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Molecules 2016, 21(12), 1756; doi:10.3390/molecules21121756

Inhibition of Hypoxia-Induced Retinal Angiogenesis by Specnuezhenide, an Effective Constituent of Ligustrum lucidum Ait., through Suppression of the HIF-1α/VEGF Signaling Pathway

1
Laboratory of Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
2
Post-Doctoral Research Station, KangHong Pharmaceutical Group, Chengdu 610036, Sichuan, China
3
Post-Doctoral Mobile Station, West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: David J. Newman
Received: 24 October 2016 / Revised: 10 December 2016 / Accepted: 17 December 2016 / Published: 21 December 2016
(This article belongs to the Special Issue Natural Product: A Continuing Source of Novel Drug Leads)
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Abstract

Specnuezhenide (SPN), one of the main ingredients of Chinese medicine “Nü-zhen-zi”, has anti-angiogenic and vision improvement effects. However, studies of its effect on retinal neovascularization are limited so far. In the present study, we established a vascular endothelial growth factor A (VEGFA) secretion model of human acute retinal pigment epithelial-19 (ARPE-19) cells by exposure of 150 μM CoCl2 to the cells and determined the VEGFA concentrations, the mRNA expressions of VEGFA, hypoxia inducible factor-1α (HIF-1α) & prolyl hydroxylases 2 (PHD-2), and the protein expressions of HIF-1α and PHD-2 after treatment of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1, 1.0 μg/mL) or SPN (0.2, 1.0 and 5.0 μg/mL). Furthermore, rat pups with retinopathy were treated with SPN (5.0 and 10.0 mg/kg) in an 80% oxygen atmosphere and the retinal avascular areas were assessed through visualization using infusion of ADPase and H&E stains. The results showed that SPN inhibited VEGFA secretion by ARPE-19 cells under hypoxia condition, down-regulated the mRNA expressions of VEGFA and PHD-2 slightly, and the protein expressions of VEGFA, HIF-1α and PHD-2 significantly in vitro. SPN also prevented hypoxia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy in vivo. These results indicate that SPN ameliorates retinal neovascularization through inhibition of HIF-1α/VEGF signaling pathway. Therefore, SPN has the potential to be developed as an agent for the prevention and treatment of diabetic retinopathy. View Full-Text
Keywords: specnuezhenide; angiogenesis; hypoxia-inducible factor-1; oxygen-induced retinopathy; vascular endothelial growth factor specnuezhenide; angiogenesis; hypoxia-inducible factor-1; oxygen-induced retinopathy; vascular endothelial growth factor
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MDPI and ACS Style

Wu, J.; Ke, X.; Fu, W.; Gao, X.; Zhang, H.; Wang, W.; Ma, N.; Zhao, M.; Hao, X.; Zhang, Z. Inhibition of Hypoxia-Induced Retinal Angiogenesis by Specnuezhenide, an Effective Constituent of Ligustrum lucidum Ait., through Suppression of the HIF-1α/VEGF Signaling Pathway. Molecules 2016, 21, 1756.

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