Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 19, 2023

Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism transmembrane transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, other specific molecules activate JAK-STAT signaling drive a series physiological pathological processes, including proliferation, metabolism, immune response, inflammation, malignancy. Dysregulated related genetic mutations are strongly associated activation cancer progression. Insights into structures functions have led development approval diverse drugs for clinical treatment diseases. Currently, been developed mainly target commonly divided three subtypes: cytokine or receptor antibodies, JAK inhibitors, STAT inhibitors. And novel agents also continue be tested in preclinical studies. effectiveness safety each kind drug warrant further scientific trials before put being applications. Here, we review current understanding fundamental composition function pathway. We discuss advancements JAK-STAT–related pathogenic mechanisms; targeted therapies various diseases, especially disorders, cancers; newly inhibitors; challenges directions field.

Language: Английский

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JAK–STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 8, 2022

Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality life. AD has complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)–signal transducer and activator transcription (STAT) pathway plays central role in modulating multiple immune axes involved the immunopathogenesis AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, thymic stromal lymphopoietin, which contribute to symptoms chronic inflammation pruritus AD, are mediated by JAK–STAT signal transduction. Furthermore, regulation epidermal barrier modulation peripheral nerves related transduction pruritus. Targeting may attenuate these signals show clinical efficacy through suppression various pathways associated Topical oral JAK inhibitors variable selectivity have emerged as promising therapeutic options Notably, topical ruxolitinib, upadacitinib, abrocitinib were approved U.S. Food Drug Administration treating patients Accordingly, present study reviewed pathogenesis explored updated applications

Language: Английский

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JAK-STAT pathway inhibitors in dermatology

Anais Brasileiros de Dermatologia, Journal Year: 2023, Volume and Issue: 98(5), P. 656 - 677

Published: May 23, 2023

The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs that interfere with different patterns have potential indications for various medical conditions. main dermatological targets of inhibitors are inflammatory or autoimmune diseases psoriasis, vitiligo, atopic dermatitis alopecia areata; however, several dermatoses under investigation to expand this list indications. As should gradually occupy a relevant space in prescriptions, review presents the available drugs, their immunological effects, pharmacological characteristics, related clinical efficacy safety, aiming validate best practice.

Language: Английский

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The JAK/STAT Pathway and Its Selective Inhibition in the Treatment of Atopic Dermatitis: A Systematic Review

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(15), P. 4431 - 4431

Published: July 29, 2022

In recent years, the broadening understanding of pathogenesis atopic dermatitis (AD) has led to development novel therapeutic molecules, that target core inflammatory components disease. The Janus kinase (JAK)/signal transducer and activation transcription (STAT) pathway constitutes principal signaling cascade for a large number cytokines growth factors is involved in intracellular signal transduction subsequent regulation gene transcription. Current knowledge suggests robust T-helper (Th)-2 [interleukin (IL)-4, IL-5, IL-13, IL-31] Th22 (IL-22) immune responses both skin serum plays pivotal role immunopathogenesis AD especially at acute stage, followed by variable degree Th1 (interferon-γ, tumor necrosis factor alpha) Th17 (IL-17) chronic Of note, most aforementioned utilize JAK/STAT downstream transduction, explaining emerging JAK inhibitors armamentarium AD. present systematic review aims discuss involvement summarize clinical data available on efficacy safety which have been used treatment thus far.

Language: Английский

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Hidradenitis Suppurativa and JAK Inhibitors: A Review of the Published Literature

Medicina, Journal Year: 2023, Volume and Issue: 59(4), P. 801 - 801

Published: April 20, 2023

Background: Hidradenitis suppurativa (HS), also known as acne inversa or Verneuil’s disease, is a chronic, inflammatory, recurrent, and debilitating skin disease of the hair follicles characterized by painful, deep-rooted lesions in areas body presence apocrine glands. Unfortunately, huge unmet needs still remain for its treatment. Objective: The purpose our review was collecting all cases, case series, trials, ongoing studies available literature on use this class drugs HS. Materials Methods: investigated manuscripts included reviews, letters to editor, real-life studies, reports. Manuscripts were identified, screened, extracted relevant data following PRISMA (preferred reporting items systematic reviews meta-analyses) guidelines. Results: We selected 56 articles which 25 met selection criteria review. Among JAK inhibitors date, there only one published clinical trial (Janus kinase 1 inhibitor INCB054707), study with 15 patients up week 24 upadacitinib used series where tofacitinib successfully used. Conversely, are several trials. Conclusions: Results date show promising levels efficacy safety Several trials underway from it will be very important compare data. There too few conducted low sample size, so remains critical investigate issue further future involving large order provide safe viable therapeutic alternatives

Language: Английский

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Filaggrin and beyond

Annals of Allergy Asthma & Immunology, Journal Year: 2023, Volume and Issue: 132(2), P. 187 - 195

Published: Sept. 25, 2023

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide, affecting 20% of children and 5% adults. One critical component in pathophysiology AD epidermal barrier, with its outermost layer, stratum corneum (SC), conferring biochemical properties that enable resilience against environmental threats maintain homeostasis. The barrier may be conceptualized as a key facilitator complex interactions between genetics, host immunity, cutaneous microbiome, exposures. genetic risk factor for development persistence loss-of-function mutation FLG, recent advances genomics focusing on rare variant discovery, establishment pathogenic mechanisms, exploration role other differentiation gene variants AD. Aberrant type 2 responses down-regulate transcription genes, alter composition SC lipids, induce further injury through neurocutaneous feedback loop itch-scratch cycle. dysbiotic epidermis exhibits reduced bacterial diversity enhanced colonization Staphylococcus Malassezia species, which contribute to both direct action toxins perpetuation cascades. Enhanced understanding each mechanisms underpinning disruption has led novel topical systemic molecules, including interleukin (IL)-4Ra, IL-13, PDE4, Janus-associated kinase inhibitors, whose clinical effectiveness exceeds conventional treatment modalities. In this narrative review, we aim summarize current above-mentioned pathophysiological therapeutic focus genetic, cellular, molecular development.

Language: Английский

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Chronic Prurigo Including Prurigo Nodularis: New Insights and Treatments

American Journal of Clinical Dermatology, Journal Year: 2023, Volume and Issue: 25(1), P. 15 - 33

Published: Sept. 17, 2023

Chronic prurigo (CPG) is a neuroinflammatory, fibrotic dermatosis that defined by the presence of chronic pruritus (itch lasting longer than 6 weeks), scratch-associated pruriginous skin lesions and history repeated scratching. Patients with CPG experience significant psychological burden notable impairment in their quality life. nodular type (CNPG; synonym: nodularis) represents most common subtype CPG. As CNPG representative for all subtypes, we refer this review to both We provide an overview clinical characteristics assessment CPG, disease underlying pathophysiology including associated therapeutic targets. The information provided results from PubMed search latest publications database current trials (ClinicalTrials.gov, EU Clinical Trials Register [European Medicines Agency]; using following terms or combinations terms: 'chronic prurigo', 'prurigo', 'prurigo nodularis', 'pathophysiology', 'therapy', 'biologics', 'treatment'). Dupilumab first authorized systemic therapy European Agency (EMA) US Food Drug Administration (FDA) date. Topical agents are currently under investigation randomized, placebo-controlled phase II III such as biologics (e.g., nemolizumab, vixarelimab/KPL-716, barzolvolimab/CDX-0159), small molecules (ruxolitinib cream, povorcitinib/INCB054707, abrocitinib) opioid modulator nalbuphine highlighted. In last past 15 years, several milestones have been reached regarding understanding transcriptomic analysis, terminology, guideline, approval 2022, which contributed improved medical care affected patients. broad range identified targets, case observations initiated offers possibility more drug approvals near future.

Language: Английский

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EuroGuiderm guideline on lichen sclerosus—Treatment of lichen sclerosus

Journal of the European Academy of Dermatology and Venereology, Journal Year: 2024, Volume and Issue: 38(10), P. 1874 - 1909

Published: June 1, 2024

Lichen sclerosus (LS) is an inflammatory skin disease affecting all ages. LS typically involves the anogenital site where it causes itching and soreness; may lead to sexual urinary dysfunction in females males; however, be asymptomatic. First signs of are usually a whitening genital skin, sometimes preceded by redness oedema; fissuring, scarring, shrinkage fusion structures follow its course. associated with increased risk cancer. has huge impact on quality life affected patients, important raise more awareness this not uncommon order diagnose treat early.

Language: Английский

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Real-World Effectiveness and Safety of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis: A 16-Week Study in Japan

Dermatitis, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract: Background: Real-world data on the effectiveness and safety of lebrikizumab for atopic dermatitis (AD) are limited.

Language: Английский

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Updated Review on Treatment of Atopic Dermatitis

Journal of Investigational Allergology and Clinical Immunology, Journal Year: 2023, Volume and Issue: 33(3), P. 158 - 167

Published: June 15, 2023

Atopic dermatitis (AD) is a chronic or chronically recurrent Inflammatory dermatosis associated with multiple triggers that has complex pathophysiological mechanism. It characterized by heterogeneous clinical expression, signs, and symptoms. Its etiology pathogenesis are influenced immune-mediated factors. Treatment of AD can also be complex, given the high number available drugs therapeutic targets. In this review, we summarize current literature on efficacy safety topical systemic to treat moderate-to-severe AD. We begin treatments such as corticosteroids calcineurin inhibitors subsequently address latest treatments, Janus kinase (upadacitinib, baricitinib, abrocitinib, gusacitinib) interleukin (IL) inhibitors, which have proven efficacious in AD, namely, dupilumab (IL-4 IL-13), tralokinumab (IL-13), lebrikizumab nemolizumab (IL-31). Given large available, pivotal trials for each drug, evaluate recent real-world experience terms purposes compilation, provide evidence guide optimal choice therapy.

Language: Английский

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