The abnormal deposition of Aβ amyloid deposits in the brain is a hallmark of Alzheimer's disease (AD). Based on this evidence, many current therapeutic approaches focus on the development of small molecules halting Aβ aggregation. However, due to the temporary and elusive structures of amyloid assemblies, the rational design of aggregation inhibitors remains a challenging task. Here we combine ThT assays and MD simulations to study Aβ aggregation in the presence of the natural compounds tyrosol (TY), 3-hydroxytyrosol (HDT), and 3-methoxytyrosol (homovanillyl alcohol - HVA). We show that albeit HDT is a potent inhibitor of amyloid growth, TY and HVA catalyze fibril formation. An inspection of MD simulations trajectories revealed that the different effects of these three molecules on Aβ_1-40 aggregation are ascribable to their capacity to arrange H-bonds network between the ligand (position C-3) and the peptide (Glu22). We believe that our results may contribute to the design of more effective and safe small molecules able to contrast pathogenic amyloid aggregation.

Keywords: Alzheimer's disease; Aβ anti-aggregation; Homovanillyl alcohol; Hydroxytyrosol; Tyrosol.

The system Fe(III)/H2O2 has been used to oxidise an aqueous solution of p-hydroxybenzoic acid (pHB) in the absence of light. In the process, typical operating variables such as reagent concentration exert a positive influence in the pHB degradation rate. Optimum pH has been found to be around 3. The kinetic study suggests that the mechanism involved in this system differs to some extent from that reported for the classic Fenton's chemistry in pure water. Thus, formation of a complex Fe(III)-pHB seems to be a key step to initiate the oxidising mechanism. Stoichiometric measurements of the H2O2 consumption per mole of pHB degraded indicate a possible reduction of complexed Fe(III). Simultaneous oxidation of pHB (and other similar compounds such as tyrosol (Ty) or p-coumaric acid (pCu)) and atrazine have shown a synergistic effect of the first substance to remove the pesticide.

We hypothesized that polyphenols contained in olive oil play a role in reducing the risk of atherosclerosis. The aim of this study was to determine if the polyphenols in olive oil, oleuropein (Ole), hydroxytyrosol (HT), and tyrosol (Tyr) could inhibit smooth muscle cell (SMC) proliferation through its influence on cell cycle regulation. Bovine vascular SMC were cultured in the presence of Ole, HT, or Tyr at concentration of 1, 10, or 100 μmol/L. On days 1, 3, and 5, numbers of cells were counted. Cell cycle analysis was performed by flow cytometry on day 1 after SMC were stained with propidium iodide. Cell populations grown in the presence of Ole or HT at 100 μmol/L concentration were significantly inhibited after 5 days of exposure. Tyr had a similar tendency but it did not attain significance. Cell cycle analysis revealed that 66% of cells were in G1 phase in Ole group, compared with 48% in control group. To examine the cell cycle block between G1 and S phases, we performed Western blotting and found that ERK1/2 activation was inhibited by Ole or HT. We conclude that olive oil polyphenols could inhibit SMC proliferation through a cell cycle block between G1 and S phases which may be regulated by ERK1/2. These results demonstrate a mechanism by which olive oil consumption may be atheroprotective by inhibiting SMC proliferation.

Phenolic compounds have shown to inhibit LDL oxidation in vitro and ex vivo; however, they are hydrosoluble compounds while LDL is a lipoprotein. Analysis of phenolic compounds in LDLs by HPLC is necessary to demonstrate their binding capacity to lipoproteins. We developed and validated a solid phase extraction method (SPE) that allowed us the purification of LDL samples and their analysis by HPLC. This methodology allowed us to demonstrate the in vitro binding capacity of tyrosol, one of the main phenolic compounds in olive oil, to LDL. In the intervention dietary study with volunteers, food rich in phenolic compounds affected LDL composition. Changes in LDL phenolics composition are not observed after the short-term ingestion of food rich in phenolic compounds. However, after one week of olive oil consumption and Mediterranean diet there was an increase in phenolics (p=0.021). An accumulative effect seems necessary to observe significative differences in LDL phenolic composition.

In the present study, the technique of electrocoagulation (EC) followed by filtration was explored at the laboratory scale for the removal of organic compounds from olive debittering wastewater (ODW). Different parameters such as electrode type and distance as well as sample pH, current density, and electrolysis time were investigated in batch experiments with identical electrode geometries. Our results showed that highest pollutant removal efficiency and lowest operational cost were achieved using two Al electrodes at a distance of 1 cm apart with a sample pH of 4.0. Moreover, rises in the electrolysis time and current density (up to 60 min and 15 mA cm^-2, respectively) led to improvements in the removal of chemical oxygen demand (COD), total polyphenolic compounds (TPC), and turbidity. Under optimized conditions, the removal of COD, TPC and turbidity reached 78.51, 90.44 and 97.92%, respectively; the values of 1.01 g m^-3, 12.0 kWh cm^-3 and 0.12 USD m^-3 were calculated as the electrode consumption, electrical energy consumption and operating cost, respectively. Chromatography results revealed tyrosol and catechin as the main phenolic compounds present in both the initial effluent and the generated sludge.

The consumption of extra virgin olive oil (EVOO) has been associated with a lower incidence of cardiovascular diseases partly due to its polyphenol content. The metabolites hydroxytyrosol sulfate and hydroxytyrosol acetate sulfate were shown to be the most concentrated polyphenol metabolites found in plasma after EVOO consumption. Therefore, the capacity of hydroxytyrosol, hydroxytyrosol acetate, homovanillyl alcohol, homovanillyl alcohol acetate and tyrosol sulfate metabolites, to protect red blood cells (RBCs) from oxidative injury induced by the radical initiator 2,2'-azo-bis(2-amidinopropane) dihydrochloride (AAPH) was evaluated. In the presence of AAPH, all non-sulfated compounds and the hydroxytyrosol and hydroxytyrosol acetate monosulfate metabolites showed a significant protective activity against RBCs induced oxidative hemolysis. Moreover, even at 5 μM, the protection was highly significant for hydroxytyrosol acetate, hydroxytyrosol and hydroxytyrosol acetate 3' and 4' monosulfates. The morphological changes of RBC and the nature of their hemoglobin were in accordance with the hemolysis assay. Results showed that a free phenolic hydroxyl group is needed for the antioxidant protection given by compounds. Hydroxytyrosol metabolites present as phase II sulfate conjugates are actually able to protect RBC from oxidative injury by a non-transcriptional mechanism and are likely to contribute for the anti-atherosclerosis properties of regular EVOO consumption.

Daxueteng, the liana stem of Sargentodoxa cuneata, is a widely used Traditional Chinese Medicine facing the overflow of its commercial adulterants. A method for discriminating adulterants and screening potential candidate alternatives of S. cuneata was thus established. Total phenols and flavonoids of S. cuneata and its six adulterants and their abilities to scavenge DPPH^• and ABTS•+, to absorb peroxyl radicals (ORAC), and to inhibit AAPH-induced supercoiled plasmid DNA strand scission were comprehensively assessed. Polygonum cuspidatum and Bauhinia championii, two of the six adulterants of S. cuneate, shared considerably higher antioxidant activities as well as phenolic contents and, therefore, were considered as potential candidate alternatives. Phenolic compositions of the two potential candidate alternatives and S. cuneata itself were further determined by UPLC-QTOF-MS/MS. Totally 38 phenolics, including four hydroxybenzoic acids, two tyrosols, two caffeoylquinic acids, seven flavanol or its oligomers, two lignans, three hydroxycinnamic acids, six stilbenes, seven anthraquinones, and five flavanones were determined from three species. Furthermore, contents of different phenolic categories were semi-quantified and the major antioxidant contributors of S. cuneata and the two potential candidate alternatives were subsequently determined. It is concluded that tyrosols and caffeoylquinic acids were unique categories making great antioxidant contributions in S. cuneata and thus were considered as effective biomarkers in distinguishing its potential candidate alternatives.

Salidroside, the 8-O-beta-D-glucoside of tyrosol, is a novel adaptogenic drug extracted from the medicinal plant Rhodiola sachalinensis A. Bor. Due to the scarcity of R. sachalinensis and its low yield of salidroside, there is great interest in enhancing the production of salidroside by biotechnological process. Glucosylation of tyrosol is thought to be the final step in salidroside biosynthesis. In our related works, three UGT clones were isolated from the roots and the cultured cells. Our intention was to combine the catalytic specificity of these UGTs in vitro in order to change the level of salidroside in vivo by over-expression of the above UGTs. However, as the aglycone substrate of salidroside, the biosynthetic pathway of tyrosol and its regulation are less well understood. The results of related studies revealed that there are two different possibilities for the tyrosol biosynthetic pathway. One possibility is that tyrosol is produced from a p-coumaric acid precursor, which is derived mainly from phenylalanine. The second possibility is that the precursor of tyrosol might be tyramine, which is synthesized from tyrosine. Our previous work demonstrated that over-expression of the endogenous phenylalanine ammonia-lyase gene (PALrs1) and accumulation of p-coumaric acid did not facilitate tyrosol biosynthesis. In contrast, the data presented in our recent work provide in vitro and in vivo evidence that the tyrosine decarboxylase (RsTyrDC) is most likely to have an important function in the initial reaction of the salidroside biosynthesis pathway in R. Sachalinensis.

(1) Background: Verticillium wilt (VW) of hop is a devastating disease caused by the soil-borne fungi Verticillium nonalfalfae and Verticillium dahliae. As suggested by quantitative trait locus (QTL) mapping and RNA-Seq analyses, the underlying molecular mechanisms of resistance in hop are complex, consisting of preformed and induced defense responses, including the synthesis of various phenolic compounds. (2) Methods: We determined the total polyphenolic content at two phenological stages in roots and stems of 14 hop varieties differing in VW resistance, examined the changes in the total polyphenols of VW resistant variety Wye Target (WT) and susceptible Celeia (CE) on infection with V. nonalfalfae, and assessed the antifungal activity of six commercial phenolic compounds and total polyphenolic extracts from roots and stems of VW resistant WT and susceptible CE on the growth of two different V. nonalfalfae hop pathotypes. (3) Results: Generally, total polyphenols were higher in roots than stems and increased with maturation of the hop. Before flowering, the majority of VW resistant varieties had a significantly higher content of total polyphenols in stems than susceptible varieties. At the symptomatic stage of VW disease, total polyphenols decreased in VW resistant WT and susceptible CE plants in both roots and stems. The antifungal activity of total polyphenolic extracts against V. nonalfalfae was higher in hop extracts from stems than those from roots. Among the tested phenolic compounds, only p-coumaric acid and tyrosol markedly restricted fungal growth. (4) Conclusions: Although the correlation between VW resistance and total polyphenols content is not straightforward, higher levels of total polyphenols in the stems of the majority of VW resistant hop varieties at early phenological stages probably contribute to fast and efficient activation of signaling pathways, leading to successful defense against V. nonalfalfae infection.

Keywords: Humulus lupulus; antifungal; hop extract; p-coumaric acid; plant disease resistance; tyrosol.

The present investigation determines the phytochemical analysis, antioxidant and antibacterial potential of methanol extract of Himalayan Fraxinus micrantha (Lingelsh) leaves. Chemical analysis of extract revealed the presence of fifty five compounds. The extract was strongly characterised by tyrosol, esculetin, β-sitosterin, l-(+)-ascorbic acid 2,6-dihexadecanoate, (Z,Z)-6,9-cis-3,4-epoxy nonadecadiene as main components (62.6%). The F. micrantha extract presents IC₅₀, 43.93 µg/ml and 68.90 µg/ml using DPPH and H₂O₂ scavenging assay, respectively. The antibacterial activity of F. micrantha was evaluated for five microorganisms showed that the extract had a remarkable inhibitory potential with a mean zone diameter of inhibition ranging from 11 to 22 mm. The MIC of the extracts ranged from 7.8 to 250 µg/ml and MBC value range 31.25 to 125 µg/ml. F. micrantha showed significant antibacterial activity against B. subtilis (22 mm, ZOI) with MIC and MBC values 7.8 and 31.25 µg/ml respectively.

OBJECTIVE

To study the chemical constituents of Sargentodoxa cuneata.

METHODS

To isolate compounds with chromatography technology and to elucidate their structures by spectral analysis.

RESULTS

Ten phenolics were isolated from Sargentodxa cuneata and their structures were determined as 1-O-(vanillic acid )-6-O-( 3", 5"-dimethoxy-galloyl)-beta-D-glycoside (I), (-)-epicatechin (II), phydroxyphenylethanol ferulate (III), chlorogenic acid (IV), methyl chlorogenate (V), apocynin (VI), vanillic acid (VII), protocatechuic acid (VIII), 3,4-dihydroxy-phenylethanol (IX), tyrosol (X).

CONCLUSIONS

Compound I is new compound, compound III-VI and VIII-X were isolated from Sargentodoxa cuneata for the first time.

Different natural aromatic/heterocyclic l-amino acids were biotransformed into aryl/heteroaryl ethanol metabolites via oxidative deamination, decarboxylation and reduction cascades using live baker's yeast cells producing intracellular human CYP2D6 enzyme. Among the three yeast strains expressing 3 different CYP2D6 variants, CYP2D6(2) (i.e. CYP2D6 wild-type) provided the best result under neutral pH conditions at RT. We have successfully converted six natural amino acids into their corresponding alcohols, having one carbon atom less, with moderate yields. Some of the downstream products like tryptophol and tyrosol induced the pTrKB (Tropomyosin receptor kinase B) activation pattern similar to that of BDNF (brain-derived neurotrophic factor), thereby depicting potential antidepressant activity. Control experiments and molecular modelling studies revealed that this tandem bio-transformation probably happens via a pyruvate intermediate. This study establishes that CYP2D6-expressing live yeast cells can be a powerful tool for the enzymatic C-N, C-C bond cleavage of amino-acids.

The presence of intrauterine contraceptive devices (IUDs) provides a solid surface for attachment of microorganisms and an ideal niche for the biofilm to form and flourish. Vaginal candidiasis is often associated with the use of IUDs. Treatment of vaginal candidiasis that develops in connection with IUD use requires their immediate removal. Here, we present in vitro evidence to support the use of combination therapy to inhibit Candida biofilm. Twenty-three clinical Candida isolates (10 C. krusei and 13 C. tropicalis) recovered from endocervical swabs obtained from IUD and non-IUD users were assessed for biofilm-formation ability. The rate of isolation of Candida did not differ significantly among IUD and non-IUD users (P = 0.183), but the biofilm-formation ability of isolates differed significantly (P = 0.02). An in vitro biofilm model with the obtained isolates was subjected to treatment with amphotericin B, tyrosol, and a combination of amphotericin B and tyrosol. Inhibition of biofilm by amphotericin B or tyrosol was found to be concentration dependent, with 50% reduction (P < 0.05) at 4 mg/l and 80 μM, respectively. Hence, a combination effect of tyrosol and amphotericin B was studied. Interestingly, approximately 90% reduction in biofilm was observed with use of 80 μM tyrosol combined with 4 mg/l amphotericin B (P < 0.001). This represents a first step in establishing an appropriate antibiofilm therapy when yeasts are present.

OBJECTIVE

Fungal quorum-sensing molecules may have an inhibitory effect as adjuvant against Candida biofilms. Therefore, in vitro activity of caspofungin and micafungin was evaluated against Candida parapsilosis biofilms in the presence of tyrosol.

RESULTS

Interactions were assessed using fractional inhibitory concentration index (FICI) determination, metabolic activity-based time-kill experiments and scanning electron microscopy (SEM). Tyrosol caused 1-16-fold and 2-32-fold decrease in median caspofungin and micafungin MICs respectively. Based on FICI, synergy was observed in isolates 27001 and 17820 with caspofungin and 27001 with micafungin. In time-kill experiments, the metabolic activity reduction was higher for micafungin compared to caspofungin at 24 h especially when used in 64 and 256 mg l-1 concentrations. In the case of micafungin, the 256 mg l-1 + 1 mmol l-1 combination caused significantly higher decrease in metabolic activity compared to the corresponding concentration alone (256 mg l-1 ) at 24 h (P < 0·05). SEM confirmed the higher killing effect of tested echinocandins with tyrosol.

CONCLUSIONS

Considerable metabolic activity reduction and cell damage was detected for combinations especially in the case of micafungin.

CONCLUSIONS

Our findings support the development of new alternative therapeutic strategies against C. parapsilosis biofilms.

This study aimed at assessing the regenerative effect of p-tyrosol in transient global cerebral ischemia modeled in adult male Wistar rats by reversible occlusion of the three major vessels originating from the aortic arch and supplying the blood to the brain. p-Tyrosol was administered intraperitoneally in a dose of 20 mg/kg over 10 days after surgery. The death of NeuN⁺ mature neurons and the number of newly formed DCX⁺ neurons were assessed in the CA1 field of the hippocampus that is highly susceptible to damage in this model. We found that ischemia induced death of more than 50% mature neurons in the hippocampal CA1 field (p<0.001). p-Tyrosol stimulated the formation and growth of new neurons in the normally non-proliferative CA1 region of the hippocampus (p<0.05) and produced a neuroprotective effect on mature neurons (p<0.01).

The Funding Information is missing in the original article.

This work details the scalable and solventless synthesis of a potential fully biobased monobenzoxazine resin derived from tyrosol and furfurylamine. The structure of the monomer was studied by nuclear magnetic resonance (NMR) spectroscopy and Fourier transform infrared (FTIR). The curing of the precursors was characterized by differential scanning calorimetry (DSC), rheological measurements, and thermogravimetric analysis (TGA). The properties of the resulting biobased polybenzoxazine were then determined by thermogravimetric analysis (TGA) and dynamic mechanical thermal analysis (DMA). A thermally stable resin was obtained with 5% and 10% weight-reduction-temperature (T_d5 and T_d10) values of 349 and 395 °C, respectively, and a char yield of 53%. Moreover, the low melting temperature, low viscosity, and excellent thermomechanical behavior make this fully biobased resin a promising candidate for coating applications.

Keywords: fully biobased; high performance; polybenzoxazine; tyrosol.

In the current research, the potential of Spanish-style green olive processing wastewaters (lye and washing waters) exploitation toward natural β-carotene production by Blakeslea trispora was tested for the first time. Mating culture generated by the joint cultivation of the heterothallic fungal strains ATCC 14271 and 14272 in the non-sterile lye and washing waters was able to grow, achieving the phytotoxic hydroxytyrosol degradation by 57.3% and 66.8%, respectively. However, the low sugar and nitrogen content of the streams did not favor carotenogenesis. Alternatively, in the nutrient-enriched effluents, a notable quantity of β-carotene was produced, accounted for 61.2 mg/L (lye) and 64.1 mg/L (washing waters) (82-88% of total carotenoid content). Above all, enriched streams had a noteworthy stimulating effect on the β-carotene synthesis, because both the maximum β-carotene yield per volume of enriched effluents and specific β-carotene production rate were higher when compared with the respective values obtained from trials with synthetic reference medium without added effluents. Hydroxytyrosol and tyrosol showed high stability during the non-sterile process for β-carotene production by B. trispora grown in the enriched effluents. This finding strengthens the potential toward the generation of multiple high-value products, which could lower the natural β-carotene production costs.

Keywords: Blakeslea trispora; hydroxytyrosol; natural β-carotene; table olive wastewaters; tyrosol.

The olive mill wastewaters obtained from two different processes, press extraction olive mill wastewater (POMW) from Portugal and two-phase system olive mill wastewater (2POMW) from Spain, were treated to recover phenolic compounds and water sequentially, by the integration of liquid-liquid extraction with Fenton's processes. From the recovered fractions, squalene, oleic acid, tyrosol, syringic acid, and p-coumaric acid were identified, and oleic acid appears in a higher concentration for 2POMW wastewater for all used solvents compared to POMW samples. Recovered fractions presented higher antioxidant activity, but remained antioxidants were found in the residual water. The wastewaters coming from a two-phase extraction method (2POMW) present higher phytotoxicity according to germination index, but the application of Fenton's process was able to improve the water quality to be re-used since an increase on the water biodegradability (BOD5/COD) and toxicity reduction were achieved.

Keywords: Antioxidants; Fenton’s process; Liquid-liquid extraction; Olive mill wastewater; Phenolic compounds; Water reuse.

Argan oil is widely used in Morocco in traditional medicine. Its ability to treat cardiovascular diseases is well-established. However, nothing is known about its effects on neurodegenerative diseases, which are often associated with increased oxidative stress leading to lipid peroxidation and the formation of 7-ketocholesterol (7KC) resulting from cholesterol auto-oxidation. As 7KC induces oxidative stress, inflammation and cell death, it is important to identify compounds able to impair its harmful effects. These compounds may be either natural or synthetic molecules or mixtures of molecules such as oils. In this context: (i) the lipid profiles of dietary argan oils from Berkane and Agadir (Morocco) in fatty acids, phytosterols, tocopherols and polyphenols were determined by different chromatographic techniques; and (ii) their anti-oxidant and cytoprotective effects in 158N murine oligodendrocytes cultured with 7KC (25-50 µM; 24 h) without and with argan oil (0.1% v/v) or α-tocopherol (400 µM, positive control) were evaluated with complementary techniques of cellular and molecular biology. Among the unsaturated fatty acids present in argan oils, oleate (C18:1 n-9) and linoleate (C18:1 n-6) were the most abundant; the highest quantities of saturated fatty acids were palmitate (C16:0) and stearate (C18:0). Several phytosterols were found, mainly schottenol and spinasterol (specific to argan oil), cycloartenol, β-amyrin and citrostadienol. α- and γ-tocopherols were also present. Tyrosol and protocatechic acid were the only polyphenols detected. Argan and extra virgin olive oils have many compounds in common, principally oleate and linoleate, and tocopherols. Kit Radicaux Libres (KRL) and ferric reducing antioxidant power (FRAP) tests showed that argan and extra virgin olive oils have anti-oxidant properties. Argan oils were able to attenuate the cytotoxic effects of 7KC on 158N cells: loss of cell adhesion, cell growth inhibition, increased plasma membrane permeability, mitochondrial, peroxisomal and lysosomal dysfunction, and the induction of oxiapoptophagy (OXIdation + APOPTOsis + autoPHAGY). Altogether, our data obtained in 158N oligodendrocytes provide evidence that argan oil is able to counteract the toxic effects of 7KC on nerve cells, thus suggesting that some of its compounds could prevent or mitigate neurodegenerative diseases to the extent that they are able to cross the blood-brain barrier.

This work reports a novel approach to generate a new group of tyrosol-based amphiphilic lipid alkylsuccinylated tyrosol by lipase-catalyzed succinylation of tyrosol with alkylsuccinic anhydrides of varying alkyl chain lengths, in high yields (80-95%). The structures of the compounds were confirmed by MS, FTIR &1H NMR; and their properties were characterized by Temperature-Ramp FTIR, DSC & CMC measurements. The synthesized compounds integrate water-soluble phenylethanoid and hydrophobic alkyl into one molecule thus are endowed with dual functions: retaining the antioxidant property of tyrosol and entailing tyrosol with new surface-active property. The DPPH activity of tyrosol (13.77%) was significantly enhanced by 2-dodecen-1-ylsuccinylated tyrosol (16.01%). Compared to tyrosol-based emulsions (76.63%), the lipid oxidation is reduced to 21.57% and 42.32% in 2-octen-1-ylsuccinylated/2-dodecen-1-ylsuccinylated tyrosol emulsions, respectively. This work brings new members to the library of functional lipid excipients and open a novel and effective synthetic pathway for derivation of phenyl alcohols.

The application of thermal pretreatments to facilitate its anaerobic digestion has associated phenols and furans production, which are commonly identified as inhibitory compounds. Phenols and furans extraction can be done from a liquid phase produced after the thermal pretreatment. In the present study this dephenolized liquid phase (DLP) showed an increase of 42% in methane yield compared to the raw liquid phase (LP) demonstrating the inhibitor character of such compounds. The main extracted phenols and furans were: 3,4-Dihydroxyphenylglycol (DHPG), Hydroxytyrosol (HT), Tyrosol (Ty), Vanillic acid (AcV), Hydroxymethylfurfural (HMF), Vanillin (V) and Furfural (F).This study also aimed to evaluate the individual effect on methane production of these specific phenols and furans the within the mixture of several ones from LP. The evaluation of the individual compounds over the methanogenesis of a dephenolized liquid phase showed that only V was inhibitory on both methane yield and methane production rate. HMF had a significantly negative effect on methane yield, but improved the methane production rate instead. Ty, F, DHPG and HT favoured the methane yield and production rate. Additionally, it was observed that negative effect of some individual phenols and furans was counteracted by the positive effect of other compounds.

Keywords: Methane production; Phenolic and furan compounds; Plackett-Burman Design; thermal pretreated OMSW.