Medda Rituparna, Lyros Orestis, Schmidt Jamie L, Jovanovic Nebojsa, Nie Linghui, Link Benjamin J, Otterson Mary F, Stoner Gary D, Shaker Reza, Rafiee Parvaneh
Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA.
Division of Gastroenterology/Hepatology, The Medical College of Wisconsin, Milwaukee, WI, USA.
Microvasc Res. 2015 Jan;97:167-80. doi: 10.1016/j.mvr.2014.10.008. Epub 2014 Oct 28.
Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF-α/IL-1β with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-α/IL-1β-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1β activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.
浆果中的多酚类化合物（花青素、黄酮糖苷）可部分通过抗炎途径预防大鼠消化道和食管中癌症发生的起始、促进和进展。血管生成与慢性炎症和肿瘤发生的发病机制有关。在本研究中，我们研究了黑树莓提取物（BRE）对分别从手术切除的人体肠道和供体废弃食管中分离出的两种器官特异性原代人肠道微血管内皮细胞（HIMEC）和人食管微血管内皮细胞（HEMEC）的抗炎和抗血管生成作用。用或不用BRE刺激HEMEC和HIMEC与TNF-α/IL-1β。基于COX-2、ICAM-1和VCAM-1基因及蛋白表达、PGE2产生、NFκB p65亚基核转位以及内皮细胞与白细胞的黏附来评估BRE的抗炎作用。在VEGF刺激后，基于细胞迁移、增殖和管形成以及Akt、MAPK和JNK信号通路的激活来评估BRE的抗血管生成作用。BRE抑制TNF-α/IL-1β诱导的HEMEC中NFκB p65核转位、PGE2产生、COX-2、ICAM-1和VCAM-1基因及蛋白表达上调以及白细胞结合，但在HIMEC中无此作用。BRE减弱了VEGF诱导的HEMEC和HIMEC中的细胞迁移、增殖和管形成。BRE的抗血管生成作用是通过抑制Akt、MAPK和JNK磷酸化介导的。在TNF-α/IL-1β激活后，BRE在HEMEC和HIMEC之间发挥不同的抗炎作用，而在两种细胞系中VEGF刺激后显示出相似的抗血管生成作用。这些发现可能为深入了解BRE在人类疾病和癌症中的抗肿瘤发生能力提供更多信息。
