Mariana Trujillo

Hydroxytyrosol induces antioxidant/detoxificant enzymes and Nrf2 translocation via extracellular regulated kinases and phosphatidylinositol‐3‐kinase/protein kinase B pathways in HepG2 cells

Hydroxytyrosol (HTy) is a natural polyphenol abundant in olive oil, which possesses multiple biological actions. Particularly, HTy has cytoprotective activity against oxidative-stress-induced cell damage, but the underlying mechanisms of action remain unclear. Here, we have investigated the molecular mechanism involved in the protection exerted by HTy on tert-butyl hydroperoxide-induced damage in human HepG2 liver cells. Treatment of HepG2 cells with HTy increased the expression and the activity of glutathione-related enzymes such as glutathione peroxidase, glutathione reductase and glutathione S-transferase. HTy also induced the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Moreover, two important signalling proteins involved in Nrf2 translocation, the protein kinase B and the extracellular regulated kinases, were also activated by HTy. Further studies with specific inhibitors confirmed that both molecular pathways are critical for the nuclear translocation of Nrf2, the increased enzyme expression and activity and the beneficial effect against oxidative stress induced by HTy. In conclusion, together with the inherent radical scavenging activity of HTy, our results provide an additional mechanism of action to prevent oxidative stress damage through the modulation of signalling pathways involved in antioxidant/detoxifying enzymes regulation.

Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia-reoxygenation.

Hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC) are two well-known phenolic compounds with antioxidant properties that are present in virgin olive oil (VOO). Because VOO has shown neuroprotective effects in rats, the purpose of the present study was to investigate the possible neuroprotective effect of HT and HT-AC in a model of hypoxia-reoxygenation in rat brain slices after in vitro incubation of these compounds or after 7 days of oral treatment with 5 or 10 mg/kg per day. Lactate dehydrogenase (LDH) efflux to the incubation medium was measured as a marker of brain cell death. HT and HT-AC inhibited LDH efflux in a concentration-dependent manner, with 50% inhibitory concentrations of 77.78 and 28.18 microM, respectively. Other well-known antioxidants such as vitamin E and N-acetyl-cysteine had no neuroprotective effect in this experimental model. After 1 week of treatment, HT (5 and 10 mg/kg per day p.o.) reduced LDH efflux by 37.8% and 52.7%, respectively, and HT-AC reduced LDH efflux by 45.4% and 67.8%. These data are additional evidence of the cytoprotective effect of VOO administration, and provide a preliminary basis for further study of these polyphenols as potential neuroprotective compounds.

New Lipophilic Tyrosyl Esters. Comparative Antioxidant Evaluation with Hydroxytyrosyl Esters

New lipophilic esters of tyrosol, a naturally occurring phenol with interesting biological properties, have been synthesized in good yields by a chemoselective procedure, using lipase from Candida antarctica or p-toluenesulfonic acid as catalysts. Their antioxidant activities have been evaluated by the Rancimat test in lipophilic food matrices, as well as by FRAP and ABTS assays in methanolic solutions, and compared with those of previously synthesized hydroxytyrosyl esters. Free tyrosol, hydroxytyrosol, butylhydroxytoluene, and alpha-tocopherol were used as standards. All methods used for the antioxidant activity evaluation emphasized the high influence of the ortho-diphenolic structure on the antioxidant capacity, tyrosol and its derivatives being less active than hydroxytyrosol and its analogues and even less than BHT and alpha-tocopherol. In addition, the Rancimat test revealed a lower activity for ester derivatives than for their respective reference compounds (HTy or Ty), in agreement with the polar paradox. On the other hand, FRAP and ABTS methods reported an opposite behavior between the synthetic esters and their respective references. Thus, hydroxytyrosyl esters were more active than HTy, whereas tyrosyl esters were less active than Ty. The length and nature of the acyl side chain did not seem to play an important role in the antioxidant activity of either the hydroxytyrosyl or tyrosyl ester series, since no significant differences were observed among them.

Synthesis of Hydroxytyrosyl Alkyl Ethers from Olive Oil Waste Waters

The preparation of a new type of derivatives of the naturally occurring antioxidant hydroxytyrosol is reported. Hydroxytyrosyl alkyl ethers were obtained in high yield by a three-step procedure starting from hydroxytyrosol isolated from olive oil waste waters. Preliminary results obtained by the Rancimat method have shown that these derivatives retain the high protective capacity of free hydroxytyrosol.

Effects of Hydroxytyrosol and Hydroxytyrosol Acetate Administration to Rats on Platelet Function Compared to Acetylsalicylic Acid

Virgin olive oil (VOO) contains the polyphenols hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC). This study investigated the antiplatelet effect of HT and HT-AC in healthy rats and compared their effects to acetylsalicylic acid (ASA). All compounds were administered orally for 7 days. HT and HT-AC inhibited platelet aggregation in whole blood, with a 50% inhibitory dose (ID50) of 48.25 mg/kg per day for HT, 16.05 mg/kg per day for HT-AC, and 2.42 mg/kg per day for ASA. Platelet synthesis of thromboxane B2 was inhibited by up to 30% by HT and 37% by HT-AC; the ID50 of this effect for ASA was 1.09 mg/kg per day. Vascular prostacyclin production was inhibited by up to 27.5% by HT and 32% by HT-AC; the ID50 of this effect for ASA was 6.75 mg/kg per day. Vascular nitric oxide production was increased by up to 34.2% by HT, 66% by HT-AC, and 64% by ASA. We conclude that HT and HT-AC administered orally inhibited platelet aggregation in rats and that a decrease in thromboxane synthesis along with an increase in nitric oxide production contributed to this effect.

Synthesis and antioxidant activity of nitrohydroxytyrosol and its acyl derivatives.

A series of nitroderivatives has been synthesized from hydroxytyrosol, the natural olive oil phenol, to increase the assortment of compounds with putative effects against Parkinsons disease. Nitrohydroxytyrosyl esters were obtained from nitrohydroxytyrosol using a chemoselective one-step, high-yield, transesterification procedure. The antioxidant activity of these new series of nitrocatechols was evaluated using FRAP, ABTS, and ORAC assays and compared to that of free hydroxytyrosol. The nitro functional group induced a significant increase in the antioxidant activity of nitrohydroxytyrosol compared to hydroxytyrosol. Regarding nitroester derivatives, variable antioxidant activity was observed depending on the acyl side-chain length; shorter chains maintained or even enhanced the antioxidant activity compared to nitrohydroxytyrosol, decreasing the activity with longer side chains in keeping with their lipophilic nature. Therefore, it may be concluded that nitroester derivatives of hydroxytyrosol, which may be obtained by a simple, high-yield reaction, have elevated antioxidant activity and thus present potential bioactivity.

A short route to homochiral D-and L-hexose precursors from (R)-methyl-p-tolylsulfoxide

Abstract Homochiral D - and L -hexose precursors have been prepared in good overall yield from ( R )-methyl- p -tolylsulfoxide as the sole asymmetric inductor. The process involves sequential condensation of the sulfoxide with ethyl 2-furancarboxylate, stereoselective sulfoxide-monitored carbonyl reduction, Pummerer rearrangement of the sulfinyl group, reduction of the resulting aldehydes and ring-oxidation of the corresponding furfuryl alcohols.

The effect of hydroxytyrosol and its nitroderivatives on catechol-O-methyl transferase activity in rat striatal tissue

Hydroxytyrosol is a well-known phenolic compound with antioxidant properties that is found in virgin olive oil. Studies have shown that virgin olive oil has neuroprotective effects in rats; thus the purpose of the present study was to investigate the neuroprotective effect of hydroxytyrosol in rats. Additionally, this study aimed to investigate the neuroprotective potential of a homologous series of compounds with better lipophilic profiles in order to increase the assortment of compounds with a putative effect against Parkinsons disease (PD). In this context, the inhibition of catechol-O-methyl transferase (COMT) activity by hydroxytyrosol, nitrohydroxytyrosol, nitrohydroxytyrosol acetate and ethyl nitrohydroxytyrosol ether was investigated by measuring intracellular dopamine and its metabolite levels in the corpus striatum by high performance liquid chromatography (HPLC) with electrochemical detection. The animals received an acute (single dose; 20 mg kg−1; i.p.) or chronic (one daily dose for 5 days; 20 mg kg−1; i.p.) treatment of hydroxytyrosol and its nitroderivatives. For comparison, a commercial COMT inhibitor, Ro 41-0960, was also included. Our data show that acute and chronic systemic administration of these compounds produced a clear and statistically significant increase in the intracellular levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid. The increase in dopamine levels was very similar to the increase seen with Ro 41-0960 treatment. The effect of chronic treatment was stronger than that of acute treatment. With respect to the intracellular level of homovanillic acid, Ro 41-0960 produced a statistically significant decrease which it was not observed when hydroxytyrosol and its nitroderivatives were systemically administered. However, the chronic homovanillic acid treatment effect was stronger than the acute treatment. The results suggest that these compounds could inhibit COMT activity.

Studies on conformation and configuration of β-hydroxysulphoxides

Abstract In this paper, the conformational and configurational analyses of cyclic and acyclic β-oxygenated sulphoxides are reviewed. In addition, the conformational behaviour of pairs of diastereomeric 2-(alkylsulphinyl)-1-arylethanols, Ar-CH(OH)-CH 2 -SOR (R = Me, Bu τ ; Ar = phenyl, furyl, thienyl) and their O -methyl derivatives has been studied. From the 1 H-NMR and IR data obtained, together with the published results for other analogous β-oxygenated sulphoxides, the role played by stereoelectronic interactions, hydrogen bonding and steric factors on conformational equilibria has been established. Finally, the relative configurations of these pairs of diastereomers have been correlated with 13 C-NMR data. We thus establish an easy and efficient method for the configurational assignment of β-hydroxysulphoxides, based on 13 C-NMR spectroscopy.