International Heart Journal
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2025
·Vol. 66
·期 1
·114-125
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IF 1.3
Aike Fei,Li Li,Yanfei Liu,Zhe Lv,Jing Jin
Oxidative stress and cardiomyocyte apoptosis are hallmarks of heart failure (HF) development. Plant homeodomain finger protein 8 (PHF8) is a histone demethylase downregulated in failing human hearts. Nevertheless, the potential role of PHF8 in HF remains unclear. Therefore, this study aimed to explore the biological action and molecular mechanism of PHF8 in HF.
A rat model of left anterior descending coronary artery (LAD) ligation-induced HF and a cardiomyocyte
model of oxygen-glucose deprivation/reperfusion (OGD/R) were developed after gain- or loss-of-function experiments in rats and cardiomyocytes, respectively. Heart function indexes, such as left ventricular end-diastolic
diameter, left ventricular end-systolic diameter, left ventricular ejection fraction, and left ventricular fractional
shortening, were detected. Changes in myocardial tissues were examined by pathological staining. Cardiomyocyte apoptosis and oxidative stress markers, such as malondialdehyde, reactive oxygen species, superoxide dismutase, and catalase, were examined. The relationship between PHF8 and forkhead box A2 (FOXA2) was analyzed by luciferase and chromatin immunoprecipitation-quantitative polymerase chain reaction assays.
PHF8 was downregulated in LAD-ligated rats and OGD/R-exposed cardiomyocytes. Following PHF8
upregulation, pathological changes in myocardial tissues and heart dysfunction were improved in LAD-ligated
rats. Importantly, cardiomyocyte apoptosis and oxidative stress were diminished in vivo and in vitro upon PHF8
upregulation. Mechanistically, PHF8 increased FOXA2 expression in a histone demethylase-dependent manner.
FOXA2 silencing abrogated the protective effect of PHF8 upregulation on cardiomyocytes against OGD/Rinduced apoptosis and oxidative stress.
PHF8 exerts protective functions against cardiomyocyte apoptosis, oxidative stress, and heart dysfunction
in HF, in correlation with FOXA2 upregulation. These results suggest that the PHF8/FOXA2 axis may be a
promising therapeutic target to prevent HF.
CAS / MDL:
研究领域:
心血管生物学
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分子医学
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表观遗传学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2019
·
IF 3.448
Xue Li,Hao Liu,Yuan Lv,Wenqian Yu,Xiaomei Liu,Caixia Liu
Aims Congenital diaphragmatic hernia (CDH) is a lethal birth defect characterized by congenital lung malformation, and the severity of pulmonary hypoplasia directly affects the prognosis of infants with CDH. Using a nitrofen-induced CDH rat model, we previously reported that Foxa2 expression was downregulated in CDH lungs by proteomics analysis. Here, we investigate the role of miR-130a-5p/Foxa2 axis in lung development of the nitrofen-induced CDH and evaluate its potential role in vivo prenatal therapy. Main methods Nitrofen was orally administrated on embryonic day (E) 8.5 to establish a rat CDH model, and fetal lungs were collected on E13.5, E15.5, E17.5, E19.5 and E21.5. The binding sites of miR-130a-5p on Foxa2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-130a-5p and Foxa2 were detected using qRT-PCR, ISH, IHC and western blotting. The role of miR-130a-5p/Foxa2 axis in CDH-associated lung development was investigated in ex vivo lung explants. Key findings We found that Foxa2 was downregulated in CDH lung tissues, and Foxa2 upregulating improved CDH branching morphogenesis in ex vivo lung explants. Meanwhile, we also showed that miR-130a-5p was significantly upregulated in CDH lungs and thus inversely correlated with Foxa2. Increasing miR-130a-5p abundance with mimics decreases Foxa2-driven Shh/Gli1 signaling and inhibits branching morphogenesis in ex vivo lung explants. Significance This study was the first to show that the miR-130a-5p/Foxa2 axis played a crucial role in CDH-associated pulmonary hypoplasia. These findings may provide relevant insights into the prenatal diagnosis and prenatal therapy of CDH.
研究领域:
发育生物学
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分子生物学
·
儿科
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PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2023
·Vol. 50
·期 7
·561-572
·
IF 2.9
Yawei He,Wanjing Chen,Liang Yu,Yanwei Liu,Yunsheng Cheng,Xianghua Li,Gang Yu
Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β-catenin pathway.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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转录调控
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代谢途径
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DOI
PubMed
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
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2022
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IF 13.934
Xiangyang Liu,Song Hou,Rui Xiang,Chengqing Hu,Zhenzhen Chen,Na Li,Han Yan,Xiaoxing Yu,Xin Li,Yujing Chi,Jichun Yang
Mitochondrial FAM3A has been revealed to be a viable target for treating diabetes and nonalcoholic fatty liver disease (NAFLD). However, its distinct mechanism in ameliorating hepatic steatosis remained unrevealed. High-throughput RNA sequencing revealed that carnitine palmityl transferase 2 (CPT2), one of the key enzymes for lipid oxidation , is the downstream molecule of FAM3A signaling pathway in hepatocytes. Intensive study demonstrated that FAM3A-induced ATP release activated P2 receptor to promote the translocation of calmodulin (CaM) from cytoplasm into nucleus, where it functioned as a co-activator of forkhead box protein A2 (FOXA2) to promote the transcription of CPT2, increasing free fatty acid oxidation and reducing lipid deposition in hepatocytes. Furthermore, antidepressant imipramine activated FAM3A-ATP-P2 receptor-CaM-FOXA2-CPT2 pathway to reduce lipid deposition in hepatocytes. In FAM3A-deficient hepatocytes, imipramine failed to activate CaM-FOXA2-CPT2 axis to increase lipid oxidation. Imipramine administration significantly ameliorated hepatic steatosis , hyperglycemia and obesity of obese mice mainly by activating FAM3A-ATP-CaM-FOXA2-CPT2 pathway in liver and thermogenesis in brown adipose tissue (BAT). In FAM3A-deficient mice fed on high-fat-diet, imipramine treatment failed to correct the dysregulated lipid and glucose metabolism, and activate thermogenesis in BAT. In conclusion, imipramine activates FAM3A-ATP-CaM-FOXA2-CPT2 pathway to ameliorate steatosis. For depressive patients complicated with metabolic disorders , imipramine may be recommended in priority as antidepressive drug.
研究领域:
药理学
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肝病学
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代谢学
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分子生物学
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DOI
PubMed
高影响因子
KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
·
2025
·
IF 3.1
Rui-Shi Wei,Yong-Ping Liu,Chun-Dong Gu,Shi-Lei Zhao,Li Feng,Jian-Rong Yu
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a 5-year survival rate of less than 20% and a high risk of recurrence despite advances in treatment. This study aimed to identify new therapeutic targets to increase the effectiveness of NSCLC treatments. We examined the role of USP54 in ferroptosis using an MTT assay and assessed the levels of reactive oxygen species (ROS), ferrous iron (Fe 2+ ), and malondialdehyde (MDA). To explore the underlying molecular mechanism, the intermolecular interactions was assessed using coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. We found that USP54 expression was reduced in NSCLC and that its overexpression inhibited NSCLC cell proliferation while inducing ferroptosis, as indicated by increased ROS, Fe 2+ , and MDA levels, along with changes in SLC7A11, GPX4, and ACSL4 expression. Additionally, USP54 mediated the deubiquitination of FOXA2, decreasing its degradation. And FOXA2 promoted ACSL4 transcription, which further induced ferroptosis in NSCLC cells. In conclusion, USP54 promotes ferroptosis and inhibits NSCLC progression by stabilizing FOXA2, which in turn activates ACSL4 transcription. This study provides a theoretical foundation for the development of therapies targeting USP54 or ACSL4 for NSCLC treatment.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
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