Experimental and Therapeutic Medicine
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2015
·Vol. 10
·期 4
·1404-1412
·
IF 1.269
Jianfeng Zhao,Yu Geng,Hairong Hua,Biyun Cun,Qianbo Chen,Xiaoting Xi,Liushu Yang,Yan Li
The aim of the present study was to examine the mechanisms through which fenofibrate inhibits the ability of human retinal pigment epithelial cells (RPE cells) exposed to hypoxia to stimulate the proliferation and migration of human umbilical vein endothelial cells (HUVECs). For this purpose, RPE cells and HUVECs were divided into the following groups: RPE-normoxia, RPE + fenofibrate, RPE-hypoxia, RPE hypoxia + fenofibrate; HUVECs normal culture and HUVECs + RPE-hypoxia culture supernatant. RPE cell hypoxia was induced by cobalt(II) chloride (CoCl2). A superoxide anion probe was used to measure the production of superoxide anion, which is indicative of hypoxic conditions. Cell proliferation was assessed by MTT assay, and the expression of vascular endothelial growth factor C (VEGFC) and vascular endothelial growth factor receptor-3 (VEGFR-3) in the RPE cell culture supernatant was measured by enzyme-linked immunosorbent assay (ELISA). The migration ability of the HUVECs was determined by scratch-wound assay, and the angiogenic ability of the HUVECs was examined by measuring cell lumen formation. The mRNA and protein expression levels of VEGFC and VEGFR-3 in the RPE cells were measured by RT-qPCR and western blot analysis, respectively. Our results revealed that fenofibrate inhibited the increase in the expression and release of VEGFC and VEGFR-3 into the RPE cell culture supernatant induced by exposure to hypoxia. The culture of HUVECs in medium supernatant of RPE cells epxosed to hypoxia enhanced the viability and migration ability of the HUVECs and promoted lumen formation; these effects were inhibited by fenofibrate. In conclusion, our data demonstrated that the exposure of RPE cells to hypoxia induced the expression and release of VEGFC and VEGFR-3 into the cell culture supernatant. The culture of HUVECs in conditioned medium from RPE cells exposed to hypoxia increased VEGFC and VEGFR-3 expression, and promoted the proliferation and migration of the HUVECs, as well as capillary tube formation, suggesting that RPE cells play an important role in the formation of choroidal neovascularization resulting from hypoxia. Fenofibrate inhibited the upregulation of VEGFC and VEGFR-3 in the RPE cells exposed to hypoxia, and thus reduced the ability of HUVECs to form new blood vessels.
研究领域:
眼科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Jingya Li,Ao Nie,Xinyi Li,Zheng Chen,Kai Xu,Junbin Yan,Kannan Yao,Xiaojie Lin,Wei Mao,Zhiyun Chen,Wei Hong
Background Naringin (NAR) has shown anti-fibrotic effects. This study found it alleviates non-alcoholic steatohepatitis (NASH)-associated liver fibrosis and downregulates vascular endothelial growth factor C (VEGFC). However, the pathophysiological role of VEGFC in NASH and its contribution to NAR's protection remain unclear. Objective To determine whether and how the downregulation of VEGFC contributes to the protective effect of NAR against NASH-associated hepatic fibrosis. Methods A mouse model of NASH fibrosis was induced by a 24-week high-fat diet (HFD). Mice were treated concomitantly with NAR-L (25 mg/kg/day), NAR-H (50 mg/kg/day), or SAR131675 (SAR, 30 mg/kg/day) from week 9 to 24 (16 weeks). Clinical serum VEGFC levels were measured in a hospital cohort ( n =165); human hepatic VEGFC expression was analyzed in using data from Gene Expression Omnibus (GEO) datasets (GSE162694, GSE130970). Hepatocyte-specific Vegfc knockout mice ( Vegfc Hep‑cKO ) were generated by crossing Vegfc flox/flox with Alb -CreERT2 ( Albumin-CreERT2 ) mice. In vitro , AML12 hepatocytes were pretreated (oleic acid, recombinant VEGFC, or Vegfc genetic modulation); these cells or their conditioned medium were used to stimulate bone marrow-derived macrophages to assess macrophage migration and phenotypic switching. Results NAR and SAR131675 ameliorated liver inflammation and fibrosis in mice, downregulated VEGFC and CCL2/CCR2, reduced Ly6C high monocyte infiltration, and promoted Ly6C high -to-Ly6C low macrophage phenotypic switch. Clinical data showed elevated VEGFC in NAFLD and NASH patients. Vegfc Hep‑cKO mice exhibited similar therapeutic effects. In vitro , hepatocyte-derived VEGFC promoted macrophage migration via VEGFR3 and CCL2/CCR2; inhibited phenotypic transition via regulating IL-10 or CX3CR1. NAR disrupted this axis by suppressing VEGFC in hepatocytes. Conclusion Hepatocyte-derived VEGFC is a key contributor to NASH-related liver fibrosis, functioning by regulating macrophage migration and phenotypic switch. The hepatoprotective effect of NAR is partially mediated through the inhibition of the VEGFC-mediated hepatocyte-macrophage regulatory axis.
研究领域:
肝脏病学
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分子生物学
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免疫学
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代谢性疾病研究
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药理学
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产品关联
DOI
PubMed
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）