Open Medicine
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2024
·Vol. 19
·期 1
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IF 1.7
Aohang Li,Jingxuan Wu
The aim of our study is to explore the mechanism of transcription-4 (STAT4) in acute myeloid leukemia (AML). STAT4 level in AML bone marrow samples/cells was analyzed using bioinformatics and quantitative real-time PCR. The correlation between high STAT4 expression and the prognosis of AML patients was analyzed. The viability, apoptosis, and angiogenesis of AML cells were detected. The levels of STAT4, vascular endothelial growth factor A (VEGFA), and apoptosis-related proteins (Bcl-2 and Bax) in transfected AML cells were examined. STAT4 level was upregulated in AML. STAT4 silencing decreased the viability and angiogenesis, yet increased the apoptosis of AML cells, while overexpressed STAT4 did conversely. VEGFA silencing counteracted the impacts of overexpressed STAT4 upon promoting viability and angiogenesis as well as repressing the apoptosis of AML cells. High STAT4 expression was correlated with poor prognosis of AML patients and facilitated disease progression via upregulating VEGFA expression.
研究领域:
肿瘤学
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血液学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
INFLAMMATION
·
2019
·Vol. 42
·期 4
·1179-1189
·
IF 2.939
Xue Yu-Long,Zhang Sheng-Xiao,Zheng Chao-Feng,Li Yu-Feng,Zhang Li-Hui,Hao Yu-Fei,Wang Shu,Li Xue-Wen
Signal transducer and activator of transcription 4 (STAT4) has been implicated in the progression of myocarditis. The aim of the current study was to investigate the role by which STAT4 influences autoimmune myocarditis in an attempt to identify a theoretical therapeutic perspective for the condition. After successful establishment of an autoimmune myocarditis rat model, the expression patterns of STAT4, NF-κB pathway–related genes, Th1 inflammatory cytokines (IFN-γ and IL-2), and Th2 inflammatory cytokines (IL-6 and IL-10) were subsequently determined. The rats with autoimmune myocarditis were treated with oe-STAT4 or sh-STAT4 lentiviral vectors to evaluate the role of STAT4 in autoimmune myocarditis, or administrated with 1 mL 10 μmol/L of BAY11-7082 (the NF-κB pathway inhibitor) via tail vein to investigate the effect of the NF-κB pathway on autoimmune myocarditis. Finally, cell apoptosis was evaluated. The serum levels of IFN-γ and IL-2, extent of IκBα and P65 phosphorylation, and the expression of STAT4 were elevated, while the serum levels of IL-6 and IL-10 as well as the expression of IκBα were reduced among the rats with autoimmune myocarditis, which was accompanied by an increase in the apoptotic cells. More importantly, the silencing of STAT4 or the inhibition of the NF-κB pathway was detected to result in a decrease in the serum levels of IFN-γ and IL-2 and an elevation of the serum levels of IL-6 and IL-10, and inhibited myocardial cell apoptosis in rats with autoimmune myocarditis. Moreover, STAT4 silencing was also observed to decrease the extent of IκBα and P65 phosphorylation while acting to elevate the expression of IκBα. Taken together, silencing of STAT4 could hinder the progression of autoimmune myocarditis by balancing the expression of Th1/Th2 inflammatory cytokines via the NF-κB pathway, which may provide a novel target for experimental autoimmune myocarditis (EAM) treatment.
研究领域:
免疫学
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心脏病学
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分子生物学
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DOI
PubMed
高影响因子
Molecular Therapy-Nucleic Acids
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2021
·
IF 8.886
Tingyu Zong,Yanyan Yang,Xiaotong Lin,Shaoyan Jiang,Hui Zhao,Meixin Liu,Yuanyuan Meng,Yong Li,Liang Zhao,Guozhang Tang,Kun Gong,Zhibin Wang,Tao Yu
Accumulating evidence shows that tRNA-derived fragments are a novel class of functional small non-coding RNA; however, their roles in aortic dissection (AD) are still unknown. In this study, we found that 5′-tiRNA-Cys-GCA was significantly downregulated in human and mouse models of aortic dissection. The abnormal proliferation, migration, and phenotypic transition of vascular smooth muscle cells (VSMCs) played a crucial role in the initiation and progression of aortic dissection, with 5′-tiRNA-Cys-GCA as a potential phenotypic switching regulator, because its overexpression inhibited the proliferation and migration of VSMCs and increased the expression of contractile markers. In addition, we verified that signal transducer and activator of transcription 4 (STAT4) was a direct downstream target of 5′-tiRNA-Cys-GCA. We found that the STAT4 upregulation in oxidized low-density lipoprotein (ox-LDL)-treated VSMCs, which promoted cell proliferation, migration, and phenotypic transformation, was reversed by 5′-tiRNA-Cys-GCA. Furthermore, 5′-tiRNA-Cys-GCA treatment reduced the incidence and prevented the malignant process of angiotensin II- and β-aminopropionitrile-induced AD in mice. In conclusion, our findings reveal that 5′-tiRNA-Cys-GCA is a potential regulator of the AD pathological process via the STAT4 signaling pathway, providing a novel clinical target for the development of future treatment strategies for aortic dissection.
研究领域:
心血管疾病
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分子生物学
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非编码RNA
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病理生理学
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2020
·
IF 3.701
Liu Tang,Xiaolei Li,Liping Wan,Huiling Wang,Qianting Mai,Zixin Deng,Hong Ding
The present research was designed to evaluate the protective effects and underlying mechanisms of different ratios of linoleic acid (LA) and α-linolenic acid (ALA), two essential polyunsaturated fatty acids (PUFAs) fatty acids, on atopic dermatitis (AD)-like skin lesions induced by 2, 4-dinitrofluorobenzene (DNFB). The dorsal flank and ear pinnas of mice were sensitized and challenged with DNFB for four weeks in order to establish AD model. Simultaneously, the mice were orally administered different ratios of LA/ALA (v/v; 4:1 or 1:1), or dexamethasone (Dex; 0.1 mg/kg). Results showed that different LA/ALA ratios, especially a ratio of 4:1 treatment, could effectively ameliorate DNFB-induced skin lesions, ear edema, scratching behavior and skin inflammation, as reflected by the reduced inflammatory blood cells, IgE serum levels, and skin levels of the pro-inflammatory lipid mediators, including PGE 2 and LTB 4 . These findings were further confirmed by skin pathological examination. Moreover, LA/ALA administration markedly suppressed the proliferation and infiltration of T cells, the production of T helper cell type 1 (Th1), Th2 and Th17 cytokines in dorsal skin and serum of DNFB-treated mice. Western blotting and immunohistochemistry staining revealed that LA/ALA downregulated the protein expressions of JAK2 and STAT4, and thus reducing the synthesis of type Th1 cytokine IFN-γ. Taken together, these results suggest that optimal nutrition ratio of LA/ALA has beneficial effects on AD-like symptoms, which provide theoretical basis for its therapeutic potential in the clinical prevention and treatment of AD.
研究领域:
免疫学
·
营养学
·
皮肤病学
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DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Xin Qiao,Shuang Xu,Zhitao Dai,Ke Zhang,Rui Guo,Aijun Li,Xiaofang Li,Qiong Zhang
p-STAT4 directly binds to the Ak4 promoter to drive its transcription. • STAT4-AK4 signaling engages in the production of mitochondrial DNA (mtDNA). • TAMR inhibits Ak4 transcription and mtDNA synthesis in a STAT4-dependent manner. • TAMR ameliorates UC by suppressing the JAK2-STAT4 signaling pathway. • The JAK2-STAT4-AK4-mtDNA axis represents a novel therapeutic target for UC. Background Ulcerative colitis (UC), a chronic inflammatory bowel disease with increasing global incidence, has inadequate existing treatments, highlighting the urgent need for new therapeutic agents and strategies. The total alkaloids from Menispermi Rhizoma (TAMR) has been clinically used to treat inflammatory diseases in traditional Chinese medicine, but its specific therapeutic effects and mechanisms in UC remain poorly elucidated. Purpose This study aimed to systematically clarify the therapeutic efficacy of TAMR against UC and elucidate its potential molecular mechanisms. Methods A dextran sulfate sodium (DSS)-induced murine colitis model was used to evaluate the efficacy of TAMR, with RNA sequencing providing mechanistic insights. A variety of molecular biology experiments were conducted for subsequent pathway validation in RAW264.7 macrophage cells. STAT4-AK4 interactions were further explored via Stat4 knockdown and chromatin immunoprecipitation (ChIP) assays. Results TAMR treatment effectively ameliorated colonic pathological lesions and reestablished M1/M2 macrophage polarization in DSS-challenged mice. Integrated RNA-seq and Western blot profiling revealed that TAMR specifically suppressed JAK2-STAT4 signaling cascade and AK4 expression, whose inhibition curbed excessive mitochondrial DNA (mtDNA) synthesis in inflammatory macrophages. Notably, STAT4 overexpression entirely negated TAMR-driven AK4 and mtDNA suppression. ChIP experiments confirmed that p-STAT4 directly bound to the Ak4 promoter, and STAT4 silencing abrogated LPS-induced Ak4 transcription and mtDNA synthesis. Conclusions TAMR exerts its anti-colitis effects by inhibiting the JAK2-STAT4 signaling pathway, which in turn suppresses AK4-mediated mtDNA overproduction. This study provides a scientific basis for the clinical application of TAMR in UC treatment and identifies a novel JAK2-STAT4-AK4-mtDNA regulatory axis as a potential therapeutic target for UC. Download: Download high-res image (436KB) Download: Download full-size image
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高影响因子
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