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首页> 外文期刊>Drug Target Insights >Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent
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Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent

机译：白藜芦醇靶向致癌物诱导的脑内皮细胞炎症生物标志物MMP-9和COX-2是Sirt1独立的。

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The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects, has recently been inferred. While brain endothelial cells play an essential role as structural and functional components of the blood-brain barrier (BBB), increased BBB breakdown is thought to be linked to neuroinflammation. Chemopreventive mechanisms targeting both MMPs and COX-2 however remain poorly investigated. In this study, we evaluated the pharmacological targeting of Sirt1 by the diet-derived and antiinflammatory polyphenol resveratrol. Total RNA, cell lysates, and conditioned culture media from human brain microvascular endothelial cells (HBMEC) were analyzed using qRT-PCR, immunoblotting, and zymography respectively. Tissue scan microarray analysis of grade I–IV brain tumours cDNA revealed increased gene expression of Sirt-1 from grade I–III but surprisingly not in grade IV brain tumours. HBMEC were treated with a combination of resveratrol and phorbol 12-myristate 13-acetate (PMA), a carcinogen known to increase MMP-9 and COX-2 through NF-κB. We found that resveratrol efficiently reversed the PMA-induced MMP-9 secretion and COX-2 expression. Gene silencing of Sirt1, a critical modulator of angiogenesis and putative target of resveratrol, did not lead to significant reversal of MMP-9 and COX-2 inhibition. Decreased resveratrol inhibitory potential of carcinogen-induced IκB phosphorylation in siSirt1-transfected HBMEC was however observed. Our results suggest that resveratrol may prevent BBB disruption during neuroinflammation by inhibiting MMP-9 and COX-2 and act as a pharmacological NF-κB signal transduction inhibitor independent of Sirt1.
机译：最近已经推断出金属蛋白酶（MMPs）的释放与环氧合酶（COX）-2的表达之间的功能关系的发生，这是两种具有重要促血管生成作用的诱导型促炎生物标志物。虽然脑内皮细胞作为血脑屏障（BBB）的结构和功能组件起着至关重要的作用，但人们认为BBB分解的增加与神经炎症有关。然而，针对MMP和COX-2的化学预防机制仍然研究不足。在这项研究中，我们评估了饮食衍生的抗炎多酚白藜芦醇对Sirt1的药理作用。使用qRT-PCR，免疫印迹和酶谱分析法分别分析了人脑微血管内皮细胞（HBMEC）的总RNA，细胞裂解液和条件培养基。对I–IV级脑肿瘤的组织扫描微阵列分析cDNA显示，来自I–III级的Sirt-1基因表达增加，但令人惊讶的是在IV级脑肿瘤中没有。用白藜芦醇和佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）组合治疗HBMEC，已知致癌物会通过NF-κB增加MMP-9和COX-2。我们发现白藜芦醇可以有效地逆转PMA诱导的MMP-9分泌和COX-2表达。 Sirt1是血管生成的重要调节剂和白藜芦醇的假定靶标，其基因沉默并未导致MMP-9和COX-2抑制作用的显着逆转。然而，在siSirt1转染的HBMEC中观察到致癌物诱导的IκB磷酸化的白藜芦醇抑制潜力降低。我们的结果表明，白藜芦醇可以通过抑制MMP-9和COX-2来预防神经炎症过程中的血脑屏障破坏，并且可以作为独立于Sirt1的药理性NF-κB信号转导抑制剂。

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