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Background: Hydrophilic Interaction Liquid Chromatography (HILIC) is an outstanding strategy for the challenging analysis of hydrophilic and polar components. Nevertheless, analysis under HILIC mode typically consumes 70%-95 % acetonitrile with the disadvantage of high analytical costs, being environmentally unfriendly and causing biohazards, which is not in line with the concept of green chromatography. Research has shown that Per Aqueous Liquid Chromatography (PALC) simultaneously emphasizes efficient analytical performance for hydrophilic analytes and green analytical concepts. The development of new PALC stationary phases with superior performance is necessary., Results: In this paper, silanized silica was sequentially subjected to esterification reaction, polymerization reaction and covalent bonding through five steps to obtain SiO 2 -RHP-AuNPs material, which was prepared as a novel stationary phase for PALC. Comprehensive characterization of the materials by means of Fourier transform infrared spectroscopy, Transmission scanning electron microscope, Elemental analysis and Thermogravimetric analysis showed the successful bonding of the functionalized groups on the original silica. The polymeric stationary phase based on Radix hedysari polysaccharide and Au nanoparticles had higher density of hydroxyl and ester functionalized groups. The Au nanoparticles upgraded their mesoporous structure and thermal stability, providing exceptional chromatographic performance and selectivity for chromatographic analysis. The influence of mobile phase water content, salt concentration, pH and column temperature on the retention behavior was evaluated. The novel Column was found to exhibit a dual mechanism of hydrophobic interactions/ion exchange interactions in a mobile phase with high water content., Significance and Novelty: The separation efficiency and selectivity of SiO 2 -RHP-AuNPs columns for synthetic pigments and organic acids in PALC mode were superior to those of commercial HILIC and C 18 columns. In addition, a method for the determination of seven active ingredients in Fructus Ligustri Lucidi by SiO 2 -RHP-AuNPs column in PALC mode was developed. The method had good stability, reproducibility and accuracy, which was capable of realizing the quality evaluation of Chinese Materia Medicas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic wounds significantly impact the patients' quality of life, creating an urgent interdisciplinary clinical challenge. The development of novel agents capable of accelerating the healing process is essential. Caffeic acid phenethyl ester (CAPE) has demonstrated positive effects on skin regeneration. However, its susceptibility to degradation limits its pharmaceutical application. Chemical modification of the structure improves the pharmacokinetics of this bioactive phenol. Hence, two novel series of CAPE hybrids were designed, synthesized, and investigated as potential skin regenerative agents. To enhance the stability and therapeutic efficacy, a caffeic acid frame was combined with quinolines or isoquinolines by an ester (1a-f) or an amide linkage (2a-f). The effects on cell viability of human gingival fibroblasts (HGFs) and HaCaT cells were evaluated at different concentrations; they are not cytotoxic, and some proved to stimulate cell proliferation. The most promising compounds underwent a wound-healing assay in HGFs and HaCaT at the lowest concentrations. Antimicrobial antioxidant properties were also explored. The chemical and thermal stabilities of the best compounds were assessed. In silico predictions were employed to anticipate skin penetration capabilities. Our findings highlight the therapeutic potential of caffeic acid phenethyl ester (CAPE) derivatives 1a and 1d as skin regenerative agents, being able to stimulate cell proliferation, control bacterial growth, regulate ROS levels, and being thermally and chemically stable. An interesting structure-activity relationship was discussed to suggest a promising multitargeted approach for enhanced wound healing., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.

Hydroxytyrosol-typed phenylpropanoid glycosides (HPGs), composed of phenylethanol and various complex oligosaccharides, are widespread and abundant in different plant, and have a diverse range of biological activities. All HPGs reported previously have been isolated from natural sources, and most of them showed significant bioactivities, such as anti-inflamatory, anti-cancer, cytoprotection, neuro-protective effects, enzyme-inhibitory, anti-microbial effects, and cardiovascular activity. The goal of this review is to summarize the structures of HPGs reported over the past few decades, as well as to introduce their pharmacological effects. We also introduce the possible relationship between the structures of HPGs and their source plants, as well as the structure-activity relationships of some important activities. This review will serve as a resource for future research into this class of compounds, and demonstrate their potential value., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cardiovascular diseases (CVDs) contribute to major public health issues. Some studies have found that caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) may effectively prevent or treat CVDs. However, there is a major need to sum up our current understanding of the possible beneficial or detrimental effects of CA and CAPE on CVDs and related mechanisms. Therefore, this study aimed to summarize the data on this topic. A methodical search was carried out on key databases, including Pubmed, Google Scholar, Scopus, and Web of Science, from the beginning to June 2024. Studies were then assessed for eligibility based on inclusion and exclusion criteria. Treatment with CA and CAPE significantly and positively affected cardiovascular health in various aspects, including atherosclerotic diseases, myocardial infarction, hypertension, cardiac arrhythmias, and hypercoagulation state. Several mechanisms were proposed to mediate these effects, including transcription factors and signaling pathways associated with antioxidant, cytostatic, and anti-inflammatory processes. CA and CAPE were found to have several beneficial effects via multiple mechanisms during the prevention and treatment of various CVDs. However, these promising effects were only reported through in vitro and animal studies, which reinforces the need for further evaluation of these effects via human clinical investigations., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Caffeic acid phenethyl ester (CAPE) is a naturally occurring phenolic compound with various biological activities. However, poor water solubility and storage stability limit its application. In this context, sorghum peptides were used to encapsulate CAPE. Sorghum peptides could self-assemble into regularly spherical nanoparticles (SPNs) by hydrophobic interaction and hydrogen bonds. Solubility of encapsulated CAPE was greatly increased, with 9.44 times higher than unencapsulated CAPE in water. Moreover, the storage stability of CAPE in aqueous solution was significantly improved by SPNs encapsulation. In vitro release study indicated that SPNs were able to delay CAPE release during the process of gastrointestinal digestion. Besides, fluorescence quenching analysis showed that a static quenching existed between SPNs and CAPE. The interaction between CAPE and SPNs occurred spontaneously, mainly driven by hydrophobic interactions. The above results suggested that SPNs encapsulation was an effective approach to improve the water solubility and storage stability of CAPE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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.

Phenylethanoid glycosides (PhGs) are naturally occurring glycosides derived from plants with various biological activities. Glycosyltransferases catalyze the production of PhGs from phenylethanols via a transglycosylation reaction. The low activity and stability of glycosyltransferase limit its industrial application. An ancestral glycosyltransferase, UGTAn85, with heat resistance, alkali resistance, and high stability was resurrected using ancestral sequence reconstruction technology. This enzyme can efficiently convert phenylethanols to PhGs. The optimal reaction temperature and pH for UGTAn85 were found to be 70 °C and pH 10.0, respectively. This study employed a combination of structure-guided rational design and co-evolution analysis to enhance its catalytic activity. Potential mutation sites were identified through computer-aided design, including homology modeling, molecular docking, Rosetta dock design, molecular dynamics simulation, and co-evolution analysis. By targeted mutagenesis, the UGTAn85 mutant Q23E/N65D exhibited a 2.2-fold increase in enzyme activity (11.85 U/mg) and elevated affinity ( K m = 0.11 mM) for 2-phenylethanol compared to UGTAn85. Following a fed-batch reaction, 36.16 g/L 2-phenylethyl-β-d-glucopyranoside and 51.49 g/L salidroside could be produced within 24 h, respectively. The findings in this study provide a new perspective on enhancing the stability and activity of glycosyltransferases, as well as a potential biocatalyst for the industrial production of PhGs.

Oleuropein (OP) is an appreciated compound present not only in fruits but also in leaves of olive trees, which can be transformed into hydroxytyrosol (HT), a substance with high antioxidant activity. In this work, the transformation of an agricultural residue containing OP (olive leaves or wastewater from mills) to the high added value compound HT is accomplished through different enzymatic strategies. Different enzymes were used, immobilized on various supports by diverse binding forces: beta-glucosidase encapsulated in siliceous material, esterases and lipases immobilized on hydrophobic supports (octyl-functionalized amorphous silica and periodic mesoporous organosilica), and esterase immobilized on amine-functionalized ordered mesoporous silica. All these biocatalysts were tested for oleuropein hydrolysis through two different reaction approaches: a) split of glucosidic bond catalyzed by beta-glucosidase (β-glu), followed by hydrolysis of the aglycon and further ester hydrolysis. 5 mg·mL -1 of β-glu fully hydrolyzed 5 mM OP at pH 7 and 50°C in 7 days, and further enzymatic hydrolysis of the aglycon yielded near to 0.5 mM HT in the best conditions tested. b) via direct hydrolysis of the ester bond to produce hydroxytyrosol in a one-step reaction using esterases or lipases. The latter reaction pathway catalyzed by lipase from Penicillium camemberti immobilized on octyl-silica (4 mg·mL -1 ) at 35°C and pH 6 directly produced 6.8 mM HT (1 mg·mL -1 ), transforming in 12 days near to 30% of the initial 25 mM OP from a commercial olive leaves extract.

There has been a growing interest in hydroxytyrosol (HT) due to its powerful antioxidant and free-radical scavenging properties when added to formulations such as pharmaceuticals and cosmetics. To study the stability and transdermal properties of hydrogels and creams (HT-based formulations), a high-performance liquid chromatography method was developed for determining HT. In the Franz diffusion cell system, both hydrogel and cream show a rapid and similar penetration profile through the Bama miniature pig skin. However, the Strat-M® membrane exhibits slightly lower permeability and is selective to different formulations; that is, the cream has a permeability value of 10.69%, while the hydrogel has a value of 5.27%. The dynamics parameters from the permeation assays indicate that the model using the Strat-M® membrane can be used as a screening tool to evaluate the skin uptake and permeation efficacy of different formulations. Adding 3-O-ethyl-L-ascorbic acid to HT-based formulations can effectively prevent discoloration under prolonged high-temperature storage, while combining multiple antioxidants delays degradation most effectively. This study provides novel ideas for functional formulation optimization to enhance the realism and reproducibility of cosmetic products containing HT and provides scientific evidence for the production, packaging, shelf life, storage, and transportation of products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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.

Increasing incidences of fungal infections and prevailing antifungal resistance in healthcare settings has given rise to an antifungal crisis on a global scale. The members of the genus Candida, owing to their ability to acquire sessile growth, are primarily associated with superficial to invasive fungal infections, including the implant-associated infections. The present study introduces a novel approach to combat the sessile/biofilm growth of Candida by fabricating nanofibers using a nanoencapsulation approach. This technique involves the synthesis of tyrosol (TYS) functionalized chitosan gold nanocomposite, which is then encapsulated into PVA/AG polymeric matrix using electrospinning. The FESEM, FTIR analysis of prepared TYS-AuNP@PVA/AG NF suggested the successful encapsulation of TYS into the nanofibers. Further, the sustained and long-term stability of TYS in the medium was confirmed by drug release and storage stability studies. The prepared nanomats can absorb the fluid, as evidenced by the swelling index of the nanofibers. The growth and biofilm inhibition, as well as the disintegration studies against Candida, showed 60-70 % biofilm disintegration when 10 mg of TYS-AuNP@PVA/AG NF was used, hence confirming its biological effectiveness. Subsequently, the nanofibers considerably reduced the hydrophobicity index and ergosterol content of the treated cells. Considering the challenges associated with the inhibition/disruption of fungal biofilm, the fabricated nanofibers prove their effectiveness against Candida biofilm. Therefore, nanocomposite-loaded nanofibers have emerged as potential materials that can control fungal colonization and could also promote healing., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC 50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC 50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f , was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC 50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC 50 = 91 µM) than CAPA. A different CAPA analogue, 3g , was found to have similar effects against BE(2)-C cells (IC 50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.

Utilizing Density Functional Theory (DFT) calculations at the B3LYP/QZVP level and incorporating the Conductor-like Polarizable Continuum Model (C-PCM) for solvation, the thermodynamic and chemical activity properties of 21-(hydroxymethoxy)henicosadecaenal, identified in cultured freshwater pearls from the mollusk Hyriopsis cumingii , have been elucidated. The study demonstrates that this compound releases formaldehyde, a potent antimicrobial agent, through dehydrogenation and deprotonation processes in both hydrophilic and lipophilic environments. Moreover, this polyenal exhibits strong anti-reductant properties, effectively scavenging free radicals. These critical properties classify the pearl-derived ingredient as a natural multi-functional compound, serving as a coloring, antiradical, and antimicrobial agent. The 2-(hydroxymethoxy)vinyl (HMV) moiety responsible for the formaldehyde release can be transferred to other compounds, thereby enhancing their biological activity. For instance, tyrosol (4-(2-hydroxyethyl)phenol) can be modified by substituting the less active 2-hydroxyethyl group with the active HMV one, and hinokitiol (4-isopropylotropolone) can be functionalized by attaching this moiety to the tropolone ring. A new type of meso-carrier, structurally modeled on pearls, with active substances loaded both in the layers and the mineral part, has been proposed.

Hydroxytyrosol, a naturally occurring compound with antioxidant and antiviral activity, is widely applied in the cosmetic, food, and nutraceutical industries. The development of a biocatalytic approach for producing hydroxytyrosol from simple and readily accessible substrates remains a challenge. Here, we designed and implemented an effective biocatalytic cascade to obtain hydroxytyrosol from 3,4-dihydroxybenzaldehyde and l-threonine via a four-step enzymatic cascade composed of seven enzymes. To prevent cross-reactions and protein expression burden caused by multiple enzymes expressed in a single cell, the designed enzymatic cascade was divided into two modules and catalyzed in a stepwise manner. The first module (FM) assisted the assembly of 3,4-dihydroxybenzaldehyde and l-threonine into (2 S ,3 R )-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, and the second module (SM) entailed converting (2 S ,3 R )-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid into hydroxytyrosol. Each module was cloned into Escherichia coli BL21 (DE3) and engineered in parallel by fine-tuning enzyme expression, resulting in two engineered whole-cell catalyst modules, BL21(FM01) and BL21(SM13), capable of converting 30 mM 3,4-dihydroxybenzaldehyde to 28.7 mM hydroxytyrosol with a high space-time yield (0.88 g/L/h). To summarize, the current study proposes a simple and effective approach for biosynthesizing hydroxytyrosol from low-cost substrates and thus has great potential for industrial applications.

Inter-cellular signaling, referred to as quorum sensing (QS), regulates the production of virulence factors in numerous gram-negative bacteria, such as the human pathogens Pseudomonas aeruginosa and Chromobacterium violaceum. QS inhibition may provide an opportunity for the treatment of bacterial infections. This represents the initial study to examine the antibiofilm and antivirulence capabilities of rose absolute and its primary component, phenylethyl alcohol. QS inhibition was assessed by examining extracellular exopolysaccharide synthesis, biofilm development, and swarming motility in P. aeruginosa PAO1, along with violacein production in C. violaceum ATCC 12472. Molecular docking analysis was conducted to explore the mechanism by which PEA inhibits QS. Our results indicate that rose absolute and PEA caused decrease in EPS production (60.5-33.5%), swarming motility (94.7-64.5%), and biofilm formation (98.53-55.5%) in the human pathogen P. aeruginosa PAO1. Violacein production decreased by 98.1% and 62.5% with an absolute (0.5 v/v %) and PEA (2 mM). Moreover, the molecular docking analysis revealed a promising competitive interaction between PEA and AHLs. Consequently, this study offers valuable insights into the potential of rose absolute and PEA as inhibitors of QS in P. aeruginosa and C. violaceum., (© 2024. The Author(s).)

Parkinson's disease is the neurodegenerative motor disorder with the highest incidence worldwide. Among other factors, Parkinson's disease is caused by the accumulation of α-synuclein aggregates in a patient's brain. In this work, five molecules present in the diet are proposed as possible nutraceuticals to prevent and/or reduce the formation of α-synuclein oligomers that lead to Parkinson's disease. The olive oil polyphenols tyrosol, hydroxytyrosol (HT), hydroxytyrosol acetate (HTA) and dihydroxyphenyl acetic acid (DOPAC) besides vitamin C were tested using a cellular model of α-synuclein aggregation and a Caenorhabditis elegans Parkinson's disease animal model. Levodopa was included in the assays as the main drug prescribed to treat the disease as well as dopamine, its direct metabolite. HTA and DOPAC completely hindered α-synuclein aggregation in vitro , while dopamine reduced the aggregation by 28.7%. The Parallel Artificial Membrane Permeability Assay (PAMPA) showed that HTA had the highest permeability through brain lipids among the compounds tested. Furthermore, the C. elegans Parkinson's disease model made it possible to assess the chosen compounds in vivo . The more effective substances in vivo were DOPAC and HTA which reduced the αS aggregation inside the animals by 79.2% and 76.2%, respectively. Moreover, dopamine also reduced the aggregates by 67.4% in the in vivo experiment. Thus, the results reveal the potential of olive oil tyrosols as nutraceuticals against α-synuclein aggregation.

Hemerocallis L. possesses abundant germplasm resources and holds significant value in terms of ornamental, edible, and medicinal aspects. However, the quality characteristics vary significantly depending on different varieties. Selection of a high-quality variety with a characteristic aroma can increase the economic value of Hemerocallis flowers. The analytic hierarchy process (AHP) is an effective decision-making method for comparing and evaluating multiple characteristic dimensions. By applying AHP, the aromatic character of 60 varieties of Hemerocallis flowers were analyzed and evaluated in the present study. Headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) was employed to identify volatile components in Hemerocallis flowers. Thirteen volatile components were found to contribute to the aroma of Hemerocallis flowers, which helps in assessing their potential applications in essential oil, aromatherapy, and medical treatment. These components include 2-phenylethanol, geraniol, linalool, nonanal, decanal, (E)- β -ocimene, α-farnesene, indole, nerolidol, 3-furanmethanol, 3-carene, benzaldehyde and benzenemethanol. The varieties with better aromatic potential can be selected from a large amount of data using an AHP model. This study provides a comprehensive understanding of the characteristics of the aroma components in Hemerocallis flowers, offers guidance for breeding, and enhances the economic value of Hemerocallis flowers.

The olive oil industry recently introduced a novel multi-phase decanter with the "Leopard DMF" series, which gives a by-product called pâté, made up of pulp and olive wastewater with a high content of phenolic substances and without pits. This study aims to create a new culture medium, the Olive Juice Broth (OJB), from DMF pâté, and apply it to select bacteria strains able to survive and degrade the bitter substances normally present in the olive fruit. Thirty-five different bacterial strains of Lactiplantibacillus plantarum from the CREA-IT.PE Collection of Microorganisms were tested. Seven strains characterized by ≥50% growth in OJB (B31, B137, B28, B39, B124, B130, and B51) showed a degradation of the total phenolic content of OJB ≥ 30%. From this set, L. plantarum B51 strain was selected as a starter for table olive production vs. spontaneous fermentation. The selected inoculant effectively reduced the debittering time compared to spontaneous fermentation. Hydroxytyrosol, derived from oleuropein and verbascoside degradation, and tyrosol, derived from ligstroside degradation, were produced faster than during spontaneous fermentation. The OJB medium is confirmed to be useful in selecting bacterial strains resistant to the complex phenolic environment of the olive fruit.

Background: Propolis and its major phenolic compound, caffeic acid phenethyl ester (CAPE), have garnered considerable scientific interest due to their anti- inflammatory properties and potential therapeutic applications., Objectives: This narrative review explores the potential utility of CAPE in cancer treatment., Methods: We comprehensively reviewed relevant studies from scientific databases (PubMed and Web of Science) from 2000 to 2022. Our search focused on keywords such as cancer, natural drugs, caffeic acid phenethyl ester, CAPE, cancer cell lines, antitumor effects, and propolis., Results: CAPE exhibits diverse biological benefits, including antimicrobial, antioxidant, antiviral, anti-inflammatory, cytotoxic, and potentially anti-carcinogenic properties. Numerous studies have demonstrated its wide-ranging antitumor effects on various cancer cell lines, including growth inhibition, apoptosis induction, tumor invasiveness prevention, malignancy suppression, and anti-angiogenic activity., Conclusion: Following comprehensive preclinical toxicity assessments, further evaluation of CAPE's efficacy and safety through clinical trials is highly recommended to elucidate its potential health benefits in diverse forms of human cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: DNA methyltransferases (DNMTs) have been reported to be potential drug targets in various cancers. The major hurdle in inhibiting DNMTs is the lack of knowledge about different DNMTs and their role in the hypermethylation of gene promoters in cancer cells. Lack of information on specificity, stability, and higher toxicity of previously reported DNMT inhibitors is the major reason for inadequate epigenetic cancer therapy. DNMT1 and DNMT3A are the two DNMTs that are majorly overexpressed in cancers., Objective: In this study, we have presented computational and experimental analyses of the potential of some natural compounds, withaferin A (Wi-A), withanone (Wi-N), and caffeic acid phenethyl ester (CAPE), as DNMT inhibitors, in comparison to sinefungin (SFG), a known dual inhibitor of DNMT1 and DNMT3A., Methods: We used classical simulation methods, such as molecular docking and molecular dynamics simulations, to investigate the binding potential and properties of the test compounds with DNMT1 and DNMT3A. Cell culture-based assays were used to investigate the inactivation of DNMTs and the resulting hypomethylation of the p16 INK4A promoter, a key tumour suppressor that is inactivated by hypermethylation in cancer cells, resulting in upregulation of its expression., Results: Among the three test compounds (Wi-A, Wi-N, and CAPE), Wi-A showed the highest binding affinity to both DNMT1 and DNMT3A; CAPE showed the highest affinity to DNMT3A, and Wi-N showed a moderate affinity interaction with both. The binding energies of Wi-A and CAPE were further compared with SFG. Expression analysis of DNMTs showed no difference between control and treated cells. Cell viability and p16 INK4A expression analysis showed a dose-dependent decrease in viability, an increase in p16 INK4A , and a stronger effect of Wi-A compared to Wi-N and CAPE., Conclusion: The study demonstrated the differential binding ability of Wi-A, Wi-N, and CAPE to DNMT1 and DNMT3A, which was associated with their inactivation, leading to hypomethylation and desilencing of the p16 INK4A tumour suppressor in cancer cells. The test compounds, particularly Wi-A, have the potential for cancer therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The recent COVID-19 (coronavirus disease 2019) pandemic triggered research on the development of new vaccines/drugs, repurposing of clinically approved drugs, and assessment of natural anti-COVID-19 compounds. Based on the gender difference in the severity of the disease, such as a higher number of men hospitalized and in intense care units, variations in sex hormones have been predicted to play a role in disease susceptibility. Cell surface receptors (Angiotensin-Converting Enzyme 2; ACE2 and a connected transmembrane protease serine 2- TMPSS2) are upregulated by androgens. Conversely, androgen antagonists have also been shown to lower ACE2 levels, implying their usefulness in COVID-19 management., Objectives: In this study, we performed computational and cell-based assays to investigate the anti- COVID-19 potential of Withaferin-A and Caffeic acid phenethyl ester, natural compounds from Withania somnifera and honeybee propolis, respectively., Methods: Structure-based computational approach was adopted to predict binding stability, interactions, and dynamics of the two test compounds to three target proteins (androgen receptor, ACE2, and TMPRSS2). Further, in vitro , cell-based experimental approaches were used to investigate the effect of compounds on target protein expression and SARS-CoV-2 replication., Results: Computation and experimental analyses revealed that (i) CAPE, but not Wi-A, can act as androgen antagonist and hence inhibit the transcriptional activation function of androgen receptor, (ii) while both Wi-A and CAPE could interact with ACE2 and TMPRSS2, Wi-A showed higher binding affinity, and (iii) combination of Wi-A and CAPE (Wi-ACAPE) caused strong downregulation of ACE2 and TMPRSS2 expression and inhibition of virus infection., Conclusion: Wi-A and CAPE possess multimodal anti-COVID-19 potential, and their combination (Wi-ACAPE) is expected to provide better activity and hence warrant further attention in the laboratory and clinic., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The increasing prevalence of type 2 diabetes, has become a global concern, making it imperative to control. Chemical drugs commonly recommended for diabetes treatment cause many complications and drug resistance over time., Methods: The polyphenol tyrosol has many health benefits, including anti-diabetes properties. Tyrosol's efficacy can be significantly increased when it is used as a niosome in the treatment of diabetes. In this study, Tyrosol and nano-Tyrosol are examined for their effects on genes implicated in type 2 diabetes in streptozotocin-treated rats. Niosome nanoparticles containing 300 mg surfactant (span60: tween60) and 10 mg cholesterol were hydrated in thin films with equal molar ratios. After 72 hours, nano-niosomal formulas were assessed for their physicochemical properties. MTT assays were conducted on HFF cells to assess the cellular toxicity of the nano niosome contacting optimal Tyrosol. Finally, the expression of PEPCK, GCK, TNF-ɑ, IL6, GLUT2 and GLUT9 was measured by real-time PCR. Physiochemical properties of the SEM images of niosomes loaded with Tyrosol revealed the nanoparticles had a vehicular structure., Results: In this study, there were two stages of release: initial release (8 hours) and sustainable release (72 hours). Meanwhile, free-form drugs were considerably more toxic than niosomal drugs in terms of their cellular toxicity. An in vivo comparison of oral Tyrosol gavage with nano-Tyrosol showed a significant increase in GCK (P < 0.001), GLUT2 (P < 0.001), and GLUT9 (P < 0.001). Furthermore, nano-Tyrosol decreased the expression of TNF-ɑ (P < 0.05), PEPCK (P < 0.001), and IL-6 (P < 0.05) which had been increased by diabetes mellitus. The results confirmed nano-Tyrosol's anti-diabetes and anti-inflammatory effects., Conclusion: These findings suggest that nano-Tyrosol has potential applications in diabetes treatment and associated inflammation. Further research is needed to better understand the mechanism of action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nowadays, there is a lot of public and scientific interest in using phytochemicals to treat human ailments. Existing cancer medicines still run across obstacles, despite significant advancements in the field. For instance, chemotherapy may result in severe adverse effects, increased drug resistance, and treatment failure. Natural substances that are phytochemically derived provide innovative approaches as potent therapeutic molecules for the treatment of cancer. Bioactive natural compounds may enhance chemotherapy for cancer by increasing the sensitivity of cancer cells to medicines. Propolis has been found to interfere with the viability of cancer cells, among other phytochemicals. Of all the components that make up propolis, caffeic acid phenethyl ester (CAPE) (a flavonoid) has been the subject of the most research. It demonstrates a broad spectrum of therapeutic uses, including antitumor, antimicrobial, antiviral, anti-inflammatory, immunomodulatory, hepatoprotective, neuroprotective, and cardioprotective effects. Studies conducted in vitro and in vivo have demonstrated that CAPE specifically targets genes involved in cell death, cell cycle regulation, angiogenesis, and metastasis. By altering specific signaling cascades, such as the NF-κB signaling pathway, CAPE can limit the proliferation of human cancer cells. This review highlights the research findings demonstrating the anticancer potential of CAPE with a focus on multitargeted molecular and biological implications in various cancer models., (© 2023 John Wiley & Sons Ltd.)

Caffeic acid phenylethyl ester (CAPE) is a natural polyphenol extracted from propolis, which is reported to have several pharmacological effects such as antibacterial, antitumor, antioxidant and anti-inflammatory activities. Hemoglobin (Hb) is closely related to the transport of drugs, and some drugs, including CAPE, can lead to a change in Hb concentration. Herein, the effects of temperature, metal ions and biosurfactants on the interaction between CAPE and Hb were studied using ultraviolet-visible spectroscopy (UV-Vis), fluorescence spectroscopy, circular dichroism (CD), dynamic light scattering (DLS) and molecular docking analysis. The results showed that the addition of CAPE led to changes in the microenvironment of Hb amino acid residues as well as the secondary structure of Hb. Hydrogen bonding and van der Waals force were found to be the main driving forces for the interaction between CAPE and Hb through fluorescence spectroscopy and thermodynamic parameter data. The results of fluorescence spectroscopy also showed that lowering the temperature, adding biosurfactants (sodium cholate (NaC) and sodium deoxycholate (NaDC)) and the presence of Cu 2+ increased the binding force between CAPE and Hb. These results provide useful data for the targeted delivery and absorption of CAPE and other drugs.

Caffeic acid phenethyl ester (CAPE), a main active component of propolis and a flavonoid, is one of the natural products that has attracted attention in recent years. CAPE, which has many properties such as anti-cancer, anti-inflammatory, antioxidant, antibacterial and anti-fungal, has shown many pharmacological potentials, including protective effects on multiple organs. Interestingly, molecular docking studies showed the possibility of binding of CAPE with replication enzyme. In addition, it was seen that in order to increase the binding security of the replication enzyme and CAPE, modifications can be made at three sites on the CAPE molecule, which leads to the possibility of the compound working more powerfully and usefully to prevent the proliferation of cancer cells and reduce its rate. Also, it was found that CAPE has an inhibitory effect against the main protease enzyme and may be effective in the treatment of SARS-CoV-2. This review covers in detail the importance of CAPE in alternative medicine, its pharmacological value, its potential as a cancer anti-proliferative agent, its dual role in radioprotection and radiosensitization, and its use against coronavirus disease 2019 (COVID-19)., (© 2022 John Wiley & Sons Ltd.)

Caffeic acid phenethyl ester (CAPE) is an efficient bioactive polyphenol ester derived from propolis. However, its poor water solubility, bioavailability, and stability significantly limit its application. Based on the assembly properties of some natural small molecules (NSMs), asiatic acid-caffeic acid phenethyl ester nanoparticles (ASA-CAPE NPs) were prepared to overcome the above defects. After proportion optimization, the encapsulation and loading efficiencies of ASA-CAPE NPs reached 47.72 ± 0.17 % and 11.62 ± 0.42 %, respectively. Characterization results showed that ASA-CAPE NPs, mainly assembled by hydrogen bonds and hydrophobic forces, possessed regular spherical morphology with a diameter size of less than 300 nm. Additionally, ASA-CAPE NPs presented improved water solubility, stability, and bioactivities than free CAPE. Besides, ASA-CAPE NPs also exhibited good sustained release of CAPE during the gastrointestinal digestion in vitro. Above all, ASA-CAPE NPs provide a new idea for efficiently utilizing hydrophobic active compounds in the functional food field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The main by-product generated from the olive oil two-phase extraction system, or alperujo, is undoubtedly a rich source of bioactive components, among which phenolics are one of the most important. The evolution of four of its main phenolics: hydroxytyrosol (HT), hydroxytyrosol 4-β-d-glucoside (Glu-HT), 3,4-dihydroxyphenylglycol (DHPG) and tyrosol (Ty) was studied over two seasons and in ten oil mills under similar climatological and agronomic conditions, for the first time using organic extraction and high-performance liquid chromatography (HPLC-DAD) determination. The results show that HT (200-1600 mg/kg of fresh alperujo) and Ty (10-570 mg/kg) increase, while DHPG (10-370 mg/kg) decreases only in the last month of the season and Glu-HT (1400-0 mg/kg) decreases drastically from the beginning. This evolution is similar between different seasons, with a high correlation between Glu-HT, HT, and Ty. On the other hand, it has been verified that a mixture of alperujos from all the oil mills, which is what the pomace extractor receives, is a viable source of a liquid fraction which is rich in the phenolics studied through organic extractions and especially after the application of a thermal treatment, obtaining values of 4.2 g/L of HT, 0.36 g/L of DHPG, and 0.49 g/L of Ty in the final concentrated liquid fraction.

Gas-phase spectroscopic studies of alcohol clusters offer accurate information on the influence of non-covalent interactions on molecular recognition, and are of paramount importance to model supramolecular and biological chemical processes. Here, we examine the role of the aliphatic side chain in the self-aggregation of aromatic alcohols, using a multi-methodological gas-phase approach which combines microwave spectroscopy and mass-resolved electronic and vibrational laser spectroscopy. Spectroscopic and electronic structure computations were carried out for the dimer, trimer and tetramer of 2-phenylethanol, extending previous investigations on smaller aromatic alcohols. While the conformational flexibility of the ethyl group anticipates a variety of torsional isomers, the intra- and inter-molecular interactions restrict molecular conformations and favour particularly stable isomers. The conformational landscape of the clusters is very shallow and multiple competing isomers were rotationally and/or vibrationally detected, including three dimer species, two trimers and two tetramers. Cluster growth is associated with a tendency to form cyclic hydrogen bond structures.

Phenolic lipids have been approved as safe and effective antioxidants, and are a potential ingredient for functional foods. However, the characteristics of gastrointestinal distribution and microbial hydrolysis in the gastrointestinal tract (GI) are not clear. In this study, the above characteristics of tyrosol-myristic acid ester (T-C14:0), tyrosol-palmitic acid ester (T-C16:0) and tyrosol-stearic acid ester (T-C18:0) were estimated by an in vivo mice model and in vitro anaerobic fermentation model. HPLC-UV measurements indicate that tyrosol (TYr) was rapidly and almost completely absorbed in the small intestine. By contrast, oral T-C14:0, T-C16:0 and T-C18:0 were remarkably stable in the stomach environments of the mice, and could be further hydrolyzed to free TYr by gut microbiota including Lactobacillus johnsonii , Lactobacillus reuteri and Lactobacillus gasseri (in the colon and cecum). Further, the liberated TYr and fatty acids can participate in regulating the composition of the gut microorganisms, which may lead to some additional health benefits. Therefore, the production of phenolic lipids such as tyrosol fatty acid esters provides a new approach to prolong the action time of polyphenol in vivo , and could also lead to additional health benefits including the regulation of gut microorganisms.

The antiradical properties and possible mechanisms of action of the tautomers of curcumin, caffeic acid phenethyl ester (CAPE), and chicoric acid (CA) have been studied within density functional theory (DFT). We calculated global chemical reactivity descriptors from conceptual DFT, pK a , bioavailability, and toxicity to evaluate the antiradical properties and characterize these species. Our final level of theory is the M06-2X functional with the 6-31 + G* basis set; we selected this level after performing a benchmark calibration and validation among different levels. Solvent effects were modeled via the continuum solvation model based on density (SMD). We used water and pentyl ethanoate as solvents to simulate the physiological conditions. The free radical scavenger capacity was analyzed for three possible oxidative stress mechanisms: single electron transfer (SET), hydrogen atom transfer (HAT), and xanthine oxidase (XO) inhibition. The results indicate that neutral curcumin, CA, and CAPE behave as antireductants. The most favorable mechanism turns out to be HAT, where CA and CAPE stand out. In conclusion, our DFT study strongly indicates that neutral curcumin, CAPE, and CA would very likely perform well as antiradical drugs with recommended therapeutic use, supported by their non-toxic nature., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hydroxytyrosol is one of the phenolic compounds of olive oil and can induce anticancer effects on colorectal cancer cells., Objective: The aim of the present study was to evaluate the free hydroxytyrosol and nano-capsulated hydroxytyrosol effects on the cell cycle arrest in HT-29 colorectal cancer cell line., Methods: The nano-capsulated hydroxytyrosol was synthesized in poly lactide-co-glycolide-co-polyacrylic acid (PLGA-PAA) copolymer. MTT assay was performed to evaluate the anti-proliferative and anti-tumor effects of the free hydroxytyrosol and nano-capsulated hydroxytyrosol. Finally, the relative expression of CDKN1A, CDKN1B, and CCND1 genes was evaluated in control and treated colorectal cancer cells by using Real-Time PCR., Results: The obtained results from the MTT assay showed that the cytotoxic effects of the nano-capsulated hydroxytyrosol on the colorectal cancer cell line (IC50= 6PPM) were significantly more than free hydroxytyrosol (IC50= 12PPM) after 72h. Also, nano-capsulated hydroxytyrosol showed more significant effects on the upregulation of CDKN1A and CDKN1B genes and down-regulation of the CCND1 gene in colorectal cancer cells., Conclusion: In conclusion, the present study showed that hydroxytyrosol led to the death of colorectal cancer cells through cell cycle arrest. Also, the PLGA-PAA copolymer dramatically caused to increase the cytotoxic effects of the hydroxytyrosol on the colorectal cancer cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Rosmarinic acid (RA) is a polyphenol that occurs in plants of the Lamiaceae family. Phenethyl ester of RA (PERA), a novel RA derivative, has been developed and evaluated in vivo in an animal model of type 1 diabetes (T1D)., Methods: T1D was induced in male C57BL/6 mice using multiple low doses of streptozotocin (STZ) administered intraperitoneally for 5 consecutive days. Intraperitoneal administration of PERA (2.5 mg/kg bw) began from the first STZ injection and continued for 20 days., Key Findings: PERA-treated mice exhibited lower incidence of T1D (monitored up to 38 days from the disease induction), and fluorescent histochemical analysis showed that their pancreatic islets expressed more insulin. PERA treatment significantly down-regulated the proportions of CD11b + and CD11c + myeloid cells in the immune cell infiltrates in the pancreatic islets early during T1D pathogenesis (on day 9 after T1D induction), while on day 15, PERA significantly reduced the proportions of CD11c + , CD8 + , Th1 and Th17 cells. Simultaneously, it was found that the cells from the pancreatic infiltrates of PERA-treated mice produced significantly less reactive oxygen species than cells from the control group., Significance: These findings suggest that PERA efficiently prevented T1D development in mice. Interestingly, PERA attenuated the inflammatory process in the islets through temporally specific interference with the innate and adaptive immune response and therefore shows great promise for further clinical evaluation as a novel T1D therapeutic., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Tyrosol (T) and hydroxytyrosol (HOT) and their glycosides are promising candidates for applications in functional food products or in complementary therapy. A series of phenylethanoid glycofuranosides (PEGFs) were synthesized to compare some of their biochemical and biological activities with T and HOT. The optimization of glycosylation promoted by environmentally benign basic zinc carbonate was performed to prepare HOT α-L-arabino-, β-D-apio-, and β-D-ribofuranosides. T and HOT β-D-fructofuranosides, prepared by enzymatic transfructosylation of T and HOT, were also included in the comparative study. The antioxidant capacity and DNA-protective potential of T, HOT, and PEGFs on plasmid DNA were determined using cell-free assays. The DNA-damaging potential of the studied compounds for human hepatoma HepG2 cells and their DNA-protective potential on HepG2 cells against hydrogen peroxide were evaluated using the comet assay. Experiments revealed a spectrum of different activities of the studied compounds. HOT and HOT β-D-fructofuranoside appear to be the best-performing scavengers and protectants of plasmid DNA and HepG2 cells. T and T β-D-fructofuranoside display almost zero or low scavenging/antioxidant activity and protective effects on plasmid DNA or HepG2 cells. The results imply that especially HOT β-D-fructofuranoside and β-D-apiofuranoside could be considered as prospective molecules for the subsequent design of supplements with potential in food and health protection.

Nitric oxide (NO) is an important signaling molecule involved in many pathophysiological processes. NO mediates vasodilation and blood flow in the arteries, and its action contributes to maintaining vascular homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Dietary antioxidants and their metabolites have been found to be directly and/or indirectly involved in the modulation of the intracellular signals that lead to the production of NO. The purpose of this study was to investigate the contribution of conjugated metabolites of hydroxytyrosol (HT) and tyrosol (TYR) to the release of NO at the vascular level, and the related mechanism of action, in comparison to their parental forms. Experiments were performed in human aortic endothelial cells (HAEC) to evaluate the superoxide production, the release of NO and production of cyclic guanosine monophosphate (cGMP), the activation of serine/threonine-protein kinase 1 (Akt1), and the activation state of endothelial nitric oxide synthase (eNOS). It was observed that the tested phenolic compounds enhanced NO and cGMP concentration, inhibiting its depletion caused by superoxide overproduction. Moreover, some of them enhanced the activation of Akt (TYR, HT metabolites) and eNOS (HT, HVA, TYR-S, HT-3S). Overall, the obtained data showed that these compounds promote NO production and availability, suggesting that HT and TYR conjugated metabolites may contribute to the effects of parental extra virgin olive oil (EVOO) phenolics in the prevention of cardiovascular diseases.

Objective: The aim of the study was to show the effect that two naturally occurring compounds, a cyclodextrin and hydroxytyrosol, can have on the entry of SARS-CoV-2 into human cells., Materials and Methods: The PubMed database was searched to retrieve studies published from 2000 to 2020, satisfying the inclusion criteria. The search keywords were: SARS-CoV, SARS-CoV-2, coronavirus, lipid raft, endocytosis, hydroxytyrosol, cyclodextrin. Modeling of alpha-cyclodextrin and hydroxytyrosol were done using UCSF Chimera 1.14., Results: The search results indicated that cyclodextrins can reduce the efficiency of viral endocytosis and that hydroxytyrosol has antiviral properties. Bioinformatic docking studies showed that alpha-cyclodextrin and hydroxytyrosol, alone or in combination, interact with the viral spike protein and its host cell receptor ACE2, thereby potentially influencing the endocytosis process., Conclusions: Hydroxytyrosol and alpha-cyclodextrin can be useful against the spread of SARS-CoV-2.

In response to the increasing interest of western consumers in high antioxidant activity of green tea but their low acceptance of its green odor, we employed a new starter culture, Wolfiporia cocos to tune flavor of green tea infusion. After submerged fermentation for 17 h, W. cocos changed the characteristic green odor to an attractive floral, jasmine-like, and slightly citrus-like flavor while preserving most of in vitro antioxidant activity. By application of mSBSE-GC-MS-O combined with sensorial tests, the formed pleasant aroma was mainly attributed to methyl anthranilate (OAV 802), linalool (OAV 190), 2-phenylethanol (OAV165), and geraniol (OAV 118). Concurrently, the catechin profile determined by UHPLC-MS showed diverse reduction rates (10-50%) for the individual catechins after fermentation. Nevertheless, up to 80% of in vitro antioxidant activity in DPPH assay was preserved. Overall, our findings provide an innovative approach to naturally flavor green tea while retaining the antioxidant activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Polyphenols from olive oil are endowed with several biological activities. Chemical modifications have been recently applied to these compounds to improve their therapeutic activity in different pathological settings, including cancer. Herein, we describe the in vitro effects on multiple myeloma (MM) cells of oleil hydroxytyrosol (HTOL), a synthetic fatty ester of natural hydroxytyrosol with oleic acid. HTOL reduced the viability of various human MM cell lines (HMCLs), even when co-cultured with bone marrow stromal cells, triggering ER stress, UPR and apoptosis, while it was not cytotoxic against healthy peripheral blood mononuclear cells or B lymphocytes. Whole-transcriptome profiling of HTOL-treated MM cells, coupled with protein expression analyses, indicate that HTOL antagonizes key survival pathways for malignant plasma cells, including the undruggable IRF4-c-MYC oncogenic axis. Accordingly, c-MYC gain- and loss-of-function strategies demonstrate that HTOL anti-tumor activity was, at least in part, due to c-MYC targeting. Taken together, these findings underscore the anti-MM potential of HTOL, providing the molecular framework for further investigation of HTOL-based treatments as novel anti-cancer agents.

In this study, we report the characterization of three glycosyltransferases involved in the biosynthesis of ligupurpuroside B, a complex acylated phenolic glycoside in Ligustrum robustum . UGT85AF8 catalyzed the formation of salidroside from tyrosol. UGT79G7, an osmanthuside A 1,3-rhamnosyltransferase, and UGT79A19, an osmanthuside B 1,4-rhamnosyltransferase, sequentially converted osmanthuside A into ligupurpuroside B. Orthologs of UGT79G7 were also discovered from other plants producing verbascoside. These rhamnosyltransferases expand the toolbox for the biosynthesis of natural products with various sugar chains.

Nowadays, increasing interest in olive pomace (OP) valorization aims to improve olive's industry sustainability. Interestingly, several studies propose a high-value application for OP extracts containing its main phenolic compounds, hydroxytyrosol and oleuropein, as therapy for ocular surface diseases. In this work, the stability and accessibility of OP total phenolic and flavonoid content, main representative compounds, and antioxidant activity were assessed under different pretreatment conditions. Among them, lyophilization and supercritical CO 2 extraction were found to increase significantly most responses measured in the produced extracts. Two selected extracts (CONV and OPT3) were obtained by different techniques (conventional and pressurized liquid extraction); Their aqueous solutions were characterized by HPLC-DAD-MS/MS. Additionally, their safety and stability were evaluated according to EMA requirements towards their approval as ophthalmic products: their genotoxic effect on ocular surface cells and their 6-months storage stability at 4 different temperature/moisture conditions (CPMP/ICH/2736/99), together with pure hydroxytyrosol and oleuropein solutions. The concentration of hydroxytyrosol and oleuropein in pure or extract solutions was tracked, and possible degradation products were putatively identified by HPLC-DAD-MS/MS. Hydroxytyrosol and oleuropein had different stability as standard or extract solutions, with oleuropein also showing different degradation profile. All compounds/extracts were safe for ophthalmic use at the concentrations tested.

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 IC 50 , 43.93 µg/ml and 68.90 µg/ml using DPPH and H 2 O 2 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.

Phenolic compounds from olive oil (ArOH-EVOO) are recognized for their antioxidant and neuroprotective capacities, but are often studied individually or through a natural extract. As their reactivity towards reactive oxygen species (ROS) depends on their structure and could implicate different complementary mechanisms, we hypothesized that their effects could be enhanced by an innovative combination of some of the most abundant ArOH-EVOO. Using electrochemical methods, we have compared their reactivity towards hydrogen peroxide and the superoxide anion radical. The mixture containing oleuropein, p -coumaric acid and tyrosol (Mix1), was more efficient than the mixture containing hydroxytyrosol, the oleuropein catechol moiety, and the two monophenols (Mix2). On neuronal SK-N-SH cells challenged with H 2 O 2 or Paraquat, low concentrations (0.1 and 1 µM) of the Mix1 improved neuronal survival. These neuroprotective effects were supported by a decrease in intracellular ROS, in the protein carbonyl levels and the prevention of the redox-sensitive factors Nrf2 and NF-κB activation. These intracellular effects were supported by the demonstration of the internalization of these ArOH-EVOO into neuronal cells, evidenced by LC-HRMS. Our results demonstrated that this combination of ArOH-EVOO could be more efficient than individual ArOH usually studied for their neuroprotective properties. These data suggest that the Mix1 could delay neuronal death in neurodegenerative diseases related to oxidative stress such as Alzheimer's (AD) and Parkinson's diseases (PD).

Two series of 3,5-disubstituted isoxazoles (6a-e) and 1,4-disubstituted triazoles (8a-e) derivatives have been synthesized from tyrosol (1), a natural phenolic compound, detected in several natural sources such as olive oil, and well-known by its wide spectrum of biological activities. Copper-catalyzed microwave-assisted 1,3-dipolar cycloaddition reactions between tyrosol-alkyne derivative 2 and two series of aryl nitrile oxides (5a-e) and azides (7a-e) regiospecifically afforded 3,5-disubstituted isoxazoles (6a-e) and 1,4-triazole derivatives (8a-e), respectively in quantitative yields. Synthesized compounds were purified and characterized by spectroscopic means including 1D and 2D NMR techniques and HRMS analysis. The newly prepared hybrid molecules have been evaluated for their anticancer and hemolytic activities. Results showed that most derivatives displayed significant antiproliferative activity against human glioblastoma cancer cells (U87) in a dose-dependent manner. Compounds 6d (IC 50  = 15.2 ± 1.0 μg/mL) and 8e (IC 50  = 21.0 ± 0.9 μg/mL) exhibited more potent anticancer activity. Moreover, most derivatives displayed low hemolytic activity, even at higher concentrations which suggested that these classes of compounds are suitable candidates for further in vivo investigations. The obtained results allow us to consider the newly synthesized isoxazole- and triazole-linked tyrosol derivatives as promising scaffolds for the development of effective anticancer agents., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Polysaccharide substrates loaded with antioxidant and antimicrobial compounds, effectively protected by cyclodextrin moieties, can be a long-lasting solution to confer certain properties to fabrics, paper and other materials. β-Cyclodextrin was attached to α-cellulose, bleached pulp and starch by a two-step esterification with a tetracarboxylic acid. The resulting derivatives were characterized by spectroscopy, thermal degradation analysis and capability of phenolphthalein inclusion. The carriers, containing between 89 and 171 μmol of β-cyclodextrin per gram, were loaded with carvacrol, cuminaldehyde, cinnamaldehyde and hydroxytyrosol. From a stoichiometric addition, the percentage of compound retained ranged from 49% (hydroxytyrosol in pulp-cyclodextrin) to 92% (carvacrol in starch-cyclodextrin). Finally, the release rate to aqueous ethanol was measured over eight days and fitted to kinetic models. From the analysis of the mean dissolution time, it can be concluded that inserting β-cyclodextrin units enhanced the long-term holding of phenolic active compounds in carbohydrate matrices., (Copyright © 2021. Published by Elsevier Ltd.)

Propolis is a resinous natural product collected by honeybees ( Apis mellifera and others) from tree exudates that has been widely used in folk medicine. The present study was carried out to investigate the fatty acid composition, chemical constituents, antioxidant, and xanthine oxidase (XO) inhibitory activity of Jordanian propolis, collected from Al-Ghour, Jordan. The hexane extract of Jordanian propolis contained different fatty acids, which are reported for the first time by using GC-FID. The HPLC was carried out to identify important chemical constituents such as fatty acids, polyphenols and α-tocopherol. The antioxidant and xanthine oxidase inhibitory activities were also monitored. The major fatty acid identified were palmitic acid (44.6%), oleic acid (18:1∆ 9 cis , 24.6%), arachidic acid (7.4%), stearic acid (5.4%), linoleic acid (18:2∆ 9-12 cis , 3.1%), caprylic acid (2.9%), lignoceric acid (2.6%), cis -11,14-eicosaldienoic acid (20:2∆ 11-14 cis , 2.4%), palmitoleic acid (1.5%), cis -11-eicosenoic acid (1.2%), α-linolenic acid (18:3∆ 9-12-15 cis , 1.1%), cis -13,16-docosadienoic acid (22:2∆ 13-16 cis , 1.0%), along with other fatty acids. The major chemical constituents identified using gradient HPLC-PDA analysis were pinocembrin (2.82%), chrysin (1.83%), luteolin-7- O -glucoside (1.23%), caffeic acid (1.12%), caffeic acid phenethyl ester (CAPE, 0.79%), apigenin (0.54%), galangin (0.46%), and luteolin (0.30%); while the minor constituents were hesperidin, quercetin, rutin, and vanillic acid. The percentage of α-tocopherol was 2.01 µg/g of the lipid fraction of propolis. Antioxidant properties of the extracts were determined via DPPH radical scavenging. The DPPH radical scavenging activities (IC 50 ) of different extracts ranged from 6.13 to 60.5 µg/mL compared to ascorbic acid (1.21 µg/mL). The xanthine oxidase inhibition (IC 50 ) ranged from 75.11 to 250.74 µg/mL compared to allopurinol (0.38 µg/mL). The results indicate that the various flavonoids, phenolic compounds, α-tocopherol, and other constituents which are present in propolis are responsible for the antioxidant and xanthine oxidation inhibition activity. To evaluate the safety studies of propolis, the pesticide residues were also monitored by LC-MS-MS 4500 Q-Trap. Trace amounts of pesticide residue (ng/mL) were detected in the samples, which are far below the permissible limit as per international guidelines.

To identify and analyze the characteristics of the microorganisms involved in the formation of the desirable flavor of Doenjang , a total of 179 strains were isolated from ninety-four Doenjang collected from six regions in South Korea, and fourteen strains were selected through a sensory evaluation of the aroma of each culture. The enzyme activities of amylase, protease and lipase was shown in the various strains. Bacillus sp.-K3, Bacillus sp.-K4 and Bacillus amyloliquefaciens -J2 showed relatively high protease activity, at 317.1 U, 317.3 U and 319.5 U, respectively. The Bacillus sp.-K1 showed the highest lipase activity at 2453.6 U. In the case of amylase, Bacillus subtilis -H6 showed the highest activity at 4105.5 U. The results of the PCA showed that Bacillus subtilis -H2, Bacillus subtilis -H3, and Bacillus sp.-K2 were closely related to the production of 3-hydroxy-2-butanone (23.51%~43.37%), and that Bacillus subtilis -H5 and Bacillus amyloliquefaciens -J2 were significantly associated with the production of phenethyl alcohol (0.39% and 0.37%). The production of peptides was observed to vary among the Bacillus cultures such as Val-Val-Pro-Pro-Phe-Leu and Pro-Ala-Glu-Val-Leu-Asp-Ile. These peptides are precursors of related volatile flavor compounds created in Doenjang via the enzymatic or non-enzymatic route; it is expected that these strains could be used to enhance the flavor of Doenjang .

The extraction of phenolic compounds from olive mill wastes is important, not only to avoid environmental damages, but also because of the intrinsic value of those biophenols, well-known for their high antioxidant potential and health benefits. This study focuses on tyrosol (Tyr) and hydroxytyrosol (HT), two of the main phenolic compounds found in olive mill wastes. A new, simple, and eco-friendly extraction process for the removal of phenolic compounds from aqueous solutions using native β-cyclodextrin (β-CD) in the solid state has been developed. Several β-CD/biophenol molar ratios and biophenol concentrations were investigated, in order to maintain β-CD mostly in the solid state while optimizing the extraction yield and the loading capacity of the sorbent. The extraction efficiencies of Tyr and HT were up to 61%, with a total solid recovery higher than 90% using an initial concentration of 100 mM biophenol and 10 molar equivalents of β-CD. The photochemical stability of the complexes thus obtained was estimated from ∆E*ab curve vs. illumination time. The results obtained showed that the phenols encapsulated into solid β-CD are protected against photodegradation. The powder obtained could be directly developed as a safe-grade food supplement. This simple eco-friendly process could be used for extracting valuable biophenols from olive mill wastewater.

(1) Background: Autophagy, the major cytoplasmic process of substrate turnover, declines with age, contributing to proteostasis decline, accumulation of harmful protein aggregates, damaged mitochondria and to ROS production. Accordingly, abnormalities in the autophagic flux may contribute to many different pathophysiological conditions associated with ageing, including neurodegeneration. Recent data have shown that extra-virgin olive oil (EVOO) polyphenols stimulate cell defenses against plaque-induced neurodegeneration, mainly, through autophagy induction. (2) Methods: We carried out a set of in vitro experiments on SH-SY5Y human neuroblastoma cells exposed to toxic Aβ 1-42 oligomers to investigate the molecular mechanisms involved in autophagy activation by two olive oil polyphenols, oleuropein aglycone (OleA), arising from the hydrolysis of oleuropein (Ole), the main polyphenol found in olive leaves and drupes and its main metabolite, hydroxytyrosol (HT). (3) Results: Our data show that the mixture of the two polyphenols activates synergistically the autophagic flux preventing cell damage by Aβ 1-42 oligomers., in terms of ROS production, and impairment of mitochondria. (4) Conclusion: Our results support the idea that EVOO polyphenols act synergistically in autophagy modulation against neurodegeneration. These data confirm and provide the rationale to consider these molecules, alone or in combination, as promising candidates to contrast ageing-associated neurodegeneration.

Caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) are bioactive molecules with poor solubility. We investigated the interaction between CA/CAPE and micellar casein (MC), and the physico-chemical and antioxidant properties of the complexes. Fluorescence spectroscopy analysis showed that both CA and CAPE formed complexes with MC via hydrophobic interactions. The binding constant was higher for CAPE than for CA at each temperature. The complexes were confirmed by FTIR and XRD. The secondary structure of MC was not affected by CAPE, but its morphology changed. CA/CAPE did not induce the dissociation of casein micelles. CA and CAPE increased and decreased, respectively, the bulk and tapped densities of MC. The complexes had higher thermal stability and DPPH radical scavenging capacity than free MC or CA/CAPE., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Psidium guineense Sw. (Myrtaceae) is a shrub distributed all over South America and Brazil. Its leaves are traditionally used to treat digestive problems and infections. Several biological activities have been reported for P. guineense extracts, however phytochemical studies are scarce. The present study is on the isolation of compounds from P. guineense leaf extracts using chromatographic and spectroscopic techniques and evaluation of their antibacterial activity. Araçain, a tyrosol derivative was isolated as a natural product for the first time. Other compounds isolated were ursolic acid, a phaeophorbide and three flavonoids. The extracts were tested for their antimicrobial activity against Klebsiella pneumoniae strains and they showed moderate to high antibacterial activity.