BIOLOGY OF REPRODUCTION
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2025
·
IF 3
Liao Shiying,Cheng Jinhua,Zhao Weimin,Dai Chaohui,Fu Yanfeng,Li Bixia,Deng Yanfei,Li Hui
Kynurenine (KYN) is a primary tryptophan derivative found in the human body and fermented foods. Previous studies have shown that KYN is an Aryl hydrocarbon receptor (AHR) agonist and is important in regulating various physiological activities, including female reproduction. Progesterone is a vital steroid hormone that facilitates embryo implantation and maintains pregnancy. However, whether KYN affects its biosynthesis remains unclear. To gain understanding, in vitro luteinized porcine granulosa luteal (pGL) cells were treated with KYN. The results showed that KYN disrupted progesterone biosynthesis by decreasing the expression of STAR and HSD3B in pGL cells. In addition, the expression of three transcription factors of STAR and HSD3B (GATA4, GATA6, and CEBPB) decreased after KYN treatment. Furthermore, the AHR blockade results showed comparable to those of KYN treatment, and subsequent knockdown experiments confirmed these results. These findings suggest that KYN inhibits progesterone biosynthesis in pGL cells by downregulating GATA4, GATA6, and CEBPB expression through AHR. Thus, our results showed for the first time, a previously unknown connection between KYN and progesterone biosynthesis.
研究领域:
生殖生物学
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内分泌学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Guan-feng Xu,Ya-Xuan Wang,Hao-fang Wan,Jia-huan Shen,Yong-qi Li,Jie-hong Yang,Yu He,Hai-tong Wan
ISO induces myocardial injury, collagen accumulation, and cardiac fibrosis. • Luteolin alleviates ISO-induced myocardial fibrosis and Ang II-induced endothelial cell injury. • Luteolin inhibits oxidative stress, apoptosis, EndMT, and extracellular matrix remodeling. • Multi-method analysis identifies the ERK1/2-GATA4 axis as a potential target of luteolin. • Blocking ERK1/2 partly abolishes the protective effects of luteolin against myocardial fibrosis. Introduction Myocardial fibrosis is a common pathological feature of cardiovascular diseases and is closely associated with oxidative stress, apoptosis, extracellular matrix remodeling, and endothelial-to-mesenchymal transition (EndMT). Luteolin (Lut), a naturally occurring flavonoid, exhibits cardioprotective properties; however, its anti-fibrotic effects and underlying mechanisms remain unclear. Methods Myocardial fibrosis was induced in rats by subcutaneous isoproterenol injection for 7 days, followed by Lut treatment. Cardiac function was evaluated by echocardiography, while myocardial injury and fibrosis were assessed by histological and molecular analyses. Potential anti-fibrotic targets of Lut were identified using network pharmacology and validated by molecular docking and molecular dynamics simulation. In vitro , HUVECs were stimulated with angiotensin II (Ang II) and then incubated with Lut. Oxidative stress, mitochondrial membrane potential (MMP), apoptosis, and ERK1/2-GATA4 signaling were examined. The involvement of ERK1/2 was further confirmed using the pharmacological inhibitor PD98059. Results Lut significantly improved cardiac function, alleviated myocardial injury, reduced collagen deposition, and attenuated myocardial fibrosis in ISO-treated rats. In Ang II-induced HUVECs, Lut suppressed ROS generation, preserved MMP, and inhibited apoptosis. Mechanistically, Lut activated ERK1/2 and GATA4 phosphorylation, regulated apoptosis-related proteins, and inhibited EndMT by decreasing α-SMA and FSP-1 while restoring VE-cadherin and CD31 expression. These protective effects were partially abolished by PD98059 both in vivo and in vitro . Conclusion Our findings demonstrate that Lut attenuates myocardial fibrosis by regulating oxidative stress, apoptosis, and EndMT, at least in part, via activation of the ERK1/2-GATA4 phosphorylation axis, suggesting its therapeutic potential for myocardial fibrosis.
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高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2020
·Vol. 64
·期 8
·1901251
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IF 5.309
Lingjun Tong,Haining Hao,Xinyi Zhang,Zhe Zhang,Youyou Lv,Lanwei Zhang,Huaxi Yi
Scope Milk-derived extracellular vesicles (mEVs) as nanoparticles are being developed as novel drug vehicles due to their pivotal role in cell–cell communication. As an important bioactive component in milk, little is known about their effect on the gut microbiota and intestinal immunity. Therefore, the effects of mEVs on gut microbiota and intestinal immunity in mice are investigated. Methods and results First, a new method to obtain high-yield mEVs is developed. Afterward, the colonic contents from C57BL/6 mice fed different doses of mEVs (8 weeks) are collected and the microbial composition via 16S rRNA gene sequencing is analyzed. It is found that mEVs could alter the gut microbiota composition and modulate their metabolites—short-chain fatty acids (SCFAs). Furthermore, the effects of mEVs on intestinal immunity are evaluated. It is observed that the expression levels of Muc2, RegIIIγ, Myd88, GATA4 genes, and IgA, sIgA are increased in the intestine, which are significant for the integrity of the mucus layer. Conclusion These findings reveal that the genes with critical importance for intestinal barrier function and immune regulation are modified in mice by oral administration mEVs, which also result in the changes of the relative composition of gut microbiome and SCFAs.
研究领域:
药理学
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微生物学
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免疫学
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营养科学
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2022
·Vol. 180
·期 8
·1072-1089
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IF 9.473
Jiawei Zhao,Dongsheng Bai,Lei Qi,Wangjia Cao,Jiaying Du,Chunyang Gu,Chen Zhou,Yuan Gao,Lulu Zhang,Yue Zhao,Na Lu
Background and purpose Liver fibrosis is a critical risk factor for the progression from chronic liver injury to hepatocellular carcinoma. Clinically, there is a lack of therapeutic drugs for liver fibrosis. Previous studies have confirmed that GL-V9, a newly synthesized flavonoid derivative, exhibits anti-inflammatory activity, but whether it has anti-hepatic fibrosis actions remains unclear. This study aimed to investigate the anti-fibrotic activities and potential mechanisms of GL-V9. Experimental approach Bile duct ligation (BDL) and carbon tetrachloride (CCl 4 ) challenges were used to assess the anti-fibrotic effects of GL-V9 in vivo. Mouse primary hepatic stellate cells (pHSCs) and the human HSC line LX2 also served as a liver fibrosis model in vitro. Cellular functions and molecular mechanism were analysed using senescence-associated beta-galactosidase staining, real-time PCR, western blotting, immunofluorescence, and co-immunoprecipitation. Key results GL-V9 attenuated hepatic histopathological injury and collagen accumulation, as well as decreasing the expression of fibrotic genes in vivo. GL-V9 promoted senescence and inhibited the expression of fibrogenic genes in HSCs in vitro. Mechanistic studies revealed that GL-V9 induced senescence by upregulating GATA4 expression in HSCs. Further studies confirmed that GL-V9 stabilized GATA4 by promoting autophagic degradation of P62. Conclusion and implications GL-V9 exerted potent anti-fibrotic effects both in vivo and in vitro by stabilizing GATA4, thereby promoting the senescence of HSCs, and by avoiding its activation and ultimately inhibiting liver fibrosis. This action indicated that the flavonoid GL-V9 is a potential therapeutic candidate for the treatment of liver fibrosis.
研究领域:
药理学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Chao Zhang,Huai Lan,Liming Yu,Jikai Zhao,Tao Huang,Boxuan Sun,Shan Meng,Jinfeng Duan,Jing Liu,Zijun Zhou,Zhishang Wang,Jiahui Li,Xinyi Huang,Huishan Wang
First to report that radiation-induced atrial fibrillation is driven by cellular senescence. • The GATA4-NF-κB-SASP axis is the key signaling pathway mediating this process. • Senolytic therapy with D/Q (Dasatinib+Quercetin) rescues atrial remodeling and reduces AF susceptibility. • Targeting senescence with senolytics offers a promising strategy to prevent radiation-induced AF. Radiation-induced heart disease is a well-recognized complication of thoracic radiotherapy, with atrial fibrillation (AF) being a particularly notable sequela. The mechanisms by which ionizing radiation (IR) heightens susceptibility to AF remain inadequately understood. This study seeks to elucidate the role of cellular senescence and the GATA4-NF-κB signaling pathway in radiation-induced atrial remodeling and the pathogenesis of AF. An in vivo mouse model was developed through localized cardiac irradiation using 20 Gy X-rays. The irradiated mice demonstrated dose-dependent atrial structural and electrophysiological remodeling. Transcriptomic analysis revealed significant enrichment in DNA damage response (DDR), NF-κB signaling, and aging-related pathways. IR exposure induced substantial DNA damage, activated ATM/ATR pathways, and enhanced autophagic flux. These responses culminated in the accumulation of GATA4 and phosphorylation of NF-κB, which drove the expression of the senescence-associated secretory phenotype (SASP), coinciding with increased senescence-associated β-galactosidase (SA-β-gal) activity. In vitro , these crucial findings were recapitulated using irradiated HL-1 atrial cardiomyocytes, whereas the knockdown of GATA4 effectively suppressed both cellular senescence and SASP expression. Notably, treatment with the senolytic combination of dasatinib and quercetin (D/Q) alleviated DNA damage, inhibited excessive autophagy, and suppressed the GATA4-NF-κB pathway in irradiated mice, thereby reducing SASP levels. These improvements resulted in the reversal of atrial structural and electrophysiological remodeling and a marked reduced susceptibility to AF. Overall, our findings demonstrate that IR promotes atrial remodeling by inducing DNA damage-mediated cellular senescence via the GATA4-NF-κB-SASP axis. Targeting this pathway with senolytics such as D/Q thus identifies a promising therapeutic strategy for preventing radiation-induced atrial fibrillation.
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高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2015
·Vol. 35
·期 12
·1473-1480
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IF 2.982
Bing Shen,Hong-Cui Liu,Wen-Bin Ou,Grant Eilers,Sheng-Mei Zhou,Fan-Guo Meng,Chun-Qi Li,Yong-Quan Li
Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes in the European textile ecology standard, despite insufficient toxicity data. In this study, the toxicity of these dyes was assessed in a zebrafish model, and the underlying toxic mechanisms were investigated. Basic Violet 14 and Direct Red 28 showed acute toxicity with a LC 50 value at 60.63 and 476.84 µg ml –1 , respectively, whereas the LC 50 of Acid Red 26 was between 2500 and 2800 µg ml –1 . Treatment with Basic Violet 14, Direct Red 28 and Acid Red 26 resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Hepatotoxicity was observed in zebrafish treated with Basic Violet 14, and cardiovascular toxicity was found in zebrafish treated with Acid Red 26 at concentrations higher than 2500 µg ml –1 . Basic Violet 14 also caused significant up-regulation of GCLC gene expression in a dose-dependent manner whereas Acid Red 26 induced significant up-regulation of NKX2.5 and down-regulation of GATA4 at a high concentration in a dose-dependent manner. These results suggest that Basic Violet 14, Direct Red 28 and Acid Red 26 induce developmental and organ-specific toxicity, and oxidative stress may play a role in the hepatotoxicity of Basic Violet 14, the suppressed GATA4 expression may have a relation to the cardiovascular toxicity of Acid Red 26. Copyright © 2015 John Wiley & Sons, Ltd.
研究领域:
毒理学
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分子生物学
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发育生物学
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环境科学
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高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Xin Wang,Fan Chen,Jian Lu,Mengqi Wu,Jiagao Cheng,Wenping Xu,Zhong Li,Yang Zhang
Acetochlor (ACT) is a widely used pesticide, yet the environmental and health safety of its chiral isomers remains inadequately evaluated. In this study, we evaluated the toxicity of ACT and its chiral isomers in a zebrafish model. Our findings demonstrate that ACT and its chiral isomers disrupt early zebrafish embryo development, inducing oxidative stress, abnormal lipid metabolism, and apoptosis. Additionally, ACT and its chiral isomers lead to cardiovascular damage, including reduced heart rate, decreased red blood cell (RBC) flow rate, and vascular damage. We further observed that (+)- S -ACT has a significant impact on the transcription of genes involved in cardiac and vascular development, including tbx5 , hand2 , nkx2.5 , gata4 , vegfa , dll4 , cdh5 , and vegfc . Our study highlights the potential risk posed by different conformations of chiral isomeric pesticides and raises concerns regarding their impact on human health. Overall, our results suggest that the chiral isomers of ACT induce developmental defects and cardiovascular toxicity in zebrafish, with (+)- S -ACT being considerably more toxic to zebrafish than (−)- R -ACT.
研究领域:
环境毒理学
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发育生物学
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心血管科学
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分子生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）