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In vivo Screening of Natural Products Against Angiogenesis and Mechanisms of Anti-Angiogenic Activity of Deoxysappanone B 7,4'-Dimethyl Ether.
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-07-30 , DOI: 10.2147/dddt.s252681 Kan Chen 1 , Yuqi Fan 1 , Jun Gu 1 , Zhihua Han 1 , Huasu Zeng 1 , Chengyu Mao 1 , Changqian Wang 1
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-07-30 , DOI: 10.2147/dddt.s252681 Kan Chen 1 , Yuqi Fan 1 , Jun Gu 1 , Zhihua Han 1 , Huasu Zeng 1 , Chengyu Mao 1 , Changqian Wang 1
Affiliation
Introduction: The aim of this study was to screen the leading compounds of natural origin with anti-angiogenic potential and to investigate their anti-angiogenic mechanism preliminarily.
Materials and Methods: An initial screening of 240 compounds from the Natural Products Collection of MicroSource was performed using the transgenic zebrafish strain Tg [fli1a: enhanced green fluorescent protein (EGFP)]y1. The zebrafish embryos at 24 h post-fertilization were exposed to the natural compounds for an additional 24 h; then, morphological changes in the intersegmental vessels (ISVs) were observed and quantified under a fluorescence microscope. The expression profiles of angiogenesis-related genes in the zebrafish embryos were detected using quantitative real-time PCR.
Results: Five compounds were identified with potential anti-angiogenic activity on the zebrafish embryogenesis. Among them, deoxysappanone B 7.4ʹ-dimethyl ether (Deox B 7,4) showed anti-angiogenic activity on the formation of ISVs in a dose-dependent manner. The inhibition of ISV formation reached up to 99.64% at 5 μM Deox B 7,4. The expression of delta-like ligand 4 (dll4), hes-related family basic helix-loop-helix transcription factor with YRPW motif 2, ephrin B2, fibroblast growth factor receptor (fgfr) 3, cyclooxygenase-2, protein tyrosine phosphatase, receptor type B (ptp-rb), phosphoinositide-3-kinase regulatory subunit 2, slit guidance ligand (slit) 2, slit3, roundabout guidance receptor (robo) 1, robo2, and robo4 were down-regulated, while vascular endothelial growth factor receptor-2, fgfr 1, and matrix metallopeptidase 9 were up-regulated in the zebrafish embryos treated with Deox B 7,4.
Conclusion: Deox B 7,4 has a therapeutic potential for the treatment of angiogenesis-dependent diseases and may exert anti-angiogenic activities by suppressing the slit2/robo1/2, slit3/robo4, cox2/ptp-rb/pik3r2, and dll4/hey2/efnb2a signaling pathways as well as activation of vegfr-2/fgfr1/mmp9.
Keywords: angiogenesis, natural products, deoxysappanone B 7, 4ʹ-dimethyl ether, delta-like ligand 4, slit guidance ligand/roundabout guidance receptor, protein tyrosine phosphatase, receptor type B
中文翻译：
Deoxysappanone B 7,4'-二甲醚的抗血管生成和抗血管生成活性机制的天然产物的体内筛选。
引言：本研究的目的是筛选具有抗血管生成潜力的天然来源的先导化合物，并初步研究它们的抗血管生成机制。
材料和方法：使用转基因斑马鱼菌株Tg [fli1a：增强型绿色荧光蛋白 (EGFP)] y1对来自 MicroSource 天然产物收集的 240 种化合物进行了初步筛选. 受精后 24 小时的斑马鱼胚胎再暴露于天然化合物 24 小时；然后，在荧光显微镜下观察和量化节间血管（ISV）的形态变化。使用定量实时 PCR 检测斑马鱼胚胎中血管生成相关基因的表达谱。
结果：鉴定出五种化合物对斑马鱼胚胎发生具有潜在的抗血管生成活性。其中，deoxysappanone B 7.4ʹ-二甲醚（Deox B 7,4）对ISVs的形成具有剂量依赖性的抗血管生成活性。在 5 μM Deox B 7,4 下，ISV 形成的抑制率高达 99.64%。δ样配体4( dll4)的表达)、hes 相关家族基本螺旋-环-螺旋转录因子，具有 YRPW 基序 2、肝配蛋白 B2、成纤维细胞生长因子受体 ( fgfr ) 3、环氧合酶 2、蛋白酪氨酸磷酸酶、受体 B 型 ( ptp-rb )、磷酸肌醇- 3-激酶调节亚基 2、狭缝引导配体 ( slit ) 2、slit3、迂回引导受体 ( robo ) 1、robo2和robo4下调，而血管内皮生长因子受体 2、fgfr 1 和基质金属肽酶 9在用 Deox B 7,4 处理的斑马鱼胚胎中上调。
结论：Deox B 7,4 具有治疗血管生成依赖性疾病的治疗潜力，可能通过抑制 slot2/robo1/2、slit3/robo4、cox2/ptp-rb/pik3r2 和 dll4/hey2/ 发挥抗血管生成活性efnb2a 信号通路以及 vegfr-2/fgfr1/mmp9 的激活。
关键词：血管生成，天然产物，deoxysappanone B 7, 4′-二甲醚，δ样配体4，狭缝导向配体/迂回导向受体，蛋白酪氨酸磷酸酶，B型受体
更新日期：2020-07-30
Materials and Methods: An initial screening of 240 compounds from the Natural Products Collection of MicroSource was performed using the transgenic zebrafish strain Tg [fli1a: enhanced green fluorescent protein (EGFP)]y1. The zebrafish embryos at 24 h post-fertilization were exposed to the natural compounds for an additional 24 h; then, morphological changes in the intersegmental vessels (ISVs) were observed and quantified under a fluorescence microscope. The expression profiles of angiogenesis-related genes in the zebrafish embryos were detected using quantitative real-time PCR.
Results: Five compounds were identified with potential anti-angiogenic activity on the zebrafish embryogenesis. Among them, deoxysappanone B 7.4ʹ-dimethyl ether (Deox B 7,4) showed anti-angiogenic activity on the formation of ISVs in a dose-dependent manner. The inhibition of ISV formation reached up to 99.64% at 5 μM Deox B 7,4. The expression of delta-like ligand 4 (dll4), hes-related family basic helix-loop-helix transcription factor with YRPW motif 2, ephrin B2, fibroblast growth factor receptor (fgfr) 3, cyclooxygenase-2, protein tyrosine phosphatase, receptor type B (ptp-rb), phosphoinositide-3-kinase regulatory subunit 2, slit guidance ligand (slit) 2, slit3, roundabout guidance receptor (robo) 1, robo2, and robo4 were down-regulated, while vascular endothelial growth factor receptor-2, fgfr 1, and matrix metallopeptidase 9 were up-regulated in the zebrafish embryos treated with Deox B 7,4.
Conclusion: Deox B 7,4 has a therapeutic potential for the treatment of angiogenesis-dependent diseases and may exert anti-angiogenic activities by suppressing the slit2/robo1/2, slit3/robo4, cox2/ptp-rb/pik3r2, and dll4/hey2/efnb2a signaling pathways as well as activation of vegfr-2/fgfr1/mmp9.
Keywords: angiogenesis, natural products, deoxysappanone B 7, 4ʹ-dimethyl ether, delta-like ligand 4, slit guidance ligand/roundabout guidance receptor, protein tyrosine phosphatase, receptor type B
中文翻译：
Deoxysappanone B 7,4'-二甲醚的抗血管生成和抗血管生成活性机制的天然产物的体内筛选。
引言：本研究的目的是筛选具有抗血管生成潜力的天然来源的先导化合物，并初步研究它们的抗血管生成机制。
材料和方法：使用转基因斑马鱼菌株Tg [fli1a：增强型绿色荧光蛋白 (EGFP)] y1对来自 MicroSource 天然产物收集的 240 种化合物进行了初步筛选. 受精后 24 小时的斑马鱼胚胎再暴露于天然化合物 24 小时；然后，在荧光显微镜下观察和量化节间血管（ISV）的形态变化。使用定量实时 PCR 检测斑马鱼胚胎中血管生成相关基因的表达谱。
结果：鉴定出五种化合物对斑马鱼胚胎发生具有潜在的抗血管生成活性。其中，deoxysappanone B 7.4ʹ-二甲醚（Deox B 7,4）对ISVs的形成具有剂量依赖性的抗血管生成活性。在 5 μM Deox B 7,4 下，ISV 形成的抑制率高达 99.64%。δ样配体4( dll4)的表达)、hes 相关家族基本螺旋-环-螺旋转录因子，具有 YRPW 基序 2、肝配蛋白 B2、成纤维细胞生长因子受体 ( fgfr ) 3、环氧合酶 2、蛋白酪氨酸磷酸酶、受体 B 型 ( ptp-rb )、磷酸肌醇- 3-激酶调节亚基 2、狭缝引导配体 ( slit ) 2、slit3、迂回引导受体 ( robo ) 1、robo2和robo4下调，而血管内皮生长因子受体 2、fgfr 1 和基质金属肽酶 9在用 Deox B 7,4 处理的斑马鱼胚胎中上调。
结论：Deox B 7,4 具有治疗血管生成依赖性疾病的治疗潜力，可能通过抑制 slot2/robo1/2、slit3/robo4、cox2/ptp-rb/pik3r2 和 dll4/hey2/ 发挥抗血管生成活性efnb2a 信号通路以及 vegfr-2/fgfr1/mmp9 的激活。
关键词：血管生成，天然产物，deoxysappanone B 7, 4′-二甲醚，δ样配体4，狭缝导向配体/迂回导向受体，蛋白酪氨酸磷酸酶，B型受体
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