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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Type 2 chronic inflammatory diseases: targets, therapies and unmet needs

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(9), P. 743 - 767

Published: Aug. 1, 2023

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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Recent Advancements in the Atopic Dermatitis Mechanism

Frontiers in Bioscience-Landmark, Journal Year: 2024, Volume and Issue: 29(2)

Published: Feb. 22, 2024

Atopic dermatitis (AD) is a recurrent, chronic, inflammatory, itchy skin disorder that affects up to 20% of the pediatric population and 10% adult worldwide. Onset typically occurs early in life, although cardinal disease features are similar across all ages, different age groups ethnicities present distinct clinical characteristics. The imposes significant burden health-related quality life domains, both children adults, substantial economic cost at individual national levels. pathophysiology AD includes complex multifaceted interplay between impaired dysfunctional epidermal barrier, genetic predisposition, environmental contributors, such as chemical and/or biological pollutants allergens, context dysregulated TH2 TH17 skewed immune response. Regarding component, loss function mutations encoding structural proteins filaggrin, fundamental protein, more recently identified variations differentiation well-established determinants resulting an barrier AD. More recently, epigenetic factors have facilitated development, including dysbiotic microbiome effect external exposome, combined with dietary disorders. Notably, interleukin (IL)-31 network, comprising several cell types, macrophages, basophils, generated cytokines involved pathogenesis itch AD, has been explored. Unraveling specific endotypes, highlighting implicated molecular pathogenetic mechanisms clinically relevant phenotypes, emerged crucial step toward targeted therapies for personalized treatment patients. This review aims state-of-the-art knowledge regarding multifactorial interactive pathophysiological

Language: Английский

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Neuroimmune interplay during type 2 inflammation: Symptoms, mechanisms, and therapeutic targets in atopic diseases

Journal of Allergy and Clinical Immunology, Journal Year: 2023, Volume and Issue: 153(4), P. 879 - 893

Published: Aug. 25, 2023

Type 2 inflammation is characterized by overexpression and heightened activity of type cytokines, mediators, cells that drive neuroimmune activation sensitization to previously subthreshold stimuli. The consequences altered differ tissue disease; they include skin inflammation, pruritogens, itch amplification in atopic dermatitis prurigo nodularis; airway and/or hyperresponsiveness, loss expiratory volume, airflow obstruction increased mucus production asthma; sense smell chronic rhinosinusitis with nasal polyps; dysphagia eosinophilic esophagitis. We describe the interactions underlie various sensory autonomic pathologies inflammatory diseases present recent advances targeted treatment approaches reduce its associated symptoms these diseases. Further research needed better understand mechanisms chronic, sustained related inflammation. immunity a specialized, evolutionarily conserved arm immune system combats ectoparasitic endoparasitic helminths, expels toxins, promotes repair.1Gandhi N.A. Bennett B.L. Graham N.M.H. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (392) Google Scholar, 2Gandhi N.M. Commonality IL-4/IL-13 pathway diseases.Expert Clin Immunol. 2017; 13: 425-437Crossref (276) 3Kopp E.B. Agaronyan K. Licona-Limon I. Nish S.A. Medzhitov R. Modes response initiation.Immunity. 2023; 56: 667-694Abstract Full Text PDF (1) 4Molofsky A.B. Locksley R.M. ins outs innate adaptive immunity.Immunity. 704-722Abstract (0) Scholar When epithelial barrier breached, alarmin cytokines (eg, thymic stromal lymphopoietin [TSLP], IL-25, IL-33) activate tissue-resident (such as mast cells, dendritic group lymphoid [ILC2s]) while simultaneously recruiting granulocytes, including eosinophils basophils. Collectively, orchestrate polarized through histamine, other mediators neutralize expel parasitic helminths toxins repair turnover, remodeling, fibrosis. Although processes are protective intended restore homeostasis, setting allergy continuous stress become pathologic, resulting variety Mechanical reflexes such scratching, constriction, coughing, sneezing, gastrointestinal motility also protect surfaces triggered direct neurons, often concert input target organs. Many manifestations pathologically dysregulation (Fig 1), (but not limited to) (AD), nodularis (PN), asthma, food allergy, polyps (CRSwNP), esophagitis (EoE).1Gandhi Scholar,2Gandhi Scholar,5Hamilton J.D. Harel S. Swanson B.N. Brian W. Chen Z. Rice M.S. et al.Dupilumab suppresses biomarkers across multiple atopic, allergic diseases.Clin Exp Allergy. 2021; 51: 915-931Crossref (59) Scholar,6Le Floc'h A. Allinne J. Nagashima Scott Birchard D. Asrat al.Dual blockade IL-4 IL-13 dupilumab, an IL-4Rα antibody, required broadly inhibit inflammation.Allergy. 2020; 75: 1188-1204Crossref (163) extent similarities among pathways regulating mechanical responses remains be fully defined (Table I7Kulka M. Sheen C.H. Tancowny B.P. Grammer L.C. Schleimer R.P. Neuropeptides human cell degranulation chemokine production.Immunology. 2008; 123: 398-410Crossref (340) 8Liang Y. Marcusson J.A. Jacobi H.H. Haak-Frendscho Johansson O. 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Boguniewicz Sher adolescents uncontrolled trial.JAMA 156: 44-56Crossref (254) 25Paller Wollenberg Arkwright P.D. children 6 11 years old placebo-controlled 83: 1282-1293Abstract (174) 26Paller ages months younger than randomised, double-blind, 400: 908-919Abstract 27Wollenberg Worm Lynde Lacour J.P. al.Tralokinumab for results 52-week, multicentre, (ECZTRA ECZTRA 2).Br 437-449Crossref (214) 28Wollenberg Howell M.D. Silverberg Kell Ranade al.Treatment tralokinumab, anti-IL-13 mAb.J. Clin. 143: 135-141Abstract (252) 29Gutermuth Pink A.E. Soldbro Bjerregård Øland Weidinger Tralokinumab plus inadequate intolerance ciclosporin A: trial 7).Br 186: 440-452Crossref (26) 30Silverberg Toth Alexis A.F. Elewski B.E. trial.Br 450-463Crossref (133) 31Simpson Carsten Flohr Eichenfield L.F. Sofen Taïeb lebrikizumab (an antibody) inadequately controlled corticosteroids: II (TREBLE).J 2018; 78: 863-871.e11Abstract (239) 32Guttman-Yassky Armstrong A.W. Drew lebrikizumab, high-affinity interleukin 13 inhibitor, dermatitis. A 2b 411-420Crossref 33Silverberg Irvine A.D. Stein Gold 388: 1080-1091Crossref (16) 34Silverberg Pinter Pulka Poulin Bouaziz al.Phase 2B study nemolizumab pruritus.J 145: 173-182Abstract (159) 35Kabashima Matsumura Komazaki Kawashima Nemolizumab JP01 JP02 Study Group. agents (AD) provide improvement signs up 68 weeks: III, long-term studies.Br 642-651Crossref 36Ständer Legat F.J. Paul Narbutt al.Trial nodularis.N 382: 706-716Crossref (144) 37Kamata Tada Optimal use Jak inhibitors biologics on basis current evidence.JID Innov. 3100195Abstract 38Bieber Kabashima al.Atopic pathomechanisms lessons learned novel systemic therapeutic options.JEADV. 36: 1432-1449Google 39Lee K.P. Plante Korte J.E. Elston D.M. Oral Janus kinase systematic review meta-analysis.Skin Health Dis. 3: e133Crossref 40Rodriguez-Roy Ficheux A.-S. 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Zhang Lee Van Dyken al.Pulmonary neuroendocrine amplify asthma 360eaan8546Crossref (228) 64Hara Jha M.K. Mattoo Nash Khan Orengo al.Interleukin 4 directly olfactory induces mice.J 151: AB128Abstract 65Rouyar Classe Gorski Bock Le-Guern Roche al.Type 2/Th2-driven impairs neurogenesis model.Allergy. 74: 549-559Crossref (14) 66Backaert Steelant Hellings P.W. Talavera Gerven TRiP roles transient potential cation channels upper inflammation.Curr Asthma Rep. 21: 20Crossref 67Li Jiang Shen al.Sneezing reflex mediated peptidergic nose brainstem.Cell. 3762-3773Abstract (23) 68Samivel D.W. Son H.R. role CD4+ cell-mediated rhinitis.Oncotarget. 2015; 7: 148-160Crossref 69Yu Chang Yu Capsaicin-sensitive vagal afferent nerve-mediated interoceptive signals esophagus.Molecules. 26: 3929Crossref (3) 70O'Shea K.M. Aceves S.S. Dellon E.S. Pathophysiology esophagitis.Gastroenterology. 154: 333-345Abstract 71Akiho Ihara Motomura Nakamura Cytokine-induced alterations disorders.World Gastrointest Pathophysiol. 2011; 2: 72-81Crossref 72Hu Liu al.Increased acid responsiveness guinea pig esophagitis.Am Physiol Liver 307: G149-G157Crossref (21) 73Zhang Shoda Arva N.C. Chehade Collins M.H. al.Mast cell-pain connection esophagitis.Allergy. 77: 1895-1899Crossref (8) Scholar).Table INeuroimmune affecting AD, PN, CRSwNP, EoEConditionSymptomsNeuroimmune interactionsType profileADPruritus•Colocalization cells7Kulka Scholar,8Liang Scholar•Type OSM promote pruritogen sensitization9Sonkoly Scholar•Neuropeptide proinflammatory basophils)7Kulka Scholar,10Tominaga Scholar•Scratching causes alarmins IL-33), which can act neurons9Sonkoly Scholar,11Garcovich Scholar,14Liu Scholar•Some express receptors IL-13, IL-31, TRPA1, TRPV118Oetjen Scholar,19Cevikbas Scholar•Reducing reduces itch20Blauvelt

Language: Английский

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Upadacitinib: Mechanism of action, clinical, and translational science

Clinical and Translational Science, Journal Year: 2023, Volume and Issue: 17(1)

Published: Nov. 21, 2023

Upadacitinib is a selective Janus kinase (JAK) inhibitor which approved by the US Food and Drug Administration, European Medicines Agency, as well other agencies around world for treatment of several chronic inflammatory diseases, including rheumatic, dermatologic, gastrointestinal diseases. Through inhibition JAK, upadacitinib inhibits phosphorylation downstream effector proteins, consequently cytokine signaling key pathways involved in more potently JAK1 than JAK isoforms. The pharmacokinetics, pharmacodynamics, efficacy, safety were characterized many clinical trials, demonstrated superiority over placebo or an active comparator rheumatoid arthritis, psoriatic ankylosing spondylitis, non-radiographic axial spondyloarthritis, atopic dermatitis, Crohn's disease, ulcerative colitis. profile supported favorable benefit-risk across all indications. In this article, we review mechanism action describe how JAK-STAT (Janus kinase-signal transducers activators transcription) pathway pathogenesis progressive immune-mediated addition, also provides overview trials that conducted relevant data development informed recommended dose(s) each

Language: Английский

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The safety of systemic Janus kinase inhibitors in atopic dermatitis: A systematic review and meta‐analysis of randomized controlled trials

Journal of the European Academy of Dermatology and Venereology, Journal Year: 2023, Volume and Issue: 38(1), P. 52 - 61

Published: Aug. 19, 2023

Abstract Janus kinase (JAK) inhibitors have been recently approved by the FDA and are widely used in treatment of patients with atopic dermatitis. However, a comprehensive safety profile JAK dermatitis has not analysed. This study aimed to establish clinical evidence for systemic Medline, Embase, Clinicaltrials.gov , Cochrane Central Register Controlled Trials (CENTRAL) International Clinical Registry Platform (ICTRP) were considered search databases. Randomized controlled trials reporting adverse events therapy included. The risk 11 was compared between placebo groups. Fourteen randomized analysed published 2019 2022. included analysis abrocitinib (10, 30, 100 200 mg), baricitinib (1, 2 4 mg) upadacitinib (7.5, 15 30 mg). herpes zoster, headache, acne, elevated blood creatinine phosphokinase nausea significantly increased, but serious infection, non‐melanoma skin cancer (NMSC), malignancies other than NMSC, major cardiovascular event, venous thromboembolism nasopharyngitis increased. provides on various since follow‐up periods studies this review mostly limited 16 weeks or less, it is recommended that long‐term observational be conducted determine any potential associated malignancies, which typically prolonged courses.

Language: Английский

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Challenges and Future Trends in Atopic Dermatitis

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(14), P. 11380 - 11380

Published: July 12, 2023

Atopic dermatitis represents a complex and multidimensional interaction that potential fields of preventive therapeutic management. In addition to the treatment armamentarium available for atopic dermatitis, novel drugs targeting significant molecular pathways in biologics small molecules are also being developed given condition’s pathophysiology. While most patients expecting better efficacy long-term control, response these would still depend on numerous factors such as genotype, diverse environmental triggers microbiome-derived signals, and, importantly, dynamic immune responses. This review article highlights challenges recently pharmacological agents based pathogenesis this condition, creating specific approach toward more personalized medicine.

Language: Английский

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Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer

Molecular and Cellular Biochemistry, Journal Year: 2024, Volume and Issue: 480(1), P. 1 - 17

Published: March 22, 2024

Language: Английский

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A Maximum-Use Trial of Ruxolitinib Cream in Children Aged 2–11 Years with Moderate to Severe Atopic Dermatitis

American Journal of Clinical Dermatology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Ruxolitinib cream has demonstrated anti-inflammatory and antipruritic activity was well tolerated in a phase 3 study patients aged 2–11 years with mild to moderate atopic dermatitis (AD). This examined the safety, tolerability, pharmacokinetics, efficacy, quality of life (QoL) ruxolitinib under maximum-use conditions longer-term use. Eligible were severe AD [Investigator's Global Assessment (IGA) score 3–4], ≥ 35% affected body surface area (BSA). Patients applied 1.5% twice daily all baseline-identified lesions during 4-week period, then active only up week 52 (patients ≤ 20% BSA from 8). Safety assessed by frequency severity adverse events. Pharmacokinetic parameters as secondary endpoints, efficacy QoL exploratory endpoints. Overall, 29 (median age 5 years) enrolled. Treatment-emergent events reported 9/29 (31.0%); there no special interest (i.e., serious infections, malignancies, major cardiovascular events, or thromboses) period. Mean steady-state plasma concentration period below known half-maximal inhibitory Janus kinase–mediated myelosuppression adults. Reductions IGA observed at 4 sustained as-needed use through weeks. Improvements patient-reported outcomes measures consistent results. These results support safety children (2–11 AD, including those extensive disease, are previous findings. NCT05034822, first registered 30 August 2021. is approved USA for 12 treatment (AD) involving body, recent studies supporting younger AD. Maximum-use trials look treatments more areas skin, assessing potential side effects. trial absorption, effectiveness when weeks body. needed weeks, disease control assessed. During 31% Only one patient experienced treatment-related effects application site. As-needed did not cause any other concern. The average blood level low. As expected low levels, associated oral drugs same class (e.g., levels white cells, cancers, clots) seen. decreased size relief itching treatment, amount thereafter. Disease maintained cream. findings help confirm children.

Language: Английский

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