Investigating the Suitability of Mare's Milk-Derived Exosomes as Potential Drug Carriers.

Exosomes are cell-derived, membrane-surrounded particles that deliver bioactive molecules to various cells. Due to their small size, low immunogenicity, extended blood circulation, and involvement in cellular communication, they hold potential as effective drug carriers. Exosomes are present in various biological fluids, including mare's milk, a traditional drink in Central Asia. This study aims to compare exosome isolation methodologies and determine the stability of mare's milk-derived exosomes as potential therapeutic carriers. Three extraction methods-immunoprecipitation, size exclusion chromatography, and total exosome isolation-were compared in terms of exosome characteristics, purity, and content. The isolated exosomes were then loaded with quercetin, and their ability to increase its bioavailability was tested in vitro and in vivo. Total exosome isolation was identified as the most efficient method for producing high-quality exosomes. These exosomes were loaded with quercetin and compared to free quercetin and exosomes alone. Exosomes loaded with 80 µM quercetin significantly restored ß-galactosidase activity and cellular viability in doxorubicin-treated cells, exhibiting similar potency to 160 µM free quercetin. In aged model animals, treatment with quercetin-loaded exosomes resulted in significantly less acute and subacute damage to the myocardium, kidneys, and liver compared to untreated control animals. This study provides a proof-of-concept that mare's milk-derived exosomes can be effectively absorbed by cells and animal tissues, supporting their potential use as drug carriers.

Synthesis, Computational Study, and In Vitro α-Glucosidase Inhibitory Action of Thiourea Derivatives Based on 3-Aminopyridin-2(1H)-Ones.

Reactions with allyl-, acetyl-, and phenylisothiocyanate have been studied on the basis of 3-amino-4,6-dimethylpyridine-2(1H)-one, 3-amino-4-phenylpyridine-2-one, and 3-amino-4-(thiophene-2-yl)pyridine-2(1H)-one (benzoyl-)isothiocyanates, and the corresponding thioureide derivatives 8-11a-c were obtained. Twelve thiourea derivatives were obtained and studied for their anti-diabetic activity against the enzyme α-glucosidase in comparison with the standard drug acarbose. The comparison drug acarbose inhibits the activity of α-glucosidase at a concentration of 15 mM by 46.1% (IC50 for acarbose is 11.96 mM). According to the results of the conducted studies, it was shown that alkyl and phenyl thiourea derivatives 8,9a-c, in contrast to their acetyl-(benzoyl) derivatives and 10,11a-c, show high antidiabetic activity. Thus, 1-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9a has the highest inhibitory activity against the enzyme α-glucosidase, exceeding the activity of the comparison drug acarbose, which inhibits the activity of α-glucosidase by 56.6% at a concentration of 15 mm (IC50 = 9,77 mM). 1-(6-methyl-2-oxo 4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9c has inhibitory activity against the enzyme α-glucosidase, comparable to the comparison drug acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mm per 41.2% (IC50 = 12,94 mM). Compounds 8a, 8b, and 9b showed inhibitory activity against the enzyme α-glucosidase, with a lower activity compared to acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mM by 23.3%, 26.9%, and 35.2%, respectively. The IC50 against α-glucosidase for compounds 8a, 8b, and 9b was found to be 16.64 mM, 19.79 mM, and 21.79 mM, respectively. The other compounds 8c, 10a, 10b, 10c, 11a, 11b, and 11c did not show inhibitory activity against α-glucosidase. Thus, the newly synthesized derivatives of thiourea based on 3-aminopyridine-2(1H)-ones are promising candidates for the further modification and study of their potential anti-diabetic activity. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.

Gut microbiome-immune interactions and their role in rheumatoid arthritis development.

Objective: The primary objective is to study the impact of gut microbiota and their interactions with diverse immunological markers on the development of rheumatoid arthritis. Methods: This study was performed in Astana, Kazakhstan, and included 77 Kazakh female patients older than 18 years, who met the American College of Rheumatology 2010 classification criteria for rheumatoid arthritis (RA), and 113 healthy controls. The DNA was extracted from fecal samples obtained from all study participants for subsequent sequencing at the 16S rRNA gene V1-V3 locus, facilitating the analysis of the gut microbiome. The Multiplex immunoassay was employed to measure the concentrations of inflammatory cytokines, chemokines, and immunoglobulins in both fecal and plasma samples. Results: Our taxonomic analysis revealed significant differences in the composition of the gut microbiota between the healthy control cohort and the cohort with rheumatoid arthritis RA. Alpha diversity was significantly lower in the RA group. Lachnospiraceae were the most abundant taxon and found to be crucial, showing correlations with immunological markers such as IL5. Additionally, Lachnospiraceae and Oscillospiraceae exhibited the most predictable power and distinguished the composition of both study groups. Conclusion: Our study identifies key differences in the gut microbiome of RA patients, revealing distinct microbial patterns and specific taxa abundance. We highlight potential biomarkers in immunological and bacterial pathways, offering insights into RA development and indicating possibilities for personalized treatment.

Synthesis, Computational Study, and In Vitro α-Glucosidase Inhibitory Action of 1,3,4-Thiadiazole Derivatives of 3-Aminopyridin-2(1H)-ones.

This article reports on the synthesis of nine promising new 1,3,4-thiadiazole derivatives based on 3-aminopyridones, containing various acidic linkers. The synthesis was carried out by cyclizing the corresponding thiohydrazides 4a-c and anhydrides of glutaric, maleic, and phthalic acids upon heating in acetic acid solution. The conducted bio-screening of the synthesized new 1,3,4-thiadiazole derivatives containing different acidic linkers (butanoic, acrylic, and benzoic acids) showed that they have significant inhibitory activity against α-glucosidase (up to 95.0%), which is 1.9 times higher than the value for the reference drug acarbose (49.5%). Moreover, one of the 1,3,4-thiadiazole derivatives with a benzoic acid linker-2-(5-((6-Methyl-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)carbamoyl)-1,3,4-thiadiazol-2-yl)benzoic acid (9'b)-showed an IC50 value of 3.66 mM, nearly 3.7 times lower than that of acarbose (IC50 = 13.88 mM). High inhibitory activity was also shown by 1,3,4-thiadiazole derivatives with a butanoic acid linker (compounds 7b, 7c)-with IC50 values of 6.70 and 8.42 mM, respectively. A correlation between the structure of the compounds and their activity was also established. The results of molecular docking correlated well with the bioanalytical data. In particular, the presence of a butanoic acid linker and a benzoic fragment in compounds 7b, 7c, and 9b increased their binding affinity with selected target proteins compared to other derivatives 3-6 (a-c). Calculations according to Lipinski's rule of five also showed that the synthesized compounds 7b, 7c, and 9b fully comply with Ro5 and meet all criteria for good permeability and acceptable oral bioavailability of potential drugs. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.

The Trajectory of Successful Aging: Insights from Metagenome and Cytokine Profiling.

INTRODUCTION: The longevity is influenced by genetic, environmental, and lifestyle factors. The specific changes that occur in the gut microbiome during the aging process, and their relationship to longevity and immune function, have not yet been fully understood. The ongoing research of other microbiome based on longevity cohort in Kazakhstan provides preliminary information on longevity-related aging, where cytokine expression is associated with specific microbial communities and microbial functions. METHODS: Metagenomic shotgun sequencing study of 40 long-lived individuals aged 90 years and over was carried out, who were conditionally healthy and active, able to serve themselves, without a history of serious infection and cancer, who had not taken any antimicrobials, including probiotics. Blood serum was analyzed for clinical and laboratory characteristics. The cytokine and chemokine profile in serum and stool samples was assessed using multiplex analysis. RESULTS: We found a significant increase in the expression of pro-inflammatory cytokines IL-1a, IL-6, 12p70, IP-10, IFNα2, IL-15, TNFa, as well as chemokines MIP-1a/CCL3 and MIP-1b/CCL4, chemokine motif ligands MCP-3/CCL7 and MDC/CCL22(1c). Nonagenerians and centenarians demonstrated a greater diversity of core microbiota genera and showed an elevated prevalence of the genera Bacteroides, Clostridium, Escherichia, and Alistipes. Conversely, there was a decrease in the abundance of the genera Ruminococcus, Fusicatenibacter, Dorea, as well as the species Fusicatenibacter saccharivorans. Furthermore, functional analysis revealed that the microbiome in long-lived group has a high capacity for lipid metabolism, amino acid degradation, and potential signs of chronic inflammatory status. CONCLUSION: Long-lived individuals exhibit an immune system imbalance and observed changes in the composition of the gut microbiota at the genus level between to the two age-groups. Age-related changes in the gut microbiome, metabolic functions of the microbial community, and chronic inflammation all contribute to immunosenescence. In turn, the inflammatory state and microbial composition of the gut is related to nutritional status.

Modeling Mediated Crossover Acute and Subacute Damage to the Pulmonary System During Systemic (Subcutaneous) Administration of Bleomycin in Mice to Test the Potential Therapeutic Effect of Polyphenols / Modelado del Daño Agudo y Subagudo Cruzado Mediado al Sistema Pulmonar Durante la Infección Sistémica (Subcutánea) de Administración de Bleomicina a Ratones para Probar el Posible Efecto Terapéutico de los Polifenoles

SUMMARY: The potential anti-inflammatory and antifibrotic activity of polyphenolic extracts of blueberry and grape was evaluated in a mouse model of lung damage induced by subcutaneous administration of bleomycin. The results of testing the polyphenolic extracts on two different systemic administration variants of bleomycin (intraperitoneal and subcutaneous) were compared. It was found that regardless of the method of bleomycin administration, indirect cross-acute and subacute damage to the pulmonary system was observed. Both patterns exhibited the same prevalence and severity. The administration of polyphenolic extracts of blueberry and grape to mice resulted in a significant decrease in theseverity of acute and subacute patterns of lung damage, suggesting their protective properties for the microcirculatory bed and a pronounced anti-inflammatory effect.

La potencial actividad antiinflamatoria y antifibrótica de los extractos polifenólicos de arándano y uva se evaluó en un modelo de daño pulmonar en ratón inducido por la administración subcutánea de bleomicina. Se compararon los resultados de las pruebas de los extractos polifenólicos en dos variantes diferentes de administración sistémica de bleomicina (intraperitoneal y subcutánea). Se encontró que, independientemente del método de administración de bleomicina, se observaba daño indirecto cruzado, agudo y subagudo al sistema pulmonar. Ambos patrones exhibieron la misma prevalencia y gravedad. La administración de extractos polifenólicos de arándano y uva a ratones dio como resultado una disminución significativa en la gravedad de los patrones agudos y subagudos de daño pulmonar, lo que sugiere sus propiedades protectoras del lecho micro- circulatorio y un efecto antiinflamatorio pronunciado.

The Effect of Different Glucose Concentrations on the Antiproliferative Activity of Metformin in MCF-7 Breast Cancer Cells.

The glucose-lowering drug metformin has been reported to have anticancer properties through unknown mechanisms. Other unknown factors that may influence its anticancer potential include the glycemic status of the patient. Therefore, the objective of this study is to determine the effect of different glucose environments on the antiproliferative potency and the cellular mechanism of action of metformin. Human breast cancer cells, MCF-7, were incubated in low, normal, elevated, and high glucose environments and treated with metformin. The antiproliferative potential of metformin and its effect on protein expression as well as its ability to induce cellular apoptosis and autophagy under different glucose environments, were determined using different molecular techniques. Metformin significantly inhibited cellular proliferation in a time- and glucose-concentration-dependent manner. In comparison to elevated glucose, low normal glucose alone induced a significant level of autophagy that was further increased in the presence of metformin. While glucose concentration did not appear to have an effect on the antiproliferative potency of metformin, the cellular basis of action was shown to be glucose-dependent. The antiproliferative mechanism of action of metformin in elevated and low normal glucose environments is mTOR-dependent, whereas, in the high glucose environment, the antiproliferative mechanism is independent of mTOR. This is the first study to report that both the antiproliferative potency and the cellular mechanism of action aredependent on the concentration of glucose.

Blueberry and cranberry extracts mitigate CCL4-induced liver damage, suppressing liver fibrosis, inflammation and oxidative stress.

The current study aims to evaluate potential hepatoprotective effect of lingonberry, cranberry and blueberry polyphenols on carbon tetrachloride (CCL-4)-induced acute and subacute liver injury in rats. A total of 55 male Wistar rats, divided into six experimental and control groups. With the exception of the negative control group, all groups received an intraperitoneal injection of CCl-4, twice a week for 14 days. An extract of lingonberry, cranberry, blueberry polyphenols and the positive control, silymarin were administered daily via intragastric route, for 14 consecutive days. The untreated control group showed characteristic of classical oxidative stress-mediated liver damage with vacuolization of the hepatocyte cytoplasm, infiltration by immune cells and proliferation of collagen fibers, decrease in body weight and increase in liver weight; increased levels of AST and ALT in serum, an increased lipid peroxidation in the liver. However, the use of cranberry and blueberry polyphenols significantly suppressed liver damage, exerting an effect comparable to the hepatoprotective effect of the positive control. The extracts prevented and reduced inflammatory liver damage by reducing IL-6, TNF-α and IFN-γ levels. In conclusion, blueberry and cranberry extracts have a protective effect against acute and subacute CCl4-induced hepatotoxicity in rats.

The antiproliferative potential and mechanism of action of metformin in MCF-7 cells.

Aim: The current study aimed to investigate the potential antiproliferative activity of metformin, the effective concentration range, and the mechanism of action. Materials & methods: Human breast cancer cells, MCF-7 were treated with a serial dilution of metformin (10-150 µM) for 24 and 48 h. Potential antiproliferative activity of metformin and its ability in inducing cellular apoptosis and autophagy were also investigated. Results: Metformin inhibited MCF-7 proliferation in a concentration and time dependent manner, with 80 µM as the most effective concentration. Compared with nontreated cells, metformin induced significant levels of autophagy and apoptosis, which were confirmed by the reduction of mTOR and BCL-2 protein expression. Conclusion: The study confirms the antiproliferative activity of metformin, which may likely occur through AMPK signaling pathway.

The antidiabetic drug, metformin is tested in this work for its possible ability to inhibit the growth of breast cancer cells. Using different concentrations of the drug over different time points, the results showed that the drug was able to inhibit cancer growth through different mechanisms. The results also showed that the drug inhibits cancer growth by stimulating program cell death (apoptosis), as well as autophagy, where the cell breaks old and abnormal cellular substances.

Potential antifibrotic effect of blueberry and grape polyphenol extracts in acute and subacute bleomycin-induced lung tissue injury models in mice / Potencial efecto antifibrótico de los extractos de polifenoles de arándano y uva en modelos de lesión tisular pulmonar aguda y subaguda inducida por bleomicina en ratones

SUMMARY: An experimental morphological and morphometric study of the antifibrotic function of blueberry and grape extracts was carried out on a model of lung injury in mice induced by intraperitoneal administration of bleomycin. During intraperitoneal administration of bleomycin to mice, acute and subacute damage to the pulmonary system was noted. Both patterns had the same prevalence and severity. The administration of polyphenolic extracts of blueberry and grape to mice showed a significant reduction in the severity of the acute and subacute pattern of lung injury. Blueberry and grape extracts reduce the acute phase of damage to the microvasculature, enhance phagocytic function, have an anti-inflammatory effect, reducing the degree of lymphohistiocytic infiltration and locoregional foci of residual inflammatory effects.

Se realizó un estudio experimental morfológico y morfométrico de la función antifibrótica de extractos de arándano y uva en un modelo de lesión pulmonar en ratones inducida por la administración intraperitoneal de bleomicina. Durante la administración intraperitoneal de bleomicina a ratones, se observaron daños agudos y subagudos en el sistema pulmonar. Ambos patrones tuvieron la misma prevalencia y severidad. La administración de extractos polifenólicos de arándano y uva a ratones mostró una reducción significativa en la severidad del patrón agudo y subagudo de lesión pulmonar. Los extractos de arándano y uva reducen la fase aguda del daño a la microvasculatura, mejoran la función fagocítica, tienen un efecto antiinflamatorio, reducen el grado de infiltración linfohistiocítica y los focos locorregionales de efectos inflamatorios residuales.

Design, synthesis, spectroscopic characterization, computational analysis, and in vitro α-amylase and α-glucosidase evaluation of 3-aminopyridin-2(1H)-one based novel monothiooxamides and 1,3,4-thiadiazoles.

Due to the growth in the incidence of diabetes mellitus throughout the world, the urgency in the search for new safe and effective inhibitors of α-amylase and α-glucosidase is increasing. In this work, we attempted to carry out studies on the synthesis, modification and comprehensive computer and biological research of new derivatives of monothiooxamides. It was shown that monothiooxamides based on 3-aminopyridin-2(1H)-ones enter into transamidation reactions with hydrazine hydrate to form the corresponding thiohydrazides. Furthermore, under the action of chloroacetyl chloride and succinic anhydride, these thiohydrazides are cyclized into conjugated 1,3,4-thiadiazole derivatives. The possible biological activity of the obtained products was evaluated by molecular docking using the AutoDock Vina program. Compounds 7a and 8b showed higher binding affinities for selected target proteins compared to the known anti-diabetic drugs acarbose and TAK-875. The obtained new derivatives of 1,3,4-thiadiazole showed sufficiently high values of inhibitory activity in the in vitro test against the enzymes α-amylase and α-glucosidase as well as sufficiently low IC50 values (for 8b 122.2 µM), which is 8 times less than the value for the reference drug acarbose (998.3 µM). All synthesized derivatives of monothiooxamides 5-8(a-c) showed no cytotoxic properties at physiological concentrations in the MTT test in human neonatal dermal fibroblasts. Moreover, some compounds (6a-c, 7a-c, 8b,c) showed pronounced cytoprotective activity. Thus, the compounds 5-8(a-c) synthesized by us, both according to the results of computer calculations and in vitro biological screening, showed their potential antidiabetic activity and high prospects for further in-depth studies, including in vivo studies.

Crystal structure and antidiabetic activity of 2-aminospiropyrazolinium tosylates and the product of O-tosylation of ß-(benzimidazol-1-yl)propioamidoxime.

2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium salts possess bioactivity tuned by the nature of the heteroatoms in the six-membered ring and the counter-ion. The molecular environment of these cations in solids provides an opportunity to establish the conformations and hydrogen-bonding patterns typical for this family. ß-Aminopropioamidoxime tosylation products [2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylates and the product of the O-tosylation of ß-(benzimidazol-1-yl)propioamidoxime, namely, 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylate, C8H16N3+·C7H7O3S- (6), 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylate, C7H14N3O+·C7H7O3S- (7), the monohydrate of 7, C7H14N3O+·C7H7O3S-·H2O (7a), 2-amino-8-thia-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylate, C7H14N3S+·C7H7O3S- (8), 2-amino-8-phenyl-1,5,8-triazaspiro[4.5]dec-1-en-5-ium tosylate, C13H19N4+·C7H7O3S- (9), and 3-(1H-benzimidazol-1-yl)-N'-(tosyloxy)propanimidamide, C17H18N4O3S (10)] were investigated using X-ray diffraction to study peculiarities of their molecular geometry and intermolecular interactions. In vitro antitubercular and antidiabetic screening of the ß-aminopropioamidoxime tosylation products was also carried out. It was revealed that this series of compounds does not have activity against drug-sensitive and multidrug-resistant M. tuberculosis strains, and exhibits high and moderate antidiabetic α-amylase and α-glucosidase activity. Using the hydrogen-bond propensity tool, we found that the inclination of counter-ions and atoms to act as acceptors of hydrogen bonds for the amino group decreases passing from tosylate O atoms to water molecules and the N atoms of five-membered rings. This fact is probably the reason for the formation in the solids of hydrogen-bonded tetramers consisting of two anions and two cations, and the rare occurrence of 2-aminospiropyrazolinium salt hydrates.

Cytoprotective Activity of Newly Synthesized 3-(Arylmethylamino)-6-Methyl-4-Phenylpyridin-2(1H)-Ones Derivatives.

Currently, studies are being conducted on the possible role of the cytoprotective effect of biologically active substances in conditions of cerebral hypoxia or cardiomyopathies. At the same time, oxidative stress is considered one of the important mechanisms of cellular cytotoxicity and a target for the action of cytoprotectors. The aim of this study is to search for derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones. The probability of cytoprotective action was assessed by measuring cell viability using two tests (with neutral red dye and MTT test). It was found that some derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones under the conditions of our experiment had a pronounced cytoprotective activity, providing better cell survival in vitro, including the MTT test and conditions of blood hyperviscosity. To correlate the obtained results in vitro, molecular docking of the synthesized derivatives was also carried out. The standard drug omeprazole (co-crystallized with the enzyme) was used as a standard. It was shown that all synthesized derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones had higher affinity for the selected protein than the standard gastro-cytoprotector omeprazole. The studied derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones also fully satisfy Lipinski's rule of five (RO5), which increases their chances for possible use as orally active drugs with good absorption ability and moderate lipophilicity. Thus, the results obtained make it possible to evaluate derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones as having a relatively high cytoprotective potential.

Therapeutic Potential of Metabolites from Lactobacillus rhamnosus and Mare's Milk in the Treatment of Dysbiosis.

Ulcerative colitis is an inflammatory bowel disease that forms ulcerations in the mucous membrane of the colon and rectum, in which gut microbiota plays a pivotal role in its pathogenesis. Agents modulating microbial dysbiosis caused by colitis can help in the remission of this disease. The current study describes the potential therapeutic effects of active metabolites from Lactobacillus rhamnosus and mare's milk which have potential therapeutic values on the intestinal microbiota and proinflammatory cytokines. The analysis of the V1-V3 16S rDNA site revealed significant changes in the intestinal microbiome composition before and after treatment in the treated group compared to the positive control group that was treated with 5-aminosalicylic acid (5-ASA). So the effect of the study product on dextran sulfate sodium-induced dysbiosis was shown to be more potent than the positive control, 5-ASA. The level of proinflammatory cytokines also decreased under the influence of a biological product.

Prolonged Inhalation Exposure to Coal Dust on Irradiated Rats and Consequences.

The purposes of this study were to research immune system changes and liver and lung tissues in irradiated rats after prolonged exposure to coal dust. A study was carried out on 30 male Wistar rats that were divided into 3 groups: group I, intact animals; group II, exposure to coal dust and 0.2 Gy γ-irradiation; and group III, combined exposure to 6 Gy γ-irradiation and coal dust. The combination of a low and sublethal dose of γ-irradiation with coal dust leads to a significant change in immunity at the remote period. Particularly, the increase in radioactivity at the combined effect causes weakening of phagocytosis, and reduction in T lymphocytes by a factor of 2, immunoglobulin imbalance, and cytokine dysfunction develop secondary immune failure. During prolonged inhalation with coal dust of irradiated animals with the dose of 0.2 Gy, fibrosis and perivascular sclerosis of the bronchial wall of the lungs are formed, and perivascular fibrosis is formed in the liver. The increase in exposure dose up to 6 Gy in combination with coal, in the distant period, caused pulmonary hypertension amid hypertrophy of light arterial vessels and fibrous changes in arteriole, and destructive changes and collection necrosis develop in liver parenchyma. In the case of dust radiation synergy, the increase in doses leads to a significant immune deficiency, which occurs according to the "dose effect" principle; increases damage to animal tissues; and leads to liver tissue necrosis, pulmonary fibrosis, and pulmonary hypertension.

Antiproliferative and cytotoxic activity of Geraniaceae plant extracts against five tumor cell lines.

AIM: To determine the antiproliferative and cytotoxic activities of Geranium and Erodium species against human cancer and noncancer cell lines, respectively. METHODS: Twenty-one species of Geranium and Erodium were extracted and screened against cancerous and noncancerous human cell lines. RESULTS: In a dose-response manner, G. glaberrimum, G. asphodeloides, E. brandianum and E. leucanthum were able, with variable potency, to inhibit cellular proliferation. Except for E. brandianum, all extracts induced cellular autophagy in tumor cells with similar levels to that of rapamycin; but, only E. brandianum induced cellular apoptosis, likely through Bcl2 and BAX protein expressions. DISCUSSION: This is the first study to report the potential antiproliferative effects of ethanol extracts of several Geraniaceae species.

Antiradical and Cytoprotective Properties of Allium nutans L. Honey Against CCL4-Induced Liver Damage in Rats.

The aim of this study is determine the in vitro and in vivo antiradical properties and the cytoprotective activity of Allium nutans L. honey extract. The antiradical properties of the extracts were investigated in rabbit alveolar macrophages and human foreskin fibroblast (hFFs) cells in the presence of doxorubicin, a cytotoxic substance using DPPH and ABTS assays. The cytoprotective activities were determined using 18 Wistar rats divided into three different groups, a negative control, and two other groups with experimentally induced hepatotoxicity by a single intraperitoneal injection of 50% carbon tetrachloride (CCl4) oil solution. A positive control group, received drinking water only and an experimental group that was treated with Allium nutans L. honey extracts for 7 days. In vitro treatment with Allium nutans L. honey extracts resulted in 78% reduction in radical activity in DPPH and 91.6% inhibition using the ABTS. Also, honey extracts were able to preserve 100% of cell viability in the presence of the cytotoxic, doxorubicin. Furthermore, the treatment with honey extracts resulted in a significant reduction in damage to the structure of liver tissue, as well significant reduction in the levels of ALT and AST in the experimental group compared to the control group.

Cardioprotective effect of grape polyphenol extract against doxorubicin induced cardiotoxicity.

Doxorubicin is a chemotherapeutic agent known to cause cardiotoxicity that is thought to be associated with oxidative stress. The aim of the current study is to investigate the role of grape polyphenols' antioxidant property as cardioprotective against doxorubicin-induced cardiotoxicity. Adult Wistar rats weighing 200 ± 20 g were divided into 3 different groups: a doxorubicin group that received a single intraperitoneal administration of doxorubicin (8.0 mg/kg body weight), an experimental group that received doxorubicin and grape polyphenol concentrate (25 mg/kg) via intragastric route, and the third group was a negative control group that received water only. On day 8, blood samples and tissues were harvested for analyses. The results indicated that grape polyphenol concentrate was able to reduce the signs of cardiotoxicity of doxorubicin through the reduction of aspartate aminotransferase activation, increasing the plasma antioxidant levels and decreasing the level of free radicals. The results also showed that grape polyphenol concentrate was able to reverse doxorubicin-induced microscopic myocardial damage. The myocardial protective effect of grape polyphenol might likely be due to the increase in the level and activity of the antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. In conclusion, grape polyphenol concentrate displayed cardioprotective effect and was able to reverse doxorubicin-induced-cardiomyopathy in experimental rats.

Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research.

It has been thought that caloric restriction favors longevity and healthy aging where autophagy plays a vital role. However, autophagy decreases during aging and that can lead to the development of aging-associated diseases such as cancer, diabetes, neurodegeneration, etc. It was shown that autophagy can be induced by mechanical or chemical stress. In this regard, various pharmacological compounds were proposed, including natural polyphenols. Apart from the ability to induce autophagy, polyphenols, such as resveratrol, are capable of modulating the expression of pro- and anti-apoptotic factors, neutralizing free radical species, affecting mitochondrial functions, chelating redox-active transition metal ions, and preventing protein aggregation. Moreover, polyphenols have advantages compared to chemical inducers of autophagy due to their intrinsic natural bio-compatibility and safety. In this context, polyphenols can be considered as a potential therapeutic tool for healthy aging either as a part of a diet or as separate compounds (supplements). This review discusses the epigenetic aspect and the underlying molecular mechanism of polyphenols as an anti-aging remedy. In addition, the recent advances of studies on NAD-dependent deacetylase sirtuin-1 (SIRT1) regulation of autophagy, the role of senescence-associated secretory phenotype (SASP) in cells senescence and their regulation by polyphenols have been highlighted as well. Apart from that, the review also revised the latest information on how polyphenols can help to improve mitochondrial function and modulate apoptosis (programmed cell death).

Osteoprotective properties of RNA-containing drug osteochondrin S on the model of insufficiency of sex hormones in rats / Propiedades osteoprotectoras del fármaco que contiene ARN de osteocondrina S sobre un modelo de insuficiencia de hormonas sexuales en ratas

SUMMARY: The aim of the study was to evaluate the osteoprotective properties of RNA-containing drug Osteochondrin S on rats with experimental model of osteoporosis. Osteochondrin S contains yeast RNA and RNA of connective tissue of cattle. In order to model osteoporosis in rats bilateral ovariectomy was used. Rats were divided into 3 groups: 1 - ovariectomized rats receiving Osteochondrin S; 2 - ovariectomized rats receiving saline; 3 - sham-ovariectomized rats. Rats in group 1 received Osteochondrin S, Group 2 - physiological saline three times a week for 12 weeks. Based on morphological data and on the results of densitometry, Osteochondrin S prevents a decrease in bone density, i.e. exhibits osteoprotective properties. Under the condition of lack of sex hormones in rats Osteochondrin S reduces reactive oxygen species in blood plasma and limits the degree of decrease in antioxidant capacity of blood plasma.

RESUMEN: El objetivo de este estudio fue evaluar las propiedades osteoprotectoras del fármaco que contiene ARN Osteocondrina S en ratas, como modelo experimental de osteoporosis. La Osteocondrina S contiene ARN de levadura y ARN de tejido conectivo de bovinos. Para modelar la osteoporosis en ratas se utilizó ovariectomía bilateral. Las ratas se dividieron en 3 grupos: grupo 1, ratas ovariectomizadas que recibieron Osteocondrin S; grupo 2, ratas ovariectomizadas recibieron solución salina; grupo 3 - ratas ovariectomizadas simuladas. Las ratas del grupo 1 recibieron Osteocondrina S, el grupo 2 solución de suero fisiológico tres veces por semana durante 12 semanas. En base a los datos morfológicos y los resultados de la densitometría, Osteocondrina S evita una disminución de la densidad ósea, es decir, exhibe propiedades osteoprotectoras. Ante la falta de hormonas sexuales en ratas, Osteocondrina S reduce las especies reactivas de oxígeno en el plasma sanguíneo y limita el grado de disminución de la capacidad antioxidante del plasma sanguíneo.