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Background and Purpose: Clozapine is an effective antipsychotic for treatment‐resistant schizophrenia, but its discontinuation leads to discontinuation syndrome/catatonia complicated by benzodiazepine‐resistance and rhabdomyolysis. Experimental Approach: This study determined time‐dependent effects of exposure and subsequent discontinuation of clozapine on expression of connexin43, 5‐HT receptors, intracellular L‐β‐aminoisobutyrate (L‐BAIBA) and 2nd‐messengers and signalling of AMPK, PP2A and Akt in cultured astrocytes and rat frontal cortex. Key Results: Intracellular L‐BAIBA levels increased during clozapine exposure but immediately recovered after discontinuation. Both exposure to clozapine and L‐BAIBA increased connexin43 and signalling of AMPK/Akt time‐dependently, but reduced PP2A signalling, 5‐HT receptor expression and IP3 level. These changes recovered within 2 weeks after discontinuation, while 5‐HT receptors and IP3 transiently increased during the recovery process. L‐BAIBA activated AMPK signalling, leading to attenuated PP2A signalling. Astroglial D‐serine release was increased by clozapine exposure but continued to increase within 1 week after discontinuation via activation of IP3 receptor function. Conclusion and Implications: Clozapine discontinuation restored PP2A signalling due to decreased L‐BAIBA, increased 5‐HT receptor expression via probably enhanced 5‐HT receptor recycling, but increased astroglial D‐serine release persisted by transiently activated IP3 receptors via transiently increased IP3 level. Decreased L‐BAIBA caused by clozapine discontinuation is, at least partially, involved in the transiently increased 5‐HT receptor and astroglial D‐serine release. [ABSTRACT FROM AUTHOR]

Freezing-thawing procedures and semen manipulation for in vitro fertilization induce oxidative stress, which in turn leads to impaired sperm quality. The aim of this study was to evaluate whether incubation of frozen-thawed buffalo semen with olive fruit extracts (OFE), known to contain a high concentration of phenolic antioxidants, would improve semen quality by reducing oxidative stress. Frozen sperm (4 ejaculates/4 bulls/3 replicates) were thawed and diluted to 30 × 106/mL in IVF medium with 0, 72, 143, and 214 μL/mL of OFE, corresponding to 0 (D0-control), 50 (D50), 100 (D100), and 150 (D150) μM hydroxytyrosol. Sperm viability, acrosome integrity, membrane functionality, motility, and sperm kinetics were evaluated immediately after thawing (T0) and after 1 (T1) and 2 h (T2) of incubation at 38.7 °C. Based on the results, sperm biological antioxidant potential (BAP) and ROS levels (ROMs) were assessed in D0 and D100 groups at T1 and T2. To assess the effect of OFE on fertilizing ability, heterologous penetration rates were also evaluated, using bovine abattoir-derived oocytes. The treatment with OFE at all concentrations tested increased (P < 0.05) the percentage of acrosome intact spermatozoa compared to the D0-control at T1, but the effect was more evident (P < 0.01) with D100 (54.5 ± 3.0, 60.5 ± 1.5, 65.2 ± 3.3, and 62.5 ± 1.7, with D0, D50, D100, and D150 OFE, respectively). Total motility, progressive motility, rapid velocity, and progressive velocity decreased (P < 0.05) at T2 only in the D0-control group. The percentage of rapidly progressive sperm and the progressive motility tended to increase (P < 0.10) at T1 and T2, respectively, in D100 compared to D0 (24.7 ± 4.1 vs 16.4 ± 1.6 and 22.8 ± 2.7 vs 17.0 ± 1.2, respectively). The treatment with D100 OFE of frozen-thawed sperm increased (P < 0.05) some kinetic parameters (VAP and WOB). Spermatozoa incubated with D100 OFE exhibited higher (P < 0.01) total and normospermic oocyte penetration rates compared to D0 (86.5 ± 1.4 vs 78.5 ± 0.7, and 70.6 ± 1.5 vs 63.8 ± 1.1, respectively). Additionally, D100 OFE increased sperm BAP concentrations at both T1 and T2, while ROS levels were unaffected. These results suggest that incubating frozen-thawed buffalo semen with OFE is an effective strategy for preserving semen quality and in vitro fertilization ability by enhancing sperm antioxidant capacity. • Olive fruit extract supplementation enhanced in vitro fertilization ability of buffalo sperm. • The addition of olive fruit extract improves buffalo sperm biological antioxidant potential. • The treatment with olive fruit extract increased the percentage of acrosome intact spermatozoa. [ABSTRACT FROM AUTHOR]

This review explores the potential health benefits and applications of phenolic secoiridoids derived from olive oil by-products in the prevention of Alzheimer's disease (AD). As reviewed herein, polyphenols, such as epigallocatechin-3-gallate, epicatechin, and resveratrol, show in vitro and in vivo antioxidant, anti-inflammatory, and neuroprotective properties, and are particularly relevant in the context of AD, a leading cause of dementia globally. The olive oil industry, particularly in the Mediterranean region, produces significant amounts of waste, including leaves, pomace, and wastewater, which pose environmental challenges but also offer an untapped source of bioactive compounds. Despite promising in vitro and in vivo studies indicating that olive-derived polyphenols, such as oleuropein and hydroxytyrosol, may mitigate AD pathology, human clinical trials remain limited. The variability in extraction methods and the complex nature of AD further complicate research. Future studies should focus on standardizing the protocols and conducting robust clinical trials to fully assess the therapeutic potential of these compounds. This approach not only supports the development of new treatments for AD but also promotes environmental sustainability by valorizing olive oil industry waste. [ABSTRACT FROM AUTHOR]

The European olive tree, Olea europaea L., and its polyphenols hold great therapeutic potential to treat neuroinflammation and cognitive impairment. This review examines the evidence for the anti-inflammatory and neuroprotective actions of olive polyphenols and their potential in the treatment of long COVID and neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Key findings suggest that olive polyphenols exhibit antioxidant, anti-inflammatory, neuroprotective, and antiviral properties, making them promising candidates for therapeutic intervention, especially when formulated in unique combinations. Recommendations for future research directions include elucidating molecular pathways through mechanistic studies, exploring the therapeutic implications of olive polyphenol supplementation, and conducting clinical trials to assess efficacy and safety. Investigating potential synergistic effects with other agents addressing different targets is suggested for further exploration. The evidence reviewed strengthens the translational value of olive polyphenols in conditions involving cognitive dysfunction and emphasizes the novelty of new formulations. [ABSTRACT FROM AUTHOR]

The phenolic composition of virgin olive oil (VOO) primarily depends on the phenolic content of the olive fruit. The purpose of this work was to characterize the first metabolic step in the synthesis of tyrosol (Ty) and hydroxytyrosol (HTy), whose derivatives are by far the predominant phenolics in both olive fruit and VOO. To this end, two genes encoding tyrosine/DOPA decarboxylase enzymes, OeTDC1 and OeTDC2, have been identified and functionally and physiologically characterized. Both olive TDC proteins exclusively accept aromatic amino acids with phenolic side chains, such as tyrosine and 3,4-dihydroxyphenylalanine (DOPA), as substrates to produce tyramine and dopamine, respectively. These proteins exhibited a higher affinity for DOPA than for tyrosine, and the catalytic efficiency of both proteins was greater when DOPA was used as a substrate. Both olive TDC genes showed a fairly similar expression profile during olive fruit ontogeny, with OeTDC1 consistently expressed at higher levels than OeTDC2. Expression was particularly intense during the first few weeks after fruit set, coinciding with the active accumulation of Ty and HTy derivatives. The data suggest that both olive TDCs are responsible for the initial step in the synthesis of the most important phenolics, both quantitatively and functionally, in VOO. [ABSTRACT FROM AUTHOR]

Within the circular economy framework, the valorisation of olive leaves as an effective source of organic compounds rather than an agricultural waste, represents a great opportunity. Olive leaves contain bioactive polyphenols, such as the health‐enhancing catechol hydroxytyrosol (HT), derived primarily from oleuropein. This study establishes a novel and sustainable approach for the extraction of HT from olive leaves, utilizing eco‐friendly deep eutectic solvents derived from natural sources (NADES). By optimizing the extraction process, the study highlights the efficacy of the eutectic mixture cholinium/glycerol (1:2 mol/mol) in achieving HT‐rich extracts from olive leaves (0.12 ± 0.03 g HT/g of dry extract). Indeed, the method demonstrates a remarkable yield of HT, reaching 12.3 ± 0.9 g/kg of leaf powder, under optimized conditions. The antioxidant properties of the extract are thoroughly assessed, suggesting its potential health benefits. Significantly, the study underscores the scalability of the extraction method, showcasing its viability for large‐scale production while maintaining excellent outcomes. Furthermore, the sustainability of the extraction method is boosted by the reuse of NADES across multiple extraction cycles, enhancing resource efficiency and reducing environmental impact. This research unlocks the potential of olive leaves as a valuable source of bioactive compounds and outlines a sustainable extraction approach aligning with the principles of the circular economy. [ABSTRACT FROM AUTHOR]

Hydroxytyrosol (HT) is a polyphenol found in the olive plant (Olea europaea) that has garnered attention from the food, feed, supplement, and pharmaceutical industries. HT has evolved from basic separation and extraction to chemical and biocatalytic synthesis. The yield of HT can reach 1.93 g/L/h through chemical synthesis and 7.7 g/L/h through biocatalysis; however, both methods are subject to inherent limitations. Furthermore, the potential health benefits associated with HT have been highlighted, including its ability to act as an antioxidant, reduce inflammation, combat cancer and obesity, and exert antibacterial and antiviral effects. Its neuroprotective effects, skin protection, and wound healing capabilities are also discussed. Given these remarkable biological properties, HT stands out as one of the most extensively investigated natural phenols. This review highlights future methods and pathways for the synthesis of HT, providing insights based on its bioactivity characteristics, health benefits, and potential future applications. [ABSTRACT FROM AUTHOR]

Olive leaves are generated in large quantities in olive oil and table olive factories. This waste is currently used for multiple purposes, one of them being the extraction of bioactive substances, in particular phenolic compounds. The aims of this study were (i) to obtain a new polyphenolic extract from potassium hydroxide (KOH) -treated olive leaves; and (ii) to reduce acrylamide formation in black olives by using this extract. The results showed that olive leaves and leafless branches of the Manzanilla cultivar treated with 10 g/L KOH provide a solution that, concentrated under vacuum, had >6000 mg/L hydroxytyrosol and >2000 mg/L of hydroxytyrosol 4-glucoside. Moreover, the residual material generated after the treatment with KOH could be used for agronomic purposes, due to its high potassium content. The employment of this non-bitter extract during the darkening step of black ripe olive processing then resulted in darker fruits with higher potassium content. Likewise, the addition of the extract into the packing brine reduced the acrylamide formation by up to 32%, although this effect was batch-dependent. KOH olive extract could be useful for the reduction in acrylamide in black ripe olives along with the enrichment of this product in phenolic compounds and potassium. [ABSTRACT FROM AUTHOR]

Background: Cancer is a persistent global health challenge, demanding continuous exploration of innovative therapeutic strategies. Hydroxytyrosol (HT), derived from olive oil, has garnered attention for its potent antioxidant and anti-inflammatory properties, revitalizing interest due to recent breakthroughs in comprehending its intricate anticancer mechanisms. Main Body: This review conducts a detailed analysis of hydroxytyrosol's molecular mechanisms in cancer. Delve into the complex pathways and processes underlying its anticancer properties, including its impact on critical cellular events such as inhibiting cancer cell growth, proliferation, metastasis, and apoptosis. We meticulously evaluate HT efficacy and safety through scrutiny of preclinical and clinical studies. Additionally, we explore the potential synergistic effects of combining HT with conventional cancer therapies to improve treatment outcomes while reducing side effects, offering a comprehensive approach to cancer management. Conclusion: This review stands as a valuable resource for researchers, clinicians, and policymakers, providing profound insights into HT potent anticancer activity at the molecular level. It underscores the immense potential of natural compounds in the intricate realm of cancer management and highlights the urgent need for further research to translate these discoveries into effective clinical applications. Ultimately, it fosters the development of targeted and personalized therapeutic approaches, reigniting hope in the ongoing battle against cancer and enhancing the quality of life for those afflicted by this relentless disease. [ABSTRACT FROM AUTHOR]

Tyrosol and hydroxytyrosol are powerful phenolic antioxidants occurring in olive oil and in by-products from olive processing. Due to their high polarity, esterification or other lipophilization is necessary to make them compatible with lipid matrices. Hydroxytyrosol methyl carbonate is a more effective antioxidant than dibutylhydroxytoluene or α-tocopherol and together with tyrosol methyl carbonate exerts interesting pharmacological properties. The purpose of this work was the enzymatic preparation of alkyl carbonates of tyrosol and hydroxytyrosol. A set of 17 hydrolases was tested in the catalysis of tyrosol methoxycarbonylation in neat dimethyl carbonate to find an economically feasible alternative to the recently reported synthesis of methyl carbonates catalyzed by Novozym 435. Novozym 435 was, however, found to be the best performing catalyst, while Novozym 735, pig pancreatic lipase, lipase F-AK and Lipex 100T exhibited limited reactivity. No enzyme accepted 1,2-propylene carbonate as the acylation donor. Under optimized reaction conditions, Novozym 435 was used in the batch preparation of tyrosol methyl carbonate and hydroxytyrosol methyl carbonate in quantitative yields. The enzymatic methoxycarbonylation of tyrosol and hydroxytyrosol can also be used as a method for their selective protection in enzymatic syntheses of phenylethanoid glycosides catalyzed with enzymes comprising high levels of acetyl esterase side activity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Currently, olive leaves are considered waste, although their high phenolic content makes them a source of antioxidants that could be used directly. The aim of this work was to study the behavior of phenolic compounds contained in olive leaf from the olive mill production chain during their gastrointestinal digestion. RESULTS: Phenolic compounds in the gastric digestion analyzed by high‐performance liquid chromatography–diode array detection–mass spectrometry increased by 58% to 314.5% compared to the meal, while in the intestinal stage they ranged from 1.87 to 9.04 times higher. An increase of between 187% and 903% in bioaccessibility of phenolic compounds in the intestinal phase was observed, except for verbascoside. Furthermore, such compounds were fully bioavailable, except for apigenin‐7‐O‐glucoside, which showed a bioavailability of 56%. CONCLUSION: The current study showed that the concentration of oleuropein, apigegin‐7‐O‐glucoside, hydroxytyrosol hexoside and hydroxytyrosol contained in olive leaf continued to be extracted during the gastrointestinal digestion process. Furthermore, the results obtained with respect to their bioaccessibility and bioavailability suggest a good disposition to pass into the bloodstream where they could exert beneficial effects. Therefore, these results are promising for olive leaf becoming a consumable by‐product that could be directly ingested through a simple infusion. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

In the present study, the olive mill wastewater (OMW) phenolics were extracted with soy lecithin using the cloud point extraction method, and this enriched lecithin (OMW-L) was converted into spray-dried powders using maltodextrin (MD) and whey protein concentrate to be utilized as a dry food ingredient in a cake premix. The inlet temperature of 170 °C and a 3 mL/min feed flow rate yielded the highest powder yield (70.88 ± 2.12%) with a moisture content of 3.78 ± 0.03% when the mass ratio of lecithin to MD was 1:3 (w:w). The hydroxytyrosol and tyrosol contents of the powder were 42.60 ± 4.51 mg/100 g and 15.48 ± 2.50 mg/100 g, respectively. Vanillic acid, caffeic acid, 3-hydroxybenzoic acid, catechin, and rutin were also identified in the powders. The spray-dried OMW-L powder with a higher loading of polyphenols was then used in a cake premix, replacing 1% and 3% of wheat flour. This substitution significantly reduced the K value of the cake batter, as determined by rheological analyses. The addition of spray-dried OMW-L powder to the cake samples, particularly at higher concentrations (3%), influenced both crust and crumb color, causing changes in L*, a*, and b* values. The hardness values of the cake samples did not alter when blank or OMW-enriched lecithin powders were added; rather, the hardness value was influenced by the powder content. Overall, this research offers a different perspective on the use of OMW phenolics in food applications, especially in ready-to-use blends, and demonstrates the effects of the obtained spray-dried lecithin powders on batter rheology and cake characteristics. [ABSTRACT FROM AUTHOR]

Abstract Background Cancer is a persistent global health challenge, demanding continuous exploration of innovative therapeutic strategies. Hydroxytyrosol (HT), derived from olive oil, has garnered attention for its potent antioxidant and anti-inflammatory properties, revitalizing interest due to recent breakthroughs in comprehending its intricate anticancer mechanisms. Main Body This review conducts a detailed analysis of hydroxytyrosol’s molecular mechanisms in cancer. Delve into the complex pathways and processes underlying its anticancer properties, including its impact on critical cellular events such as inhibiting cancer cell growth, proliferation, metastasis, and apoptosis. We meticulously evaluate HT efficacy and safety through scrutiny of preclinical and clinical studies. Additionally, we explore the potential synergistic effects of combining HT with conventional cancer therapies to improve treatment outcomes while reducing side effects, offering a comprehensive approach to cancer management. Conclusion This review stands as a valuable resource for researchers, clinicians, and policymakers, providing profound insights into HT potent anticancer activity at the molecular level. It underscores the immense potential of natural compounds in the intricate realm of cancer management and highlights the urgent need for further research to translate these discoveries into effective clinical applications. Ultimately, it fosters the development of targeted and personalized therapeutic approaches, reigniting hope in the ongoing battle against cancer and enhancing the quality of life for those afflicted by this relentless disease.

Moderate red wine intake has been associated with lower cardiovascular mortality, due in part to the intake of polyphenols and anthocyanins, whose content can vary from varietal and year of harvest. This study assessed the vascular effects in response to a single intake of 2015 and 2018 Zweigelt red wines from Hokkaido, Japan. Healthy men were randomly assigned to consume 240 mL each of a red wine, or a sparkling white grape juice as a control in a randomized three-arm cross-over design with a 7 day washout between arms. The augmentation index (AI; a measure of arterial stiffness) and AI at 75 beats/min (AI75), reactive hyperemia index, systolic and diastolic blood pressure (SBP and DBP, respectively), and platelet reactivity were assessed at baseline and two and four hours after each beverage intake. Changes from the baseline were analyzed using a linear mixed model. Significant treatment effects (p = 0.02) were observed, with AI 13% lower after the intake of the 2015 or 2018 vintages compared to the control. Intake of the 2018 vintage reduced SBP and DBP (-4.1 mmHg and -5.6 mmHg, respectively; p = 0.02) compared to the 2015 wine and the control drink. The amount of hydroxytyrosol in the 2018 wine was almost twice the amount as in the 2015 wine, which may help explain the variable blood pressure results. Future studies exploring the vascular effects of the same red wine from different vintage years and different phenolic profiles are warranted.

Background: Hydroxytyrosol (HT) is a bioactive compound present in a limited number of foods such as wines, olives, and olive oils. During alcoholic fermentation, yeast converts aromatic amino acids into higher alcohols such as tyrosol, which can undergo hydroxylation into HT. The aim of this study was to validate an analytical method using ultra performance liquid chromatography coupled with mass spectrometry (UPLC/MS‐MS) to quantify HT and its precursors (tyrosine, hydroxyphenylpyruvic acid, hydroxyphenylacetaldehyde, 4‐hydroxyphenylacetic acid, and tyrosol) in wines. Their occurrence was evaluated in a total of 108 commercial Spanish wine samples. Results: The validated method simultaneously determined both HT and its precursors, with adequate limits of detection between 0.065 and 21.86 ng mL−1 and quantification limits between 0.199 and 66.27 ng mL−1 in a 5 min run. The concentration of HT in red wines was significantly higher (0.12–2.24 mg L−1) than in white wines (0.01–1.27 mg L−1). The higher the alcoholic degree, the higher was the content of HT. The bioactive 4‐hydroxyphenylacetic acid was identified in Spanish wines for the first time at 3.90–127.47 mg L−1, being present in all the samples. Conclusion: The highest HT concentrations were found in red wines and in wines with higher ethanol content. These data are useful for a further estimation of the intake of these bioactive compounds and to enlarge knowledge on chemical composition of wines. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Purpose: The effect of solid-state fermentation (SSF), employing different microbial strains (single or co-cultured), to the chemical composition of olive leaves (OL) and the possible perspectives of the derived material for high added-value applications was explored. Methods: Emphasis was given on bioactives (oleuropein, OLE, hydroxytyrosol, HT, elenolic acid (EA) related compounds, maslinic (MA) and oleanolic (OA) acids). In parallel, the levels of other chemical components with nutritional/antinutritional interest for feed application and certain minerals were also measured. Results: A gradual decrease in OLE and an EA derivative till their complete loss was found. HT progressively increased and then consumed reaching low levels. MA and OA were unaffected. A. niger resulted in the highest formation of HT (1 mg/g dw), and the lowest loss of OL antioxidant potential (13.8% at 72 h). Varying levels of protein production were observed potentially improving their nutritional value. Conclusion: The study demonstrated that fermented OL significantly altered phenolic compounds, particularly OLE and HT, and maintained triterpenic acids such as MA and OA. Despite reductions in certain phenolics, fermented OL showed improved nutritional profiles, particularly in protein content and antioxidant potential, suggesting their potential for added-value applications in various industrial sectors, including animal feed. To our knowledge this is the first time that the co-cultures selected in the present study were employed for OL SSF and that under all conditions examined the triterpentic acids MA and OA were the dominant bioactives despite some improvements in HT formation [ABSTRACT FROM AUTHOR]

Aim: A protocol relying on quantum chemical calculations to assist prioritization of phenolic compounds as antioxidants in terms of hydrogen atom donation efficiency is presented. The use of reference compounds, an important metrological issue for a future harmonization and standardization of computational approaches in research is also considered. Methods: A density functional theory (DFT) approach, namely B3LYP/6-311G++(2d,2p)//B3LYP/6-31G in the gas-phase was used for structure optimization, frequency calculation and single point energy (SPE) calculation to obtain the bond dissociation enthalpy (BDE) value of the most active O-H of olive oil phenols. For some of them used as a test set and for comparison, BDE values were calculated using three more approaches, M05-2X in the gas-phase, Becke three-parameter Lee-Yang-Parr (B3LYP) and implicit solvent effects (n-heptane to model bulk oils) with the integral equation formalism version of the polarizable continuum model (IEF-PCM), Minnesota 05 functional with double nonlocal exchange (M05-2X) at a single step using 6-31G+(d) basis set and solvation model density (SMD) as solvation model. Phenol and Trolox were used as reference compounds for ΔBDE calculation. Results: The proposed protocol was faster by 1.35-, 1.6-, and 8.3-fold respectively than the other three and provided almost the same activity trend application to other type of olive oil phenols indicated that prioritization based on ΔBDE values was in accordance with the limited existing experimental findings in bulk oils, and the order of activity was generally in agreement with the structure-antioxidant activity criteria. Conclusions: Present findings highlighted the usefulness of quantum chemical calculations as a tool to screen/prioritize molecules with an established structure saving experimental effort and waste production. The expression of results relatively to phenol and Trolox BDE values, may assist comparisons among research findings and facilitate standardization. Based on the findings hydroxytyrosol and related compounds should be efficient hydrogen atom donors compared to other potent virgin olive oil phenols.

This study aims to extract phenolic-enriched compounds, specifically oleuropein, luteoloside, and hydroxytyrosol, from olive leaves using ball milling-assisted extraction (BMAE). Response surface methodology (RSM) and the Box–Behnken design (BBD) were used to evaluate the effects of the temperature, solvent-to-solid ratio, and milling speed on extraction recovery. The contents of the extract were determined by ultra-high-performance liquid chromatography–mass spectrometry (UPLC-MS) and converted to recoveries to evaluate the extraction efficiency. The optimal extraction conditions for oleuropein, luteoloside, and hydroxytyrosol were identified. Oleuropein had a recovery of 79.0% ± 0.9% at a temperature of 56.4 °C, a solvent-to-solid ratio of 39.1 mL/g, and a milling speed of 429 rpm. Luteoloside's recovery was 74.6% ± 1.2% at 58.4 °C, 31.3 mL/g, and 328 rpm. Hydroxytyrosol achieved 43.1% ± 1.3% recovery at 51.5 °C, 32.7 mL/g, and 317 rpm. The reason for the high recoveries might be that high energy ball milling could reduce the sample size further, breaking down the cell walls of olive leaves, to enhance the mass transfer of these components from the cell to solvent. BMAE is displayed to be an efficient approach to extracting oleuropein, luteoloside, and hydroxytyrosol from olive leaves, which is easy to extend to industrial production. [ABSTRACT FROM AUTHOR]

Olive oil extraction by two-phase systems generates a by-product called "alperujo" which presents several difficulties for its valorization. The present work evaluated an industrial approach, based on the application of thermal treatments to alperujo followed by solid/liquid separation using standard two-phase olive oil mill equipment. Treatments consisted of the thermo-malaxation of alperujo at 70 °C for 45 or 90 min, with or without acid addition, followed by solid/liquid separation in an industrial decanter. The solid was characterized concerning subsequent use for composting, while total and hydrophilic phenolics were analyzed in liquid for their recovery. Additionally, a laboratory-scale trial to compare phenolic purification by ethylic acetate extraction with chromatographic procedures was also included. The static respiration index showed that solid fractions presented higher susceptibility to biodegradation processes than raw alperujo. The phenolic content of treated liquid fractions was higher than in raw alperujo. Total phenolics were maximum at the longest exposure time without acid addition, while hydrophilic phenolics were highest at the shortest exposure time in acidified samples. The use of non-ionic resins seemed attractive for obtaining highly concentrated phenolic fractions. The proposed thermal treatments can be applied in olive oil industries, allowing in situ pomace valorization and the recovery of phenolic-enriched liquid fractions. [ABSTRACT FROM AUTHOR]

Summary: Although the health effects of olive phenolics, hydroxytyrosol (HX), are well known, their utilisation is not at the forefront of the phenolics market. Besides, 99% of olive phenolics are lost during olive oil production (2.2 million tons year−1). This study aims to develop a functional hydrogel for functional foods using commercial olive powder derived from olive mill wastewater and methylcellulose (MC). The final hydrogel recipe, a multi‐hydrocolloid recipe (MC and gelatine with low gelling temperature) based on minimum HX loss and acceptable sensory properties, was created by examining interactions of HX with salt, sugar, and citric acid in MC by a modified UPLC‐UV method and expert sensory panellists. Finally, two dairy bases were created for the hydrogel with the best aroma match, and consumer‐accepted dessert (72%) and appetiser (58%) providing the health claims of European Food Safety Authority (EFSA) (2 mg day−1 of HX) were produced. Moreover, a sample methodology has been developed. [ABSTRACT FROM AUTHOR]

Achilles tendinopathy (TP) is characterized as the third most common disease of the musculoskeletal system, and occurs in three phases. There is currently no evidence of effective treatment for this medical condition. In this study, the modulatory effects of the minimally invasive technique intratissue percutaneous electrolysis (EPI) and combinations of EPI with four nutritional factors included in the diet, hydroxytyrosol (HT), maslinic acid (MA), glycine, and aspartate (AA), on hepatic intermediary metabolism was examined in Wistar rats with induced tendinopathy at various stages of TP. Results obtained showed that induced tendinopathy produced alterations in the liver intermediary metabolisms of the rats. Regarding carbohydrate metabolism, a reduction in the activity of pro-inflammatory enzymes in the later stages of TP was observed following treatment with EPI alone. Among the combined treatments using nutritional factors with EPI, HT+EPI and AA+EPI had the greatest effect on reducing inflammation in the late stages of TP. In terms of lipid metabolism, the HT+EPI and AA+EPI groups showed a decrease in lipogenesis. In protein metabolism, the HT+EPI group more effectively reduced the inflammatory effects of induced TP. Treatment with EPI combined with nutritional factors might help regulate intermediary metabolism in TP disease and reduce the inflammation process. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, research has focused on identifying and studying natural bioactive compounds that may have potential implications in the prevention and treatment of cardiovascular diseases. Phenolic ingredients such as Tyrosol and hydroxytyrosol, found in olive oil, attract particular attention due to their potential cardioprotective properties. The aim of this study is to provide a comprehensive research review of the current knowledge of the cardioprotective effects of tyrosol and hydroxytyrosol, highlighting their potential health benefits and identifying research gaps for future research. Aim: The aim of this study is to investigate the cardioprotective effect of phenolic compounds found in olive oil, such as tyrosol and hydroxytyrosol, which is an important health care problem due to the prevalence of deaths caused by cardiovascular diseases. The aim of the study is to understand the effectiveness of natural ingredients in the prevention and treatment of cardiovascular diseases and to learn the specific effects of these compounds, which may contribute to the development of new therapeutic and preventive strategies and improve the quality of life of patients. Review methods: A non-systematic review of the scientific literature was carried out according to the following keywords: Tyrosol, hydroxytyrosol, cardioprotection, cardiovascular diseases, olive oil cardioprotective role, geriatric patients, elderly people. PubMed was searched and 34 sources published up to 2023 were analysed. It was done to ensure that the knowledge contained in this article includes the most up-to-date information. Abbreviated description of the state of knowledge: Tyrosol and hydroxytyrosol, prominent in olive oil, are studied for their potential cardioprotective properties. Linked to a Mediterranean diet, these compounds show promise in reducing cardiovascular disease risk. They counter oxidative stress, improve lipid profiles, and modulate inflammatory processes. Clinical studies suggest their positive impact, with tyrosol also explored as a potential anticoagulant. Ongoing research aims to uncover optimal doses and mechanisms, highlighting their significance in cardiovascular health. Conclusions: Tyrosol and hydroxytyrosol, found in olive oil, show promise in cardioprotection by combating oxidative stress, improving lipid profiles, and modulating inflammation. Clinical studies suggest their positive impact on cardiovascular health. Tyrosol has potential as a anticoagulant and exhibits antioxidant effects. These compounds present a compelling avenue for future therapeutic interventions, with emphasis on understanding mechanisms and optimizing supplementation. [ABSTRACT FROM AUTHOR]

Purpose of Review: Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide significant biological information for the pathophysiology of the disease but may also reveal biomarkers for diagnosis or therapeutic targets. The present systematic review aims to synthesize the evidence regarding the proteome of adult patients with FMS using data from observational studies. Recent Findings: An extensive literature search was conducted in MEDLINE/PubMed, CENTRAL, and clinicaltrials.gov from inception until November 2022. The study protocol was published in OSF. Two independent reviewers evaluated the studies and extracted data. The quality of studies was assessed using the modified Newcastle–Ottawa scale adjusted for proteomic research. Ten studies fulfilled the protocol criteria, identifying 3328 proteins, 145 of which were differentially expressed among patients with FMS against controls. The proteins were identified in plasma, serum, cerebrospinal fluid, and saliva samples. The control groups included healthy individuals and patients with pain (inflammatory and non-inflammatory). Summary: The most important proteins identified involved transferrin, α-, β-, and γ-fibrinogen chains, profilin-1, transaldolase, PGAM1, apolipoprotein-C3, complement C4A and C1QC, immunoglobin parts, and acute phase reactants. Weak correlations were observed between proteins and pain sensation, or quality of life scales, apart from the association of transferrin and a2-macroglobulin with moderate-to-severe pain sensation. The quality of included studies was moderate-to-good. FMS appears to be related to protein dysregulation in the complement and coagulation cascades and the metabolism of iron. Several proteins may be dysregulated due to the excessive oxidative stress response. [ABSTRACT FROM AUTHOR]

Objective: Hydroxytyrosol (HT), a polyphenolic component identified in olive oil and leaves, represents one of the most extensively investigated natural phenol due to its diverse beneficial biological properties. Recent studies have shown that HT exhibits protective effects on reproductive function and can improve sperm quality. However, the precise effect and underlying mechanism of HT on oligozoospermia remain unclear. This study aims to investigate the effect and mechanism of HT across varying concentrations on oligozoospermia. Methods: Oligozoospermia was induced in ICR male mice via intraperitoneal injection of busulfan (BUS, 30 mg/ kg). The mice were randomly categorized into five groups as Normal, BUS, HT 10 mg/kg, HT 30 mg/kg and HT 50 mg/kg. The efficacy of HTon oligozoospermia was assessed through sperm concentration and motility using a computer-assisted sperm analysis system. Testicular and epididymal histology was examined via hematoxylin-eosin staining, while cytoskeletal integrity was evaluated by immunofluorescence. Hormone levels, along with reactive oxygen species (ROS) and malondialdehyde (MDA) were examined by ELISA kits. Differentially expressed genes were identified through RNA sequencing, and the expression levels of key genes were validated by qPCR. Results: The results indicated that HT (50 mg/kg) significantly increased sperm concentration, promoted morphological recovery of testicular tissue, heightened the levels of serum testosterone, follicle-stimulating hormone, luteinizing hormone, as well as decreased the accumulation of ROS and MDA in mice with oligozoospermia. RNA sequencing analysis and RT-qPCR results revealed that HT could restore spermatogenesis and ameliorate oligozoospermia by up-regulating genes related to cilium organization, microtubule-based movement, and spermatid differentiation and development. Conclusions: HT demonstrates therapeutic efficacy against busulfan-induced oligozoospermia. The mechanism of HT on oligozoospermia may be related to its influence on cilium and microtubule-based movement, along with the differentiation and development of spermatids. HT shows potential as a prospective therapeutic intervention for the treatment of oligozoospermia. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) triggers mitochondrial dysfunction and neural inflammation, leading to cognitive impairment and mental issues. However, the mechanism involving mitochondrial dysfunction and neural inflammation still remains unclear. Here, we report that SD rats exhibited multiple behavioral disorders, brain oxidative stress, and robust brain mitochondrial DNA (mtDNA) oxidation. In particular, SD activated microglia and microglial mtDNA efflux to the cytosol and provoked brain pro-inflammatory cytokines. We observed that the mtDNA efflux and pro-inflammatory cytokines significantly reduced with the suppression of the mtDNA oxidation. With the treatment of a novel mitochondrial nutrient, hydroxytyrosol butyrate (HTHB), the SD-induced behavioral disorders were significantly ameliorated while mtDNA oxidation, mtDNA release, and NF-κB activation were remarkably alleviated in both the rat brain and the N9 microglial cell line. Together, these results indicate that microglial mtDNA oxidation and the resultant release induced by SD mediate neural inflammation and HTHB prevents mtDNA oxidation and efflux, providing a potential treatment for SD-induced mental issues. [ABSTRACT FROM AUTHOR]

Bioactive compounds that can be recovered by the solid wastes of the olive oil sector, such as polyphenols, are known for their significant antioxidant and antimicrobial activities with potential application in nutraceutical, cosmetic, and food industries. Given that industrial demands are growing, and the polyphenol market value is ever increasing, a systematic study on the recovery of natural antioxidant compounds from olive pomace using ultrasound-assisted extraction (UAE) was conducted. Single-factor parameters, i.e., the extraction solvent, time, and solid-to-liquid ratio, were investigated evaluating the total phenolic content (TPC) recovery and the antioxidant activity of the final extract. The acetone–water system (50% v/v, 20 min, 1:20 g mL−1) exhibited the highest total phenolic content recovery (168.8 ± 5.5 mg GAE per g of dry extract). The olive pomace extract (OPE) was further assessed for its antioxidant and antibacterial activities. In DPPH, ABTS, and CUPRAC, OPE exhibited an antioxidant capacity of 413.6 ± 1.9, 162.72 ± 3.36 and 384.9 ± 7.86 mg TE per g of dry extract, respectively. The antibacterial study showed that OPE attained a minimum inhibitory activity (MIC) of 2.5 mg mL−1 against E. coli and 10 mg mL−1 against B. subtilis. Hydroxytyrosol and tyrosol were identified as the major phenolic compounds of OPE. Furthermore, active chitosan–polyvinyl alcohol (CHT/PVA) films were prepared using different OPE loadings (0.01–0.1%, w/v). OPE-enriched films showed a dose-dependent antiradical scavenging activity reaching 85.7 ± 4.6% (ABTS) and inhibition growth up to 81% against B. subtilis compared to the control film. Increased UV light barrier ability was also observed for the films containing OPE. These results indicate that OPE is a valuable source of phenolic compounds with promising biological activities that can be exploited for developing multifunctional food packaging materials. [ABSTRACT FROM AUTHOR]

Olive oil phenols are recognized as molecules with numerous positive health effects, many of which rely on their antioxidative activity, i.e., the ability to transfer hydrogen to radicals. Proton-coupled electron transfer reactions and hydrogen tunneling are ubiquitous in biological systems. Reactions of olive oil phenols, hydroxytyrosol, tyrosol, oleuropein, oleacein, oleocanthal, homovanillyl alcohol, vanillin, and a few phenolic acids with a DPPH• (2,2-diphenyl-1-picrylhydrazyl) radical in a 1,4-dioxane:water = 95:5 or 99:1 v/v solvent mixture were studied through an experimental kinetic analysis and computational chemistry calculations. The highest rate constants corresponding to the highest antioxidative activity are obtained for the ortho-diphenols hydroxytyrosol, oleuropein, and oleacein. The experimentally determined kinetic isotope effects (KIEs) for hydroxytyrosol, homovanillyl alcohol, and caffeic acid reactions are 16.0, 15.4, and 16.7, respectively. Based on these KIEs, thermodynamic activation parameters, and an intrinsic bond orbital (IBO) analysis along the IRC path calculations, we propose a proton-coupled electron transfer mechanism. The average local ionization energy and electron donor Fukui function obtained for the phenolic compounds show that the most reactive electron-donating sites are associated with π electrons above and below the aromatic ring, in support of the IBO analysis and proposed PCET reaction mechanism. Large KIEs and isotopic values of Arrhenius pre-exponential factor AH/AD determined for the hydroxytyrosol, homovanillyl alcohol, and caffeic acid reactions of 0.6, 1.3, and 0.3, respectively, reveal the involvement of hydrogen tunneling in the process. [ABSTRACT FROM AUTHOR]

An eco-friendly approach towards the recovery of value-added extracts from olive tree leaves with the aid of supercritical CO2 at 30 MPa was carried out. The impact of extraction temperature (35–90 °C) and presence of co-solvents (ethanol, water, and aqueous ethanol) on the total phenolic, flavonoid, and pigment content, as well as oleuropein, hydroxytyrosol, tyrosol, and α-tocopherol content was determined. In addition, the antioxidant activity of extracts from tree leaves using DPPH, ABTS, and CUPRAC assays was investigated. The results of the study showed that the most effective supercritical CO2 extraction was at 90 °C with an addition of ethanol, which enabled the separation of extract with the highest content of tested compounds. Some of the highest recorded values were for oleuropein 1.9 mg/g, for carotenoids 5.3 mg/g, and for α-tocopherol 2.0 mg/g. Our results are expected to contribute to the efforts towards the valorization of olive leaves as a sustainable source of valuable compounds, and boost local economies as well as the interest of pharmaceutical, food, and cosmetic industries for novel food by-product applications. [ABSTRACT FROM AUTHOR]

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea, and of these, only a relatively small fraction have been characterised. Utilising the OliveNetTM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein–peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet. [ABSTRACT FROM AUTHOR]

Infants and young animals often suffer from intestinal damage caused by oxidative stress, which may adversely affect their overall health. Hydroxytyrosol, a plant polyphenol, has shown potential in decreasing intestinal oxidative stress, but its application and mechanism of action in infants and young animals are still inadequately documented. This study selected piglets as a model to investigate the alleviating effects of hydroxytyrosol on intestinal oxidative stress induced by diquat and its potential mechanism. Hydroxytyrosol improved intestinal morphology, characterized by higher villus height and villus height/crypt depth. Meanwhile, hydroxytyrosol led to higher expression of Occludin, MUC2, Nrf2, and its downstream genes, and lower expression of cytokines IL-1β, IL-6, and TNF-α. Both oxidative stress and hydroxytyrosol resulted in a higher abundance of Clostridium_sensu_stricto_1, and a lower abundance of Lactobacillus and Streptococcus, without a significant effect on short-chain fatty acids levels. Oxidative stress also led to disorders in bile acid (BA) metabolism, such as the lower levels of primary BAs, hyocholic acid, hyodeoxycholic acid, and tauroursodeoxycholic acid, which were partially restored by hydroxytyrosol. Correlation analysis revealed a positive correlation between these BA levels and the expression of Nrf2 and its downstream genes. Collectively, hydroxytyrosol may reduce oxidative stress-induced intestinal damage by regulating BA metabolism. [ABSTRACT FROM AUTHOR]

Semen cryopreservation is one of the most important reproduction techniques in the livestock and poultry industry. Cryopreservation induces cold stress, generating reactive oxygen species (ROS) and oxidative stress causing structural and biochemical damages in sperm. In this study, we evaluated the effects of the hydroxytyrosol (HT), as an antioxidant, at the concentrations of 0, 25, 50, and 100 μg/mL on post‐thaw semen quality metrics in rooster. Semen samples were collected twice a week from 10 roosters (29 weeks), processed and frozen according to experimental groups. Different quality parameters, including total motility, progressive motility, viability, morphology, membrane integrity, and malondialdehyde were measured after thawing. Results showed that 25 and 50 μg/mL of HT produced the highest percentage of total motility (51.01 ± 2.19 and 50.15 ± 2.19, respectively) and progressive motility (35.74 ± 1.34 and 35.15 ± 1.34, respectively), membrane integrity (48.00 ± 2.18 and 46.75 ± 2.18, respectively) as well as viability (53.00 ± 2.17 and 52.50 ± 2.17, respectively) compared with the other groups (p <.05). The group with 25 μg/mL of HT showed the lowest significant (p <.05) MDA concentration (1.81 ± 0.25). Our results showed that the effect of HT was not dose‐dependent and optimum concentration of HT could improve functional parameters of rooster sperm after freezing–thawing. These findings suggest that HT may have protective effects on the rooster sperm during the freezing–thawing process. [ABSTRACT FROM AUTHOR]

Because olive pomace (the main by-product of olive oil production) is phytotoxic, new applications must be investigated to minimize its negative environmental impact. In this work, olive pomace was fermented for 4 and 32 days at room temperature, having in view its valorization as a novel food, thereby creating opportunities for the food industry and addressing a challenge of the olive oil sector. The chemical and microbiological modifications that occurred along the fermentation were followed. The results showed no significant differences (p > 0.05) in total protein between the control and the fermented samples; however, the latter exhibited higher levels of essential amino acids. The major nonessential and essential amino acids were glutamic acid and leucine in all samples. There was a significant increase in the total fat of the 32-day sample and the main fatty acid was oleic acid in all samples. There were considerable reductions in total vitamin E, phenolics, and antioxidant activity values post-fermentation. Hydroxytyrosol replaced oleacein as the main phenolic in the 32-day sample. A sharp increase in total microorganisms occurred (2.20 × 102 to 3.00 × 104–2.01 × 107 colony forming units/mL) but no pathogenic microorganisms were detected. Overall, olive pomace fermentation creates novel products for the food industry with a balanced nutritional composition. [ABSTRACT FROM AUTHOR]

Olive anthracnose, caused by Colletotrichum fungi, and the olive fruit fly Bactrocera olea are, respectively, the most important fungal disease and pest affecting olive fruits worldwide, leading to detrimental effects on the yield and quality of fruits and olive oil. This study focuses on the content of hydroxytyrosol (HYT) and its derivatives (the "olive oil polyphenols" health claim) in olive oils extracted from fruits of 'Galega Vulgar' and 'Cobrançosa' cultivars, naturally affected by olive anthracnose and olive fly. The olives, with different damage levels, were harvested from organic rainfed orchards, located in the center of Portugal, at four harvest times over three years. Galega oils extracted from olives with a higher anthracnose and olive fly incidence showed no conformity for the extra virgin olive oil (EVOO) and virgin olive oil (VOO) categories, presenting high acidity and negative sensory notes accompanied by the disappearance of oleacein. Conversely, no sensory defects were observed in Cobrançosa oils, regardless of disease and pest incidence levels, and quality criteria were still in accordance with the EVOO category. The total HYT and tyrosol (TYR) content (>5 mg/20 g) allows for the use of the "olive oil polyphenols" health claim on the label of all the analyzed Cobrançosa olive oils. [ABSTRACT FROM AUTHOR]

Hydroxytyrosol (HT), a plant-derived phenolic compound, is recognized for its potent antioxidant capabilities alongside a spectrum of pharmacological benefits, including anti-inflammatory, anti-cancer, anti-bacterial, and anti-viral properties. These attributes have propelled HT into the spotlight as a premier nutraceutical and food additive, heralding a new era in health and wellness applications. Traditional methods for HT production, encompassing physico-chemical techniques and plant extraction, are increasingly being supplanted by biotechnological approaches. These modern methodologies offer several advantages, notably environmental sustainability, safety, and cost-effectiveness, which align with current demands for green and efficient production processes. This review delves into the biosynthetic pathways of HT, highlighting the enzymatic steps involved and the pivotal role of genetic and metabolic engineering in enhancing HT yield. It also surveys the latest progress in the biotechnological synthesis of HT, examining innovative strategies that leverage both genetically modified and non-modified organisms. Furthermore, this review explores the burgeoning potential of HT as a nutraceutical, underscoring its diverse applications and the implications for human health. Through a detailed examination of both the biosynthesis and biotechnological advances in HT production, this review contributes valuable insights to the field, charting a course towards the sustainable and scalable production of this multifaceted compound. [ABSTRACT FROM AUTHOR]

Surgical tissue reconstruction often uses random skin flaps, but ischemic necrosis at the distal end remains a problem. Hydroxytyrosol, a phenolic compound from olive oil, has anti-inflammatory and antioxidative properties. This study investigated whether hydroxytyrosol could promote flap survival and its underlying mechanisms using a mouse model with random skin flaps. Flap necrosis was assessed seven days after surgery, with angiogenesis, apoptosis, oxidative stress, and autophagy evaluated in flap specimens. Compared to controls, the hydroxytyrosol-treated group showed reduced necrotic areas and edema. Immunohistochemistry and Western blotting revealed decreased oxidative stress and apoptosis, with increased angiogenesis. Laser Doppler imaging confirmed enhanced angiogenesis with hydroxytyrosol treatment. The reversal of hydroxytyrosol’s effects by 3-methyladenine underscores autophagy’s role, mediated by SIRT1 activation. Our research indicates that hydroxytyrosol enhances random skin flap survival by activating SIRT1-mediated autophagy.

Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.

The bioactive potential of phenolic extracts derived from olive mill solid by-product (OMSbP), also called alperujo, and olive mill water (OMW), remains a topic of significant interest due to the amount of these, especially in Mediterranean regions, and their potential health benefits. In this study, the antioxidant and immunomodulatory properties of phenolic extracts obtained from OMSbP and OMW (OMSbP-P and OMW-P, respectively) in intestinal cells were evaluated. Initially, phenol-rich extracts were prepared by ethanol/ethyl acetate extraction and were characterized by HPLC-DAD analyses. The in vitro antioxidant activity showed potent bioactivities for all extracts evaluated. Toxicity assays did not reveal adverse effects on Caco-2 cell viability at concentrations relevant to immunomodulatory activity. Subsequently, the immunomodulatory effects of these extracts were assessed by measuring gene expression of pro- and anti-inflammatory cytokines. The results demonstrate that both OMSbP-P and OMW-P exhibit significant immunomodulatory activities, as evidenced by modulated cytokine gene expression in intestinal cells. Furthermore, molecular docking analyses of the identified phenols with the TLR4/MD2 receptor showed binding affinity, increasing the evidence that these extracts could exert immunomodulatory activity. Overall, our findings suggest that OMSbP-P and OMW-P possess promising immunomodulatory properties in intestinal cells, thus emphasizing their potential as natural therapeutic agents for managing immune-related disorders and promoting gut health. Further elucidation of the molecular mechanisms underlying these effects and in vivo studies are warranted to fully exploit the therapeutic potential of these extracts.

The Mediterranean Diet (MD) has garnered increasing attention for its potential protective effects against gastric cancer (GC). The MD's rich content of antioxidants, polyphenols, and other bioactive compounds contributes to its ability to modulate gene expression, inhibit tumor growth, and regulate apoptosis. Studies have shown significant reductions in inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) among individuals adhering to the MD, suggesting its pivotal role in mitigating chronic inflammation-associated with cancer development. Furthermore, the MD's anti-angiogenic properties, particularly in components like olive oil, red wine, fish, and tomatoes, offer promising avenues for reducing GC risk by inhibiting tumor angiogenesis. Additionally, the MD's influence on intestinal microbiota composition underscores its potential in maintaining immune homeostasis and reducing systemic inflammation, factors crucial in GC prevention. Despite challenges such as variability in dietary adherence scoring systems and the need for further gender and geographical-specific studies, evidence supports the MD as a cost-effective and holistic approach to GC prevention. Emphasizing the role of nutrition in public health is a promising strategy with broad implications for global health and cancer prevention initiatives. Therefore, this review explores the multifaceted impacts of the MD on GC prevention, delving into its anti-inflammatory, anti-angiogenic, and molecular mechanisms. [ABSTRACT FROM AUTHOR]

Upgrading lignin-derived monomeric products presents a compelling prospect for synthesizing value-added products. Despite the potential benefits, the conversion of lignin-derived phenols into hydroxytyrosol (HT), a potent natural antioxidant predominantly sourced from olives, remains underexplored. Herein, we envisioned three novel one-pot cascade biocatalytic approaches for converting lignin-derived catechol and phenol into HT by integrating four or five main reactions: C–C coupling, hydroxylation, decarboxylation, deamination and reduction. By co-expressing the corresponding enzymes in recombinant Escherichia coli (E. coli) resting cells, we achieved HT conversions of 65.4% and 89.0% from 10 mM catechol using recombinant E. coli (CFK-RTA) resting cells, which co-expressed tyrosine phenol-lyase (FnTPL), tyrosine decarboxylase (TDC), amine transaminase (ATA) and aldehyde reductase (yahK), and E. coli (RFK-EAL) resting cells, which co-expressed FnTPL, L -amino acid deaminase (LAAD), α-keto acid decarboxylase (ARO10) and yahK, respectively. Additionally, a 75.3% conversion of HT from 10 mM phenol was achieved with E. coli (CFK-EBC-RAL) resting cells co-expressing FnTPL, 4-hydroxyphenylacetate 3-hydroxylase (HpaBC), LAAD, ARO10 and yahK. The highest HT titers of 20.6 mM (3.18 g L−1) and 18.5 mM (2.85 g L−1) were obtained from 30 mM catechol and phenol, respectively, by utilizing recombinant E. coli (RFK-EAL) and E. coli (CFK-EBC-RAL) resting cells in a fed-batch strategy. These cascade biocatalysis processes rely on biomass-derived phenol or catechol and inexpensive pyruvate as substrates, with NH4Cl serving as the amine donor, offering new and viable routes for the sustainable and environmentally friendly production of HT. [ABSTRACT FROM AUTHOR]

Key Message: This study identified 16 pyridoxal phosphate-dependent decarboxylases in olive at the whole-genome level, conducted analyses on their physicochemical properties, evolutionary relationships and characterized their activity. Group II pyridoxal phosphate-dependent decarboxylases (PLP_deC II) mediate the biosynthesis of characteristic olive metabolites, such as oleuropein and hydroxytyrosol. However, there have been no report on the functional differentiation of this gene family at the whole-genome level. This study conducted an exploration of the family members of PLP_deC II at the whole-genome level, identified 16 PLP_deC II genes, and analyzed their gene structure, physicochemical properties, cis-acting elements, phylogenetic evolution, and gene expression patterns. Prokaryotic expression and enzyme activity assays revealed that OeAAD2 and OeAAD4 could catalyze the decarboxylation reaction of tyrosine and dopa, resulting in the formation of their respective amine compounds, but it did not catalyze phenylalanine and tryptophan. Which is an important step in the synthetic pathway of hydroxytyrosol and oleuropein. This finding established the foundational data at the molecular level for studying the functional aspects of the olive PLP_deC II gene family and provided essential gene information for genetic improvement of olive. [ABSTRACT FROM AUTHOR]

Hydroxytyrosol (HT) is a bioactive olive oil phenol with beneficial effects in a number of pathological situations. We have previously demonstrated that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic-stroke-associated damage in mice. Our exploratory pilot study examined this effect in humans. Particularly, a nutritional supplement containing 15 mg of HT/day was administered to patients 24 h after the onset of stroke, for 45 days. Biochemical and oxidative-stress-related parameters, blood pressure levels, serum proteome, and neurological and functional outcomes were evaluated at 45 and 90 days and compared to a control group. The main findings were that the daily administration of HT after stroke could: (i) favor the decrease in the percentage of glycated hemoglobin and diastolic blood pressure, (ii) control the increase in nitric oxide and exert a plausible protective effect in oxidative stress, (iii) modulate the evolution of the serum proteome and, particularly, the expression of apolipoproteins, and (iv) be beneficial for certain neurological and functional outcomes. Although a larger trial is necessary, this study suggests that HT could be a beneficial nutritional complement in the management of human stroke. [ABSTRACT FROM AUTHOR]

Background: Adverse medication reactions affecting one or more organ systems can manifest as side effects of antibiotics. There is a possibility that some antibiotics will have adverse effects that are fatal. The present study aims to examine the ability of hydroxytyrosol (HT) to protect the liver, heart, and improvement of kidney function against the adverse effects of azithromycin. Methods: Thirty adult male rats were randomly divided into three equal groups of 10 animals each. The first group, designated negative control (NC), was the daily oral administration of normal saline. The second group (T1) was subject to daily oral administration of azithromycin (30 mg/kg). The last third group (T2) was administered azithromycin (30 mg/kg) with hydroxytyrosol (50 mg/kg). After two weeks the animals were sacrificed for serum collection, histopathological specimens, and drug docking evaluation using Auto Dock Vina. Result: The present study showed that score binding in 18gs Glutathione S-transferase was preferable in hydroxytyrosol with (-5.95 Kcal/mol), while vitamin E was in (-7.80 Kcal/mol) and (-6.16 Kcal/mol) for glutathione. On the other aspect, antioxidant coenzyme Q10 showed less binding with 18gs Glutathione Stransferase to recorded binding at (-4.9) with Root Mean Square Deviation (RMSD) (29.3, 30.3, 23.9 Kcal/mol) and (28.6) Kcal/mol, respectively. The histopathological result for T1 showed several histological effects in the liver, heart, and kidney, while in T2 group showed improvement in tissue architecture. Conclusion: The study concluded that hydroxytyrosol binding glutathione S-transferase could predict potent antioxidants near glutathione, might be responsible for scavenger free radicals, and protect the tissue against the toxic effects of azithromycin. [ABSTRACT FROM AUTHOR]

The Mediterranean diet, renowned for its health benefits, especially in reducing cardiovascular risks and protecting against diseases like diabetes and cancer, emphasizes virgin olive oil as a key contributor to these advantages. Despite being a minor fraction, the phenolic compounds in olive oil significantly contribute to its bioactive effects. This review examines the bioactive properties of hydroxytyrosol and related molecules, including naturally occurring compounds (-)-oleocanthal and (-)–oleacein, as well as semisynthetic derivatives like hydroxytyrosyl esters and alkyl ethers. (-)-Oleocanthal and (-)–oleacein show promising anti-tumor and anti-inflammatory properties, which are particularly underexplored in the case of (-)–oleacein. Additionally, hydroxytyrosyl esters exhibit similar effectiveness to hydroxytyrosol, while certain alkyl ethers surpass their precursor's properties. Remarkably, the emerging research field of the effects of phenolic molecules related to virgin olive oil on cell autophagy presents significant opportunities for underscoring the anti-cancer and neuroprotective properties of these molecules. Furthermore, promising clinical data from studies on hydroxytyrosol, (-)–oleacein, and (-)–oleocanthal urge further investigation and support the initiation of clinical trials with semisynthetic hydroxytyrosol derivatives. This review provides valuable insights into the potential applications of olive oil-derived phenolics in preventing and managing diseases associated with cancer, angiogenesis, and atherosclerosis. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the impact of including hydroxytyrosol (HT) antioxidant on the viability of sperm after the processes of cooling and freezing. HT antioxidants were used in the HF-20 extender at concentrations of 1.25, 2.5, 5, and 10 μg/ml. The HF-20 extender was a basic extender and was used for the control group. The post-thawed semen exhibited significantly higher total motility in the 2.5 HT and 10 HT treatment groups than the control group. The straight line velocity (VSL) of the 2.5 HT group exhibited a significantly high value compared with the control group. However, the average path velocity (VAP), linearity (LIN), straightness index (STR), and wobble (WOB) revealed identical findings across all groups. The findings of the analysis of HOST, normal morphology, major abnormalities, and minor abnormalities revealed that there were no significant differences between the HT groups and the control groups. Nevertheless, the use of HT antioxidant for freezing semen led to a notable enhancement (p < 0.05) in both acrosome integrity and vitality tests when compared to the control group. In this case, the lower quantities of HT (1.25 and 2.5 μg/ml; p < 0.05) preserve the DNA fragmentation compared with the 5 HT, 10 HT, and control groups. In conclusion, the HT antioxidant has shown the capacity to enhance the quality of frozen-thawed spermatozoa and positively influence the viability and integrity of DNA inside the frozen-thawed spermatozoa. Additional research should be conducted to assess the fertility potential of cryopreserved stallion semen. [ABSTRACT FROM AUTHOR]

The laccase-catalyzed oxidation of hydroxytyrosol (HT) towards the formation of its bioactive oligomer derivatives was investigated. The biocatalytic oligomerization was catalyzed by laccase from Trametes versicolor in aqueous or various water-miscible organic solvents and deep eutectic solvent (DES)-based media. Mass Spectroscopy and Nuclear Magnetic Resonance were used for the characterization of the products. The solvent system used significantly affects the degree of HT oligomerization. The use of 50 % v/v methanol favored the production of the HT dimer, while other organic solvents as well as DESs led to the formation of hydroxytyrosol trimer and other oligomers. In vitro studies showed that the HT dimer exhibits 3- to 4-fold enhanced antibacterial activity against Gram-positive and Gram-negative bacteria compared to the parent compound. Moreover, the ability of HT dimer to inhibit the activity of soybean lipoxygenase and Candida rugosa lipase was 1.5-fold higher than HT, while molecular docking supported these results. Furthermore, HT dimer showed reduced cytotoxicity against HEK293 cells and exhibited a strong ability to inhibit ROS formation. The enhanced bioactivity of HT dimer indicates that this compound could be considered for use in cosmetics, skin-care products, and nutraceuticals. • Laccase catalyzes the formation of bioactive hydroxytyrosol dimer. • The composition of the reaction medium affects the biocatalytic process. • Hydroxytyrosol dimer showed enhanced antibacterial and enzyme inhibitory activity. • Hydroxytyrosol dimer showed reduced cytotoxicity against HEK293 cells. • Hydroxytyrosol dimer presented enhanced inhibitory activity against ROS formation. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide, making the search for alternatives for its control a critical issue. In this context, exploring alternatives from natural sources, such as certain vegetables containing a variety of secondary metabolites with beneficial effects on the body and that play a crucial role in the fight against cancer, is essential. Among the compounds with the greatest efficacy in controlling this disease, those with antioxidant activity, particularly phenolic com-pounds, stand out. A remarkable example of this group is protocatechuic acid (PCA), which has been the subject of various revealing research on its activities in different areas. These studies sustain that protocatechuic acid has anti-inflammatory, antimutagenic, antidiabetic, antiulcer, antiviral, antifibrogenic, antiallergic, neuroprotective, antibacterial, anticancer, antiosteoporotic, anti-aging, and analgesic properties, in addition to offering protection against metabolic syndrome and con-tributing to the preservation of hepatic, renal, and reproductive functionality. Therefore, this paper aims to review the biological activities of PCA, focusing on its anticancer potential and its in-volvement in the control of various molecular pathways involved in tumor development, sup-porting its option as a promising alternative for cancer treatment. [ABSTRACT FROM AUTHOR]