[Drosophila melanogaster Lifespan Is Regulated by nejire Gene Expression in Peripheral Tissues and Nervous System].

Histone acetyltransferases of the CBP/p300 family are involved in transcriptional regulation and many biological processes (cell proliferation and differentiation, development, and regulation of the stress response and metabolism). Overexpression and knockdown of the nejire (nej) gene (codes for an ortholog of human CBP/p300 proteins) in various tissues (the fat body, intestine, and nervous system) and at various stages of the life cycle (throughout all developmental stages or in adulthood only) were tested for effect on lifespan in the fruit fly Drosophila melanogaster. The activation of nej exerted a positive or a negative effect on the lifespan, depending on the induction mode and the sex. A 6-15% greater lifespan was observed in females with conditional overexpression of nej in the intestine and constitutive overexpression of nej in the nervous system. A decrease (to 44%) or lack of significant changes in lifespan was detected in all other cases observed. In addition, stress response genes (Sod1, Gadd45, Hsp27, Hsp68, and Hif1) were regulated by nej activation. nej knockdown caused a pronounced negative effect on the D. melanogaster lifespan in most variants of the experiment.

[The Antioxidant and Geroprotective Properties of an Extract of Mountain Ash (Sorbus aucuparia L.) Fruits].

Plant polyphenols are characterized by a wide range of biological activities, including antioxidant properties, and have a high geroprotective potential. The purpose of this work was to investigate the effect of the extract of rowan berries (Sorbus aucuparia L.) on the lifespan and stress resistance of Drosophila melanogaster with the identification of possible mechanisms of its biological activity. It has been established that an ethanol extract of S. aucuparia berries, the main components of which are rutin and cyanidin-3-rutinoside, has a pronounced antioxidant activity in vitro. At the same time, treatment with rowan berry extract increased the resistance of D. melanogaster males to starvation, but reduced resistance to hyperthermia. In females, the extract reduced resistance to oxidative stress but increased resistance to hyperthermia. The effects of rowan berry extract on longevity depended both on its concentration and on the sex of fruit flies. In response to treatment with rowan berry extract, D. melanogaster males and females showed slight differences in the background level of expression of cellular stress response genes, including heat shock genes (hsp27, hsp68, and hsp83), oxidative stress resistance genes (hif1, nrf2, and sod1), circadian rhythm genes (clk and per), and the longevity gene sirt1, which may explain the differences in the observed effects.

[Polyphenols as promising bioactive compounds].

Polyphenols are diverse and widespread bioactive plant-based compounds. These compounds are found in various foods such as berries, fruits, vegetables, cereals, nuts, coffee, cacao, spices, seeds. They are divided into phenolic acids, stilbenes, flavonoids, lignans depending on their molecular structure. They attract the attention of researchers due to wide range of biological effects on human body. The purpose of this work was to analyze modern scientific publications on the biological effects of polyphenols. Material and methods. The review is based on publications presented in the PubMed, Google Scholar, ResearchGate, Elsevier, eLIBRARY, Cyberleninka databases using "polyphenols", "flavonoids", "resveratrol", "quercetin", "catechins" as key words. Preference was given to original researches over the past 10 years published in refereed journals. Results. Oxidative stress, chronic inflammation, microbiome disorders, insulin resistance, excessive protein glycation, and genotoxic effects are at the heart of the pathogenesis of many diseases, including those associated with age. A large amount of material has been accumulated on the antioxidant, anticarcinogenic, epigenetic, metabolic, geroprotective, anti-inflammatory and antiviral effects of polyphenols. This gives reasons to consider polyphenols as very promising micronutrients, which inclusion in the diet can reduce the risk of developing cardiovascular, oncological, neurodegenerative diseases, diabetes mellitus, obesity, metabolic syndrome, premature aging, that is, the main causes of death, a decrease in the duration and quality of life of a modern person. Conclusion. Expanding the range of products enriched with polyphenols with their high bioavailability is a promising area of scientific research and development of production in order to prevent socially significant age-associated diseases.

[About attitude of graduates of medical specialties to job placement in primary health care and post-graduate training].

In order to study attitude of graduates of medical specialties to employment in primary health care system and to postgraduate medical education, anonymous survey was carried out on sampling of 188 graduates of medical institute of the Belgorod State National Research University in 2020-2021. The analysis established that married students more often than single ones seek permanent job with guaranteed salary and social protection. The advanced graduates easier get their future specialty than weak and satisfactory ones. The graduates-foreign citizens and stateless ones consider themselves under-prepared for medical practice as compared with graduates-residents of city and oblast. The youths more often than girls meet future employers. the weak graduates meet the employers less often than advanced graduates. The satisfactory graduates, as compared with weak and advanced graduates, more often have close relatives among medical workers. By the time they graduate, youths more often than girls get experience of practical medical activity. The advanced graduates also more frequently get practical medical experience than weak and satisfactory graduates.

Psychological Continuum of Elderly Patients Suffering from Arterial Hypertension with Metabolic Syndrome, Against the Background of Chronotherapy with a Fixed Combination of Amlodipine, Lisinopril and Rosuvastatin.

Aim        To study the psychological continuum in elderly patients with arterial hypertension associated with metabolic syndrome during the chronotherapy with a fixed combination (FC) of amlodipine, lisinopril, and rosuvastatin.Material and methods        In the inpatient conditions, 63 patients aged 60-74 years with arterial hypertension associated with metabolic syndrome were treated with chronotherapy with a FC of amlodipine, lisinopril, and rosuvastatin (5 / 10 / 10 mg/day in the evening). These patients composed the main group. The control group (58 patients aged 60-74 years with arterial hypertension associated with metabolic syndrome) was treated with the FC of amlodipine, lisinopril, and rosuvastatin at the same dose of 5 / 10 / 10 mg/day in the morning.Results   At one year, the disorders of psychological continuum were significantly decreased with the chronotherapy (evening dosing) with the antihypertensive FC of amlodipine, lisinopril, and rosuvastatin compared to the traditional treatment (morning dosing) at the same dose of 5 / 10 / 10 mg/day in both groups. With the chronotherapeutic approach, the dynamic of cognitive disorders in patients aged 60-74 years with arterial hypertension associated with metabolic syndrome was characterized by a significant increase in the Mini-Mental-State-Examination scale score from 17.8±0.3 at baseline to 23.5±0.4 with the evening dosing (р<0.001) vs. the increase from 16.9±0.3 to 20.4±0.4 (р<0.001) with the morning dosing. The situational anxiety score decreased from 40.0±2.2 to 30.6±1.8 (р<0.05) and from 40.8±2.5 to 33.5±1.9  (р<0.05), and the trait anxiety score decreased from 48.8±2.0 to 26.4±1.9 (р<0.001) and from 44.9±1.9 to 30.7±1.7  (р<0.01) with the evening and morning dosing, respectively. Depressive disorders slightly decreased with the chronotherapy by 14.1 % vs. 7.7 % with the traditional regimen; nevertheless, they were consistent with depressive spectrum disorders in both groups.Conclusion            The study results showed a higher effectiveness of the chronotherapeutic treatment compared to the traditional treatment with FC of amlodipine, lisinopril, and rosuvastatin in arterial hypertension with metabolic syndrome.

[The experience of reforming primary health care in conditions of demographic trends of average population age increasing].

The article presents experience of reforming of primary health care in the Belgorod Oblast in 2016-2019. In the course of reforming the original organizational model of interaction between doctors and patients developed and implemented. The measures were applied to strengthen the material-technical base and personnel potential of primary medical care. The offices of General Practitioners were arranged within step accessibility for patients. The continuous training of family physicians was organized at the workplace. The unified regional medical information system was developed and implemented enabling corporate conference communication, remote consultations, population feedback and remote arrangement of making appointment with physician. The differentiated approach to medical personnel remuneration of labor was brought on the basis of key performance indices that permitted to increase their salary and quality of work. As a result of the reforms, the percentage of people covered by family physicians dispensary observation increased by 13%, number of emergency calls decreased by 3.3% and number of calls because of illness reduced by 17%. The mortality rate of people older than able-bodied age began to decrease and population life expectancy reached prognosticated numbers of 74 years in 2019.

[Key Molecular Mechanisms of Aging, Biomarkers, and Potential Interventions].

The mechanisms of aging are described at the molecular, cell, tissue, and systemic levels. Primary age-dependent molecular lesions activate the cell stress response to compensate for the resulting defects, but the mechanisms that recover and maintain homeostasis are gradually deteriorated. When the amount of errors reaches a critical threshold in regulatory networks, a phase transition from health to disease occurs at the systemic level. The review considers the approaches to quantitative assessment of the aging process (biomarkers of aging) and promising interventions to slow down the aging process and to reduce the risk of age-dependent diseases.

[The effects of cloudberry extract on Drosophila melanogaster lifespan and stress resistance.]

We have previously shown that carotenoids increase lifespan of model organisms Drosophila melanogaster and Caenorhabditis elegans. In the present study, we investigated the effects of cloudberry extract, an abundant food for people in North, with a relatively large carotenoid content on Drosophila melanogaster lifespan parameters and resistance to different stress conditions. It was shown that the cloudberry extract increased the median lifespan and the age of 90% mortality of females up to 11-19%. The rate of aging was decreased up to 13%. The effects of cloudberry extract on lifespan of males were less expressed. In some cases, they were even negative. The extract had no effects on males and females' resistance to starvation. However, it decreased the resistance of males to oxidative stress.

[The relationship of lifespan with characteristics of life cycle and stress resistance in 12 species of Drosophila].

In the present study, we investigated the relationship of lifespan with different characteristics of the life history (length of the developmental period, imago body weight, fecundity) and stress resistance (response to oxidative stress, hyperthermia, starvation, and ionizing radiation) in flies of 12 species of the Drosophila genus. It was shown, that D. virilis has the highest maximum lifespan, but the lifespan of D. kikkawai was lowest. The investigated features have a positive (length of the developmental period, imago body weight, stress resistance) or negative (fecundity) correlation with species lifespan. Apparently, the observed differences are caused by adaptations of the species to different environmental conditions of their natural habitat, and lifespan is a key indicator of integrative fitness, reflecting the viability and various characteristics of life history and stress resistance.

[Genetic Control of Circadian Rhythms and Aging].

The review establishes a link between a group of genes which are conserved in evolution and form a molecular oscillator responsible for generation of circadian rhythms and genetic determinants of aging including associated pathways of intracellular signaling. An analysis of mechanisms of development of age-dependent pathologies is conducted from the viewpoint of circadian genetics. Systematic data of circadian gene expression studies in animals demonstrating different rates of aging from accelerated to negligible are presented.

[Role of DNA repair genes in radiation-induced changes of lifespan of Drosophila melanogaster].

One of the main effects of various stress factors, including ionizing radiation, is DNA damage. Accumulation of DNA damage and somatic mutations in the somatic tissues is regarded as one of the basic mechanisms of aging. We have developed an approach to the study of molecular and genetic mechanisms of radioadaptation, which is based on the analysis of changes in the lifespan of Drosophila with a transformed genotype. In this study we investigated the radioadaptive response and hormesis by radiation-induced changed of the lifespan of different strains of Drosophila melanogaster, such as a wild type strain Canton-Sand strains with mutations in DNA damage response gene (homologue of GADD45), excision repair genes (homologues of XPF, XPC, PCNA) and double-strand breaks repair genes (homologues of RAD54, XRCC3, BLM). The exposure to irradiation at the dose rate of 40 cGy was performed chronically through the stages of fly development; an acute exposure at the dose rate of 30 Gy was applied to the adult stages of flies. Also, we investigated the resistance to acute gamma-radiation of Drosophila with conditional ubiquitous overexpression of genes that are involved in DNA damage recognition (homologues of GADD45, HUS1, CHK2), excision repair (homologues of XPF, XPC, AP-endonuclease-1) and double-strand break repair (homologues of BRCA2, XRCC3, KU80, WRNexo). In the wild type strain Canton-S, manifestation of the radioadaptive response and radiation hormesis were observed. In individuals with DNA repair gene mutations, no radioadaptive response was observed, or observed to a lesser extent than in wild type flies. Mifepristone--inducible transgene activation does not lead to an increase in resistance to acute irradiation by the parameters of lifespan of Drosophila. Overexpression of DNA repair genes led to a sharp decline in lifespan also in the absence of irradiation.

Geroprotective effects of activation of D-GADD45 DNA reparation gene in Drosophila melanogaster nervous system.

The expression of D-GADD45 gene involved in DNA reparation in Drosophila melanogaster decreases with age. Overexpression of D-GADD45 in the drosophila nervous system prolongs the median and maximum life span without deterioration of the quality of life parameters (fertility and neuromuscular activity). The life span prolongation effect is due to more effective DNA reparation, as spontaneous level of DNA aberrations in the nerve tissue of larvae with D-GADD45 overexpression is reduced significantly.

Radiation hormesis and radioadaptive response in Drosophila melanogaster flies with different genetic backgrounds: the role of cellular stress-resistance mechanisms.

The purpose of this work is to investigate the role of cellular stress-resistance mechanisms in the low-dose irradiation effects on Drosophila melanogaster lifespan. In males and females with the wild type Canton-S genotype the chronic low dose irradiation (40 cGy) induced the hormetic effect and radiation adaptive response to acute irradiation (30 Gy). The hormesis and radioadaptive responses were observed in flies with mutations in autophagy genes (atg7, atg8a) but absent in flies with mutations in FOXO, ATM, ATR, and p53 homologues. The hormetic effect was revealed in Sirt2 mutant males but not in females. On the contrary, the females but not males of JNK/+ mutant strain showed adaptive response. The obtained results demonstrate the essential role of FOXO, SIRT1, JNK, ATM, ATR, and p53 genes in hormesis and radiation adaptive response of the whole organism.

Increase of Drosophila melanogaster lifespan due to D-GADD45 overexpression in the nervous system.

The GADD45 protein family plays an important role in stress signaling and participates in the integration of cellular response to environmental and physiological factors. GADD45 proteins are involved in cell cycle control, DNA repair, apoptosis, cell survival and aging, and inflammatory response by complicated protein-protein interactions. In Drosophila melanogaster a single D-GADD45 ortholog (GG1086) has been described. Our data show that overexpression of the D-GADD45 gene in the nervous system leads to a significantly increase of Drosophila lifespan without a decrease in fecundity and locomotor activity. The lifespan extension effect is more pronounced in males than in females, which agrees with the sex-dependent expression of this gene. The longevity of D. melanogaster with D-GADD45 overexpression is apparently due to more efficient recognition and repair of DNA damage, as the DNA comet assay showed that the spontaneous DNA damage in the larva neuroblasts is reduced with statistical significance.

Effect of PARP-1 overexpression and pharmacological inhibition of NF-kB on the lifespan of Drosophila melanogaster.

Age-dependent accumulation of genome rearrangements leads to cellular senescence, overall aging and lifespan decreasing of the organism. In this respect, it is important to study the effect of overexpression of DNA repair genes on the lifespan and aging parameters (rates of age-related decline of fertility and locomotor activity). The present work investigates how the overexpression of the PARP-1 gene, which is involved in various mechanisms of DNA repair (base excision repair and DNA double-strand breaks repair), combined with a pharmacological inhibition of the NF-kB transcription factor that controls the genes of inflammatory response, affects the lifespan of Drosophila melanogaster. It is demonstrated that in males, constitutive activation of PARP-1 overexpression in the nervous system throughout the lifetime results in reduced median (by 14%) and maximum (by 8%) lifespan, whereas in females the median (by 14%) and maximum (by 20%) lifespan increases. Activation of PARP-1 overexpression in the imago (conditionally) results in extension of the median (by 3-16%) and the maximum (by 10-15%) lifespan in females and males, respectively. The lifespan increase in females with PARP-1 conditional overexpression was accompanied by decrease of fertility. Selective pharmacological inhibition of transcription factor NF-kB with pyrrolidine dithiocarbamate increases the median (by 13-20%) and the maximum (by 11-14%) lifespan in females and males, respectively. No synergic effect between conditionally activated PARP-1 expression and NF-kB inhibition is observed. The geroprotective effect of PARP-1 overexpression depends on the sex and the life history stage of overexpression induction.

[Evolution conceptions about the nature of aging].

The work presents aging as the age-dependant fractal process consisting in increasing of quantity of homeostasis disturbances at molecular, subcellular, cell-tissue and system levels. The facts testifying to simultaneous evolutional complication of aging and anti-aging forms are considered. The evolutional stages of the beginnings of "molecular", "segregational", "conditional", "clonal", postmitotic and systemic aging types are displayed.

[Lignins of Rhodiola rosea and Serratula coronata: peculiarities of chemical structure and antioxidant properties].

Data on comparative investigations of chemical structure of lignins from medical grassy plants Rhodiola rosea and Serratula coronata lignins were obtained. The NMR and ESR spectroscopy, and functional and element analysis were used. The high antioxidant activity of lignins was shown. Experimental evidence of anti-aging activity of Rhodiola rosea lignin on model objects Drosophila melanogaster were presented.

[FOXO tanscription factor role in radiation adaptive response and hormisis in Drosophila melanogaster].

Previously we put forward a hypothesis about the role of FOXO-dependent mechanisms of stress-response gene activation after irradiation in radiation hormesis (Moskalev, 2008). To testify this assumption we analyze the influence of gamma-irradiation on duration of larvae development and imago lifespan in Drosophila strains with different FOXO function activity. We revealed that in FOXO hypomorphic allele homozygote strains the hormesis and adaptive response (increasing of larvae stage duration and longevity) were absent, in contrast to B wild type strain Canton-S and FOXO-heterozygotes.

[Pharmacological PI 3-kinase inhibitors induce radioprotective effect in Drosophila melanogaster imago].

Phosphatidylinositol 3-kinase (PI3K) signaling cascade is involved in many cell processes that are required for radioresistance, including proliferation, survival, growth, metabolism, and death. At the whole organism level PI3K signaling cascade is involved in lifespan control. In this study the contribution of PI3-signaling cascade to radioresistance of Drosophila melanogaster imago was investigated. It is shown that pretreatment with Pl3-kinase specific inhibitor LY294002 (5, 100 micromol/l) and wortmannin (5 micromol/1) leads to increase of male and female survival after acute irradiation in dose of 30 Gy. The obtained results demonstrate that PI3K specific inhibition induces radioprotective effect on Drosophila melanogaster imago.