Cyclodextrins are cyclic oligosaccharides made up by glucose units. Their hydrophobic internal cavity and hydrophilic surface allows them to form inclusion complexes by encapsulating low polar molecules inside. This molecular encapsulation is widely use in biomedicine to improve the water solubility of bioactive compounds. For this reason, cyclodextrins have been used to modify the water-based ORAC method to measure the antioxidant activity of lipophilic phytochemicals. However, the literature shows some discrepancy between authors on the role played by these encapsulating agents in the medium. In this work, the effect of cyclodextrins on the ORAC method is investigated in the presence and absence of the antioxidant oxyresveratrol, a hydrophobic stilbene that is naturally synthesised in mulberry trees. By means of a physicochemical and computational approach, it was concluded that cyclodextrins are able to modify the fluorescent signal of the ORAC method both in the presence and in the absence of the antioxidant oxyresveratrol. This interference was dependent on the type of cyclodextrin and the concentration. It seems that the main cause of this undesirable effect is the encapsulation of other reagents in the medium, in particular fluorescein and AAPH. These results are of interest for future studies in which the antioxidant activity of poorly water-soluble biomolecules is analysed.

Stilbenes are secondary metabolites produced by some plant species like grapes, peanuts or mulberries as a defence mechanism against biotic and abiotic stress conditions (fungal infections, UV radiation, etc.). These compounds are produced through the shikimic acid pathway and they share the 1,2-diphenylethylene structure with different substituents. These substituents are responsible for the vast variety of stilbenes that we know (resveratrol, piceatannol, pterostilbene, gnetol, pinosylvin, piceid, etc.), as well as responsible of their different physicochemical properties (solubility, polarity, stability, fluorescence and spectrophotometric features, among others) and their different biological activities (anticancer, antifungal, antioxidant, cardioprotective, antiobesity, etc.). Resveratrol is the most studied stilbene, but recently there is a growing interest for other stilbenes (both natural and synthetic) with better properties due to their structure.

However, these beneficial properties that stilbenes have are accompanied by some pharmacokinetic and physicochemical drawbacks that have to be solved to use them in cosmetic, food and pharmaceutical industries. Among these problems, the most important is the low water solubility of stilbenes (they are highly hydrophobic) and their fast degradation because of pH, temperature, oxidation or radiation. Moreover, the good bioactive results showed in in vitro studies do not correspond with those seen in the in vivo ones, probably because of the low bioavailability of stilbenes and their fast metabolization. To overcome these issues, 2 possible solutions have been proposed: the molecular encapsulation of stilbenes in cyclodextrins and the structural modification of native stilbenes.

The molecular encapsulation of stilbenes can be performed with liposomes, cyclodextrins or nanosponges, among other encapsulating agents. All of them have hydrophobic regions where stilbenes can be included, enhancing their water solubility and protecting them from degradation. On the other hand, the stilbene derivatization with different functional groups (hydroxyl, methoxyl, glycosyl, etc.) frequently improves the physicochemical properties and/or biological activities of native stilbenes.

Gnetol, a natural stilbene particularly found in genus Gnetum, has anti-inflammatory, anti-thrombotic, cardio-protective, and anti-cancer activity. However, the applications of this stilbene as a bioactive ingredient in foods, cosmetic or pharmaceutical industries, may be limited due to its low water solubility and its easy degradation. The encapsulation in cyclodextrins could solve these problems.

This study compares the antioxidant activity of gnetol with other stilbenes analogues, encapsulates it in different cyclodextrins and evaluates the effect that this process has in water solubility. In addition, the effect of pH and temperature on the encapsulation constant is analysed.

Our results reveal that the antioxidant activity of gnetol was higher than that of resveratrol, and similar or higher to that of oxyresveratrol. Moreover, the solubility in water of gnetol was 0.31 mg/mL, but the highest concentration of HPβCD used could increase almost threefold the basal solubility, as well as its stability after storage for a week. Gnetol-HPβCD encapsulation constants were influenced by changes in pH and temperature, decreasing when either of these parameters increased. All these results could increase the interest in gnetol, as well as aid in the development of more stable inclusion complexes that improve its aqueous solubility and stability for industrial use.

Acknowledgements: This research was funded by the Spanish Ministry of Science and Innovation (PID2021-122896NB-100 (MC/AEI/FEDER, UE), by University of Murcia [Murcia-Españia) (FPU-UMU), by Eundacio Séneca (Murcia-España) (21269/FP1/19), by Ministry of Universities (España) (FPU) and by Ministry dell' Universita e della Ricecca. (Italia) (1052/2021).

The endocrine disorder polycystic ovarian syndrome (PCOS) is complicated. In India, two out of every ten women have PCOS. PCOS can also be identified by polycystic ovary morphology and an ovulatory hyperandrogenism. Polycystic ovarian syndrome (PCOS), one of the most common female endocrine diseases, affects about 20–25% of women of reproductive age and is thought to be one of the primary causes of female infertility. Metabolic abnormalities, irregular periods, hypertension, and increased insulin levels are more prone to occur in women with PCOS. Increased production of androgens like testosterone from the ovaries; more sub-follicular cysts. Low vitamin levels in PCOS women place them at a high risk for developing severe COVID 19, a risk that may be increased by limited sun exposure brought on by COVID 19 quarantine measures. Therefore, there is a greater need public awareness for PCOS. PCOS is a treatable illness that can be treated with safe and effective natural remedies, including the use of various herbs and seeds. To decrease the cost, length, and side effects of current treatments, polyherbal formulations must be developed based on the aforementioned variables. By altering a woman's diet, exercising, doing yoga asanas, and altering her lifestyle, PCOS can be controlled. An effort has been made to review utilization of natural remedies for PCOS treatment.

Glioblastoma is an aggressive type of cancer that accounts for about 50% of all malignant tumors of the CNS. Hydroxy derivatives of cinnamic acid have promising antitumor properties. Taraxacum officinale F.H. Wigg (TO) is an important source of cinnamic acid hydroxy derivatives.

The aim of the study was to evaluate the antitumor activity of TO extracts on U-138 MG cells and correlate this activity with the concentration of chicoric (ChA), chlorogenic (CGA), and cafftaric (CA) acids (mg/mL) in the extract.

TO dry leaves were extracted with DMSO and ethanol of different concentrations (20%, 50%, 80%). The filtrates of TO were dried and weighted for dried mass content calculation, which was reported per Liter. The concentration of acids was determined by liquid chromatograph (Agilent 1260 with diode array detector). The viability of U-138 MG glioblastoma cells (Cell Lines Service, Germany) was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (% of viable cells). The activity of TO was compared with that of doxorubicin.

All studied TO extracts suppressed the viability of U-138 MG glioblastoma cells. The best antitumor activity was shown by TO extracts prepared with DMSO (110.000 µg/L – 17.3±8%, that contained ChA – 8976x10^-6 mg/mL, CGA – 316.8 x10^-6 mg/mL, CA – 1628 x10^-6 mg/mL), with 50% ethanol (150.000 µg/L – 13.7±3.2%, that contained ChA – 52.500 x10^-6 mg/mL, CGA – 1746 x10^-6 mg/mL, CA – 8460 x10^-6 mg/mL) and with 80% ethanol (40.000 µg/L – 16.1±9%, that contained ChA – 904 x10^-6 mg/mL, CGA – 114.4 x10^-6 mg/mL, CA – 70.4 x10^-6 mg/mL). TO extracts activity was close to that of doxorubicin, which reduced the viability of U-138 MG cells to 8.64±1.65% at the concentration of 54.350 µg/L and to 15.32±0.86% at the concentration of 10⁵ µg/L.

The results obtained allow us to conclude that Taraxacum officinale significantly suppresses the viability of glioblastoma cells. This activity depends on the type of extractant and its concentration, as well as on the content of cinnamic acids and their ratio.

Major depressive disorder (MDD) exhibits negative emotional symptoms with various degrees of psychomotor manifestation. The disturbance of the tryptophan-kynurenine (KYN) metabolic system has been implicated in MDD. Kynurenine/α-aminoadipate aminotransferase (KAT II) is a mitochondrial enzyme that catalyzes the reaction of KYN to kynurenic acid. Little is known about the impact of the gene aadat knockout (KAT II KO^-/-) on behaviors. We studied negative emotional and motor domains at 4 and 12 weeks of male KAT II KO^-/- mice and the wild-type counterpart C57BL/6N.

Depression-like, anxiety-like, and motor behaviors were assessed by modified forced swim test (FST), elevated plus-maze (EPM) test, light-dark box (LDB) test, and open field (OF) test.

FST showed significantly more depression-like behaviors at 4 and 12 weeks in KAT II KO^-/- mice than the wild-type and the older mice were more prominent in both strains. Both strains spent significantly more time in the light at week 12 than week 4 in LDB test. The OF test showed significantly shorter ambulation time at week 12 in KAT II KO^-/- mice than the wild-type and significantly longer time spent in the center zone at week 12 than week 4 in both strains.

We show here that KAT II KO^-/- mice exhibit more depression-like behaviors in an age-dependent manner, accompanied with decreasing anxiety and motor activity. Thus, the aadat gene knock-out influences behavioral domains in such a manner that the strain potentially serves as an animal model of a subtype, depression with psychomotor retardation.

Here, potential inhibitors of the SARS-CoV-2 papain-like protease (PL^pro) are reported. A drug molecule (PL^pro-50) designed de novo interacts with PL^pro via hydrogen bonding, forming a salt bridge and π-π stacking, making it a promising drug against the protease. ADMET studies showed that PL^pro-50 shows minimal side effects. Molecular dynamics analysis revealed the stability of the receptor-ligand complex of PL^pro-50 and PL^pro. Further studies should be done to determine whether the determined drug candidates are efficacious in treating COVID-19 infections. The discovery of inhibitors of SARS-CoV-2 could complement current vaccination programs in preventing excess deaths

Here, novel potential inhibitors of SARS-CoV-2 variants were designed de novo using generative neural networks. The top-performing ligand based on docking performance and ADMET profile is CID #526. It forms several hydrogen bonds with the wild SARS-CoV-2, indicating its potential as an inhibitor of the receptor binding domain. Mutated variants of the RBD also showed good interactions with CID #526, implying the inhibitory properties of our top-performing compound against various variants. Molecular dynamics analysis showed a stable ligand-RBD complex. As our computer-aided organic retrosynthesis study implied, CID #526 can easily be synthesized using low-cost starting molecules. Overall, the generated ligands merit further investigation to determine their efficacy and safety as a treatment against COVID-19.

Abstract: We found the logical way to prove the mechanism that reverses biodegradation of cervical spine cartilage and normalizes left ventricular hypertrophy after we restore access to arterial blood flow through cervical vertebral arteries to rhomboid fossa. It is based on the consideration of the human body as a dissipative structure. Then the recovery of the body should be considered as a redirection of the energy flows from decay towards restoration. It looks, that the recovery of cervical spine cartilage through redirecting of inner dissipative flow requires to take into account the role of the information about oxygen availability that is provided from rhomboid fossa to cerebellum. We proposed the approach to explain already collected data, that satisfies all the scientific requirements. This allows us to draw conclusions that allow reconsidering the way of dealing with multiple chronic diseases.

Introduction.

Obesity is one of the most common chronic diseases in the world. Genetic factors are involved in the formation of obesity and one of the candidate genes for obesity are genes associated with the age of menarche. It is believed that women with early menarche have a higher risk of developing obesity and polymorphisms associated with early menarche may also be risky for the obesity development.

The aim of the study: To study the association of the menarche-correlated rs555621 FSHB gene with the obesity in women.

Materials and Methods. The DNA samples of 171 women served as material for the study. Genotyping of the rs555621 FSHB gene was carried out. For each woman, the body mass index was calculated and the age of menarche was estimated.

Results. Among women with obesity the frequencies of the A allele and AA genotype of the rs555621 were 1,32 times (OR=2.04 95% CI 1.19-3.51 p=0.009) and 2.01 times (OR=3.03 95% CI 1.41-6.53 p=0.004) respectively higher than in women without obesity. The G allele rs555621 was associated with the obesity in the additive (OR=0.51 95%CI 0.29-0.89, p_perm=0.02) and dominant (OR=0.38 95%CI 0.18-0.79, p_perm=0.009) models. It was found that in women with obesity, menarche occurs 0.7 years earlier than in women without obesity (p<0.001). The rs555621 FSHB was associated with the age of menarche: earlier menarche was observed in women with the AA genotype (12.57 years), and later menarche was detected in women with the GG genotype (13.00 years, p<0,001).

Conclusions. Thus, it was found that the AA genotype of the rs555621 FSHB was associated with early menarche and was associated with an increased risk of obesity.