Frontiers in Cell and Developmental Biology
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2022
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IF 6.081
Heming Ma,Xiaomei Wang,Xu Liu,Chang Wang,Xiuzhu Gao,Junqi Niu
Liver fibrosis (LF) is a major disease that threatens human health. Hepatic stellate cells (HSCs) contribute directly to LF via extracellular matrix (ECM) secretion. Moreover, RXRα is an important nuclear receptor that plays a key regulatory role in HSC activation. Meanwhile, microRNAs (miRNAs) have been identified as significant regulators of LF development. In particular, miR-654-5p is involved in cellular migration and proliferation, and via bioinformatics analysis, has been identified as a potential factor that targets RXRα in humans and in mice. However, the precise relationship between miR-654-5p and RXRα in the context of LF, remains unknown and is the primary focus of the current study. To establish in vitro activated cell model human primary HSCs were cultured in vitro and LX-2 cells were stimulated with recombinant human TGF-β1. mRNA and protein levels of RXRα, miR-654-5p and fibrogenic genes were compared in quiescent and activated HSCs. Moreover, after transfected with miR-654-5p mimics, the expression changes of above related genes in LX-2 cells were estimated. Meanwhile, cell proliferation and apoptosis were detected in miR-654-5p overexpressed LX-2 cells. Simultaneously, the targeted binding between miR-654-5p and RXRα was verified in LX-2 cells. Carbon tetrachloride (CCl 4 )-induced mouse model with liver fibrosis was use to research the role of the miR-654-5p in vitro . Our results show that miR-654-5p expression levels increased in activated human HSCs and TGFβ-treated LX-2 cells. Moreover, miR-654-5p mimics markedly promoted LX-2 cell proliferation while inhibiting their apoptosis. Accordingly, the expression levels of RXRα are decreased in activated HSCs and LX-2 cells. Additionally, dual-luciferase reporter assay results reveal direct targeting of RXRα by miR-654-5p. Similarly, in vivo miR-654-5p overexpression aggravates LF in mice that are intraperitoneally injected with CCl 4 . Taken together, our findings elucidated a novel molecular mechanism with potential use for treatment of LF.
研究领域:
分子生物学
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肝病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Haonan Sun,Yumin Liu,Xuedong Wang,Luan Shu
The effective treatment of diabetes with comorbid depression is a big challenge so far. Honokiol, a bioactive compound from the dietary supplement Magnolia officinalis extract, possesses multiple health benefits. The present study aims to propose a network pharmacology-based method to elucidate potential targets of honokiol in treating diabetes with comorbid depression and related mechanisms. The antidepressant-like efficacy of honokiol was evaluated in high-fat diet (HFD) induced diabetic mice using animal behavior testing, immuno-staining and western blotting assay. Through network pharmacology analysis, retinoid X receptor alpha (RXRα) and vitamin D receptor (VDR) were identified as potential targets related to diabetes and depression. The stable binding conformation between honokiol and RXR/VDR was determined by molecular docking simulation. Moreover, hononkiol effectively alleviated depression-like behaviors in HFD diabetic mice, presented anti-diabetic and anti-neuroinflammatory functions, and protected the hippocampal neuroplasticity. Importantly, honokiol could activate RXR/VDR heterodimer in vivo . The beneficial effects of honokiol on HFD mice were significantly suppressed by UVI3003 (a RXR antagonist), while enhanced by calcitriol (a VDR agonist). Additionally, the disruption of autophagy in the hippocampus of HFD mice was ameliorated by honokiol, which was attenuated by UVI3003 but strengthened by calcitriol. Taken together, the data provide new evidence that honokiol exerts the antidepressant-like effect in HFD diabetic mice via activating RXR/VDR heterodimer to restore the balance of autophagy. Our findings indicate that the RXR/VDR-mediated signaling might be a potential target for treating diabetes with comorbid depression.
研究领域:
药理学
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神经科学
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内分泌学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL RESEARCH
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2025
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IF 7.7
Yinling He,Zhendong Sun,Ning Wu,Chuanhai Li,Qunfang Zhou,Ligang Hu,Chunyang Liao,Guibin Jiang
Mounting evidence suggests that certain environmental contaminants can influence adipogenesis and function as obesogens, many of which act by activating the key regulator peroxisome proliferator-activated receptor γ (PPARγ). Synthetic phenolic antioxidants (SPAs) are ubiquitously detected in both environmental matrices and human samples, whereas their potential effects on lipid metabolism and the underlying molecular mechanisms remain largely unexplored. In this study, we aimed to assess the agonistic effects of SPAs on PPARγ, glucocorticoid receptor (GR), and retinoid X receptor α (RXRα), as well as their adipogenic potential. Luciferase reporter gene assays showed that among the ten commonly used SPAs evaluated, only 2,4,6-tri- tert -butylphenol (AO 246) exhibited efficacious agonistic activity toward RXRα. Environmentally relevant level exposure to AO 246 significantly promoted adipogenesis in 3T3-L1 cells, as evidenced by increased lipid accumulation and adipogenic gene expression, which could be alleviated by the RXRα antagonist UVI 3003. Further analysis revealed that the early stage of differentiation (Days 0–2) was the critical window for AO 246 to enhance adipogenesis and modify the gene expression profile. This study first demonstrated the adipogenic effects of AO 246 by activating RXRα but not PPARγ or GR, emphasizing its possible implications in obesity and associated health risks.
研究领域:
环境毒理学
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分子生物学
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药理学
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内分泌学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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