Anti-Inflammatory and Antitumor Effects of Hydroxytyrosol but Not Oleuropein on Experimental Glioma In Vivo. A Putative Role for the Renin-Angiotensin System

Figures

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  Figure 1. Tumor volumes after the implantation of C6 glioma cells into the subcutaneous region after the treatment with vehicle (Control), 100 µg/d oleuropein (OLEU), 100 µg/d hydroxytyrosol (HTX) and 100 µg oleuropein plus 100 µg of hydroxytyrosol/d (OLEU + HTX) for five days. Results are expressed in cm3 (Mean ± SEM; n = 8; ** p < 0.01).

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  Figure 2. Renin-angiotensin system-regulating (A) aspartyl aminopeptidase (ASAP); (B) aminopeptidase A (APA); (C) aminopeptidase N (APN); (D) aminopeptidase B (APB); and (E) insulin-regulated aminopeptidase (IRAP) specific activities, in sera of animals with C6 glioma implanted into the subcutaneous region, treated with vehicle (Control), 100 µg/d oleuropein (OLEU), 100 µg/d hydroxytyrosol (HTX) and 100 µg oleuropein plus 100 µg of hydroxytyrosol/d (OLEU + HTX) for five days. Results are expressed in picomoles of the corresponding aminoacyl-ß-naphthylamide hydrolyzed per minute and per mg of protein (Mean ± SEM; n = 8; * p < 0.05; ** p < 0.01).

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  Figure 3. Interleukin-6 (IL-6) (A) and tumor necrosis factor α (TNF-α) (B) production in sera of animals with C6 glioma implanted into the subcutaneous region, treated with vehicle (Control), 100 µg/d oleuropein (OLEU), 100 µg/da hydroxytyrosol (HTX) and 100 µg oleuropein plus 100 µg of hydroxytyrosol/d (OLEU + HTX) for five days. Results are expressed in picograms per mL (Mean ± SEM; n = 8; * p < 0.05; ** p < 0.01).

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  Figure 4. Angiotensin peptides are derived from the precursor protein angiotensinogen through several enzymatic conversion pathways. The decapeptide angiotensin I (AngI) is formed by renin acting upon the amino terminal of angiotensinogen. AngI serves as a substrate for angiotensin converting enzyme-1 (ACE-1), a zinc metalloprotease that hydrolyzes the carboxyl terminal dipeptide His-Leu to form the octapeptide angiotensin II (AngII). AngII is converted to the heptapeptide angiotensin III (AngIII) by aminopeptidase A (APA) and aspartyl aminopeptidase (ASAP), which cleaves the Asp residue at the N-terminal. Aminopeptidase N (APN) and/or aminopeptidase B (APB) cleaves Arg at the N-terminal of AngIII to form the hexapeptide angiotensin IV (AngIV). AngIV can be further converted to inactive peptide fragments and amino acid constituents. Angiotensins exert their actions through the different angiotensin receptor subtypes AT1, AT2 and AT4. The AT4 receptor has been proposed to be the insulin-regulated aminopeptidase (IRAP) or the hepatocyte growth factor (HGF)/c-Met receptor system. Other conversion steps are also shown. A separate pathway for the synthesis of AngIII, independent of AngII…