Ramírez-Expósito María Jesús, Martínez-Martos José Manuel
Experimental and Clinical Physiopathology Research Group CTS1039, Department of Health Sciences, School of Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, E23071 Jaén, Spain.
Biomedicines. 2018 Jan 26;6(1):11. doi: 10.3390/biomedicines6010011.
Functional roles of the angiotensin peptides of the renin-angiotensin system (RAS) cascade can be analyzed through their corresponding proteolytic regulatory enzymes aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase B (APB), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP). These enzyme activities generate active or inactive angiotensin peptides that alter the ratios between their bioactive forms, regulating several important processes such as the regulation of cardiovascular functions, body water regulation, normal memory consolidation and retrieval, but also cell growth, differentiation and apoptosis or the inflammatory response. We have previously described that the treatment with hydroxytyrosol but not with oleuropein or with the mixture of both compounds led to the significant inhibition of tumor growth in an in vivo glioma model by mechanisms not only related to redox balance. Using this glioma model, here we analyze the effects of the phenolic compounds oleuropein and hydroxytyrosol in circulating RAS-regulating ASAP, APA, APN, APB and IRAP specific activities and the pro-inflammatory cytokines IL-6 and TNFα to understand the relationship between the antitumor and anti-inflammatory effects of hydroxytyrosol, but not oleuropein, and the components of the RAS. We found that oleuropein increased all the activities analyzed and promoted a pro-inflammatory status, whereas hydroxytyrosol only modified ASAP and IRAP activities and promotes an anti-inflammatory status. When administrated together, oleuropein overrode the effects of hydroxytyrosol. Our results suggest a role for angiotensin III and angiotensin 1-7 in both tumor growth inhibition and anti-inflammatory response promoted by hydroxytyrosol.
肾素-血管紧张素系统（RAS）级联反应中的血管紧张素肽的功能作用，可以通过其相应的蛋白水解调节酶天冬氨酰氨基肽酶（ASAP）、氨基肽酶A（APA）、氨基肽酶B（APB）、氨基肽酶N（APN）和胰岛素调节氨基肽酶（IRAP）来分析。这些酶的活性产生活性或无活性的血管紧张素肽，改变它们生物活性形式之间的比例，调节几个重要过程，如心血管功能调节、身体水分调节、正常记忆巩固和检索，还有细胞生长、分化和凋亡或炎症反应。我们之前已经描述过，在体内胶质瘤模型中，用羟基酪醇而非橄榄苦苷或这两种化合物的混合物进行治疗，通过不仅与氧化还原平衡相关的机制，导致肿瘤生长受到显著抑制。利用这个胶质瘤模型，我们在此分析酚类化合物橄榄苦苷和羟基酪醇对循环中调节RAS的ASAP、APA、APN、APB和IRAP特异性活性以及促炎细胞因子IL-6和TNFα的影响，以了解羟基酪醇而非橄榄苦苷的抗肿瘤和抗炎作用与RAS各组分之间的关系。我们发现，橄榄苦苷增加了所有分析的活性并促进了促炎状态，而羟基酪醇仅改变了ASAP和IRAP的活性并促进了抗炎状态。当一起给药时，橄榄苦苷抵消了羟基酪醇的作用。我们的结果表明血管紧张素III和血管紧张素1-7在羟基酪醇促进的肿瘤生长抑制和抗炎反应中均发挥作用。
