Unravelling the druggability and immunological roles of the SOCS-family proteins DOI Creative Commons
Dylan M. Lynch,

Beth Forrester,

Thomas Webb

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Ноя. 29, 2024

The Suppressor of Cytokine Signalling (SOCS) protein family play a critical role in cytokine signalling and regulation the JAK/STAT pathway with functional consequences to immune response. Members this are implicated multiple different cascades that drive autoimmune diseases cancer, through their binding phosphotyrosine modified proteins as well ubiquitination activity part Cullin5 RING E3 ligases. Here we review SOCS members CISH SOCS1-SOCS7, focus on complex immunity. interactome network is discussed, intricate mechanisms which alter manage system assessed. We offer structural insights into how engage interacting partners native substrates at protein-protein interaction level. describe knowledge has enabled drug discovery efforts date propose strategies for therapeutic intervention using small molecules, either via direct inhibition or leveraging ligase targeted degradation.

Язык: Английский

Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics DOI Creative Commons

Tian‐Hua Wei,

Meng‐Yi Lu,

Sihui Yao

и другие.

MedComm – Oncology, Год журнала: 2024, Номер 3(1)

Опубликована: Март 1, 2024

Abstract Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited benefits due to their lack of selectivity. This review focuses on structural analysis elucidate molecular determinants JAKs specificity and discovery design selective JAKi. It includes descriptions comparison different structures binding sites, comparative JAKi modes, detailed interaction fingerprints (IFPs), an extensive structure‐selectivity relationship (SSRs). Moreover, also explores challenges possibilities using computational structure‐based methods discovering designing Other approaches, such targeting pseudokinase domain, well covalent allosteric designs, are covered. Based this analysis, key corresponding rational medicinal chemistry strategies proposed facilitate development highly Overall, we aim enhance understanding explore that can lead effective in cancer therapy, thus improving prognosis patients.

Язык: Английский

Процитировано

7
SOCS modulates JAK-STAT pathway as a novel target to mediate the occurrence of neuroinflammation: Molecular details and treatment options DOI Creative Commons
Min Yan, Zhiyuan Sun, Sen Zhang

и другие.

Brain Research Bulletin, Год журнала: 2024, Номер 213, С. 110988 - 110988

Опубликована: Май 27, 2024

SOCS (Suppressor of Cytokine Signalling) proteins are intracellular negative regulators that primarily modulate and inhibit cytokine-mediated signal transduction, playing a crucial role in immune homeostasis related inflammatory diseases. act as inhibitors by regulating the Janus kinase-signal transducer activator transcription (JAK-STAT) signaling pathway, thereby intervening pathogenesis inflammation autoimmune Recent studies have also demonstrated their involvement central immunity neuroinflammation, showing dual functionality. However, specific mechanisms nervous system remain unclear. This review thoroughly elucidates linking SOCS-JAK-STAT pathway with manifestations neurodegenerative Based on this, it proposes theory can regulate JAK-STAT occurrence neuroinflammation. Additionally, this explores detail current therapeutic landscape potential targeting brain via for offering insights into targets treatment

Язык: Английский

Процитировано

6
The Interplay Between Helicobacter pylori and Suppressors of Cytokine Signaling (SOCS) Molecules in the Development of Gastric Cancer and Induction of Immune Response DOI
Abdollah Jafarzadeh,

Zahra Jafarzadeh,

Maryam Nemati

и другие.

Helicobacter, Год журнала: 2024, Номер 29(3)

Опубликована: Май 1, 2024

Helicobacter pylori (H. pylori) colonizes the stomach and leads to secretion of a vast range cytokines by infiltrated leukocytes directing immune/inflammatory response against bacterium. To regulate responses, suppressors cytokine signaling (SOCS) proteins bind multiple components located downstream receptors, such as Janus kinase (JAK), signal transducers activators transcription (STAT). Dysfunctional SOCS in immune cells may facilitate evasion H. pylori, allowing bacteria induce chronic inflammation. Dysregulation expression function can contribute sustained pylori-mediated gastric inflammation which lead cancer (GC) development. Among molecules, dysregulated SOCS1, SOCS2, SOCS3, SOCS6 were indicated pylori-infected individuals well GC tissues cells. pylori-induced dysregulation The molecules be influenced various factors, epigenetic DNA methylation, noncoding RNAs, gene polymorphisms. Modulation epithelial considered control carcinogenesis antitumor respectively. This review aimed explain interplay between development induction provide insights regarding potential therapeutic strategies modulating molecules.

Язык: Английский

Процитировано

4
Ergothioneine attenuates psoriasis symptoms through modulation of M1/M2 macrophage polarisation via the NF-κB/JAK-STAT3 pathway DOI Creative Commons
Ang Li,

Yanjie Liu,

Ping Yu

и другие.

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Фев. 19, 2025

The underlying cause of psoriasis, a chronic inflammatory skin condition driven by an immune response, remains topic active investigation and is not yet fully elucidated. Recent studies have revealed that ergothioneine, small molecule sulfur-containing histidine derivative can be ingested from the daily diet accumulated in body, exhibits antioxidant capacity comparable to glutathione. Nevertheless, there paucity empirical data concerning precise impact ergothioneine context anti-inflammatory processes, particularly psoriasis. In light aforementioned considerations, present study was undertaken with objective conducting comprehensive evaluation potential (EGT) investigate its on pathogenesis efficacy EGT reducing extent dorsal lesions psoriasis model mice confirmed through vivo experimental observation. Furthermore, inhibitory effect responses at cellular level investigated, specifically LPS-induced mouse macrophage (RAW264.7) human keratinocyte-forming cell (HaCaT) models. results demonstrated introduction different concentrations into resulted notable effects, as evidenced reduction dose dependent decline key cytokines, including interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) tumour necrosis factor-α (TNF-α). observed reverse LPS induced increase ratio M1 M2 macrophages. also markedly suppress phosphorylation JAK/STAT3 NF-κB, offering novel insight mechanism EGT. conclusion, findings consistently had significant ameliorative imiquimod-induced modulating NF-κB/JAK-STAT3 signalling pathway. This provides strong rationale for application treatment.

Язык: Английский

Процитировано

0
Preclinical Retinal Disease Models: Applications in Drug Development and Translational Research DOI Creative Commons
Sudha Priya Soundara Pandi, Hanagh R. Winter, Madeleine Smith

и другие.

Pharmaceuticals, Год журнала: 2025, Номер 18(3), С. 293 - 293

Опубликована: Фев. 21, 2025

Retinal models play a pivotal role in translational drug development, bridging preclinical research and therapeutic applications for both ocular systemic diseases. This review highlights the retina as an ideal organ studying advanced therapies, thanks to its immune privilege, vascular neuronal networks, accessibility, imaging capabilities. Preclinical retinal disease offer unparalleled insights into inflammation, angiogenesis, fibrosis, hypoxia, utilizing clinically translatable bioimaging tools like fundoscopy, optical coherence tomography, confocal scanning laser ophthalmoscopy, fluorescein angiography, optokinetic tracking, electroretinography. These have driven innovations anti-inflammatory, anti-angiogenic, neuroprotective strategies, with broader implications diseases such rheumatoid arthritis, Alzheimer’s, fibrosis-related conditions. By emphasizing integration of 3Rs principles novel modalities, this how not only enhances precision but also minimizes ethical concerns, paving way more predictive human-relevant approaches development.

Язык: Английский

Процитировано

0
miR-216a-3p alleviates primary Sjögren's syndrome by regulating the STAT1/JAK signaling pathway DOI
Yixuan Liu, Liuxiong Guo,

Jingjing Cao

и другие.

Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер unknown, С. 151647 - 151647

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
Methyltransferase-like 3-mediated RNA N6-methyladenosine contributes to immune dysregulation: diagnostic biomarker and therapeutic target DOI Creative Commons
Deshuang Zhang, Ting Xu, Xiaoxue Gao

и другие.

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 24, 2025

Methyltransferase-like 3 (METTL3) plays a crucial role in post-transcriptional gene regulation. Substantial evidence links METTL3 to various immune dysfunctions, such as the suppression of antiviral immunity during viral infections and disruption tolerance conditions like autoimmune diseases, myeloid leukemia, skin cancers, anticancer immunotherapy. However, thorough review analysis this is currently missing, which limits understanding METTL3’s mechanisms significance dysfunctions. This aims elucidate roles these issues, highlighting its connections proposing new insights into modulation responses. Analysis results suggest that hampers immunity, worsens replication infection, disrupts tolerance; conversely, regulating enhances facilitates clearance. Moreover, clinical data corroborates findings, showing overexpression associated with increased susceptibility conditions. establishes theoretical basis for considering novel regulator, an important diagnostic biomarker, potential target treating

Язык: Английский

Процитировано

0
Cytokines are the Basis of the Development and Suppression of Inflammation in Atherosclerosis DOI Creative Commons

Alexander V. Blagov,

Alexey V. Churov, I. Starodubtseva

и другие.

Reviews in Cardiovascular Medicine, Год журнала: 2025, Номер 26(3)

Опубликована: Март 12, 2025

Cardiovascular diseases continue to be the primary cause of mortality in industrialised countries, and atherosclerosis plays a role their development. A persistent inflammatory condition affecting big medium-sized arteries is known as atherosclerosis. It brought on by dyslipidemia facilitated immune system's innate adaptive components. At every stage progression atherosclerosis, inflammation crucial role. has been demonstrated that soluble factors, or cytokines, activate cells involved pathophysiology have significant impact disease progression. Anti-inflammatory cytokines (such interleukin (IL)-5 IL-13) mitigate whereas pro-inflammatory IL-1, IL-6) quicken disease's course. Of interest fact number can exhibit both atherogenic atheroprotective properties, which topic study discussion this review. This review provides comparative analysis functions main pathogenesis Their functional relationships with each other are also shown. In addition, potential therapeutic strategies targeting these for treatment proposed, an emphasis recent clinical research area.

Язык: Английский

Процитировано

0
STAT3 Signaling Pathway in Health and Disease DOI Creative Commons
Md Abdus Samad, Iftikhar Ahmad, A. M. Mahedi Hasan

и другие.

MedComm, Год журнала: 2025, Номер 6(4)

Опубликована: Март 30, 2025

ABSTRACT Signal transducer and activator of transcription 3 (STAT3) is a critical factor involved in multiple physiological pathological processes. While STAT3 plays an essential role homeostasis, its persistent activation has been implicated the pathogenesis various diseases, particularly cancer, bone‐related autoimmune disorders, inflammatory cardiovascular neurodegenerative conditions. The interleukin‐6/Janus kinase (JAK)/STAT3 signaling axis central to activation, influencing tumor microenvironment remodeling, angiogenesis, immune evasion, therapy resistance. Despite extensive research, precise mechanisms underlying dysregulated disease progression remain incompletely understood, no United States Food Drug Administration (USFDA)‐approved direct inhibitors currently exist. This review provides comprehensive evaluation STAT3's health disease, emphasizing involvement cancer stem cell maintenance, metastasis, inflammation, drug We systematically discuss therapeutic strategies, including JAK (tofacitinib, ruxolitinib), Src Homology 2 domain (S3I‐201, STATTIC), antisense oligonucleotides (AZD9150), nanomedicine‐based delivery systems, which enhance specificity bioavailability while reducing toxicity. By integrating molecular mechanisms, pathology, emerging interventions, this fills knowledge gap STAT3‐targeted therapy. Our insights into crosstalk, epigenetic regulation, resistance offer foundation for developing next‐generation with greater clinical efficacy translational potential.

Язык: Английский

Процитировано

0
One gene to rule them all – clinical perspectives of a potent suppressor of cytokine signaling – SOCS1 DOI Creative Commons
Julia Körholz, Lan‐Sun Chen, Timmy Strauß

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Апрель 22, 2024

The discovery of Suppressor Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone understanding the regulation Janus kinase/Signal transducer and activator transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, recent insights into SOCS1 deficiencies humans underscored critical role immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, cancer. Variability disease manifestation, even within families sharing same genetic variant, raises questions about penetrance need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results controlling inflammation SOCS1-HI patients. Hematopoietic stem cell transplantation gene therapy emerge as avenues curative evolving landscape research, emphasizes nuanced variants their functional consequences.

Язык: Английский

Процитировано

3