimentation rate (ESR) at baseline (p < 0.05). Receiver Operating Characteristic (ROC) curve analyses were performed to determine optimal thresholds for predicting early therapeutic response: ESR ≥ 9 mm/h, baseline SALT score ≤ 60%, and disease duration ≤ 7 years. Conclusions: Baseline stratification using easily obtainable clinical and laboratory parameters may help identify patients most likely to benefit from initiating treatment with baricitinib. Our findings support the existence of a therapeutic window of opportunity in AA, particularly in patients with lower disease burden, shorter disease duration, and elevated ESR values. Full article

The JAK2V617F mutation is a major molecular factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and has been increasingly associated with clonal progression to acute myeloid leukemia (AML), resulting in a poorer prognosis and resistance to conventional therapies. This study integrates a comprehensive literature review with bioinformatic approaches to investigate the potential inhibitory activity of Epigallocatechin Gallate (EGCG), a green tea polyphenol widely recognized for its antioxidant and anticancer properties, on the JAK2V617F mutation. Clinical data from case reports demonstrated heterogeneity in disease progression and frequent therapeutic failures. Molecular docking analysis using the Janus Kinase 2 (JAK2) protein structure (PDB ID: 6D2I) identified a high-affinity binding pocket for EGCG near the V617F mutation site. EGCG exhibited strong binding affinity (−9.2 kcal/mol), forming key interactions with residues Lys581, Ile559, and Leu680, suggesting allosteric modulation of the JH2 pseudokinase domain. To validate our docking protocol, redocking of the known inhibitor AT9283 yielded a favorable Root Mean Square Deviation (RMSD) 2.683 Å and binding energy (−8.3 kcal/mol), confirming the reliability of our approach. Notably, EGCG demonstrated superior binding affinity compared to AT9283 and targets a distinct allosteric site, highlighting its unique mechanism of action and potential as a selective allosteric inhibitor. These findings position EGCG as a promising candidate for future preclinical evaluation, offering a novel strategy to overcome therapy resistance in JAK2V617F-driven malignancies. Full article

Background: Atopic dermatitis (AD) is a chronic inflammatory disease requiring topical and systemic treatments. This study examines healthcare service utilization and medication use in children with AD in a large healthcare organization during the year 2024. Methods: A cross-sectional case-control study was conducted comparing 128,239 children with AD to 128,239 matched controls regarding healthcare utilization and medication use. Multivariate analysis assessed differences between the groups. Results: Children with AD had increased healthcare utilization compared to the control group, with higher rates of visits to pediatricians, general practitioners, and dermatologists. A total of 144 children (0.11%) with AD were treated by immunosuppressive drugs, as compared to 78 children (0.06%) in the control group (OR 1.8, 95% CI 1.4–2.4, p-value < 0.001). A total of 410 children (0.32%) were treated with biologic drugs as compared to 12 children (0.01%) in the control group (OR 34.3, 95% CI 19.3–60.9, p-value < 0.001). A total of 34 children (0.03%) were treated with Janus kinase (JAK) inhibitors as compared to 2 children (0.002%) in the control group (OR 17, 95% CI 4.1–70.8, p-value < 0.001). Conclusions: Increased utilization of healthcare services was observed in pediatric patients with AD compared to the control group. As only a small proportion of the children with AD received immunosuppressants, biologic treatments, and JAK inhibitors, we suggest that the use of systemic medications should be strongly considered in pediatric patients with moderate to severe AD. Full article

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with cure rates exceeding 80% due to advancements in treatment protocols and supportive care. However, in children with Down syndrome (DS), ALL (DS-ALL) presents distinct genomic and clinical challenges. These include mutations in Janus kinase 2 (JAK2), neuroblastoma RAS viral oncogene homolog (NRAS), and E1A-binding protein p300 (EP300), as well as cytokine receptor-like factor 2 (CRLF2) rearrangements—such as P2RY8-CRLF2 fusion—and intrachromosomal amplification of chromosome 21 (iAMP21). These aberrations are associated with poor prognosis and increased risk of relapse. The objective of this study was to present a unique DS-ALL case with five concurrent high-risk genomic lesions and to contextualize its management in light of existing literature, emphasizing minimal residual disease (MRD)-guided therapy and supportive care. Case Report and Results: We present the case of a three-year-old boy with DS and B-cell ALL (B-ALL), in whom multiple high-risk genomic features co-occurred. Despite these adverse prognostic markers, the patient achieved complete remission following an intensive high-dose induction protocol. We also discuss therapeutic strategies that aim at balancing individualized treatment approaches with optimized supportive care to reduce toxicity and minimize relapse risk. Conclusions: This case underlines the importance of comprehensive molecular diagnostics, serial MRD monitoring, and personalized multidisciplinary care in DS-ALL. Full article

Medium and variable vessel vasculitides are a heterogeneous group of rare, immune-mediated vascular disorders that are associated with significant morbidity and mortality. The standard treatment approach involves glucocorticoids and immunosuppressive agents. However, many patients exhibit poor tolerance or respond inadequately to these medications. Recent advances in biologic therapies and Janus Kinase inhibitors (JAKis) offer promising alternatives. This review consolidates current knowledge on the pathogenesis, immunology, and therapeutic efficacy of biologics and JAKis in the management of medium and variable vessel vasculitis. While further research is needed to establish long-term safety and optimize treatment protocols, biologics and JAKis represent emerging therapeutic strategies with the potential to improve outcomes. Full article

Insulin resistance is a key driver of metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), progressing to non-alcoholic steatohepatitis (NASH). This study investigated the effects of geniposide (GP) on insulin sensitivity and hepatic fibrosis in a high-fat diet (HFD)-induced NASH model. C57BL/6 mice were fed an HFD for five weeks and subsequently divided into normal chow (NC), HFD, HFD with GP 50 mg/kg (GP50), and HFD with GP 100 mg/kg (GP100) groups. The treatments were administered orally for 12 weeks. GP treatment significantly reduced body weight as well as epididymal fat and liver weights, while no differences were observed in food intake. Improvements in glucose and lipid metabolism were observed in oral glucose tolerance tests, homeostatic model assessment of insulin resistance (HOMA-IR), and blood lipid profiles. Histological analyses revealed that GP suppressed adipocyte hypertrophy and hepatic lipid accumulation and hepatic fibrosis. To further elucidate molecular mechanisms of GP, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted in the liver tissue. GP downregulated expression of inflammatory markers, including F4/80, tumor necrosis factor (TNF)-α, and interleukin (IL)-6. GP treatment modulated genes involved in insulin signaling including Janus kinase 2 (JAK2), insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and protein kinase B (AKT1) gene expression levels. This suggests GP suppresses inflammation and mitigates insulin resistance by activating the INSR–IRS2–Akt pathway. Additionally, GP enhanced adenosine monophosphate-activated protein kinase (AMPK) expression, suggesting its potential role in improving glucose and lipid metabolism. In conclusion, GP improves insulin resistance, inflammation, and hepatic fibrosis, highlighting its therapeutic potential for NASH and related metabolic disorders. Full article