INFLAMMATION
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2025
·Vol. 49
·期 1
·13
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IF 5
Xiaoxu Ding,Hui Su,Tiancong Liu,Yu Chen,Zhao Gao,Ziwen Chang,Weiliang Bai
Allergic rhinitis (AR) is an inflammatory disease of the upper airway that primarily affects the nasal mucosa, with Th2 differentiation-driven inflammation as a key contributor. A bioinformatics analysis of dataset GSE52804 identified Six-transmembrane epithelial antigen of prostate 4 (STEAP4), a metalloreductase involved in inflammation regulation, as associated with AR progression, though its specific function remains unclear. Data obtained from nasal mucosal tissues from AR patients ( n = 13) and an ovalbumin (OVA)-induced AR mouse model demonstrated a marked upregulation of STEAP4. Subsequent loss-of-function experiments revealed that STEAP4 knockdown reduced Th1/Th2 imbalance-mediated inflammation, alleviating allergic symptoms in OVA-treated mice. Further investigations involved the purification of naïve CD4 + T cells from healthy murine splenocytes and their Th2 polarization. Consistently, STEAP4 knockdown inhibited Th2 differentiation and the production of Th2-related cytokines in vitro. Additionally, Guanine adenine thymine adenine sequence-binding protein 3 (GATA3), a transcription factor essential for Th2 differentiation, was predicted to bind to the STEAP4 promoter. CHIP-PCR and dual-luciferase assays confirmed the transcriptional regulation of STEAP4 by GATA3. More importantly, STEAP4 knockdown rescued the promoting effects of GATA3 overexpression on Th2 differentiation. In conclusion, STEAP4 functions downstream of GATA3 to promote AR development by promoting Th2 differentiation-mediated inflammation, suggesting its potential as a target for AR treatment.
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CURRENT ISSUES IN MOLECULAR BIOLOGY
·
2025
·Vol. 47
·期 12
·991
·
IF 3
Lisha Li,Zhen Yu,Xuehua Lu,Pei Yang,Shuxia Zhang,Qinghua Lin,Junyong Han
Background: Adhesion G protein-coupled receptor G6 ( ADGRG6 ), also known as GPR126 , has been implicated in several malignancies. However, its expression pattern, clinical significance, and mechanistic role in pancreatic adenocarcinoma (PAAD) remain unclear. Methods: We combined multi-omics analyses, tissue microarray immunohistochemistry, and a series of functional experiments, including 2D and 3D spheroid cultures, zebrafish xenografts, and murine tumor models—to investigate the expression, clinical significance, and mechanism of ADGRG6 in PAAD. The association between ADGRG6 expression and immune infiltration was assessed using TIMER and GEPIA databases, followed by mechanistic validation through ADGRG6 modulation in PAAD cell lines. Results: ADGRG6 was significantly overexpressed in PAAD and correlated with larger tumor size, higher grade, advanced TNM stage, and poor overall survival. Multivariate logistic regression confirmed that high ADGRG6 expression was independently associated with higher pathological grade. Functionally, ADGRG6 silencing markedly inhibited PAAD cell proliferation, migration, and invasion in both 2D and 3D cultures, as well as in zebrafish and nude mouse xenograft models. Integrated transcriptomic and immune analyses revealed that ADGRG6 expression positively correlated with mast cells, macrophages (M1/M2), Th2/Th17 subsets, and interferon–responsive neutrophils. Mechanistically, ADGRG6 silencing reduced STAT6 phosphorylation and GATA3 expression, consistent with the suppression of the NF-κB→STAT6→GATA3 axis. Conclusions: ADGRG6 functions as an oncogenic driver in PAAD, promoting tumor progression and fostering an immunosuppressive microenvironment via NF-κB/STAT6 signaling. These findings not only broaden the mechanistic understanding of ADGRG6 function but also suggest it as a promising target for therapeutic intervention in PAAD.
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BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Mengmeng Wang,Xuqin Guo,Man Yang,Yawen Zhang,Fanyi Meng,Yinshuang Chen,Mengxi Chen,Tian Qiu,Jiawei Li,Zhi Li,Qi Zhang,Fang Xu,Haiyang Zhang,Weipeng Wang
Clinically, 5-fluorouracil (5-Fu) is a first-line drug for the treatment of patients with colorectal cancer (CRC). However, chemoresistance to 5-Fu-based chemotherapy is a leading obstacle in achieving effective treatment for CRC, especially microsatellite stable (MSS) CRC. Since the cytotoxicity of 5-Fu is negatively correlated with oxytocin receptor (OXTR) expression in MSS CRC cell lines, our current study aimed to investigate the synergistic antitumor activity of 5-Fu combined with atosiban , an antagonist of OXTR. Our results suggested that atosiban remarkably potentiated the inhibitory effect of 5-Fu on the growth of MSS-type CRC cells in vitro and in vivo . Moreover, 5-Fu induced GATA3 in MSS CRC cells and tumors, which were eradicated by atosiban. Further investigation showed that atosiban strengthened the antitumor activity of 5-Fu through eradiation of 5-Fu-induced GATA3 in MSS-type CRC cells. Taken together, our findings suggest that atosiban potentiates the antitumor effect of 5-Fu by abolishing 5-Fu-induced GATA3, which provides a novel therapeutic strategy for MSS-type CRC via the combination of atosiban and 5-Fu.
研究领域:
肿瘤学
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药理学
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分子生物学
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RESPIRATORY RESEARCH
·
2026
·
IF 5.7
Hui Zhang,Wei Dai,Xuanyu Chen,Xinru Xi,Yeqing Chen,Jingjing Song,Xiangting Ge,Qiangwei Xiang,Bing Zhang,Chengguang Zhao,Weixi Zhang,Yali Zhang
Background: Allergic asthma stands as the predominant asthma phenotype propelled by aberrant type 2 immune response. Type-2 innate lymphoid cells (ILC2s) are significant for generating IL-5 and IL-13 cytokines, highlighting their vital role in triggering and escalating the progression of asthma. Myeloid differentiation primary response protein 88 (MyD88) controls innate and adaptive immune responses by orchestrating inflammatory signals. Objective: This work focused on investigating the influence of MyD88 in governing ILC2s-driven allergic airway disease alongside its underlying molecular mechanisms. Methods: We evaluated the effects of MyD88 in IL-33-induced or allergen-induced airway hyperreactivity (AHR) and airway inflammation. The role and mechanism of MyD88 in regulating ILC2s function were examined in vivo and in vitro by using transcriptome sequencing analysis, flow cytometry, clinical samples, ILC2-specific MyD88 knockout mice, and anti-Thy1.2 antibody against ILC2s in mice. Results: The results showed heightened MyD88 expression in ILC2s sourced from allergic asthmatic patients and asthmatic mice. MyD88 knockout in ILC2s was able to mitigate IL-33-induced airway inflammation, while the MyD88 inhibitor LM8 proves efficacious in attenuating allergen-induced airway inflammation and AHR. After elimination of ILC2s via anti-Thy1.2 antibody, the pharmacological activity of LM8 diminished. Mechanistic studies revealed that MyD88 mediates the activation and proliferation of ILC2s through facilitation of P38-GATA3 complex formation. Conclusions: The research highlights MyD88 as a critical regulator of ILC2s activation, suggesting its potential utility as a therapeutic target for interventions in allergic asthma.
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International Heart Journal
·
2026
·Vol. 67
·期 4
·396-405
·
IF 1.4
Xingchun Mo,Ping Lu,Xiaojing Yang
Endothelial cell pyroptosis is a key factor promoting plaque instability in atherosclerosis (AS). Serum/Glucocorticoid Regulated Kinase 1 (SGK1) is upregulated in AS, but its upstream regulatory mechanisms and role in pyroptosis remain unclear. This study aims to elucidate the mechanism of action of the GATA Binding Protein 3 (GATA3)/SGK1 axis in ox-LDL-induced endothelial cell pyroptosis.
""AS and pyroptosis"" related genes were screened using bioinformatics analysis. Transcription factor binding sites in the SGK1 promoter region were predicted using JASPAR. After establishing a pyroptosis model in ox-LDL-induced mouse aortic endothelial cells (MAECs), the effects of the GATA3/SGK1 regulatory axis on pyroptosis were detected using qRT-PCR, LDH release assays, and ELISA; the regulatory relationship was validated using the GATA3 inhibitor Pyrrothiogatain and SGK1 overexpression; and the mechanism of action of SGK1 was elucidated using a Caspase1 inhibitor (VX-765).
Bioinformatics analysis identified 65 pyroptosis-related genes that were upregulated in AS, and this study focused on SGK1. The SGK1 promoter region contains 4 GATA3 binding sites. Ox-LDL significantly upregulated GATA3, SGK1, cleaved-Caspase-1, GSDMD-N and NLRP3 expression, while pyrrothiogatain reduced SGK1 expression and alleviated cellular damage and excessive inflammation. SGK1 overexpression reversed the protective effect of Pyrrothiogatain. Mechanistic studies showed that SGK1 overexpression exacerbated ox-LDL-induced pyroptosis, while VX-765 significantly reversed this effect.
This study elucidates that GATA3 activated SGK1 transcription by directly binding to its promoter region, thereby promoting Caspase1/GSDMD-dependent endothelial cell pyroptosis.
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