A fluorescent gemcitabine prodrug that follows a nucleoside transporter-independent internalization and bears enhanced therapeutic efficacy with respect to gemcitabine.

The multiplexity of cancer has rendered it the second leading cause of mortality worldwide and theragnostic prodrugs have gained popularity in recent years as a means of treatment. Theragnostic prodrugs enable the simultaneous diagnosis and therapy of tumors via high-precision real-time drug release monitoring. Herein, we report the development of the small theragnostic prodrug GF, based on the nucleoside anticancer agent gemcitabine and the fluorescent dye 5(6)-carboxyfluorescein. We have successfully demonstrated its efficient internalization in tumor cells, showing localization throughout both the early and late endocytic pathways. Its mechanism of cell internalization was evaluated, confirming its independence from nucleoside transporters. Its cellular localization via confocal microscopy revealed a clathrin-mediated endocytosis mechanism, distinguishing it from analogous compounds studied previously. Furthermore, GF exhibited stability across various pH values and in human blood plasma. Subsequently, its in vitro cytotoxicity was assessed in three human cancer cell lines (A549, U87 and T98). Additionally, its pharmacokinetic profile in mice was investigated and the consequent drug release was monitored. Finally, its in vivo visualization was accomplished in zebrafish xenotransplantation models and its in vivo efficacy was evaluated in A549 xenografts. The results unveiled an intriguing efficacy profile, positioning GF as a compelling candidate warranting further investigation.

Improving Children's Lifestyle and Quality of Life through Synchronous Online Education: The Nutritional Adventures School-Based Program.

The early introduction of effective nutritional educational programs is pivotal for instilling sustainable healthy behaviors. The present work aims to present a best practice example of a nutrition and overall lifestyle school-based training program, the Nutritional Adventures ("Diatrofoperipeteies"). Conducted during 2020-2022 in Greek primary schools, this synchronous, online educational initiative included two 1-school-hour activities with a nutrition instructor. Additionally, schools were randomly assigned to supplementary "at-home" supported-by-parents or "in-class" supported-by-educators educational activities. In total, n = 12,451 students of 84 primary schools participated. Parent-completed questionnaires were selected in the recruitment and post-intervention phase (40% participation rate); overall, the working sample was n = 1487 students. In the post-intervention phase, a significant increase in Mediterranean diet adherence was observed (KIDMED score: mean increment = 0.25 units; p < 0.001), particularly fruit and vegetable consumption. Time spent on physical activity increased, while screen time decreased. Students' total quality of life significantly improved (PedsQL; mean increment = 1.35 units; p < 0.001), including on all of its subscales (physical, emotional, social, and school function). Supplementary educational activities that were supported by educators rather than parents yielded a more favorable impact on students' lifestyle and quality of life. The Nutritional Adventures program can be regarded as a successful initiative in primary schools, yielding immediate advantages that extend beyond promoting healthy dietary habits.

Combating Loneliness in Older Adults during the COVID-19 Pandemic: Findings from a Volunteer-Based Program in Greece.

The COVID-19 pandemic has exacerbated the feeling of loneliness, especially among older adults. This study aims to investigate any association between COVID-19 cases in Greece and the number of Loneliness Helpline calls at the Friendship at Every Age program and to assess whether the interconnection part of the program, which interconnects older adults with volunteers, can combat loneliness/social isolation in older adults. This is a supportive, volunteer-based, social intervention program. A total of 4033 calls were collected from July 2020 to November 2022, in Greece. Older adults who participated in the interconnection part completed baseline (n = 275) and follow-up questionnaires (n = 168), including the UCLA Loneliness Scale. A time-series analysis revealed a positive association in the number of calls with COVID-19 cases (Incidence Rate Ratio per 100 new COVID-19 cases = 1.012; Confidence Interval (95% CI) [1.002, 1.022]). A significant decrease in the Loneliness Scale was observed at follow-up [difference = -0.85; 95% CI (-1.16, -0.54)], with similar results by sex, educational level, and area of living. Loneliness Helpline calls increased during COVID-19 outbreaks, while the interconnection part had a positive impact on older adults, reducing their feeling of loneliness. Similar initiatives are required to better address the needs of the ageing population during and after health crises.

Development of a novel apigenin prodrug programmed for alkaline-phosphatase instructed self-inhibition to combat cancer.

Elevated levels of alkaline phosphatase (ALP) in the tumor microenvironment (TME) are a hallmark of cancer progression and thus inhibition of ALP could serve as an effective approach against cancer. Herein, we developed a novel prodrug approach to tackle cancer that bears self-inhibiting alkaline phosphatase-responsiveness properties that can enhance at the same time the solubility of the parent compound. To probe this novel concept, we selected apigenin as the cytotoxic agent since we first unveiled, that it directly interacts and inhibits ALP activity. Consequently, we rationally designed and synthesized, using a self-immolative linker, an ALP responsive apigenin-based phosphate prodrug, phospho-apigenin. Phospho-apigenin markedly increased the stability of the parent compound apigenin. Furthermore, the prodrug exhibited enhanced antiproliferative effect in malignant cells with elevated ALP levels, compared to apigenin. This recorded potency of the developed prodrug was further confirmed in vivo where phospho-apigenin significantly suppressed by 52.8% the growth of PC-3 xenograft tumors.Communicated by Ramaswamy H. Sarma.

Nutritional Value of Meals Designed for a School-Based Food Aid Program and Comparison with Similar Commercial Products: An Example of Good Practice from the DIATROFI Program.

Providing meals of high nutritional value should be the principal objective of large-scale school-based food aid programs. This study aimed at highlighting the nutritional value of meals distributed in the school-based food assistance DIATROFI Program by comparing them to their commercially available counterparts. For the purpose of this study, n = 13 DIATROFI meals and n = 50 commercial products from the 2016-2017 school year, and n = 12 DIATROFI meals and n = 40 commercial products from the 2022-2023 school year were selected. The protein, carbohydrate, total sugar, dietary fiber, total fat, sodium/salt content, and fatty acid methyl ester profile of DIATROFI meals were estimated through recipe simulation and national/international food databases, and verified through laboratory analyses while the relevant information was extracted from the label for commercial products. As verified by laboratory analyses and in comparison with food labels, most DIATROFI meals had lower total fat, saturated fatty acid, and sugar content, and most had higher dietary fiber content during both years. Many recipes' nutrient profiles also improved over time. DIATROFI meals present significant advantages over available commercial products. Such tailored-made school meals can prove to be advantageous in terms of nutrition profile compared to commercially available, which have yet to be impacted by food reformulation.

Essential Skills for Health Communication, Barriers, Facilitators and the Need for Training: Perceptions of Healthcare Professionals from Seven European Countries.

Many healthcare professionals are unaware of the necessary skills and barriers hindering interpersonal health communication. This study aimed to evaluate the healthcare professional's perception regarding health communication training's necessity, barriers, facilitators and critical skills in health communication. Data from a cross-sectional online survey in the framework of the H-Com project were utilized. The study included 691 healthcare professionals (physicians, nurses, students and allied health professionals) from seven European countries. Only 57% of participants had participated in health communication training, while 88.1% of them indicated a willingness to be trained in health communication. Nurses were more likely (OR = 1.84; 95% CI 1.16, 2.91) to have received such training, compared to physicians. Most examined communication skills, barriers and facilitators of effective communication, and perceived outcomes of successful communication were considered crucial for most participants, although physicians overall seemed to be less concerned. Most agreed perceived outcomes were improved professional-patient relations, patient and professional satisfaction, physical and psychological health amelioration and patients' trust. Nurses evaluated the importance of these communication skills and communication barriers, facilitators and outcomes higher than physicians. Physicians may underestimate the importance of communication skills more than nurses. Health communication should become an integral part of training for all health professionals.

Health-Related Quality of Life in Childhood and Adolescence: The Interrelation with Level of Adherence to Mediterranean Diet and Dietary Trajectories: Highlights from the DIATROFI Program (2021-2022).

Children's dietary habits can have a key role in contributing to an improvement in their Health-Related Quality of Life (HRQoL). This study aims to assess the connection between Mediterranean diet adherence and HRQoL in a sample of Greek students, utilizing data from the DIATROFI program. The parents of 3774 students (mean age 7.8 (2.6) years) reported their children's HRQoL and level of adherence to the Mediterranean dietary pattern at the beginning and end of the 2021-2022 school year. At baseline, most students' adherence was characterized as moderate (55.2%) or high (25.1%). Students with moderate or high adherence tο the Mediterranean diet were less likely to report a total HRQoL below the median at baseline (OR = 0.56, 95%CI = 0.44, 0.70), along with all its dimensions (physical, emotional, social, and school functions). A one-unit improvement in KIDMED score (beginning-end of schoolyear) was associated with the likelihood of an improvement in total HRQoL (beginning-end of schoolyear) (OR = 1.09, 95%CI = 1.02, 1.17), emotional (OR = 1.09, 95%CI = 1.02, 1.17), and social functions (OR = 1.13, 95%CI = 1.05, 1.22), but not with physical and school functions. The health benefits of the Mediterranean diet in children may not be limited to disease prevention but also extend to their overall wellbeing.

Older People in Emergencies; Addressing Food Insecurity, Health Status and Quality of Life: Evaluating the "365+ Days of Care" Program.

During emergencies, older adults stand among the most vulnerable, facing long-lasting food insecurity and overall health issues. The "365+ Days of Care" food aid program addressed food insecurity and poor quality of life among vulnerable older adults following a devastating wildfire in Greece. Our aim was to evaluate the program's efficiency, using a process evaluation framework and a partial cost-utility analysis. In total, n = 133 wildfire-hit residents (≥65 years) received daily tailored, pre-cooked meals and/or weekly food packages. The study outcomes were assessed from baseline to 12 months later. Focus groups and interviews (n = 30), researcher observations, and questionnaires were used to assess the beneficiaries' perception of the initiative. Within the 12-month follow-up period, food insecurity and malnutrition risk decreased, whereas Mediterranean diet adherence; quality of life; and physical, social, and mental health were improved (p < 0.05). A one-point increase in food insecurity was positively associated with improved quality of life, general health, limitation in activities, body pain, vitality, and pain/discomfort (p's < 0.05), and it was marginally associated with mobility, anxiety/depression, and self-evaluated health status (p's < 0.1). Quantitative and qualitative data characterized it as successful, acceptable, beneficial, and of high quality. The partial cost-utility ratio was one QALY gained per EUR 22.608. The utilization of well-designed food aid programs during emergencies can alleviate food insecurity and improve quality of life in older adults.

Effect of being a persistent picky eater on feeding difficulties in school-aged children.

Children who are picky eaters often develop feeding difficulties during preschool years. These difficulties may persist into adolescence in some children. The study aim was to examine feeding difficulties and maternal feeding strategies longitudinally from age 5.5-8.5 years in relation to persistent picky eating. Picky eating behaviour in children enrolled in the Avon Longitudinal Study of Parents and Children was assessed using questionnaires between 2 and 5.5 years of age. Feeding behaviours were evaluated using questionnaires between 5.5 and 8.5 years. Data were analysed using adjusted logistic regression models. Of the 7405 children with data on picky eating 1926 (26%) were classified as never picky eaters, 385 (5%) were non-persistent picky eaters and 564 (8%) were persistent picky eaters. At 5.5, 7 and 8.5 years both persistent picky eaters and non-persistent picky eaters were more likely than never picky eaters to indicate difficulties in eating what the mother wanted, deliberately eat insufficiently, refuse to eat what was on offer, be choosy, not over-eat, and be difficult to get into routine, but with the likelihood decreasing with age (e.g. in persistent picky eaters vs non-picky eaters: refused to eat offered food OR 44.2 (95% CI 29.1, 67.0) at 5.5 years, 15.5 (11.5, 20.8) at 7 years and 14.1 (10.7, 18.6) at 8.5 years). The families of children who are picky eaters at the time of entering the school system should be offered reassurance that the feeding difficulties are likely to slowly resolve over time.

Assessing Quality of Life in First- and Second-Generation Immigrant Children and Adolescents; Highlights from the DIATROFI Food Aid and Healthy Nutrition Promotion Program.

To compare first- and second-immigrant pediatric populations with a non-immigrant pediatric population in terms of quality-of-life metrics, a cross-sectional analysis using data from the DIATROFI Program was implemented. In total, n = 2277 students (mean age: 9(4) years) from public schools in Greece participating in the 2020-2021 school year were analyzed. The students' immigration status (first-generation/second-generation) was defined as per the standard definition. The students' health related-quality of life (HRQoL) was assessed using a parental-perceived quality of life questionnaire. The sample included 4.8% first-generation and 21.2% second-generation immigrant students. Compared with non-immigrants, the first-generation immigrant students were more likely to have poor HRQoL (odds ratio (OR) = 2.82; 95% confidence interval (95%CI) = 11.75, 4.53), physical (OR = 1.91; 95%CI = 1.18, 3.10), social (OR = 1.94; 95%CI = 1.16, 3.22) and school function (OR = 2.52; 95%CI = 1.54, 4.13). Similar results were observed for second-generation immigrant students regarding HRQoL (OR = 1.68; 95%CI = 1.28, 2.21), physical (OR = 1.60; 95%CI = 1.23, 2.10) and school function (OR = 2.09; 95%CI = 1.58, 2.77). Children with one parent having a country of origin different that the country of residence had elevated odds of having poor emotional health (OR = 1.19; 95%CI = 0.87, 1.64). The family's affluency level was interrelated with the connection of poor HRQoL and immigration status. The immigrant students have a poorer quality of life depending on their immigration generation and irrespective of their socioeconomic background.

Prevalence and Socioeconomic Correlates of Adult Obesity in Europe: The Feel4Diabetes Study.

To effectively tackle obesity, it is necessary to identify all specific socioeconomic factors which contribute to its development. We aimed to highlight the prevalence of adult overweight/obesity in European countries and investigate the association of various socioeconomic factors and their accumulative effect on overweight/obesity status. Cross-sectional data from the Feel4Diabetes study for 24,562 adults residing in low socioeconomic areas were collected, representing Belgium, Finland, Greece, Spain, Bulgaria, and Hungary. Socioeconomic Burden Score (SEBS) was created, accounting for unemployment, financial insecurity, and education ≤ 12 years. Data were analyzed using analysis of variance and logistic regression. In total, 19,063 adults with complete data were included (34.5% overweight and 15.8% obese). The highest overweight/obesity rates occurred in Greece (37.5%/17.8%) and Hungary (35.4%/19.7%). After adjusting for confounders, age of <45 years and female sex were inversely associated with overweight/obesity, while low educational level (≤12 years), unemployment, and financial insecurity were positively associated. The increase in SEBS (clustering of socioeconomic disadvantages) was associated with increased overweight/obesity likelihood. This association of SEBS scores with overweight/obesity was evident for males and females across all examined countries, excluding males in low-income countries (Bulgaria and Hungary), where the highest SEBS score was inversely associated with overweight/obesity. The clustering burden of socioeconomic disadvantages on overweight/obesity was found to be influenced by the countries' economic state and sex.

Phenethyl ester of rosmarinic acid ameliorates experimental autoimmune encephalomyelitis.

Rosmarinic acid is a polyphenolic compound, abundantly present in herbs of the Lamiaceae family. The aim of the study was to evaluate the immunomodulatory properties of a recently developed phenethyl ester derivative of rosmarinic acid (PERA), with enhanced ability of diffusion through biological membranes, in an animal model of the central nervous system (CNS) autoimmunity. To this end, experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis was used. Daily subcutaneous administration of PERA (30 mg/kg) from day 7 to day 22 after immunization successfully ameliorated EAE induced in Dark Agouti rats, shortening the disease duration and reducing maximal, cumulative and mean clinical score. PERA efficiently reduced production of major encephalitogenic cytokines, interferon (IFN)-γ and interleukin (IL)-17, in immune cells from the CNS or the lymph nodes draining the site of immunization of EAE rats, as well as in CD4+ T cells purified from the lymph nodes. Also, PERA inhibited NO production in the CNS and the lymph nodes, as well as in macrophages and microglial cells. Finally, microglial ability to produce pro-inflammatory cytokines IL-6, and tumor necrosis factor (TNF) were also reduced by PERA. Our results clearly imply that PERA possesses anti-encephalitogenic properties. Thus, further studies on the relevance of the observed effects for the therapy of multiple sclerosis are warranted.

Comparative Interaction Studies of Quercetin with 2-Hydroxyl-propyl-ß-cyclodextrin and 2,6-Methylated-ß-cyclodextrin.

Quercetin (QUE) is a well-known natural product that can exert beneficial properties on human health. However, due to its low solubility its bioavailability is limited. In the present study, we examine whether its formulation with two cyclodextrins (CDs) may enhance its pharmacological profile. Comparative interaction studies of quercetin with 2-hydroxyl-propyl-ß-cyclodextrin (2HP-ß-CD) and 2,6-methylated cyclodextrin (2,6Me-ß-CD) were performed using NMR spectroscopy, DFT calculations, and in silico molecular dynamics (MD) simulations. Using T1 relaxation experiments and 2D DOSY it was illustrated that both cyclodextrin vehicles can host quercetin. Quantum mechanical calculations showed the formation of hydrogen bonds between QUE with 2HP-ß-CD and 2,6Μe-ß-CD. Six hydrogen bonds are formed ranging between 2 to 2.8 Å with 2HP-ß-CD and four hydrogen bonds within 2.8 Å with 2,6Μe-ß-CD. Calculations of absolute binding free energies show that quercetin binds favorably to both 2,6Me-ß-CD and 2HP-ß-CD. MM/GBSA results show equally favorable binding of quercetin in the two CDs. Fluorescence spectroscopy shows moderate binding of quercetin in 2HP-ß-CD (520 M-1) and 2,6Me-ß-CD (770 M-1). Thus, we propose that both formulations (2HP-ß-CD:quercetin, 2,6Me-ß-CD:quercetin) could be further explored and exploited as small molecule carriers in biological studies.

Anti-Ageing Potential of S. euboea Heldr. Phenolics.

In recent years, the use of Sideritis species as bioactive agents is increasing exponentially. The present study aimed to investigate the chemical constituents, as well as the anti-ageing potential of the cultivated Sideritis euboea Heldr. The chemical fingerprinting of the ethyl acetate residue of this plant was studied using 1D and 2D-NMR spectra. Isomeric compounds belonging to acylated flavone derivatives and phenylethanoid glycosides were detected in the early stage of the experimental process through 2D-NMR techniques. Overall, thirty-three known compounds were isolated and identified. Some of them are reported for the first time not only in S. euboea, but also in genus Sideritis L. The anti-ageing effect of the ethyl acetate residue and the isolated specialized products was assessed as anti-hyaluronidase activity. In silico docking simulation revealed the interactions of the isolated compounds with hyaluronidase. Furthermore, the in vitro study on the inhibition of hyaluronidase unveiled the potent inhibitory properties of ethyl acetate residue and apigenin 7-O-ß-d-glucopyranoside. Though, the isomers of apigenin 7-O-p-coumaroyl-glucosides and also the 4'-methyl-hypolaetin 7-O-[6'''-O-acetyl-ß-d-allopyranosyl]-(1→2)-ß-d-glucopyranoside exerted moderate hyaluronidase inhibition. This research represents the first study to report on the anti-hyaluronidase activity of Sideritis species, confirming its anti-inflammatory, cytotoxic and anti-ageing effects and its importance as an agent for cosmetic formulations as also anticancer potential.

Extracurricular Sports Participation and Sedentary Behavior in Association with Dietary Habits and Obesity Risk in Children and Adolescents and the Role of Family Structure: a Literature Review.

PURPOSE OF REVIEW: Childhood obesity is considered a major problem in the modern world, associated with many health issues in youth. This review aimed the association between extracurricular sports participation, sedentary time/screen time, and "obesogenic" and "non-obesogenic" dietary habits among youth and to explore the role of family structure on the adoption of sedentary behaviors by children. RECENT FINDINGS: Increased participation in extracurricular sports was associated with a healthier dietary pattern, containing more "non-obesogenic" food choices. Opposite results were indicated by sedentary activities. Increased time in watching TV, computer/electronic games, and other screen devices was positively associated with unhealthy dietary patterns. Overall, extracurricular activities influence the quality of food choices, which may prevent or promote childhood obesity; thus, sport-related activities should be promoted through public health policies. The role of the family structure is contradictory.

Valorisation of stachysetin from cultivated Stachys iva Griseb. as anti-diabetic agent: a multi-spectroscopic and molecular docking approach.

Stachys species are considered as important medicinal plants with numerous health benefit effects. In continuation of our research on the Greek Stachys species, the chemical profile of the aerial parts of cultivated S. iva Griseb. has been explored. The NMR profiles of the plant extract/infusion were used to guide the isolation process, leading to the targeted isolation of seventeen known compounds. The rare acylated flavonoid, stachysetin, was isolated for the third time from plant species in the international literature. Identification of the characteristic signals of stachysetin in the 1D 1H-NMR spectrum of the crude extract was presented. In order to evaluate the potential of the identified chemical space in Stachys to bear possible bioactivity against diabetes, we performed an in silico screening against 17 proteins implicated in diabetes, as also ligand based similarity metrics against established anti-diabetic drugs. The results capitalized the anti-diabetic potency of stachysetin. Its binding profile to the major drug carrier plasma protein serum albumin was also explored along with its photophysical properties suggesting that stachysetin could be recognized and delivered in plasma through serum albumin and also could be tracked through near-infrared imaging. Communicated by Ramaswamy H. Sarma.

A Lightweight Convolutional Neural Network Architecture Applied for Bone Metastasis Classification in Nuclear Medicine: A Case Study on Prostate Cancer Patients.

Bone metastasis is among the most frequent in diseases to patients suffering from metastatic cancer, such as breast or prostate cancer. A popular diagnostic method is bone scintigraphy where the whole body of the patient is scanned. However, hot spots that are presented in the scanned image can be misleading, making the accurate and reliable diagnosis of bone metastasis a challenge. Artificial intelligence can play a crucial role as a decision support tool to alleviate the burden of generating manual annotations on images and therefore prevent oversights by medical experts. So far, several state-of-the-art convolutional neural networks (CNN) have been employed to address bone metastasis diagnosis as a binary or multiclass classification problem achieving adequate accuracy (higher than 90%). However, due to their increased complexity (number of layers and free parameters), these networks are severely dependent on the number of available training images that are typically limited within the medical domain. Our study was dedicated to the use of a new deep learning architecture that overcomes the computational burden by using a convolutional neural network with a significantly lower number of floating-point operations (FLOPs) and free parameters. The proposed lightweight look-behind fully convolutional neural network was implemented and compared with several well-known powerful CNNs, such as ResNet50, VGG16, Inception V3, Xception, and MobileNet on an imaging dataset of moderate size (778 images from male subjects with prostate cancer). The results prove the superiority of the proposed methodology over the current state-of-the-art on identifying bone metastasis. The proposed methodology demonstrates a unique potential to revolutionize image-based diagnostics enabling new possibilities for enhanced cancer metastasis monitoring and treatment.

Bioinspired tailoring of fluorogenic thiol responsive antioxidant precursors to protect cells against H2O2-induced DNA damage.

Natural antioxidants, like phenolic acids, possess a unique chemical space that can protect cellular components from oxidative stress. However, their polar carboxylic acid chemotype reduces full intracellular antioxidant potential due to limited diffusion through biological membranes. Here, we have designed and developed a new generation of hydrophobic turn-on fluorescent antioxidant precursors that upon penetration of the cell membrane, reveal a more polar and more potent antioxidant core and simultaneously become fluorescent allowing their intracellular tracking. Their activation is stimulated by polarity alteration by sensing intracellular signals and specifically biothiols. In our design, the carboxylic group of phenolic acids that originally restricts cell entrance is derivatized and conjugated through Copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) to a coumarin derivative that its fluorescence properties are quenched with a biothiol activatable element. This more hydrophobic precursor readily penetrates cell membrane and once inside the cell the antioxidant core is revealed upon sensing glutathione, its fluorescence is restored in a turn-on manner and the generation of a more polar character traps the molecule inside the cell. This turn-on fluorescent antioxidant precursor that can be applied to phenolic acids, was developed for rosmarinic acid and the conjugate was named as RCG. The selectivity and responsiveness of RCG towards the most abundant biothiols was monitored through a variety of biophysical techniques including UV-Vis, fluorescence and NMR spectroscopy. The electrochemical behavior and free radical scavenging capacity of the precursor RCG and the active compound (RC) was evaluated and compared with the parent compound (rosmarinic acid) through cyclic voltammetry and EPR spectroscopy, respectively. The stability of the newly synthesized bioactive conjugate RC was found significantly higher than the parent rosmarinic acid when exposed to oxygen. Cell uptake experiments were conducted and revealed the internalization of RCG. The degree of intracellular DNA protection offered by RCG and its active drug (RC) on exposure to H2O2 was also evaluated in Jurkat cells.

Preparation and Biophysical Characterization of Quercetin Inclusion Complexes with ß-Cyclodextrin Derivatives to be Formulated as Possible Nose-to-Brain Quercetin Delivery Systems.

Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que-2-hydroxypropylated-ß-cyclodextrin (Que/HP-ß-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que-methyl-ß-cyclodextrin (Que/Me-ß-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-ß-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-ß-CD more than with Me-ß-CD, possibly revealing the presence of more than one HP-ß-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-ß-CD and Que/HP-ß-CD products was approximately 7-40 times and 14-50 times as high as for pure Que at pH 1.2-6.8. In addition, the proof of concept experiment on ex vivo permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further ex vivo and in vivo evaluation toward nasal administration and nose-to-brain delivery of Que.

Exploring the oxidation and iron binding profile of a cyclodextrin encapsulated quercetin complex unveiled a controlled complex dissociation through a chemical stimulus.

BACKGROUND: Flavonoids possess a rich polypharmacological profile and their biological role is linked to their oxidation state protecting DNA from oxidative stress damage. However, their bioavailability is hampered due to their poor aqueous solubility. This can be surpassed through encapsulation to supramolecular carriers as cyclodextrin (CD). A quercetin- 2HP-ß-CD complex has been formerly reported by us. However, once the flavonoid is in its 2HP-ß-CD encapsulated state its oxidation potential, its decomplexation mechanism, its potential to protect DNA damage from oxidative stress remained elusive. To unveil this, an array of biophysical techniques was used. METHODS: The quercetin-2HP-ß-CD complex was evaluated through solubility and dissolution experiments, electrochemical and spectroelectrochemical studies (Cyclic Voltammetry), UV-Vis spectroscopy, HPLC-ESI-MS/MS and HPLC-DAD, fluorescence spectroscopy, NMR Spectroscopy, theoretical calculations (density functional theory (DFT)) and biological evaluation of the protection offered against H2O2-induced DNA damage. RESULTS: Encapsulation of quercetin inside the supramolecule's cavity enhanced its solubility and retained its oxidation profile. Although the protective ability of the quercetin-2HP-ß-CD complex against H2O2 was diminished, iron serves as a chemical stimulus to dissociate the complex and release quercetin. CONCLUSIONS: We found that in a quercetin-2HP-ß-CD inclusion complex quercetin retains its oxidation profile similarly to its native state, while iron can operate as a chemical stimulus to release quercetin from its host cavity. GENERAL SIGNIFICANCE: The oxidation profile of a natural product once it is encapsulated in a supramolecular carrier was unveiled as also it was discovered that decomplexation can be triggered by a chemical stimilus.