SHR0302 Improves Treg/Th17 Imbalance in Patients with Systemic Lupus ErythematosusMohammad, Jaafar, Maroof
Indian J Clin Biochem (2025) 40 (2), 274-283
Abstract: IL-6-mediated JAK1/STAT3 signaling pathway is involved in the development of Th17 cells, which play an essential role in the pathogenesis of various autoimmune diseases such as systemic lupus erythematosus (SLE). To evaluation of the regulatory and anti-inflammatory effects of the JAK1/STAT3 inhibition in SLE, we evaluated the effects of SHR0302 on regulatory T cell (Treg)/Th17 balance. Thirty-two patients with SLE and twenty-nine healthy subjects were enrolled in this study. The mRNA expression levels of anti- and pro-inflammatory cytokines, such as FOXP3, ROR-γt, IL-10, IL-17A, IL-21, and IRF-4, were determined using real-time PCR, and the cytokine levels of IL-6, IL-10, IL-17A, TNF-α, and IFN-γ were analyzed by ELISA. The frequency and in vitro development of CD4+ CD25+ Foxp3+ Treg and Th17 cells were evaluated by flow cytometry. SHR0302 could increase the mRNA expression and cytokine level of Treg-related molecules. Furthermore, numbers of Treg cells were increased, after treatment with SHR0302. In contrast, the mRNA expression level of Th17-related molecules, ROR-γt, IL-17A, and IL-21, were decreased. Reduction of inflammatory cytokine levels was a confirmation of the modulating effect of the SHR0302, including IL-6, IL-17, TNF-α, and IFN-γ. In addition, frequency of Th17 cells were reduced by SHR0302. Our study shows that SHR0302 regulating the JAK1/STAT3 pathway can be a new treatment option for SLE.© The Author(s), under exclusive licence to Association of Clinical Biochemists of India 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
miR-216a-3p alleviates primary Sjögren's syndrome by regulating the STAT1/JAK signaling pathwayLiu, Guo, Cao
et alBiochem Biophys Res Commun (2025) 758, 151647
Abstract: Sjögren's syndrome (SS) is a chronic systemic autoimmune It chiefly impacts the exocrine glands, specifically the salivary and lacrimal ones, causing manifestations such as dry mouth and eye. Sjögren's syndrome often coexists with other autoimmune diseases, making it difficult to study its pathogenesis. Mounting evidence suggests that microRNAs (miRNAs) play a pivotal role in the development of autoimmune diseases, yet the precise mechanisms underlying their involvement in SS remain to be fully elucidated.A cohort dataset pertaining to Sjögren's syndrome was procured from the Gene Expression Omnibus (GEO) database and subsequently analyzed using bioinformatics tools. The association between Signal Transducer and Activator of Transcription 1 (STAT1) and Sjögren's syndrome is well-established. To predict miRNAs targeting STAT1, we utilized the TargetScan database, focusing on miR-216a-3p. Furthermore, to model primary Sjögren's syndrome (pSS) in vivo, we employed a rat model established through submandibular gland protein immunization. These pSS model rats were then subjected to injections of either miR-216a-3p mimics or inhibitors. Subsequently, histological analysis was conducted to assess the resulting tissue morphology. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was employed to determine the expression levels of both STAT1 and miR-216a-3p. Cytokine levels were quantified using enzyme-linked immunosorbent assay (ELISA). To investigate the protein expression of key components of the STAT/JAK signaling pathway, Western blot analysis was performed, targeting Signal Transducer and Activator of Transcription 1 (STAT1), Janus kinase 1 (JAK1), and Janus kinase 2 (JAK2).Our findings indicate that miR-216a-3p exerts regulatory control over the JAK/STAT signaling pathway by modulating the phosphorylation of STAT1, thereby attenuating the severity of primary Sjögren's syndrome in our model. Moreover, miR-216a-3p was observed to inhibit the secretion of pro-inflammatory cytokines and mitigate B cell hyperactivation. These results collectively suggest a potentially significant role for miR-216a-3p in the pathogenesis of autoimmune diseases, warranting further investigation.Copyright © 2025. Published by Elsevier Inc.
Whole genome sequencing of 378 prostate cancer metastases reveals tissue selectivity for mismatch deficiency with potential therapeutic implicationsVis, Palit, Corradi
et alGenome Med (2025) 17 (1), 24
Abstract: Survival of patients with metastatic castration-resistant prostate cancer (mCRPC) depends on the site of metastatic dissemination.Patients with mCRPC were prospectively included in the CPCT-02 metastatic site biopsy study. We evaluated whole genome sequencing (WGS) of 378 mCRPC metastases to understand the genetic traits that affect metastatic site distribution.Our findings revealed that RB1, PIK3CA, JAK1, RNF43, and TP53 mutations are the most frequent genetic determinants associated with site selectivity for metastatic outgrowth. Furthermore, we explored mutations in the non-coding genome and found that androgen receptor (AR) chromatin binding sites implicated in metastatic prostate cancer differ in mutation frequencies between metastatic sites, converging on pathways that impact DNA repair. Notably, liver and visceral metastases have a higher tumor mutational load (TML) than bone and lymph node metastases, independent of genetic traits associated with neuroendocrine differentiation. We found that TML is strongly associated with DNA mismatch repair (MMR)-deficiency features in these organs.Our results revealed gene mutations that are significantly associated with metastatic site selectivity and that frequencies of non-coding mutations at AR chromatin binding sites differ between metastatic sites. Immunotherapeutics are thus far unsuccessful in unselected mCRPC patients. We found a higher TML in liver and visceral metastases compared to bone and lymph node metastases. As immunotherapeutics response is associated with mutational burden, these findings may assist in selecting mCRPC patients for immunotherapy treatment based on organs affected by metastatic disease.NCT01855477.© 2025. The Author(s).
膜杰作
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